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Volume 15 16 • 2021

Editor-in-Chief Bill Gogas, MD, PhD Nanjing University, Jiangsu, China

Section Editors Interventional Cardiology Research M Chadi Alraies, MD, FACC

Preventive Cardiology Aditya Khetan, MD

Interventional/Structural Rishi Puri, MD, PhD, FRACP

Detroit Medical Center, Detroit, MI

Case Western Reserve University, Cleveland, OH

Cleveland Clinic, Cleveland, OH

Electrophysiology Sourbha S Dani, MD, FACC

Cardiovascular Disease in Women Anastasia S Mihailidou, FAHA, FCSANZ

Heart Failure Andrew J Sauer, MD

Eastern Maine Medical Center, Bangor, ME

Royal North Shore Hospital, Sydney, Australia

University of Kansas Medical Center, Kansas City, KS

Acute Coronary Syndromes Farshad Forouzandeh, MD, PhD, FACC, FSCAI

Imaging Akhil Narang, MD, FACC

Heart Failure Amin Yehya, MD, MS, FACC, FHFSA

Northwestern University, Chicago, IL

Sentara Heart, Norfolk, VA

Case Western Reserve University, Cleveland, OH

Associate Editors Misbahul Ferdous, MBBS, FMD, MMed, PhD

Chad A Kliger, MD

Rajalakshmi Santhanakrishnan, MD, MBBS

Fuwai Hospital, Beijing, China

Lenox Hill Heart and Vascular Institute, New York, NY

Sahil Khera MD, MPH

Yogesh Reddy, MD, MSc

Bruce Stambler, MD

Mayo Clinic, Rochester, MN

Piedmont Healthcare, Atlanta, GA

Columbia University, New York, NY

Wright State University, Dayton, OH

Statistical Editor Juan Luis Gutiérrez-Chico, MD, PhD, FESC, FACC Cardio Care Cardiovascular Heart Centre Marbella, Marbella, Spain

Editorial Board King Fahd Armed Forces Hospital, Jeddah, Saudi Arabia

Mirvat Alasnag, MD, FSCAI

Medical University of South Carolina, Charleston, SC

Michael R Gold, MD

Sara C Martinez, MD, PhD

Danielle Belardo, MD

Martha Gulati, MD, MSM FACC, FAHA, FASPC

Johns Hopkins University School of Medicine, Baltimore, MD

Institute of Plant Based Medicine, Los Angeles, CA

Ralph G Brindis, MD

University of California, San Francisco, CA

Robert Chait, MD, FACC, FACP

University of Arizona College of Medicine, Tucson, AZ

Thomas A Haffey, DO, FACCM FACOI, FNLA

JFK Medical Center, Atlantis, FL

Western University of Health Sciences, Pomona, CA

Nita Ray Chaudhuri, MD, FAAP

Ankur Kalra, MD, FACP, FACC, FSCAI

JW Ruby Memorial Hospital, Morgantown, WV

NA Mark Estes III, MD

Tufts University School of Medicine, Boston, MA

Alexandra Frogoudaki, MD, PhD, FESC Attikon University Hospital, Athens University, Athens, Greece

Bernard J Gersh, MD, PhD Mayo Clinic, Minnesota, US

Mayo Clinic, Rochester, MN

Erin D Michos, MD, MHS

Ki Park, MD, MS, FSCAI

University of Florida and Malcom Randall VA Medical Center, Gainsville, FL

Duane Pinto, MD, MSc Harvard Medical School, Boston, MA

Krishna Pothineni, MD

Case Western Reserve University School of Medicine, Cleveland, OH

University of Arkansas for Medical Sciences, Little Rock, AR

Dinesh K Kalra, MD, FACC, FSCCT, FSCMR

Rahul Sharma, MD, FACP, FACC, FSCAI

Rush University Medical Center, Chicago, IL

Morton J Kern, MD

University of California at Irvine, Orange, CA

Jackson J Liang, MD, DO

University of Michigan, Ann Arbor, MI

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Virginia Tech Carilion School of Medicine, Roanoke, VA

Isabella Tan

Macquarie University, Sydney, Australia

W Douglas Weaver, MD

Wayne State University, Detroit, MI

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Volume 15 • 2021

Aims and Scope

• US Cardiology Review is an international, English language, • • • •

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US Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in cardiac failure practice.

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Contents Current Evidence and Future Directions of PCSK9 Inhibition Jiaqian Xu, MD, and Michael D Shapiro, DO, MCR DOI: https://doi.org/10.15420/usc.2020.17

Effect of Operator Experience on Transcatheter Mitral Valve Repair Outcomes Justin P Sheehy, MD, and Adnan K Chhatriwalla, MD DOI: https://doi.org/10.15420/usc.2020.02

Advances in Transcatheter Electrosurgery for Treating Valvular Heart Disease

Jaffar M Khan, BM BCh, PhD, Toby Rogers, BM BCh, PhD, Adam B Greenbaum, MD, Vasilis C Babaliaros, MD, John C Lisko, MD, Dursun Korel Yildirim, MS, Christopher G Bruce, MB ChB, Daniel A Herzka, PhD, Kanishka Ratnayaka, MD, and Robert J Lederman, MD DOI: https://doi.org/10.15420/usc.2020.27

Vascular Complications of Transradial Access for Cardiac Catheterization Tanawan Riangwiwat, MD, and James C Blankenship, MD, MHCM, MSCAI DOI: https://doi.org/10.15420/usc.2020.23

Cardiovascular Medical Education During the Coronavirus Disease 2019 Pandemic: Challenges, Adaptations, and Considerations for the Future Hilary Shapiro, MD, and Nosheen Reza, MD DOI: https://doi.org/10.15420/usc.2020.25

Novel Non-invasive Fractional Flow Reserve from Coronary CT Angiography to Determine Ischemic Coronary Stenosis Lavanya Cherukuri, MD, Divya Birudaraju, MD, and Matthew J Budoff, MD DOI: https://doi.org/10.15420/usc.2020.24

Optimizing Guideline-directed Medical Therapies for Heart Failure with Reduced Ejection Fraction During Hospitalization Neal M Dixit, MD, MBA, Shivani Shah, PharmD, APh, Boback Ziaeian, MD, PhD, Gregg C Fonarow, MD, and Jeffrey J Hsu, MD, PhD DOI: https://doi.org/10.15420/usc.2020.29

Management of Long QT Syndrome in Women Before, During, and After Pregnancy Caroline Taylor, PA-C and Bruce S Stambler, MD DOI: https://doi.org/10.15420/usc.2021.02

Antithrombotic Therapy in Complex Percutaneous Coronary Intervention Patients Requiring Chronic Anticoagulation

Despoina-Rafailia Benetou, MD, Panayotis K Vlachakis, MD, Charalampos Varlamos, MD, and Dimitrios Alexopoulos, MD DOI: https://doi.org/10.15420/usc.2020.31

Antithrombotic Therapy in Chronic Total Occlusion Interventions

Iosif Xenogiannis, MD, PhD, Charalampos Varlamos, MD, Despoina-Rafailia Benetou, MD, and Dimitrios Alexopoulos, MD, PhD DOI: https://doi.org/10.15420/usc.2020.37

Left Main Disease and Bifurcation Percutaneous Coronary Intervention: Focus on Antithrombotic Therapy Charalampos Varlamos, MD, Ioannis Lianos, MD, Despoina-Rafailia Benetou, MD, and Dimitrios Alexopoulos, MD DOI: https://doi.org/10.15420/usc.2020.34

Transcatheter Tricuspid Valve Intervention: Current Perspective Trevor J Simard, MD, and Mackram F Eleid, MD DOI: https://doi.org/10.15420/usc.2020.26

Door-to-balloon Time for ST-elevation MI in the Coronavirus Disease 2019 Era

Haytham Mously, MD, MPH, Nischay Shah, DO, Zachary Zuzek, MD, Ibrahim Alshaghdali, MD, Adham Karim, MD, Rahul Jaswaney, MD, Steven J Filby, MD, Daniel I Simon, MD, Mehdi H Shishehbor, DO, MPH, PhD, and Farshad Forouzandeh, MD, PhD DOI: https://doi.org/10.15420/usc.2021.05

Platelet Function Testing and Genotyping for Tailoring Treatment in Complex PCI Patients Athanasios Moulias, MD, PhD, Angeliki Papageorgiou, MD, and Dimitrios Alexopoulos, MD, PhD, FESC, FACC DOI: https://doi.org/10.15420/usc.2020.33

Describing and Classifying Shock: Recent Insights

Ashleigh Long MD, PhD, Amin Yehya, MD, MSc, Kelly Stelling, RN, and David A Baran MD DOI: https://doi.org/10.15420/usc.2021.09

Heart Transplant and Ventricular Assist: Cardiac Surgery and Heart Failure Perspective Michael T Cain, MD, Michael S Firstenberg, MD FACC FAIM, and Joseph C Cleveland Jr, MD DOI: https://doi.org/10.15420/usc.2021.11

© RADCLIFFE CARDIOLOGY 2021 Access at: www.USCjournal.com

Contents Antithrombotics in Complex Percutaneous Coronary Interventions: Type and Duration of Treatment

Despoina-Rafailia Benetou, MD,Charalampos Varlamos, MD, Christos Pappas, MD, Fotios Kolokathis, MD, and Dimitrios Alexopoulos, MD DOI: https://doi.org/10.15420/usc.2020.30

Cardiogenic Shock: Protocols, Teams, Centers, and Networks

Alex F Warren, MD, Carolyn Rosner, NP, Raghav Gattani, MD, Alex G Truesdell, MD, FSCAI, and Alastair G Proudfoot, MD, PhD DOI: https://doi.org/10.15420/usc.2021.10

The Role of Subcutaneous ICDs in the Prevention of Sudden Cardiac Death Leah A John, MD, MBA, Ahmadreza Karimianpour, DO, and Michael R Gold, MD, PhD DOI: https://doi.org/10.15420/usc.2021.01

How Old is Too Old? Closure of Patent Foramen Ovale in Older Patients

Carlos Vazquez-Sosa, MD, Stacey D Clegg, MD, FACC, FSCAI, and James C Blankenship, MD, MHCM, MACC, MSCAI DOI: https://doi.org/10.15420/usc.2020.40

Current Landscape of Temporary Percutaneous Mechanical Circulatory Support Technology Rani Upadhyay, MD, Hussayn Alrayes, MD, Scott Arno, MD, Milan Kaushik, MD, and Mir B Basir, DO DOI: https://doi.org/10.15420/usc.2021.15

Rediscovered and Unforgotten: Transcatheter Interventions for the Treatment of Severe Tricuspid Valve Regurgitation Kusha Rahgozar, MD, Sharon Bruoha, MD, Edwin Ho, MD, Ythan Goldberg, MD, Mei Chau, MD, and Azeem Latib, MD DOI: https://doi.org/10.15420/usc.2021.06

Extracorporeal Life Support for Cardiac Arrest and Cardiogenic Shock

Andrea Elliott, MD, Garima Dahyia, MD, Rajat Kalra, MBChB, MS, Tamas Alexy, MD, Jason Bartos, MD PhD, Marinos Kosmopoulos, and Demetri Yannopoulos, MD DOI: https://doi.org/10.15420/usc.2021.13

The Contemporary Cardiogenic Shock ‘Playbook’ Alexander G Truesdell, MD DOI: https://doi.org/10.15420/usc.2020.28

Shockwave and Non-transfemoral Transcatheter Aortic Valve Replacement

Eden C Payabyab, MD, Lindsay S Elbaum, MD, Navneet Sharma, MD, Isaac George, MD, and Stephanie L Mick, MD DOI: https://doi.org/10.15420/usc.2021.16

Mixed-Valve Disease: Management of Patients with Aortic Stenosis and Mitral Regurgitation: Thresholds for Surgery Versus Percutaneous Therapies Jean-Bernard Masson, MD, FRCPC, and Jessica Forcillo, MD, MPH, PhD, FRCSC DOI: https://doi.org/10.15420/usc.2021.17

© RADCLIFFE CARDIOLOGY 2021 Access at: www.USCjournal.com

Risk Prevention

Current Evidence and Future Directions of PCSK9 Inhibition Jiaqian Xu, MD,

and Michael D Shapiro, DO, MCR

Center for the Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University Baptist Medical Center, Winston Salem, NC

Abstract

Recent scientific and therapeutic advances in proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition have opened a chapter in the management of hypercholesterolemia, especially in patients who are inadequately controlled on or intolerant to statins. The two PCSK9 monoclonal antibodies, evolocumab and alirocumab, reduce LDL cholesterol by 60% and improve cardiovascular outcomes when taken in addition to statin therapy. More recently, inclisiran, a silencing RNA (siRNA) that inhibits translation of PCSK9 mRNA, demonstrated LDL cholesterol reduction by 45–50% with the advantage of dramatically reduced dose frequency. Other modes of PCSK9 inhibition include small molecule antagonists, vaccines, CRISPR gene editing, and antagonism at various steps of translation, and post-translational processing.

Keywords

Atherosclerotic cardiovascular disease, LDL cholesterol, hypercholesterolemia, proprotein convertase subtilisin/kexin type 9, silencing RNA Disclosure: JX has no conflicts of interest to declare. MS carries out scientific advisory activities with Amgen, Esperion, and Regeneron, as well as consultant activities with Novartis.

Received: March 30, 2020 Accepted: September 10, 2020 Citation: US Cardiology Review 2021;15:e01. DOI: https://doi.org/10.15420/usc.2020.17 Correspondence: Michael D Shapiro, Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston Salem, NC 27157, US. E: mdshapir@wakehealth.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Hypercholesterolemia is a central risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), the leading cause of death and disability worldwide. Although the increased utilization of lipidlowering therapy has decreased the mean LDL cholesterol (LDL-C) level from 3.26 mmol/l (126 mg/dl) in 1999–2000 to 2.88 mmol/l (111 mg/dl) in 2013–2014, recent observations suggest that long-term exposure to even modestly elevated plasma LDL-C concentrations is associated with a greater risk of coronary heart disease (CHD) later in life.1.2

the LDLR enters the cell in a ternary complex with PCSK9 and LDL bound to it. Ordinarily, after receptor-mediated endocytosis, the internalized LDL–LDLR complex decouples when the internal compartment of the endosome reaches a critical pH with LDLR recycling back to the surface.

However, when PCSK9 is bound to the LDLR, it interferes with the natural LDLR recycling loop and the entire ternary complex (LDL–LDLR–PCSK9) stays within the endosome and fuses with the lysosome where the constituent components are digested.5

Moreover, many individuals cannot achieve adequate LDL-C reduction with standard lipid-lowering therapies or are unable tolerate them, specifically statins, at the optimal dose. In addition, individuals with familial hypercholesterolemia (FH), the single most common Mendelian disorder with an estimated prevalence of around one in 250, are exposed to severe hypercholesterolemia from birth and are at considerably higher risk for premature ASCVD.3 As with patients with established ASCVD, those with FH frequently require the addition of non-statin therapies, such as ezetimibe or proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors.

As gain-of-function mutations are relatively rare, investigators sought to determine if naturally occurring loss-of-function (LOF) mutations in the PCSK9 gene existed as well. Indeed, several LOF mutations were discovered. These LOF mutations in PCSK9 were associated with lifelong reductions, albeit generally modest, in plasma LDL-C levels and marked reductions in cardiovascular risk.6–9

In 2003, a missense mutation causing gain-of-function of PCSK9 was discovered as the third genetic locus for FH.4 This discovery ushered in intense research efforts that, ultimately, elucidated the mechanism by which gain-of-function of PCSK9 leads to high plasma LDL-C. PCSK9 is secreted into the plasma primarily by hepatocytes at low concentrations where it then acts as a second ligand for the LDL receptor (LDLR). Specifically, PCSK9 binds LDLR on the hepatocyte cell surface as

These seminal observations served as proof in principle that antagonizing PCSK9 may have significant therapeutic potential. What follows is an overview of the various therapeutic classes that inhibit PCSK9, their associated clinical trial data, and future directions.

Therapeutic Monoclonal Antibodies

The development of the therapeutic anti-PCSK9 monoclonal antibodies (mAbs) serves as perhaps the best example of how genetic insights can facilitate targeted drug development. It took 12 years from the discovery of PCSK9 as a low-abundance circulating protein with an outsized impact on LDL metabolism to the regulatory approval of a therapy that antagonizes its action by the US Food and Drug Administration (FDA).

© RADCLIFFE CARDIOLOGY 2021 Access at: www.USCjournal.com

Current and Future Directions of PCSK9 Inhibition Table 1: Summary of FOURIER and ODYSSEY OUTCOMES trials

FOURIER

ODYSSEY OUTCOMES

Study drug

Evolocumab

Alirocumab

Date of publication

May 4, 2017

November 29, 2018

Study design

Randomized, double-blinded, placebo-controlled

Randomized, double-blinded, placebo-controlled

Sample size

27,564

18,924

Patient characteristics

ASCVD; LDL-C ≥1.81 mmol/l (≥70 mg/dl) on statin therapy

ACS in previous 1–12 months; LDL-C ≥1.81 mmol/l (≥70 mg/dl); non-HDL-C ≥2.59 mmol/l (≥100 mg/dl); ApoB ≥2.07 mmol/l (≥80 mg/dl); high-intensity or max tolerated statin dose

Treatment dose

Subcutaneous 140 mg every 2 weeks or 420 mg monthly

Subcutaneous 75 mg every 2 weeks

Primary endpoint

MACE: composite of cardiovascular death, MI, stroke, hospitalization for UA or coronary revascularization

MACE: composite death from CAD, nonfatal MI, fatal/nonfatal ischemic stroke or UA requiring hospitalization

Follow-up duration

48 weeks

Average of 2.8 years

Primary endpoint HR

0.85; 95% CI [0.79–0.92]; p<0.001

0.85; 95% CI [0.78–0.93]; p<0.001

Mean percentage of LDL-C reduction

59% at 48 weeks

62.7% at 4 months; 61.0% at 12 months; 54.7% at 48 months

Injection-site reaction adverse events

2.1% in treatment versus 1.6% in placebo

3.8% in treatment versus 2.1% in placebo

ApoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; HDL-C = HDL cholesterol; LDL-C = LDL cholesterol; MACE = major adverse cardiac events; UA = unstable angina.

PCSK9 inhibitors were initially approved by the FDA on the basis of their LDL-C lowering efficacy and safety while the large cardiovascular outcomes trials were ongoing. Both therapeutic antibodies are fully human, target the same region of PCSK9, and have similar LDL-C lowering efficacy (a reduction of about 60% in LDL-C) at maximum doses.10,11 While they possess some structural differences (alirocumab is an IgG1 mAb and evolocumab is an IgG2 mAb), it is unclear whether this has any clinical significance. Thus far, the results of each of the large cardiovascular outcomes trials were similar between the two drugs (Table 1).

The FOURIER trial was the first of the randomized controlled outcomes trials to be reported.10 FOURIER enrolled 27,564 patients with atherosclerotic cardiovascular disease and LDL-C levels >1.81 mmol/l (>70 mg/dl) on optimized statin therapy. Patients were randomly assigned to receive subcutaneous injections of evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or placebo. The primary endpoint was the composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (major adverse cardiac events, MACE). At 48 weeks, evolocumab therapy, compared to placebo, resulted in a 59% reduction in LDL-C. Evolocumab significantly reduced the risk of the primary endpoint compared to placebo (9.8% versus 11.3%; HR 0.85; 95% CI [0.79–0.92]; p<0.001). There were no significant differences between evolocumab and placebo with regard to adverse events including new-onset diabetes and neurocognitive events.

However, evolocumab was associated with a higher incidence of injection-site reactions.10 The following year, the ODYSSEY OUTCOMES trial was published.11 This was a randomized, double-blind, placebo-controlled trial of 18,924 subjects with recent acute coronary syndrome (within 1–12 months before randomization) that compared the effect of alirocumab subcutaneously in a 75 mg dose versus placebo on incident MACE. Most trial participants (about 90%) received treatment with high-intensity statin therapy and had one or more of the following: LDL-C 1.81 mmol/l≥ (70 mg/dl); non-HDL cholesterol ≥2.60 mmol/l≥ (100 mg/dl); or apolipoprotein B ≥ 2.07 mmol/l (80 mg/dl). The primary endpoint was time to first occurrence of a 4-point composite MACE outcome (the trial did not include revascularization as in FOURIER).12

In the intention-to-treat analysis, alirocumab therapy, compared to placebo, resulted in 62.7%, 61.0%, and 54.7% reductions in LDL-C at 4 months, 12 months, and 48 months, respectively. The primary endpoint occurred in 9.5% of subjects allocated to alirocumab and in 11.1% of subjects allocated to placebo (HR 0.85; 95% CI [0.78–0.93]; p<0.001). The incidence of adverse events and laboratory abnormalities was similar in the alirocumab and placebo groups with the exception of injection-site reactions (3.8% in alirocumab versus 2.1% in placebo; p<0.001). These injection-site reactions included itching, redness, and swelling and were generally mild and self-limiting.11 One of the interesting and unanticipated facets of PCSK9 inhibition with therapeutic mAbs is the association with plasma lipoprotein (a) (Lp(a)) lowering (Table 2). A recent meta-analysis that assessed 27 randomized controlled clinical trials enrolling 11,864 subjects demonstrated comparable reductions in Lp(a) associated with PCSK9 inhibitor treatment (Lp(a) reduction of 21.9% (95% CI [−24.3 to −19.5]).13 Given the epidemiological and genetic associations of Lp(a) with ASCVD, there is interest in evaluating the potential role of PCSK9 inhibitor-induced reduction in Lp(a) to reduce ASCVD events.14 Recent analyses from the FOURIER and ODYSSEY OUTCOMES trials lend credence to the notion that reductions in Lp(a) via PCSK9 inhibition may effectively reduce residual ASCVD risk.15 O’Donoghue et al. evaluated plasma Lp(a) concentration in the FOURIER participants and found that higher baseline Lp(a) concentration associated with an increased rate of cardiovascular events independent of LDL-C concentration.16 Evolocumab was associated with an Lp(a) reduction of 27% at 48 weeks.16 Additionally, the use of evolocumab was associated with greater cardiovascular benefit in individuals with a higher than median baseline Lp(a) than in participants with a below the median baseline Lp(a) (23% reduction; HR 0.77; 95% CI [0.67–0.88]) compared to a reduction of 7% (HR 0.93; 95% CI [0.80–1.08]) in cardiovascular events respectively.16 The ODYSSEY OUTCOMES investigators extended these findings to models of absolute change in Lp(a) as a predictor of MACE. They found, in a fully adjusted model, that for each 0.026 mmol/l (1 mg/dl) lowering of Lp(a) associated with alirocumab, the corresponding event reduction was

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Current and Future Directions of PCSK9 Inhibition Table 2: Subgroup Analyses of FOURIER/ODYSSEY OUTCOMES Groups

Trial

Cardiovascular Outcome

Clinical Significance

Baseline diabetes versus without diabetes

FOURIER, 2017

Diabetes (HR 0.82; p=0.0002) versus no diabetes (HR 0.78; p=0.0002). Incident diabetes (HR 1.05 and HR 1.0, respectively; ns)

Similar reduction in major adverse cardiovascular events in people with diabetes versus people without diabetes (HR 1.05 and 1.00); no significant difference in incident diabetes

Baseline LDL-C level of <1.81 FOURIER, 201759 mmol/l (<70 mg/dl) versus ≥1.81 mmol/l

Baseline LDL-C level of <1.81 mmol/l (<70 mg/dl; HR 0.8) versus ≥1.81 mmol/l (HR 0.86; ns)

Similar reduction in major adverse cardiovascular events according to baseline LDL-C

High intensity versus non-high FOURIER, 201760 intensity statin therapy

High intensity (HR 0.85) versus non-high intensity statin therapy (HR 0.85; ns)

Similar reduction in major adverse cardiovascular events according to intensity of statin therapy

PAD versus non-PAD

FOURIER, 201861

PAD (27% RRR) versus no PAD (19% RRR) with p=0.41; 42% RRR in major adverse limb events* (p<0.01)

Similar reduction in major adverse cardiovascular events in those with PAD and those without PAD; however, significant impact on major adverse limb events

Lp(a) reduction

FOURIER, 202062

Baseline Lp(a) >median 0.96 mmol/l (37 mg/dl) associated with 23% RRR (HR 0.77; 95% CI [0.67–0.88]) versus Lp(a) ≤median associated with 7% RRR (HR 0.93, 95% CI [0.8–1.07], ns)

Significantly greater reduction in major adverse cardiovascular events in those with Lp(a) >median compared to those with Lp(a) group versus lower baseline Lp(a) ≤median

Neurocognitive adverse effects

EBBINGHAUS Ecog score for evolocumab versus placebo (3.7% versus No significant impact on patient-reported cognition with (FOURIER subgroup) 3.6%; p=0.62) and for subdomains (memory, 6% versus 5.8%; addition of evolocumab to maximally tolerated statin therapy 201963 total executive, 3.7% versus 3.6%) at 2.2 years

58

Diabetes, prediabetes versus ODYSSEY Greater absolute reduction in the incidence of the primary normoglycemia OUTCOMES, 201964 endpoint in patients with diabetes (2.3%; 95% CI [0.4–4.2]) than in those with prediabetes (1.2%; 95% CI [0.0–0.4]) or normoglycemia (1.2%; 95% CI [−0.3, 2.7]; absolute risk reduction p-interaction=0.0019)

Significant absolute risk reduction in major adverse cardiovascular events among patients with diabetes compared to those without diabetes. Alirocumab therapy did not increase the risk of new-onset diabetes

*Major adverse limb event = acute limb ischemia, major amputations or urgent revascularization. Ecog = Every cognition scale; Lp(a)= lipoprotein a; LDL-C= LDL cholesterol; ns = not statistically significant; PAD = peripheral artery disease; PCSK9 = proprotein convertase subtilisin/kexin type 9; RRR = relative risk reduction.

0.6%. However, when modeling to more significant Lp(a) lowering, they were able to demonstrate significant relative risk reductions attributable to Lp(a) lowering. For example, absolute reductions in Lp(a) of 0.52 mmol/l (20 mg/dl) and 1.30 mmol/l (50 mg/dl) would be associated with relative risk reductions in MACE of 11% and 26%, respectively.

beyond LDLR (e.g. APOER2, LRP1, VLDLR, CD36, and TLR2 plasminogen receptors), it is conceivable that there is an Lp(a) receptor, which is, at least in part, under the regulation of PCSK9. The LDL-C/Lp(a) discordance observed in the studies described above may be because Lp(a) clearance is mediated by apolipoprotein(a) isoform size.

Importantly, the proportion of MACE reduction attributable to changes in Lp(a) and corrected LDL-C become substantial in those with the highest baseline levels of Lp(a) (greater than the 75th percentile of the population).17 The findings from the subanalyses of FOURIER and ODYSSEY OUTCOMES with respect to Lp(a) lowering are interesting and beg the question as to the potential future role of PCSK9 inhibitors for use in individuals with ASCVD and elevated Lp(a), irrespective of LDL-C.

It is also important to consider recent human metabolic studies that address the issue of PCSK9 inhibition and Lp(a) lowering. In general, these demonstrate that PCSK9 inhibitors reduce plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles without changing the apolipoprotein(a) production rate. This observation may potentially be explained by the extreme upregulation of hepatic LDLR and/or reduced competition between LDL and Lp(a) particles for LDLR once PCSK9 inhibition has dramatically reduced plasma LDL-C.23,24

At this point, the mechanisms by which PCSK9 inhibition is associated with reductions in plasma Lp(a) remains unclear. The most commonly touted hypothesis asserts that there is increased clearance of Lp(a) particles through the LDLR pathway. However, the idea that clearance of Lp(a) is facilitated by the LDLR presents a number of challenges:

• The affinity of Lp(a) for the LDLR is considerably less than that of LDL.18 • Lp(a) catabolic rates are similar in FH and non-FH patients.19 • Statins, which upregulate LDLR, are not associated with reductions in plasma Lp(a) concentration.20

Recent data suggest the possibility of alternative pathways beyond LDLRmediated clearance involved in Lp(a) reduction by PCSK9 inhibition.21,22 In these clinical studies, the investigators found a significant discordance between LDL-C and Lp(a) lowering with PCSK9 inhibition, with a significant proportion of patients demonstrating essentially no meaningful Lp(a) lowering in the face of an excellent LDL-C response to therapy. Given that PCSK9 and, by extension, PCSK9 inhibitors affect a myriad of receptors

Silencing RNA

The potential use of silencing RNA (siRNA) as a therapeutic tool to inhibit PCSK9 could be a new frontier in LDL-C management. Inclisiran is the siRNA therapeutic furthest along in development. While mAbs solely target circulating PCSK9 (extracellularly), inclisiran targets intracellular PCSK9 by inhibiting the translation of PCSK9 messenger RNA (mRNA).

Therapeutic siRNAs are short sequences of double-stranded RNA that enter the cell and bind to the RNA-induced silencing complex, allowing it to cleave the mRNA, in this case coding for PCSK9.25 Inclisiran is a longacting synthetic siRNA bound to a carbohydrate (multivalent N-acetylgalactosamine) for which the liver expresses abundant receptors, allowing hepatocyte targeting.26,27 This targeted approach means that lower doses can be used to achieve the desired effect, which decreases the risk of adverse effects.

In 2014, Fitzgerald et al. performed a single-blind, placebo-controlled phase I trial of 32 healthy volunteers randomized to receive a dose of

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Current and Future Directions of PCSK9 Inhibition ALN-PCS (the precursor to inclisiran) in various doses versus placebo.

Inclisiran at a maximum dose of 400 mg/kg reduced circulating PCSK9 concentration by 70% and reduced mean LDL-C level by 40% from baseline at 6 months compared to placebo. At lower doses of 250 mg/kg and 150 mg/kg, reductions in circulating PCSK9 plasma protein were 70% and 65%, respectively, and reductions in LDL-C level at 6 months were 28% and 22%, respectively, compared to placebo. The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. Further research into the safety of ALN-PCS revealed no drug-related serious adverse events in a cohort of 24 participants.25 A follow-up phase I trial by Fitzgerald et al. also assessed the efficacy of a single-dose phase versus a multiple-dose phase. In the single-dose phase (25 mg, 100 mg, 300 mg, 500 mg, and 800 mg of inclisiran), inclisiran at a dose of 300 mg or higher was associated with significant reductions in plasma PCSK9 concentration compared to placebo, with similar magnitudes of reduction across the 300–800 mg does range (leastsquares mean change: 69.9–74.5%). The largest reduction in plasma PCSK9 concentration was 74.5% and was observed in the group treated with 300 mg of inclisiran.

With respect to LDL-C levels, significant reductions from baseline were observed from doses of 100 mg and above, with the largest reduction of 50.7% in LDL-C occurring with the 500 mg dose. These reductions were sustained at 6 months with doses greater than 300 mg, but were not observed with the 25 mg and 100 mg doses. The multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, and 300 or 500 mg monthly for two doses) demonstrated the greatest reduction in plasma PCSK9 (84.7%) with the 500 mg monthly for two doses, and the greatest reduction of LDL-C (60%) with the 300 mg monthly for two doses.28 Ray et al. followed-up the initial studies with ORION-1, a phase II multicenter, double-blinded, randomized controlled trial of 501 subjects.

The trial assessed the LDL-C lowering efficacy of inclisiran at 180 days as the primary endpoint. Trial participants received a single dose of placebo, 200 mg, 300 mg, or 500 mg of inclisiran or two doses of placebo, 100 mg, 200 mg, or 300 mg of inclisiran at days 1 and 90. The LDL-C reduction ranged from 27.9-41.9% in subjects who received a single dose of inclisiran and 35.5–52.6% in subjects who received two doses. Two doses of inclisiran at 300 mg was the regimen associated with the greatest LDL-C lowering efficacy with percentage and mean reductions of LDL-C levels of 52.6% and 1.66 mmol/l (64.2 mg/dl), respectively, at 180 days, and 47.2% and 1.53 mmol/l (58.9 mg/dl) respectively at 240 days.

Regardless of dosing regimen, the lipid-lowering effects of inclisiran were sustained at day 240. The adverse effect profile was similar to that previously described. Importantly, the incidence of adverse events did not differ significantly between the inclisiran and placebo groups.29 Recently, two phase III randomized placebo-controlled trials were published, including the ORION-10 trial that enrolled 1,561 patients with ASCVD, and the ORION-11 trial that enrolled 1,617 patients with ASCVD or an ASCVD risk equivalent. All patients in both trials had elevated LDL-C despite maximal statin therapy, and were randomized to receive either 284 mg of subcutaneous inclisiran or placebo at day 1, day 90, and every 6 months thereafter for up to 540 days. At day 510, inclisiran reduced LDL-C levels by 52.3% (95% CI [48.8–55.7]) in the ORION-10 trial and by 49.9% (95% CI [46.6–53.1]) in the ORION-11 trial with p values <0.001 for all comparisons against placebo. All-cause adverse events were similar

between the inclisiran and placebo groups (73.5% with inclisiran versus 74.8% with placebo in ORION-10 and 82.7% with inclisiran versus 81.5% with placebo in ORION-11), with the exception of injection-site reactions, which were higher in the inclisiran group (2.6% versus 0.9% in the ORION-10 and 4.7% versus 0.5% in the ORION-11); however, such reactions were generally mild.30 Inclisiran continues to be tested in special populations. It may be a promising strategy for LDL-C management in patients with severe chronic kidney disease, where the use of statins can be challenging due to issues related to clearance, tolerability, and adverse events.31 Analysis of ORION-7, a phase I single-dose non-randomized trial evaluating subjects with various degrees of renal impairment, demonstrated that the pharmacodynamics and safety profile of inclisiran were similar in participants with normal and impaired renal function (including patients with severe renal impairment, with an estimated glomerular filtration rate of <30 ml/min/1.73 m2).32 An analysis of ORION-1 demonstrated that inclisiran was equally effective in diabetic and nondiabetic populations, with median dose-dependent LDL-C reductions of 28–53%.33 Various other phase II and III trials within the ORION program are still under way to assess the long-term safety and efficacy of inclisiran (Table 3). ORION-3 is a phase II, open-label, non-randomized trial that compares inclisiran to evolocumab in patients with clinical ASCVD, an ASCVD risk equivalent, or heterozygous FH to assess the efficacy and safety profile of inclisiran for up to 4 years. ORION-4 is a large phase III cardiovascular outcomes trial that will assess MACE at 6 years or more.

Other phase III trials, such as ORION-5 and ORION-9, will assess the efficacy of inclisiran in homozygous and heterozygous FH, respectively.34 Both trials showed significantly reduced LDL-C levels with inclisiran compared to placebo. In 482 heterozygous FH patients, at day, 510 LDL-C levels were reduced by 39.7% in the inclisiran group compared to an increase of 8.2% in placebo group (p<0.001).35 A smaller study of four subjects with homozygous FH on background high-intensity statin and ezetimibe therapy found that all participants achieved robust and durable PCSK9 reductions of 40–80% at day 180, as well as LDL-C reductions of 17–37% that were observed in three out of the four patients.36

Vaccines

Another promising approach to inhibit PCSK9 involves priming the immune system to neutralize PCSK9 using PCSK9-peptide-based vaccines. Several types of vaccines are in development. In 2017, Pan et al. used a virus-like particle (VLP)-peptide vaccine targeting PCSK9 in mouse models and found that the mice developed high titer anti-PCSK9 IgG antibodies that resulted in decreased plasma PCSK9 levels, upregulated LDLR expression in the liver, and decreased total plasma cholesterol with no detectable immune injury.37 Around the same time, Landlinger et al. developed an AT-04A anti-PCSK9 vaccine that elicited persistent elevations in anti-PCSK9 antibodies with a significant 53% reduction in total plasma cholesterol. Moreover, the treated mice exhibited reductions in LDL-C and various inflammatory markers (such as vascular endothelial growth factor). Of note, treatment with the AT-04A vaccine resulted in decreased atherosclerotic lesion area and aortic inflammation in intervention compared to control mice.38 A year later, Kawakami et al. tested a similar peptide vaccine consisting of short peptides conjugated to a carrier protein that was administered to ApoE-deficient mice and elicited a significant antibody response to PCSK9 with titers maintained at 24 weeks. These mice exhibited increased cell-

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Current and Future Directions of PCSK9 Inhibition Table 3. Summary of ORION Trials Trial

Study Study Year Design

Sample Patient Size Population

ORION-1 (NCT02597127)

Phase II, April, 2017 DB, PC

501

ORION-2 (NCT02963311)

Phase II, Pilot study (2019) 4 DB, PC

ORION-3 Phase II, Incomplete (NCT03060577) DB, PC (started March 2017)

490

Drug Dosage

Follow-up Primary Time Endpoint

Results

ASCVD or ASCVD Single dose (placebo, 200 mg, 300 mg, or 500240 days RE mg) or 2 doses (placebo, 100 mg, 200 mg, or 300 mg) at days 1 and 90

LDL reduction

27.9–41.9% in a single dose; 35.5–52.6% in 2 doses

HoFH

LDL reduction

43% on day 120

LDL reduction

Incomplete

Single dose 300 mg

180 days

ASCVD or ASCVD Inclisiran: 300 mg day 1, then every 180 days 4 years RE Evolocumab: 140 mg day 1, then every 14 days until day 336; then change inclisiran group dosing

ORION-4 Phase III, Under enrollment ~15,000 ASCVD or ASCVD 300 mg or placebo at day 1, 3 months, then (NCT03705234) DB, PC (started Oct 2018) RE every 6 months

5 years

MACE

Still under enrollment

ORION-5 (NCT03851705)

Phase III, Incomplete 56 DB, PC (started Feb 2019)

HoFH

150 days

LDL reduction

Incomplete

ORION-8 (NCT03814187)

Phase III, Incomplete 2,991 DB, PC (started April 2019)

ASCVD, ASCVD RE, Inclisiran: 300 mg day 1, 90 then every 180 HoFH or HeFH days to day 990

4 years

LDL reduction

Incomplete

ORION-9 (NCT03397121)

Phase III, Nov, 2019 DB, PC

482

HeFH

300 mg or placebo at day 1, 3 months, then every 6 months

18 months

LDL reduction

Placebo adjusted: 50%; time adjusted: 45%

ORION-10 Phase III, March, 2020 (NCT03399370) DB, PC

1,561

ASCVD

284 mg of subcutaneous inclisiran or placebo 510 days at day 1, day 90 and every 6 months thereafter for up to 540 days

LDL reduction

Mean of 52.3% (95% CI [48.8–55.7])

ORION-11 Phase III, March, 2020 (NCT03400800) DB, PC

1,617

ASCVD or ASCVD 284mg of subcutaneous inclisiran or placebo 510 days RE at day 1, day 90 and every 6 months thereafter for up to 540 days

LDL reduction

Mean of 49.9% (95% CI [46.6–53.1])

Part 1: 300 mg or placebo at day 1 and 90 Part 2: 300 mg at day

ORION-6 and ORION-7 are two phase I studies on pharmacokinetics in hepatic and renal impairment; ORION-12 is a phase I study on healthy volunteers to assess QTc and EKG effects.

ASCVD = atherosclerotic cardiovascular disease; DB = double-blinded; HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous familial hypercholesterolemia; MACE = major adverse cardiac events; PC = placebo-controlled; RE = risk equivalent.

surface LDLR expression and decreased total cholesterol, very LDL, and chylomicron concentration with effects sustained at 24 weeks.39 Another approach to vaccine development involves binding immunogenic peptides (consisting of fused PCSK9-tetanus [IFPT] linked to short PCSK9 peptides) to negatively charged nanoliposomes using DSPE-PEGmaleimide lipid (L-IFPT) and adsorbed to Alhydrogel (Croda) aluminum hydroxide gel, forming an L-IFPTA+ vaccine. In mouse models, this L-IFPTA+ vaccine induced an effective IgG antibody response with an associated 58.5% decrease in plasma PCSK9 compared to controls and decreased total cholesterol, LDL-C and VLDL-C by 44.7%, 51.7%, and 19.2%, respectively, at 8 weeks. At 16 weeks after vaccination, the LDL-C reduction was sustained and had decreased by 42% from baseline.40 Further analysis over 48 weeks demonstrated that the L-IFPTA+ vaccine was able to stimulate a long-lasting humoral immune response against the PCSK9 peptide and resulted in increased anti-inflammatory mediators, such as CD4+ Th2 cells and IL-4 within splenocytes. These findings suggest that this vaccine has the potential for long-term therapeutic cholesterol lowering.41

CRISPR

Genome editing, such as clustered regularly interspaced short palindromic repeats (CRISPR), can be leveraged as a potential therapeutic to disrupt target genes, such as PCSK9. CRISPR-associated systems (Cas) use the Cas9 (CRISPR-Cas9) nuclease derived from bacteria, such as Streptococcus pyogenes or Staphylococcus aureus, that binds to DNA and causes doublestranded breaks with the goal of introducing LOF mutations into the endogenous PCSK9 gene in vivo. Initial studies in animal models found that

on-target mutagenesis rates in the liver were as high as >50% and associated with a reduction in plasma PCSK9 concentration, increased LDLR expression, and a 35–40% reduction in plasma cholesterol. Moreover, this approach demonstrated sustained PCSK9 reduction over 24 weeks.42 Importantly, no off-target mutagenesis was detected.43 Despite these positive results with CRISPR gene editing, safety concerns continue regarding the unpredictable nature of the cellular repair of double-stranded breaks, as well as off-target mutagenesis. New advancements favor the use of base editors comprised of CRISPR-Cas9 fused to a cytosine deaminase domain that modify cytosine to thymine bases (C–T changes) at precise locations in the genome without the need for double-strand DNA breaks or DNA replication. The advantage of this approach is a superior safety profile.44 In an adult mouse model, Chadwick et al. demonstrated that the use of a base editor targeting PCSK9 resulted in >50% reduction in plasma PCSK9 concentration and a >30% reduction in plasma cholesterol levels without evidence of off-target mutagenesis.45 Despite these advances, CRISPR technology is far from clinical application.

Other Methods of PCSK9 Inhibition

Additional approaches to antagonizing PCSK9 focus on inhibiting various steps in translation, post-translational processing, and binding of PCSK9 to the LDLR. Lintner et al. created an orally active compound (PF06446846) that inhibits the translation of PCSK9 by inducing the ribosome to stall on codon 34, resulting in reduced plasma PCSK9 and total cholesterol levels in rats.46 However, one major limitation of this translational inhibitor is the lack of selectivity for PCSK9, which likely poses a challenge for future work in this area.47

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Current and Future Directions of PCSK9 Inhibition Another approach to inhibiting PCSK9 production involves posttranscriptional downregulation of PCSK9 mRNA using miRNA mimetics.

A recent study found that miR-191, miR-222, and miR-224 bind directly to the 3’ end of PCSK9 mRNA, thereby downregulating its expression into protein.48 However, these miRNA are again limited by the lack of selectivity to PCSK9.49 Downstream of translation, an emerging method targets the autocatalytic process of proPCSK9 (a zymogen) into active PCSK9.

Active PCSK9 exits the endoplasmic reticulum (ER) only after proPCSK9 undergoes this autocatalytic cleavage process to generate a heterodimer of mature PCSK9.49,50 In certain families who are heterozygous for a PCSK9 LOF mutation, a resultant proPCSK9-Q152H variant was discovered, which caused proPCSK9 to be unable to undergo autocatalytic cleavage, thereby retaining the proPCSK9 variant within the ER and resulting in very low levels of circulating PCSK9 and serum LDL-C.51 Interestingly, after cotransfection of these proPCSK9-Q152H variants with wild-type PCSK9, it was observed that the variant dimerizes with wild-type PCSK9, forcing its retention within the ER and resulting in 78% less secretion of the wild-type PCSK9 protein.50,51 The development of a small molecule inhibitor to interfere with this autocatalytic process pose challenges since the zero-order kinetics of the autocatalytic process of proPCSK9 into PCSK9 requires high doses of an inhibitor to outcompete the intramolecular reaction. Additionally, it remains to be seen whether a small molecule that can traverse both the plasma and the ER membranes can be developed.52,53 There is also interest in developing a small molecule inhibitor that targets the PCSK9-LDLR interface. PCSK9 has an epidermal growth factor precursor homology domain A (EGF-A) binding site that interacts with the EGF-A domain of LDLR. The first EGF-A-like peptide, created in 2012, was an Fc fusion protein variant of EGF66 that bound to PCSK9 with inhibition of LDLR degradation both in vitro and in vivo mouse models.54 1. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics – 2019 update: a report from the American Heart Association. Circulation 2019;139:e56– e528. https://doi.org/10.1161/CIR.0000000000000659; PMID: 30700139.

2. Navar-Boggan AM, Peterson ED, D’Agostino RB, et al.

Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation 2015;131:451–8. https:// doi.org/10.1161/CIRCULATIONAHA.114.012477; PMID: 25623155.

3. Perak AM, Ning H, de Ferranti SD, et al. Long-term risk of atherosclerotic cardiovascular disease in US adults with the familial hypercholesterolemia phenotype. Circulation 2016;134:9–19. https://doi.org/10.1161/ CIRCULATIONAHA.116.022335; PMID: 27358432 4. Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholestrolemia. Nat Genet 2003;34:154–6. https://doi.org/10.1038/ng1161; PMID: 12730697.

5. Leren TP. Sorting an LDL receptor with bound PCSK9 to intracellular degradation. Atherosclerosis 2014;237:76–81. https://doi.org/10.1016/j.atherosclerosis.2014.08.038; PMID: 25222343.

6. Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005;37:161–5. https://doi.org/10.1038/ng1509; PMID: 15654334.

7. Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2007;193:445–8. https://doi.org/10.1016/j. atherosclerosis.2006.08.039; PMID: 16989838.

8. Cohen JC BE, Mosley TH, Hobbs HH. Sequence variation in

9.

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Several years later, the same team led by Zhang et al. developed a shorter peptide sequence of 13 amino acids, Pep2–8, that bound PCSK9 with greater affinity; however it was less active than its predecessor, EGF66.55 Furthermore, refinement of a small molecule inhibitor is difficult given the flat interface of the EGF-A binding site. However, Zhang et al. discovered a vacated N-terminal groove of PCSK9 adjacent to the EGF-A binding site that is accessible to small peptides, where a small molecule inhibitor can prevent the PCSK9–EGF-A interaction. Indeed, an engineered small molecule therapeutic peptide, MESFPGWNLV(hR)IGLLR, effectively inhibits PCSK9 binding to the EGF-A domain of LDLR.56 This recent structural identification of a novel pocket in PCSK9 opens up the door to future development of an orally active, small-molecule PCSK9 inhibitor.57

Conclusion

Over the past two decades, rapid, innovative developments have emerged within the field of therapeutic cholesterol lowering, especially in the area of PCSK9 inhibition. There are two approved PCSK9 inhibitors, evolocumab and alirocumab, with potent and equivalent LDL-C reductions of around 60%. Both drugs, when given in addition to standard of care, demonstrated improvement in cardiovascular outcomes in randomized controlled trials.

In addition to the PCSK9 mAbs, the development of siRNA as a means to inhibit PCSK9 has garnered much attention because of its LDL-C lowering efficacy, as well as its sustained durability after dosing. Several trials are still under way to assess the impact of inclisiran on cardiovascular outcomes and its efficacy in special populations.

Other innovative modes of PCSK9 inhibition that are still in the early phases of development include vaccines, CRISPR editing, and PCSK9 antagonists along various stages of translation, and small-molecule inhibitors that block the PCSK9-LDLR interaction. However, these novel agents are still in early development and further research will be required to demonstrate the future role of these therapies in the treatment of hypercholesterolemia and ASCVD.

PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264–72. https://doi. org/10.1056/NEJMoa054013; PMID: 16554528.

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Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–107. https://doi.org/10.1056/ NEJMoa1801174; PMID: 30403574.

Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY Outcomes trial. Am Heart J 2014;168:682–9. https://doi.org/10.1016/j. ahj.2014.07.028; PMID: 25440796.

Cao YX, Liu HH, Li S, Li JJ. A meta-analysis of the effect of PCSK9-monoclonal antibodies on circulating lipoprotein (a) levels. Am J Cardiovasc Drugs 2019;19:87–97. https://doi. org/10.1007/s40256-018-0303-2; PMID: 30229525.

Tavori H, Christian D, Minnier J, et al. PCSK9 association with lipoprotein(a). Circ Res 2016;119:29–35. https://doi. org/10.1161/CIRCRESAHA.116.308811; PMID: 27121620.

Zenti MG, Altomari A, Lupo MG, et al. From lipoprotein apheresis to proprotein convertase subtilisin/kexin type 9 inhibitors: impact on low-density lipoprotein cholesterol and C-reactive protein levels in cardiovascular disease patients.

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17. Bittner VA, Szarek M, Aylward PE, et al. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol 2020;75:133–44. https://doi.org/10.1016/j.jacc.2019.10.057; PMID: 31948641.

18. Raal FJ, Giugliano RP, Sabatine MS, et al. PCSK9 inhibitionmediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor’s role. J Lipid Res 2016;57:1086–96. https://doi.org/10.1194/jlr.P065334; PMID: 27102113.

19. Rader D, Mann W, Cain W, et al. The low density lipoprotein receptor is not required for normal catabolims of Lp(a) in humans. J Clin Invest 1995;95:1403–8. https://doi.org/10.1172/ JCI117794; PMID: 7883987.

20. Boffa MB, Koschinsky ML. Update on lipoprotein(a) as a cardiovascular risk factor and mediator. Curr Atheroscler Rep 2013;15:360. https://doi.org/10.1007/s11883-013-0360-6; PMID: 23990263.

21. Edmiston JB, Brooks N, Tavori H, et al. Discordant response of low-density lipoprotein cholesterol and lipoprotein(a) levels to monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9. J Clin Lipidol 2017;11:667– 73. https://doi.org/10.1016/j.jacl.2017.03.001; PMID: 28506388.

22. Shapiro MD, Minnier J, Tavori H, et al. Relationship between low-density lipoprotein cholesterol and lipoprotein(a) lowering in response to PCSK9 inhibition with evolocumab.

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25. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 2014;383:60–8. https://doi.org/10.1016/ S0140-6736(13)61914-5; PMID: 24094767.

26. Kosmas CE, DeJesus E, Morcelo R, et al. Lipid-lowering interventions targeting proprotein convertase subtilisin/ kexin type 9 (PCSK9): an emerging chapter in lipid-lowering therapy. Drugs Context 2017;6:212511. https://doi.org/10.7573/ dic.212511; PMID: 29209403.

27. Nair JK, Willoughby JL, Chan A, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc 2014;136:16958–61. https://doi. org/10.1021/ja505986a; PMID: 25434769.

28. Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017;376:41–51. https://doi.org/10.1056/NEJMoa1609243; PMID: 27959715.

29. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran In patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430–40. https://doi.org/10.1056/ NEJMoa1615758; PMID: 28306389.

30. Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020;382:1507–19. https://doi.org/10.1056/ NEJMoa1912387; PMID: 32187462.

31. Zijlstra LE, Trompet S, Mooijaart SP, et al. Renal impairment, cardiovascular disease, and the short-term efficacy and safety of PCSK9 targeted by inclisiran. Mayo Clin Proc 2020;95:12–4. https://doi.org/10.1016/j.mayocp.2019.11.010; PMID: 31902406.

32. Wright RS, Collins MG, Stoekenbroek RM, et al. Effects of renal impairment on the pharmacokinetics, efficacy, and safety of inclisiran: an analysis of the ORION-7 and ORION-1 studies. Mayo Clin Proc 2020;95:77–89. https://doi. org/10.1016/j.mayocp.2019.08.021; PMID: 31630870.

33. Leiter LA, Teoh H, Kallend D, et al. Inclisiran lowers LDL-C and PCSK9 irrespective of diabetes status: the ORION-1 randomized clinical trial. Diabetes Care 2019;42:173–6. https://doi.org/10.2337/dc18-1491; PMID: 30487231.

34. German CA, Shapiro MD. Small interfering RNA therapeutic inclisiran: a new approach to targeting PCSK9. BioDrugs 2020;34:1–9. https://doi.org/10.1007/s40259-019-00399-6; PMID: 31782112.

35. Raal FJ, Kallend D, Ray KK, et al. for the treatment of heterozygous familial hypercholestrolemia. N Engl J Med 2020;382:1520–30. https://doi.org/10.1056/NEJMoa1913805; PMID: 32197277.

36. Hovingh GK, Lepor NE, Kallend D, et al. Inclisiran durably lowers low-density lipoprotein cholesterol and proprotein convertase subtilisin/kexin type 9 expression in homozygous familial hypercholesterolemia: the ORION-2 pilot study.

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37. Pan Y, Zhou Y, Wu H, et al. A therapeutic peptide vaccine against PCSK9. Sci Rep 2017;7:12534. https://doi.org/10.1038/

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38. Landlinger C, Pouwer MG, Juno C, v et al. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. Eur Heart J 2017;38:2499–507. https://doi.org/10.1093/eurheartj/ehx260; PMID: 28637178.

39. Kawakami R, Nozato Y, Nakagami H, et al. Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9) epitope in mice.

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Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis. BMC Med 2019;17:223. https://doi.org/10.1186/s12916-019-1457-8; PMID: 31818299.

41. Momtazi-Borojeni AA, Jaafari MR, Badiee A, Sahebkar A. Long-term generation of antiPCSK9 antibody using a nanoliposome-based vaccine delivery system. Atherosclerosis 2019;283:69–78. https://doi.org/10.1016/j. atherosclerosis.2019.02.001; PMID: 30797988.

42. Thakore PI, Kwon JB, Nelson CE, et al. RNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors. Nat Commun 2018;9:1674. https://doi.org/10.1038/ s41467-018-04048-4; PMID: 29700298.

43. Ding Q, Strong A, Patel KM, et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res 2014;115:488–92. https://doi.org/10.1161/ CIRCRESAHA.115.304351; PMID: 24916110.

44. Komor AC, Kim YB, Packer MS, et al. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 2016;533:420–4. https://doi. org/10.1038/nature17946; PMID: 27096365.

45. Chadwick AC WX, Musunuru K. In vivo base editing of PCSK9 as a therapeutic alternative to genome editing.

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46. Lintner NG, McClure KF, Petersen D, et al. Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biol 2017;15:e2001882. https://doi.org/10.1371/journal.pbio.2001882; PMID: 28323820.

47. Londregan AT, Wei L, Xiao J, et al. Small molecule proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: hit to lead optimization of systemic agents. J Med Chem 2018;61:5704–18. https://doi.org/10.1021/acs. jmedchem.8b00650; PMID: 29878763.

48. Naeli P, Mirzadeh Azad F, Malakootian M, et al. Posttranscriptional regulation of PCSK9 by miR-191, miR-222, and miR-224. Front Genet 2017;8:189. https://doi.org/10.3389/ fgene.2017.00189; PMID: 29230236.

49. Seidah NG, Prat A, Pirillo A, et al. Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies. Cardiovasc Res 2019;115:510–8. https://doi. org/10.1093/cvr/cvz003; PMID: 30629143.

50. Benjannet S, Hamelin J, Chretien M, Seidah NG. Loss- and gain-of-function PCSK9 variants: cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation. J Biol Chem 2012;287:33745– 55. https://doi.org/10.1074/jbc.M112.399725; PMID: 22875854.

51. Mayne J, Dewpura T, Raymond A, et al. Novel loss-offunction PCSK9 variant is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture. Clin Chem 2011;57:1415–23. https://doi.org/10.1373/clinchem.

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53. Chorba JS, Galvan AM, Shokat KM. Stepwise processing analyses of the single-turnover PCSK9 protease reveal its substrate sequence specificity and link clinical genotype to lipid phenotype. J Biol Chem 2018;293:1875–86. https://doi. org/10.1074/jbc.RA117.000754; PMID: 29259136.

54. Zhang Y, Zhou L, Kong-Beltran M, et al. Calciumindependent inhibition of PCSK9 by affinity-improved variants of the LDL receptor EGF(A) domain. J Mol Biol 2012;422:685–96. https://doi.org/10.1016/j.jmb.2012.06.018; PMID: 22728257.

55. Zhang Y, Eigenbrot C, Zhou L, et al. Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor. J Biol Chem 2014;289:942–55. https://doi.org/10.1074/jbc.M113.514067; PMID: 24225950.

56. Zhang Y, Ultsch M, Skelton NJ, et al. Discovery of a cryptic peptide-binding site on PCSK9 and design of antagonists.

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57. Seidah NG. Insights into a PCSK9 structural groove: a harbinger of new drugs to reduce LDL-cholesterol. Nat Struct Mol Biol 2017;24:785–6. https://doi.org/10.1038/nsmb.3471; PMID: 28981076.

58. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 2017;5:941–50. https://doi. org/10.1016/S2213-8587(17)30313-3; PMID: 28927706.

59. Giugliano RP, Keech A, Murphy SA, et al. Clinical efficacy and safety of evolocumab in high-risk patients receiving a statin: secondary analysis of patients with low LDL cholesterol levels and in those already receiving a maximalpotency statin in a randomized clinical trial. JAMA Cardiol 2017;2:1385–91. https://doi.org/10.1001/ jamacardio.2017.3944; PMID:29117276.

60. Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017;390:1962–71. https://doi.org/10.1016/S01406736(17)32290-0; PMID: 28859947.

61. Bonaca MP, Nault P, Giugliano RP, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2018;137:338–50. https://doi.org/10.1161/ CIRCULATIONAHA.117.032235; PMID:29133605.

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63. O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 2019;139:1483–92. https://doi.org/10.1161/ CIRCULATIONAHA.118.037184; PMID:30586750.

64. Ray KK, Colhoun HM, Szarek M, et al. Effect of alirocumab on cardiovascular and metabolic outcome after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomized controlled trial. Lancet Diabetes Endocrinol 2019;7:618–28. https://doi.org/10.1016/S2213-8587(19)301585; PMID: 31272931.

Interventional Cardiology

Effect of Operator Experience on Transcatheter Mitral Valve Repair Outcomes Justin P Sheehy, MD,

1

and Adnan K Chhatriwalla, MD

1,2

1. University of Missouri-Kansas City, Kansas City, MO; 2. Saint Luke’s Mid America Heart Institute, Kansas City, MO

Abstract

Transcatheter mitral valve repair with MitraClip is a novel, intricate therapy for mitral regurgitation that improves survival and quality of life. Similar to other medical procedures, there is a relationship between procedural experience and clinical outcomes. MitraClip results and the efficiency and safety of the procedure all improved with increasing experience at both the institutional and operator level in two large studies from the Society of Thoracic Surgeons and American College of Cardiology Transcatheter Valve Therapy Registry. Patient selection was also found to have a significant role in procedure success. The old adage of “See one, do one, teach one” does not necessarily apply to complex interventions, such as MitraClip, given that the learning curve does not appear to plateau even as operators approach a 150-case experience.

Keywords

Transcatheter mitral valve repair, MitraClip, experience, volume–outcome relationship, mitral valve regurgitation Disclosure: AKC has been on speakers bureaux for Abbott Vascular, Edwards Lifesciences, and Medtronic, a proctor for Edwards Lifesciences and Medtronic; and a consultant for Boston Scientific and Silk Road Medical. JPS has no conflicts of interests to declare.

Received: January 13, 2020 Accepted: September 7, 2020 Citation: US Cardiology Review 2021;15:e02. DOI: https://doi.org/10.15420/usc.2020.02 Correspondence: Adnan K Chhatriwalla, Saint Luke’s Mid America Heart Institute, 4330 Wornall Rd, Suite 2000, Kansas City, MO 64111. E: achhatriwalla@saint-lukes.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transcatheter mitral valve repair (TMVr) with the MitraClip is an effective therapy for mitral regurgitation. Several trials have demonstrated improved survival in appropriate patients and similar survival rates compared with surgical mitral valve repair.1,2 Not only does MitraClip improve survival compared with medical therapy alone, but it also provides a large improvement in quality of life, as demonstrated by less frequent hospitalizations for heart failure and improvements in Kansas City Cardiomyopathy Questionnaire scores.3,4 This correlates with improvements in New York Heart Association (NYHA) heart failure classification and other tangible measures, such as 6 minute walk distances, along with physiological changes, such as less regurgitant volume and reductions in left ventricular volume and left atrial size.5,6 MitraClip has been commercially available in the US as an alternative to surgical mitral repair for primary (degenerative) mitral regurgitation in patients at high risk of complications related to surgery since 2013, after the publication of the EVEREST II results and the EVEREST high-risk registry.2,7 The device was approved for use in patients with severe secondary (functional) mitral regurgitation in March 2019 following the results of the COAPT trial.1 With increasing MitraClip use, real-world data have shown >90% procedural success, defined as a reduction in residual mitral regurgitation to ≤2+ and freedom from mortality or cardiac surgery.8–10 Optimal results have further been defined as ≤1+ residual regurgitation, which correlates with improved outcomes such as increased survival and decreased heart failure hospitalizations.6 Although TMVr is a novel therapeutic option for patients, it remains a technically challenging procedure that requires collaboration between multidisciplinary specialists for both patient selection and device deployment. The operator is required to manipulate the device through a

precise transseptal puncture and meticulously traverse the complex mitral apparatus under echocardiographic guidance for successful positioning to grasp the anterior and posterior leaflets of the mitral valve while the heart is beating. Minute adjustments in clip position can have a considerable effect on procedural results, and imaging of the clip and the mitral valve leaflets, as well as assessment of residual mitral regurgitation, can be challenging. Typically, discussions between multiple team members occur prior to clip deployment to ensure optimal results.

Fortunately, despite the complexity of the procedure, complication rates have remained acceptably low, but serious adverse events still occur in up to 3% of procedures.9 Optimizing outcomes for patients remains a priority for providers, and therefore the relationship between experience and clinical outcomes, which has been apparent across procedurally based medical fields, is of great interest. However, the number of procedures performed does not simply explain this phenomenon. Rather, clinical judgment, decision making, and proper patient selection are all thought to have important roles.

In the surgical literature, higher procedural volumes have been associated with improved outcomes, particularly in intricate pancreatic resections and esophagectomies.11 Complex cardiovascular surgeries are no different, where both septal myectomies and mitral valve repair have improved clinical outcomes when performed by experienced surgeons.

For example, complication rates for both ventricular septal myectomy and alcohol septal ablation, particularly the need for postoperative pacemakers, were nearly half at high-volume centers compared with the nationwide average.12,13 Similarly, surgeons who perform more than 20 surgical mitral valve repairs per year have superior clinical outcomes and

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Effect of Operator Experience on TMVr Outcomes Figure 1: Optimal Procedural Success

rates of 30-day mortality <6%, consistent with the EVEREST II trial.2 As greater experience was gained, the efficacy remained consistent and inhospital complications decreased.9 Concomitantly, investigators began reporting their procedural results with increasing familiarity of the device, and detailing improved case selection and procedural characteristics that led to improved outcomes.8,19,20

As experience with transcatheter mitral valve repair increases, procedural outcomes improve, with a significant improvement after the operator performs 50 cases.

Figure 2: Optimal Procedural Success Stratified by Institutional Case Count 100% 90%

Procedural success

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repair durability.14 The volume–outcome relationship has been studied throughout interventional cardiology, from complex coronary intervention to newer areas of structural cardiology, particularly transcatheter aortic valve replacement (TAVR).12,15 Hospitals where more than 20 TAVRs per year were performed had shorter hospitalizations, lower cost of the procedure, and decreased in-hospital mortality.15 Similarly, a large case experience with unprotected left main percutaneous coronary intervention (PCI; >15 procedures per year) has been shown to result in an 80% reduction in major adverse cardiovascular outcomes at 1 year.16 The overarching trend is that clinical outcomes improve with experience, and it stands to reason that experience may be more important for more complex procedures.

Current Literature

Early studies were published reporting single-center experiences with MitraClip with results similar to clinical trials, achieving <2+ mitral regurgitation and acceptable rates of complications.17,18 As MitraClip became commercially available, investigators evaluated the efficacy of the device in the real world.8 Procedural success remained >90%, with

The Mayo Clinic reported procedural details of their first 75 cases and placed them in sequential cohorts (Cases 1–25, 26–50, and 51–75). In the third tertile of case experience, time to first clip delivery and fluoroscopy time were shorter and complication rates were lower compared with the first and second tertiles of experience.19 Data from Germany showed a marked decrease in procedure duration despite an increasing number of clips deployed and a shorter length of stay as experience increased over 126 cases.20 The procedure success, heart failure classification, and rates of major adverse cardiac events in short term follow-up were similar among early procedures in both studies. European cohorts had similar results to the early US operators in terms of residual regurgitation and mortality as early experience increased.10,21,22 Two larger studies using data from the Society of Thoracic Surgeons (STS) and American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) Registry have evaluated the relationship between experience and outcomes of TMVr with the MitraClip; the first study evaluated institutional experience and the second focused on individual operator experience (Figure 1).23,24 Procedures were categorized according to institutional or operator experience to examine the correlation with procedural success, procedure time, and complications. Procedural success was categorized as acceptable (≤2+ mitral residual regurgitation) and optimal (≤1+ mitral residual regurgitation) for the analyses. The mean STS predicted risk of mortality with mitral valve repair was >5% and the risk for mitral valve replacement was >8%. Most cases were performed electively for degenerative mitral regurgitation and a single MitraClip was deployed in most cases, predominantly in the A2–P2 position. Of note, sites and operators were more likely to perform urgent procedures and use more than one clip as experience increased.

In the institutional analysis, institutions were categorized according to tertiles of case experience (1–18, 19–51, or ≥52 cases) and the median case experience was 30 cases (Figure 2).23 In all, 12,334 MitraClip procedures were evaluated at 275 US sites between 2013 and 2017. Most patients had degenerative mitral disease (86%) and NYHA Class III or IV symptoms (85%). Baseline characteristics across tertiles were relatively similar, with an STS predicted mortality risk of 5.9% for valve repair; however, in the third tertile of case experience, patients had higher prevalence of functional regurgitation, hypertension, leaflet calcification, and less mitral stenosis. Procedural success was achieved in >91% of all procedures, but ‘optimal’ procedure success increased from 62% to 65.5% to 72.5% with increasing institutional experience.

Along with improved results, average procedure time decreased by 45 minutes across the three groups, despite more clips deployed per case (46% versus 38% with ≥2 clips). Although an inflection point was present at approximately 50 cases in these learning curves, procedural results continued to improve out to greater than 150 procedures, suggesting that the learning curve for the procedure is longer than may have been thought. However, after an adjusted analysis of baseline patient variables, the relationship between experience and procedural success was no longer significant, which suggests that case selection was an important factor in these results.

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Effect of Operator Experience on TMVr Outcomes Figure 3: Optimal Procedural Success Stratified by Operator Case Count 100% 90% 80% Procedural success

Similar results were demonstrated in another analysis of the STS/ACC TVT Registry, which stratified 14,923 procedures among 562 operators according to MitraClip case experience.24 Procedures were categorized based on the operator’s case experience at the time of the procedure (<25, 25–50, or >50 MitraClip procedures). In the case of two operators performing the procedure together, the procedure was categorized based on the operator with the greater case experience. Again, most cases were for 3+ or 4+ mitral regurgitation (93%) with degenerative disease (86%) in the elective setting (87%) primarily treated with one clip (53%). Baseline characteristics differed in that more experienced operators were less likely to treat patients on home oxygen or with preexisting mitral stenosis and more likely to treat unstable patients and place an atrial septal defect closure device at the conclusion of the case.

Increasing operator experience was associated with a modest improvement in procedural success (from 91% in the first 25 cases to 93.8% for ≥50 cases).

70% 60% 50% 40% 30% 20% 10% 0%

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The association between operator experience and ‘optimal’ procedure success was greater, increasing from 63% to 68% to 75% across the tertiles of experience.24 Procedure time also decreased as operators gained more experience, similar to the site-level analysis. These associations remained significant following adjustment for patient characteristics, suggesting that the improvement in outcomes observed with increasing operator experience cannot be attributed solely to case selection. To further investigate site influence on operator outcomes, a sensitivity analysis was performed to examine outcomes for early experienced operators (≤13 procedures) practicing at more experienced and less experienced centers. This revealed there were no significant differences in procedure success, time, and complications associated with site experience (Figure 3).

In both studies, complication rates decreased with increasing experience at both the institutional and individual operator level.23,24 When examining the institutional experience, complications rates were 13.6%, 12.0%, 11.5% in the lowest to highest tertile of case experience, respectively. The reduction in complications was driven by fewer vascular access and bleeding complications and fewer single-leaflet device attachments, whereas stroke, transseptal puncture complications, and mortality did not differ among the groups. Complication rates decreased from 9.7% to 8% to 7% with increasing operator experience, but again this was not driven by mortality, stroke, or transseptal complications.

The take-home message from these two studies is that both institutional and operator experiences play a role in procedural outcomes of TMVr with MitraClip. As mentioned previously, achieving optimal results from mitral repair with ≤1+ residual regurgitation is beneficial and the ability to attain these results correlates with experience; however, it is important to remember that the learning curve for the procedure does not appear to plateau even as the operators approach a 150-case experience. Different institutions and operators began their experience at different time points, therefore one explanation for this phenomenon is early high-volume operators have continued to adopt new techniques and further optimize their results.

The knowledge base for procedural planning and technical aspects of MitraClip has continued to expand and improve as the utilization of the device increases. One example of this, which led to a significant change in procedural outcomes, was the implementation of continuous left atrial pressure assessment and monitoring, which was not routinely performed in early MitraClip procedures but has since been widely adopted as an

As the operator performs an increasing number of cases, there is an increased likelihood of attaining optimal transcatheter mitral valve repair results. The continued increase in procedural success does not plateau after 200 cases have been performed.

integral aspect of decision making during the procedure. Achieving optimal echocardiographic and hemodynamic results is correlated with improved clinical outcomes.25–27 In addition, the device is now in its fourth iteration, with two clip sizes available to better accommodate individual pathology. Although the above studies did not evaluate which generation of the device was used, improvements in the technology likely also contributed to enhanced procedural results.

Another crucial aspect of the MitraClip procedure is optimal echocardiographic imaging not only for device manipulation and deployment, but also for patient selection. The experience of the echocardiographer, which contributed significantly to the institutional experience in the studies above, greatly affects the initial transesophageal study. It has been demonstrated that preprocedural imaging can predict procedural outcomes, particularly the presence of a single jet, flail leaflet, and high-quality three dimensional imaging.28 Another important echocardiographic marker for improved clinical results is the ability to place the clip in the A2–P2 position.8 Having an echocardiographer who understands these data and can perform the diagnostic study with these criteria in mind is invaluable in selecting patients in whom an optimal result can likely be achieved.

Given these data, it appears important for less experienced operators to understand their position on the learning curve for the procedure, and to pay particular attention to case selection in their early experience. With the inflection points for improved outcomes and decreased complication rates occurring at approximately 50 cases, it has been suggested that a reasonable target for procedural cadence is two or more procedures per month, in which an operator could achieve an experience of 50 cases within approximately 2 years. In addition, it would seem worthwhile for new operators early in their experience of TMVr with MitraClip to pair themselves with a more experienced operator and echocardiographer to assist in the clinical judgment of an adequate result during the procedure.

Future Horizons

The frontier for transcatheter mitral valve interventions remains broad given the complexity of the valve apparatus, multiple modes of valve failure, and variability of patient anatomy. Currently, TMVr with MitraClip is the only transcatheter mitral therapy approved in the US. Operators are

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Effect of Operator Experience on TMVr Outcomes becoming increasingly familiar with the device and excellent results are being attained, but mitral repair is not a one-size-fits-all approach. Many novel transcatheter therapies are being developed beyond edge-to-edge repair, ranging from annuloplasty technology to ring and repair combinations and to numerous valve replacement devices. Proper patient selection has already proven to be correlated with clinical outcomes, as detailed in the studies discussed above, and will remain important but, as the structural cardiologist’s toolbox expands, proper device and patient selection will both be imperative.

1. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018;379:2307–18. https://doi.org/10.1056/NEJMoa1806640; PMID: 30280640.

2. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395–406. https://doi.org/10.1056/ NEJMoa1009355; PMID: 21463154.

3. Ussia GP, Cammalleri V, Sarkar K, et al. Quality of life following percutaneous mitral valve repair with the MitraClip System. Int J Cardiol 2012;155:194–200. https://doi. org/10.1016/j.ijcard.2011.08.853; PMID: 21955607.

4. Arnold SV, Li Z, Vemulapalli S, et al. Association of transcatheter mitral valve repair with quality of life outcomes at 30 days and 1 year: analysis of the transcatheter valve therapy registry. JAMA Cardiol 2018;3:1151–9. https://doi. org/10.1001/jamacardio.2018.3359; PMID: 30476950.

5. Lim DS, Reynolds MR, Feldman T, et al. Improved functional status and quality of life in prohibitive surgical risk patients with degenerative mitral regurgitation after transcatheter mitral valve repair. J Am Coll Cardiol 2014;64:182–92. https:// doi.org/10.1016/j.jacc.2013.10.021; PMID: 24184254.

6. Grayburn PA, Foster E, Sangli C, et al. Relationship between the magnitude of reduction in mitral regurgitation severity and left ventricular and left atrial reverse remodeling after MitraClip therapy. Circulation 2013;128:1667–74. https://doi. org/10.1161/CIRCULATIONAHA.112.001039; PMID: 24014834.

7. Glower DD, Kar S, Trento A, et al. Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study. J Am Coll Cardiol 2014;64:172–81. https://doi.org/10.1016/j.jacc.2013.12.062; PMID: 25011722.

8. Sorajja P, Mack M, Vemulapalli S, et al. Initial experience with commercial transcatheter mitral valve repair in the United States. J Am Coll Cardiol 2016;67:1129–40. https://doi. org/10.1016/j.jacc.2015.12.054; PMID: 26965532.

9. Sorajja P, Vemulapalli S, Feldman T, et al. Outcomes with transcatheter mitral valve repair in the United States: an STS/ACC TVT Registry report. J Am Coll Cardiol 2017;70:2315– 27. https://doi.org/10.1016/j.jacc.2017.09.015; PMID: 29096801.

10. Eggebrecht H, Schelle S, Puls M, et al. Risk and outcomes of complications during and after MitraClip implantation: experience in 828 patients from the German TRAnscatheter

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As the field of mitral valve therapy continues to evolve, further research will be necessary into how best to select and treat our patients with the multitude of transcatheter therapies available.

mitral valve interventions (TRAMI) registry. Catheter Cardiovasc Interv 2015;86:728–35. https://doi.org/10.1002/ ccd.25838; PMID: 25601532.

Morche J, Mathes T, Pieper D. Relationship between surgeon volume and outcomes: a systematic review of systematic reviews. Syst Rev 2016;5:204. https://doi. org/10.1186/s13643-016-0376-4; PMID: 27899141.

Panaich SS, Patel N, Arora S, et al. Influence of hospital volume and outcomes of adult structural heart procedures.

World J Cardiol 2016;8:302–9. https://doi.org/10.4330/wjc. v8.i4.302; PMID: 27152142.

Kim LK, Swaminathan RV, Looser P, et al. Hospital volume outcomes after septal myectomy and alcohol septal ablation for treatment of obstructive hypertrophic cardiomyopathy: US nationwide inpatient database, 2003–11. JAMA Cardiol 2016;1:324–32. https://doi.org/10.1001/ jamacardio.2016.0252; PMID: 27438114.

LaPar DJ, Ailawadi G, Isbell JM, et al. Mitral valve repair rates correlate with surgeon and institutional experience. J Thorac Cardiovasc Surg 2014;148:995–1003. https://doi. org/10.1016/j.jtcvs.2014.06.039; PMID: 25048633.

Salemi A, Sedrakyan A, Mao J, et al. Individual operator experience and outcomes in transcatheter aortic valve replacement. JACC Cardiovas Interv 2019;12:90–7. https://doi. org/10.1016/j.jcin.2018.10.030; PMID: 30553706.

Brindis RG, Dehmer GJ. The volume–outcome relationship revisited: does it matter for high-risk PCI? JACC Cardiovas Interv 2016;9:2094–6. https://doi.org/10.1016/j. jcin.2016.08.033; PMID: 27765303.

Alozie A, Paranskaya L, Westphal B, et al. Clinical outcomes of conventional surgery versus MitraClip® therapy for moderate to severe symptomatic mitral valve regurgitation in the elderly population: an institutional experience. BMC Cardiovasc Disord 2017;17:85. https://doi.org/10.1186/s12872017-0523-4; PMID: 28320316.

Patel NJ, Badheka AO, Jhamnani S, et al. Effect of hospital volume on outcomes of transcatheter mitral valve repair: an early US experience. J Interv Cardiol 2015;28:464–71. https:// doi.org/10.1111/joic.12228; PMID: 26489974.

Eleid MF, Reeder GS, Malouf JF, et al. The learning curve for transcatheter mitral valve repair with MitraClip. J Interv Cardiol 2016;29:539–45. https://doi.org/10.1111/joic.12326; PMID: 27696544.

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20. Hamm K, Zacher M, Hautmann M, et al. Influence of experience on procedure steps, safety, and functional results in edge to edge mitral valve repair – a single center study. Catheter Cardiovasc Interv 2017;90:313–20. https://doi. org/10.1002/ccd.26806; PMID: 27649934.

21. Regueiro A, Granada JF, Dagenais F, et al. Transcatheter mitral valve replacement: insights from early clinical experience and future challenges. J Am Coll Cardiol 2017;69:2175–92. https://doi.org/10.1016/j.jacc.2017.02.045; PMID: 28449780.

22. Eggebrecht H, Mehta RH, Lubos E, et al. MitraClip in highversus low-volume centers: an analysis from the German TRAMI Registry. JACC Cardiovas Interv 2018;11:320–2. https:// doi.org/10.1016/j.jcin.2017.09.003; PMID: 29413249.

23. Chhatriwalla AK, Vemulapalli S, Holmes DR Jr, et al.

Institutional experience with transcatheter mitral valve repair and clinical outcomes: insights from the TVT Registry.

JACC Cardiovas Interv 2019;12:1342–52. https://doi. org/10.1016/j.jcin.2019.02.039; PMID: 31320029.

24. Chhatriwalla AK, Vemulapalli S, Szerlip M, et al. Operator experience and outcomes of transcatheter mitral valve repair in the United States. J Am Coll Cardiol 2019;74:2955–65. https://doi.org/10.1016/j.jacc.2019.09.014; PMID: 31568867.

25. Eleid MF, Sanon S, Reeder GS, et al. Continuous left atrial pressure monitoring during MitraClip: assessing the immediate hemodynamic response. JACC Cardiovas Interv 2015;8:e117–9. https://doi.org/10.1016/j.jcin.2015.02.010; PMID: 26003021.

26. Maor E, Raphael CE, Panaich SS, et al. Acute changes in left atrial pressure after mitraclip are associated with improvement in 6-minute walk distance. Circ Cardiovasc Interv 2017;10:e004856. https://doi.org/10.1161/ CIRCINTERVENTIONS.116.004856; PMID: 28314742.

27. Sims JR, Reeder GS, Guerrero M, et al. Characteristics and outcomes of patients with normal left atrial pressure undergoing transcatheter mitral valve repair. Heart 2020;106:898–903. https://doi.org/10.1136/ heartjnl-2019-316133; PMID: 31980440.

28. Thaden JJ, Malouf JF, Nkomo VT, et al. Mitral valve anatomic predictors of hemodynamic success with transcatheter mitral valve repair. J Am Heart Assoc 2018;7:e007315. https://doi.org/10.1161/JAHA.117.007315; PMID: 29331957.

Interventional Cardiology

Advances in Transcatheter Electrosurgery for Treating Valvular Heart Disease Jaffar M Khan, BM BCh, PhD, 1 Toby Rogers, BM BCh, PhD,1,2 Adam B Greenbaum, MD,3 Vasilis C Babaliaros, MD,3 John C Lisko, MD,3 Dursun Korel Yildirim, MS,1 Christopher G Bruce, MB ChB, 1 Daniel A Herzka, PhD, 1 Kanishka Ratnayaka, MD,1,4 and Robert J Lederman, MD 1 1. Cardiovascular Branch, Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD; 2. Medstar Washington Hospital Center, Washington, DC; 3. Structural Heart and Valve Center, Emory University Hospital, Atlanta, GA; 4. UCSD Rady Children’s Hospital, San Diego, CA

Abstract

Delivery of electrosurgery energy through catheters and guidewires enables interventionists to ‘cut’ through obstructive intravascular lesions or across cardiac chambers. A novel application of transcatheter electrosurgery is to make controlled lacerations in heart valve leaflets. This review describes three applications of transcatheter electrosurgery of aortic and mitral valve leaflets to enable transcatheter heart valve implantation.

Intentional laceration of the anterior mitral leaflet to prevent left ventricular outflow obstruction splits and splays the anterior mitral valve and enables transcatheter mitral valve replacement without left ventricular outflow tract obstruction. Technique modifications and novel applications are described. Bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction enables transcatheter aortic valve replacement without coronary artery obstruction. The technique is described and novel uses, especially in the setting of repeat transcatheter aortic valve replacement, are discussed. Finally, electrosurgical laceration and stabilization of mitral valve clip devices (ELASTAClip) enables transcatheter mitral valve replacement after MitraClip implantation. In conclusion, transcatheter electrosurgery is an important and versatile new tool in structural heart intervention.

Keywords

Bioprosthetic heart valve failure, transcatheter aortic valve replacement, transcatheter mitral valve replacement, coronary artery obstruction, left ventricular outflow tract, transcatheter mitral valve repair, structural heart disease Disclosure: JMK, TR, and RJL are co-inventors on patents, assigned to the National Institutes of Health (NIH), on catheter devices to lacerate valve leaflets. JMK has proctored for Edwards Lifesciences and Medtronic. ABG is a proctor for Edwards Lifesciences, Medtronic, and Abbott Vascular. He has equity in Transmural Systems.

VCB is a consultant for Edwards Lifesciences, Abbott Vascular and Transmural Systems, and his employer has research contracts for clinical investigation of transcatheter aortic and mitral devices from Edwards Lifesciences, Abbott Vascular, Medtronic, St Jude Medical, and Boston Scientific. TR is a consultant/proctor for Edwards Lifesciences and Medtronic. He has equity in Transmural Systems. RJL is the principal investigator on a cooperative research and development agreement between NIH and Edwards Lifesciences on transcatheter modification of the mitral valve. No other author has a financial conflict of interest related to this research.

Acknowledgement: This study is supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (Z01-HL006040).

Received: November 19, 2020 Accepted: January 7, 2021 Citation: US Cardiology Review 2021;15:e03. DOI: https://doi.org/10.15420/usc.2020.27 Correspondence: Jaffar M Khan, Cardiovascular Branch, Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health, Building 10, Room 2c713, MSC 1538, Bethesda, MD 20892–1538. Email: jaffar.khan@nih.gov Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Percutaneous intervention in cardiology typically relies on devices designed to be deployed in specific anatomies, for example, stents sized and deployed in coronary arteries, transcatheter heart valves implanted in calcified and failing valves, and occluding devices designed for the left atrial appendage or septal defects. In contrast, cardiothoracic surgeons rely on a toolkit to enable a variety of procedures that predominantly involve cutting and suturing. An important tool in the surgeon’s kit is the use of electrosurgery to cut and coagulate tissue. In this review article, we describe the novel percutaneous use of electrosurgery to enable transcatheter interventions.

Thermal cautery has been used for millennia, with the application of hot stones and iron pokers to treat maladies from battle wounds to boils.

Electrocautery uses an electrical current to heat the instrument used to deliver thermal cautery to the treatment area, typically a superficial lesion.

In contrast, electrosurgery transfers alternating current through the target

tissue, which heats through energy generated from resistance, and is used for cutting or coagulation. In transcatheter electrosurgery, alternating current is directed through guidewires insulated from the surrounding blood pool.

The first reported use of transcatheter electrosurgery was in the treatment of pulmonary atresia, using an electrified guidewire to perforate through the atretic pulmonary valve.1 It has since been use to traverse occluded vessels, between cardiovascular chambers, particularly for interatrial septal puncture and transcaval large bore access, and for valve repair.2–12 A detailed review of these applications has recently been published.13 This review focuses on a novel application of transcatheter electrosurgery, that of tissue laceration. Transcatheter electrosurgery can be focused and controlled to cut heart valve tissue to enable transcatheter heart valve replacement.

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Cardiac Transcatheter Electrosurgery Figure 1: Optimizing the Flying V

Guidewire

Leaflet

Laceration direction

D

Intact guidewire insulation

Inner surface denuded

E

Plus insulating catheters

Leaflet

C

Leaflet

Denuded surface

B

Leaflet

Microcatheters

Leaflet

A

Plus insulating catheters and dextrose

Computer simulation showing how to optimize the flying V. The aim is no maximize charge concentration in tissue without heating the surrounding blood. The best results are seen with selective inner curvature denudation and 5% dextrose flush. Source: Jaffar M Khan, National Heart, Lung, and Blood Institute.

The Cutting Edge of Transcatheter Electrosurgery

‘Cutting’ tissue requires sufficient charge concentration within the cells so they reach an internal temperature of 100°C, when intracellular water boils and the cells vaporize.

To achieve adequate charge concentration, a guidewire is modified to create a ‘flying V’ configuration, based on benchtop experiments and computer simulation, with insulating microcatheters and 5% dextrose flush (Figure 1).13 The midshaft of the guidewire is selectively denuded and kinked with a scalpel so that the current is preferentially conducted through the inner elbow.

The flying V is directed by catheters under imaging guidance to cut the target tissue. Often, but not always, the target leaflet is traversed at the base first, by electrifying the tip of the guidewire, and the flying V is saddled across the base and pulled towards the leaflet tip.

To date, there are three major applications of this technique to treat heart valve disease. The first is laceration of the anterior mitral leaflet to prevent outflow tract obstruction (LAMPOON). The second is bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction (BASILICA). The third is electrosurgical laceration and stabilization of a mitral edge-to-edge repair device (ELASTA-Clip).

Advances in LAMPOON

Transcatheter mitral valve replacement (TMVR) is a potential option for patients not suitable for surgery or transcatheter mitral valve repair.14 Transcatheter aortic valve replacement (TAVR) valves may be implanted in the mitral position inside a previous bioprosthetic mitral valve (MViV), off label inside a bioprosthetic ring (MViR) or in the native mitral annulus when there is severe mitral annular calcification (ViMAC). One dedicated mitral valve (Tendyne, Abbott) is licensed for use in Europe, and multiple transcatheter mitral valves are under investigational use in the US. Left ventricular outflow tract (LVOT) obstruction is a common and fatal complication of TMVR. LVOT obstruction is commonest in ViMAC (40%), followed by ViR (5%) and ViV (2%), with a 30-day mortality of up to 62%.15,16 LVOT obstruction is a frequent reason for screen failure in TMVR trials.

During surgical mitral valve replacement, the anterior mitral leaflet is often resected down the midline with preservation of the chords to prevent LVOT obstruction. LAMPOON is a transcatheter mimic of the surgical standard. The technique was studied in an investigator-initiated

prospective multicenter single-arm Food and Drug Administration (FDA) investigational device exemption clinical trial.17 LAMPOON traversal and laceration was technically successful in 100% of patients attempted, including in heavily calcified anatomies. LVOT obstruction was evident in only 3% on exit from the catheter laboratory despite the high risk in all.

There were no strokes, and 30-day survival was 93%.

The LAMPOON technique has undergone a few iterations for ease of use in different anatomical situations and these are described below.

Retrograde LAMPOON

This is the original technique described and studied in the clinical trial.17–19 Two catheters introduced through femoral artery sheaths are positioned either side of the anterior mitral valve leaflet, with the traversal catheter in the LVOT and the snare catheter in the left atrium (Figure 2). An Astato XS 20 guidewire (Asahi Intecc) is sheathed in an insulating microcatheter (Piggyback Wire Converter, Teleflex). The back end of the guidewire is stripped and clipped to an electrosurgery pencil and generator.

Catheter position is confirmed on transesophageal echocardiography (TEE) and the guidewire is electrified for 1 second at 30–50 W in ‘pure cut’ mode while advanced through the center and base of the anterior mitral valve leaflet. The guidewire is snared in the left atrium. The microcatheter is withdrawn and the flying V is created at the midshaft of the guidewire. The tip is snare retrieved and the flying V advanced into the body and positioned to straddle the anterior mitral leaflet. Both guiding catheters are locked on to the guidewire by means of rotating hemostatic valves and torque devices, with only a few millimeters of guidewire exposed beyond the guide catheter tips. The guidewire is connected to the electrosurgery pencil and 70 W pure-cut power is delivered as the flying V is gently retracted, lacerating the leaflet down the centerline.

The advantage of this technique is that it reproducibly creates a central laceration in line with the LVOT, as this is the direction of pull on the catheters. It is also the technique that has been most extensively studied.

The disadvantages are technical complexity in positioning the guide catheters for traversal and laceration, and that a mechanical aortic valve is a relative contraindication.

Antegrade LAMPOON

To treat patients with mechanical aortic valves, alternative routes for LAMPOON have been investigated.20 Apical LAMPOON has been performed

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Cardiac Transcatheter Electrosurgery in a handful of patients with mixed results (unpublished data). Transseptal LAMPOON has been performed with success, and was simpler in some respects than retrograde LAMPOON. Two deflectable sheaths are positioned in the left atrium through the same atrial septostomy. A balloon-wedge catheter is advanced through one deflectable sheath and floated through the main mitral orifice and into the LVOT, where it is exchanged over a rail wire for a guide catheter and snare. The second deflectable sheath directs a guide catheter to the center and base of the anterior mitral valve leaflet, guided by TEE. An Astato XS 20 guidewire is used to traverse the anterior mitral leaflet from left atrium to LVOT, where it is snared. The flying V is formed and positioned across the anterior mitral valve leaflet. The deflectable sheath tips are positioned in the center of the mitral orifice to act as a pivot for centerline laceration and the guide catheters are pulled into the sheaths during transcatheter electrosurgical laceration.

The advantages of this technique are the additional control afforded by transseptal access, as well as the ability to perform this in patients with mechanical aortic valves. There is a risk of eccentric laceration, which is mitigated by ensuring a good pivot from the sheaths in the left atrium.

Tip-to-base LAMPOON

In patients where there is a ‘backstop’ to prevent laceration of the aortomitral curtain and aortic root, for example, in patients with bioprosthetic valves or complete mitral rings, the traversal step can be omitted and mitral valve leaflet laceration can be performed from tip to base.20,21 A transseptal puncture is performed and a chord-free trajectory through the major mitral valve orifice and out of the aorta is established.

The flying V is positioned, insulated by two guiding catheters. The position of the transeptal limb is adjusted to center on the mitral valve leaflet on TEE. Both catheters are pulled till the flying V comes to a hard stop against the bioprosthetic sewing ring.

Rescue LAMPOON

A long anterior mitral valve leaflet may cause LVOT obstruction even in the setting of a capacious neoLVOT. In the setting of dynamic LVOT obstruction from systolic anterior motion of the native mitral valve leaflet tip after TMVR, rescue LAMPOON can treat LVOT obstruction. The native anterior mitral leaflet tip extending beyond the implanted transcatheter heart valve frame is lacerated using the tip-to-base LAMPOON approach, with the transcatheter heart valve frame acting as the backstop.22

LAMPOON with Dedicated Transcatheter Mitral Valves

LAMPOON has been performed with the Sapien 3 valve (Edwards Lifesciences) when there is risk of either fixed LVOT obstruction from a small neoLVOT or dynamic LVOT obstruction from a long and redundant anterior mitral valve leaflet. The open valve frame in the left ventricle allows blood flow when the anterior mitral valve leaflet is cut and parted.

Most of the dedicated mitral valve has a covered cell design so anterior mitral valve leaflet modification will not prevent fixed LVOT obstruction.

However, LAMPOON can prevent dynamic LVOT obstruction from a long anterior mitral valve leaflet and has been successfully performed in a patient prior to Tendyne valve implantation.23

LAMPOON with Septal Modification When the Skirt neoLVOT is Small

The Sapien 3 valve is designed with only the distal cells uncovered. In certain anatomies, the LVOT is small and the covered skirt of the Sapien 3 is enough to cause LVOT obstruction.24 In cases where the predicted ‘skirt neoLVOT’ is small, preparatory transcoronary alcohol septal ablation or

Figure 2: Classic Retrograde LAMPOON

A

B

C

D E F

A: Leaflet traversal with an electrified guidewire into a snare in the left atrium. B: The guidewire is snared and externalized. C and E: Left ventricular outflow tract obstruction from the anterior mitral valve leaflet after transcatheter mitral valve replacement. D and F: The anterior mitral valve leaflet splays after LAMPOON and transcatheter mitral valve replacement, preventing left ventricular outflow tract obstruction. LAMPOON = laceration of the anterior mitral leaflet to prevent outflow tract obstruction. Source: Jaffar M Khan, National Heart, Lung, and Blood Institute.

radiofrequency ablation of the septum is performed before LAMPOON and TMVR.25,26

Advances in BASILICA Coronary Artery Obstruction

Coronary artery obstruction is a rare but devastating complication of TAVR, occurring in 0.7% of all cases, and 2.3% of valve-in-valve TAVR procedures, with an in-hospital mortality of 40–50%, even with attempted bail-out.27,28 Coronary obstruction occurs when diseased leaflets are displaced against the ostia of the coronary arteries or against the sinotubular junction (STJ).

Prediction of coronary artery obstruction is imperfect. Those at higher risk have coronary artery heights <12 mm, sinus width <30 mm and virtual transcatheter heart valve to coronary distance (VTC) <4 mm.27,28 In addition, a virtual transcatheter heart valve to STJ distance <2 mm likely confers a high risk of coronary obstruction by sinus sequestration.29 Snorkelled stents are frequently underexpanded, unable to overcome the competing mechanical force from the transcatheter heart valve, and may be prone to immediate or delayed stent thrombosis.30,31 BASILICA is a transcatheter electrosurgery technique to lacerate and splay the aortic leaflets to prevent coronary artery obstruction. BASILICA has been investigated in a prospective single-arm multicenter FDA early feasibility clinical trial sponsored by the NHLBI.29 Single- and double-leaflet BASILICA was successful in 93% of patients enrolled. There was no coronary artery obstruction despite the high predicted risk in all. There was one death and disabling stoke (3%). There were no late events between 30 days and

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Cardiac Transcatheter Electrosurgery Figure 3: BASILICA Procedure

either side of the target aortic leaflet (Figure 3). The catheter in the LVOT holds a snare, and the traversal guidewire and insulating microcatheter are advanced through the catheter in the aortic root. The guidewire is briefly electrified at 30–50 W while it is advanced through the center and base of the aortic leaflet into the LVOT. The guidewire is advanced further without electrification through the snare. The microcatheter is withdrawn and the flying V created. The snared tip is then retrieved, and the flying V is introduced into the body and positioned across the aortic leaflet. A 5% dextrose flush is injected through both guiding catheters and the guidewire is electrified at 70 W while traction is applied to both limbs till the leaflet is completely lacerated down the centerline.

If double-leaflet BASILICA is planned, both flying Vs are formed and positioned, then laceration is performed sequentially. TAVR is performed as usual, with extra care being taken to land the skirt of the TAVR valve below the level of the threatened coronary ostium.

A

TAV-in-TAV

Coronary artery obstruction may become a problem of epidemic proportion as younger patients are getting TAVR and are likely to require a second or third valve in their lifetime. In CT analyses of patients after TAVR, TAV-in-TAV greatly increases the risk for coronary artery obstruction.34 For Sapien 3 valves, the predicted risk for coronary obstruction with second TAVR was 13% in a CT analysis of the Low Risk TAVR trial.35 For Evolut valves (Medtronic), the predicted risk of coronary obstruction with a second TAVR was 23%.36

B

C

Clinical experience of BASILICA to prevent TAV-in-TAV coronary obstruction is limited. In preclinical modeling, leaflet splay in newer generation transcatheter heart valves appeared to be less effective, which potentially limits the applicability of the technique to selected cases.37

D

A: Leaflet traversal with an electrified guidewire into a snare in the left ventricular outflow tract obstruction. B: Leaflet laceration with the flying V. C: Lacerated left bioprosthetic valve leaflet.

D: Leaflet splays after transcatheter mitral valve replacement, preventing coronary obstruction.

BASILICA = bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction. Source: Jaffar M Khan, National Heart, Lung, and Blood Institute.

Figure 4: Fluoroscopy Image of the ELASTA-Clip Procedure A

Dedicated BASILICA guide catheters have been designed for left and right leaflet BASILICA. Pachyderm guiding catheters (Medtronic). help direct the traversing guidewire through the base of the left and right leaflets and into the LVOT. They have been shown to decrease procedure time compared with coronary guide catheters.38

ELASTA-Clip: Burning the Bridge

B

Edge-to-edge mitral valve repair with a clip device (MitraClip, Abbott) may ‘burn the bridge’ to downstream therapy, particularly TMVR, as a result of the double orifice created. Patients who develop mitral stenosis, with or without residual or recurrent mitral regurgitation after edge-to-edge repair, have few options. ELASTA-Clip is a simple concept, where the anterior leaflet attachment of the clip device is cut using transcatheter electrosurgery, effectively burning the bridge and creating a single orifice to enable TMVR (Figure 4).39,40

C

A: The flying V is positioned through the double orifice mitral valve. B and C: The Tendyne valve is implanted after ELASTA-Clip, and the MitraClip devices are displaced posteriorly. Black arrow = flying V. White arrows = MitraClip devices. ELASTA-Clip = electrosurgical laceration and stabilization of a MitraClip. Source: Jaffar M Khan, National Heart, Lung, and Blood Institute.

1 year attributable to the BASILICA procedure (Khan et al. Circ Cardiovasc Interv, in press).

BASILICA Technique and Results

Pachyderm Catheters

The BASILICA technique has been described in detail previously. Two guiding catheters are advanced from the femoral arteries and positioned 32,33

The procedure was performed in five patients on a compassionate basis who had failed MitraClip implantation and had no other options.40 Two guiding sheaths were positioned in the left atrium through the same atrial septostomy. Guide catheters were advanced through the medial and lateral orifices either side of the MitraClip devices. An Astato guidewire was advanced and snared between the two guide catheters and the flying V formed and positioned across the MitraClip.

Under fluoroscopy and TEE guidance, the flying V was moved to the anterior attachment of the MitraClip devices. The flying V was then tensioned and electrified at 70 W under 5% dextrose flush to liberate the

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Cardiac Transcatheter Electrosurgery MitraClip devices from the anterior mitral valve leaflet. The clips remained attached to the posterior leaflet. Transapical Tendyne valve implantation was then performed as usual. The patients remained hemodynamically stable between laceration and TMVR, with elective use of an intra-aortic balloon pump upfront in all cases.

A key learning point from this experience, alongside a demonstration of feasibility, was that detaching MitraClip devices acutely increases mitral valve diameter so Tendyne valve oversizing achieves optimal results.

Future Directions

Transcatheter electrosurgery increases the versatility of percutaneous intervention. The ability to create controlled cuts in cardiac tissue using completely percutaneous techniques moves us closer to truly minimally 1. Rosenthal E, Qureshi SA, Chan KC, et al. Radiofrequencyassisted balloon dilatation in patients with pulmonary valve atresia and an intact ventricular septum. Br Heart J 1993;69:347–51. https://doi.org/10.1136/hrt.69.4.347; PMID: 8489868.

2. Foerst JR, Kim D, May TP. Percutaneous electrosurgical technique for treatment of subclavian vein occlusion: application of transcaval techniques. HeartRhythm Case Rep 2017;3:551–4. https://doi.org/10.1016/j.hrcr.2017.08.006; PMID: 29387548.

3. Baerlocher MO, Asch MR, Myers A. Successful recanalization of a longstanding complete left subclavian vein occlusion by radiofrequency perforation with use of a radiofrequency guide wire. J Vasc Interv Radiol 2006;17:1703–6. https://doi. org/10.1097/01.RVI.0000243637.23923.A7; PMID: 17057015.

4. Iafrati M, Maloney S, Halin N. Radiofrequency thermal wire is a useful adjunct to treat chronic central venous occlusions. J Vasc Surg 2012;55:603–6. https://doi. org/10.1016/j.jvs.2011.09.090; PMID: 22104339.

5. Nicholson W, Harvey J, Dhawan R. E-CART (ElectroCauteryAssisted Re-enTry) of an aorto-ostial right coronary artery chronic total occlusion: first-in-man. JACC Cardiovasc Interv 2016;9:2356–8. https://doi.org/10.1016/j.jcin.2016.09.006; PMID: 27884362.

6. Justino H, Benson LN, Nykanen DG. Transcatheter creation of an atrial septal defect using radiofrequency perforation.

Catheter Cardiovasc Interv 2001;54:83–7. https://doi. org/10.1002/ccd.1244; PMID: 11553955.

7. Khan JM, Rogers T, Eng MH, et al. Guidewire electrosurgeryassisted trans-septal puncture. Catheter Cardiovasc Interv 2018;91:1164–70. https://doi.org/10.1002/ccd.27311; PMID: 28940991.

8. Lederman RJ, Babaliaros VC, Rogers T, et al. The fate of transcaval access tracts: 12-month results of the prospective NHLBI transcaval transcatheter aortic valve replacement study. JACC Cardiovasc Interv 2019;12:448–56. https://doi. org/10.1016/j.jcin.2018.11.035; PMID: 30846083.

9. Greenbaum AB, Babaliaros VC, Chen MY, et al. Transcaval access and closure for transcatheter aortic valve replacement: a prospective investigation. J Am Coll Cardiol 2017;69:511–21. https://doi.org/10.1016/j.jacc.2016.10.024; PMID: 27989885.

10. Khan JM, Rogers T, Schenke WH, et al. Transcatheter pledget-assisted suture tricuspid annuloplasty (PASTA) to create a double-orifice valve. Catheter Cardiovasc Interv 2018;92:E175–84. https://doi.org/10.1002/ccd.27531; PMID: 29405564.

11. Greenbaum AB, Khan JM, Rogers T, et al. First-in-human transcatheter pledget-assisted suture tricuspid annuloplasty for severe tricuspid insufficiency. Catheter Cardiovasc Interv 2021;97:e130–4. https://doi.org/10.1002/ccd.28955; PMID: 32385950.

12. Heyden CM, Moore JW, Ryan JR, et al. Alternative access in congenital heart disease. JACC Case Rep 2020;2:1734–5. https://doi.org/10.1016/j.jaccas.2020.07.040; PMID: 33000000.

13. Khan JM, Rogers T, Greenbaum AB, et al. Transcatheter electrosurgery: JACC state-of-the-art review. J Am Coll Cardiol 2020;75:1455–70. https://doi.org/10.1016/j. jacc.2020.01.035; PMID: 32216915.

14. Guerrero M, Vemulapalli S, Xiang Q, et al. Thirty-day outcomes of transcatheter mitral valve replacement for degenerated mitral bioprostheses (valve-in-valve), failed surgical rings (valve-in-ring), and native valve with severe mitral annular calcification (valve-in-mitral annular calcification) in the United States. Circ Cardiovasc Interv

invasive surgery. By understanding the principles and applications, tailored therapies are possible for unique anatomies. Dedicated devices will make these procedures more accessible and reproducible, and are currently in development.

All the techniques described are advanced procedures and should be undertaken with appropriate proctoring at experienced centers.

Conclusion

Transcatheter electrosurgery is at the cutting edge of structural heart intervention. It is a versatile tool and has been applied to enable TAVR when there is risk of coronary artery obstruction, TMVR when there is a risk of LVOT obstruction, and TMVR in the setting of previous edge-toedge repair.

2020;13:e008425. https://doi.org/10.1161/ CIRCINTERVENTIONS.119.008425; PMID: 32138529.

15. Yoon SH, Whisenant BK, Bleiziffer S, et al. Outcomes of transcatheter mitral valve replacement for degenerated bioprostheses, failed annuloplasty rings, and mitral annular calcification. Eur Heart J 2019;40:441–51. https://doi. org/10.1093/eurheartj/ehy590; PMID: 30357365.

16. Guerrero M, Urena M, Himbert D, et al. 1-year outcomes of transcatheter mitral valve replacement in patients with severe mitral annular calcification. J Am Coll Cardiol 2018;71:1841–53. https://doi.org/10.1016/j.jacc.2018.02.054; PMID: 29699609.

17. Khan JM, Babaliaros VC, Greenbaum AB, et al. Anterior leaflet laceration to prevent ventricular outflow tract obstruction during transcatheter mitral valve replacement. J Am Coll Cardiol 2019;73:2521–34. https://doi.org/10.1016/j. jacc.2019.02.076; PMID: 31118146.

18. Khan JM, Rogers T, Schenke WH, et al. Intentional laceration of the anterior mitral valve leaflet to prevent left ventricular outflow tract obstruction during transcatheter mitral valve replacement: pre-clinical findings. JACC Cardiovasc Interv 2016;9:1835–43. https://doi.org/10.1016/j.jcin.2016.06.020; PMID: 27609260.

19. Babaliaros VC, Greenbaum AB, Khan JM, et al. Intentional percutaneous laceration of the anterior mitral leaflet to prevent outflow obstruction during transcatheter mitral valve replacement: first-in-human experience. JACC Cardiovasc Interv 2017;10:798–809. https://doi.org/10.1016/j. jcin.2017.01.035; PMID: 28427597.

20. Lisko JC, Greenbaum AB, Khan JM, et al. Antegrade intentional laceration of the anterior mitral leaflet to prevent left ventricular outflow tract obstruction: a simplified technique from bench to bedside. Circ Cardiovasc Interv 2020;13:e008903. https://doi.org/10.1161/ CIRCINTERVENTIONS.119.008903; PMID: 32513014.

21. Case BC, Khan JM, Satler LF, et al. Tip-to-base LAMPOON to prevent left ventricular outflow tract obstruction in valve-invalve transcatheter mitral valve replacement. JACC Cardiovasc Interv 2020;13:1126–8. https://doi.org/10.1016/j. jcin.2020.01.235; PMID: 32305393.

22. Khan JM, Trivedi U, Gomes A, et al. ‘Rescue’ LAMPOON to treat transcatheter mitral valve replacement-associated left ventricular outflow tract obstruction. JACC Cardiovasc Interv 2019;12:1283–4. https://doi.org/10.1016/j.jcin.2018.12.026; PMID: 30772294.

23. Khan JM, Lederman RJ, Devireddy CM, et al. LAMPOON to facilitate tendyne transcatheter mitral valve replacement.

JACC Cardiovasc Interv 2018;11:2014–17. https://doi. org/10.1016/j.jcin.2018.06.019; PMID: 30286861.

24. Khan JM, Rogers T, Babaliaros VC, et al. Predicting left ventricular outflow tract obstruction despite anterior mitral leaflet resection: the ‘skirt neoLVOT’. JACC Cardiovasc Imaging 2018;11:1356–9. https://doi.org/10.1016/j.jcmg.2018.04.005; PMID: 29778867.

25. Guerrero M, Wang DD, O’Neill W. Percutaneous alcohol septal ablation to acutely reduce left ventricular outflow tract obstruction induced by transcatheter mitral valve replacement. Catheter Cardiovasc Interv 2016;88:E191–7. https://doi.org/10.1002/ccd.26649; PMID: 27377756.

26. Lisko J, Kamioka N, El Chami M, et al. Septal correction to prevent iatrogenic left ventricular outflow tract obstruction (SCORPION) prior to transcatheter mitral valve replacement.

J Am Coll Cardiol 2019;749(13 suppl):B447. https://doi. org/10.1016/j.jacc.2019.08.541.

27. Ribeiro HB, Rodes-Cabau J, Blanke P, et al. Incidence, predictors, and clinical outcomes of coronary obstruction

US CARDIOLOGY REVIEW Access at: www.USCjournal.com

following transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: insights from the VIVID registry. Eur Heart J 2018;39:687–95. https://doi. org/10.1093/eurheartj/ehx455; PMID: 29020413.

28. Ribeiro HB, Webb JG, Makkar RR, et al. Predictive factors, management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: insights from a large multicenter registry. J Am Coll Cardiol 2013;62:1552–62. https://doi.org/10.1016/j.jacc.2013.07.040; PMID: 23954337.

29. Khan JM, Greenbaum AB, Babaliaros VC, et al. The BASILICA trial: prospective multicenter investigation of intentional leaflet laceration to prevent TAVR coronary obstruction.

JACC Cardiovasc Interv 2019;12:1240–52. https://doi. org/10.1016/j.jcin.2019.03.035; PMID: 31202947.

30. Pighi M, Lunardi M, Pesarini G, et al. Intravascular ultrasound assessment of coronary ostia following valve in valve transcatheter aortic valve implantation. EuroIntervention 2021;16:1148–51. https://doi.org/10.4244/EIJ-D-20-00611.

PMID: 32894228.

31. Jabbour RJ, Tanaka A, Finkelstein A, et al. Delayed coronary obstruction after transcatheter aortic valve replacement. J Am Coll Cardiol 2018;71:1513–24. https://doi.org/10.1016/j. jacc.2018.01.066; PMID: 29622157.

32. Lederman RJ, Babaliaros VC, Rogers T, et al. Preventing coronary obstruction during transcatheter aortic valve replacement: from computed tomography to BASILICA. JACC Cardiovasc Interv 2019;12:1197–216. https://doi.org/10.1016/j. jcin.2019.04.052; PMID: 31272666.

33. Khan JM, Dvir D, Greenbaum AB, et al. Transcatheter laceration of aortic leaflets to prevent coronary obstruction during transcatheter aortic valve replacement: concept to first-in-human. JACC Cardiovasc Interv 2018;11:677–89. https:// doi.org/10.1016/j.jcin.2018.01.247; PMID: 29622147.

34. Rogers T, Khan JM, Satler LF, et al. TAVR-in-TAVR? Don’t bank on it! J Am Coll Cardiol 2020;76:1003. https://doi. org/10.1016/j.jacc.2020.05.083; PMID: 32819458.

35. Rogers T, Greenspun BC, Weissman G, et al. Feasibility of coronary access and aortic valve reintervention in low-risk TAVR patients. JACC Cardiovasc Interv 2020;13:726–35. https://doi.org/10.1016/j.jcin.2020.01.202; PMID: 32192693 36. Forrestal BJ, Case BC, Yerasi C, et al. Risk of coronary obstruction and feasibility of coronary access after repeat transcatheter aortic valve replacement with the selfexpanding Evolut valve: a computed tomography simulation study. Circ Cardiovasc Interv 2020;13:e009496.https://doi. org/10.1161/CIRCINTERVENTIONS.120.009496; PMID: 33272031.

37. Khan JM, Bruce CG, Babaliaros VC, et al. TAVR roulette: caution regarding BASILICA laceration for TAVR-in-TAVR. JACC Cardiovasc Interv 2020;13:787–9. https://doi. org/10.1016/j.jcin.2019.10.010; PMID: 32192701.

38. Lisko JC, Babaliaros VC, Lederman RJ, et al. Pachydermshape guiding catheters to simplify BASILICA leaflet traversal. Cardiovasc Revasc Med 2019;20:782–5. https://doi. org/10.1016/j.carrev.2019.05.033; PMID: 31257172.

39. Khan JM, Lederman RJ, Sanon S, et al. Transcatheter mitral valve replacement after transcatheter Electrosurgical Laceration of Alfieri STItCh (ELASTIC): first-in-human report.

JACC Cardiovasc Interv 2018;11:808–11. https://doi. org/10.1016/j.jcin.2017.11.035; PMID: 29605244.

40. Lisko JC, Greenbaum AB, Guyton RA, et al. Electrosurgical detachment of mitraclips from the anterior mitral leaflet prior to transcatheter mitral valve implantation. JACC Cardiovasc Interv 2020;13:2361–70. https://doi.org/10.1016/j. jcin.2020.06.047; PMID: 33011144.

Interventional Cardiology

Vascular Complications of Transradial Access for Cardiac Catheterization Tanawan Riangwiwat, MD,

1

and James C Blankenship, MD, MHCM, MSCAI

2

1. Cardiology Department, Geisinger Medical Center, Danville, PA; 2. Cardiology Division, University of New Mexico, Albuquerque, NM

Abstract

Transradial access has been increasingly adopted for cardiac catheterization. It is crucial for operators to recognize potential vascular complications associated with radial artery access. Prevention, early detection, and prompt treatment of vascular complications are essential to prevent serious morbidities. This review aims to raise awareness of transradial access vascular complications. Radial artery spasm is treated with intra-arterial verapamil and/or nitroglycerine. Hemorrhagic complications, such as perforation, hematoma, arteriovenous fistula, and pseudoaneurysm, are treated with prolonged compression. Patent hemostasis and adequate anticoagulation are used to prevent radial artery occlusion. Hand ischemia is a rare complication not associated with abnormal results of the Allen or Barbeau test, and can be treated with intraarterial verapamil, IV heparin, and IV diltiazem. Finally, an attentive monitoring protocol for the timely detection of vascular complications should be implemented in daily practice.

Keywords

Transradial, radial access, coronary angiography, coronary intervention, cardiac catheterization, vascular complications Disclosures: The authors have no conflicts of interest to declare.

Received: August 18, 2020 Accepted: December 16, 2020 Citation: US Cardiology Review 2021;15:e04. DOI: https://doi.org/10.15420/usc.2020.23 Correspondence: Tanawan Riangwiwat, 100 N Academy Ave, MC: 27–70, Danville, PA 17822. E: tanawan.riangwiwat@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Over the past decade, transradial access has grown in popularity. With percutaneous coronary intervention success rates similar to transfemoral access, transradial coronary angiography is associated with fewer vascular and bleeding complications, earlier ambulation, greater postprocedural comfort, and better cost-effectiveness.1–5 A meta-analysis by Ferrante et al. showed a 77% reduction in major vascular complication by using transradial access (OR 0.23; 95% CI [0.16–0.35]).6 In addition, transradial access also reduces the incidence of death, MI, stroke, and overall mortality in STelevation MI patients.1 Therefore, the ‘radial-first’ strategy was recommended in the 2015 European Society of Cardiology guidelines for the management of acute coronary syndrome as a class I indication.7 Transradial access has intrinsic challenges and a steep learning curve. Its success rate is highly dependent on operator experience. Fluoroscopic time, radiation exposure, procedural success, access site crossover, and access site complications can be minimized by operator experience and proficiency.8,9 Transradial access-related vascular complications of coronary intervention requiring surgical or percutaneous intervention are reported at 0.3%.10 The need for surgical intervention can be decreased by prompt recognition of complications by operators and cardiac catheterization laboratory team members.11 This article reviews vascular complications of transradial cardiac catheterization and their management to promote awareness, limit the incidence of complications, and encourage timely intervention when complications do occur (Table 1).

Radial Artery Spasm

Radial artery spasm is recognized when catheters initially pass through the arm, but subsequent manipulation meets with resistance and causes pain in the arm (Figure 1). This is a common complication and the most common

cause of transradial access site crossover.12,13 The incidence of radial artery spasm is 4–5% in large randomized control trials (RADIAL and RIVAL trials).1,14–16 Younger age, female sex, diabetes, and lower BMI are independent predictors of radial artery spasm, as are small radial artery diameter, large sheath:artery size ratio, and multiple catheter exchanges.12 Most radial artery spasm is mild, and multiple techniques can be used to prevent and treat it.16 Adequate pain control and sedation are the key to prevent radial artery spasm. Deftereos et al. reported that patients with adequate sedation and analgesia had a lower incidence of radial artery spasm compared with patients without adequate sedation (8.3% versus 2.6%; p<0.001) and less frequent access site crossover (15% versus 9.9%; p=0.001).17 Although not common, general anesthesia or regional nerve block is an alternative option for adequate pain control.

Appropriate equipment selection can minimize the occurrence of radial artery spasm. Long radial sheaths with a tapered dilator and hydrophilic coating are associated with lower rates of radial artery spasm.12,18 Use of a ‘universal’ catheter designed to access both the left main ostium and the right coronary artery ostium (e.g. Terumo Tiger and Jacky catheter) reduces catheter exchanges, which reduces radial spasm.19 Antispasmolytics or vasodilators, such as calcium channel blockers (intra-arterial verapamil or diltiazem) and nitroglycerine, are commonly injected into the radial artery after access is obtained, and some operators repeat it after every catheter exchange.20 While many studies have evaluated the efficacy of different agents, there is no consensus on a standard regimen to prevent radial artery spasm. A systematic review by Kwok et al. proposed that intra-arterial verapamil 5 mg alone

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Vascular Complications of Transradial Access Table 1: Summary of the Radial Access Vascular Complications, Incidence, Risk Factors, Prevention, and Management Vascular Complication

Incidence Risk Factors

Prevention and Management

• Younger age • Female • Low body mass index • Small diameter radial artery • Larger sheath size • Multiple catheter exchanges

• Pain control and analgesia • General anesthesia or regional nerve block • Hydrophilic coating long radial sheath • Bi-ostial ‘universal’ catheter rather than dedicated left and right coronary

• Underlying aortic aneurysm • Acute coronary syndrome cases • Right coronary artery intervention • Aggressive catheter or guidewire manipulation • Extra support catheter • Elderly • Short stature • Female • Tortuous radial artery • Small diameter radial/brachial arteries • Presence of recurrent radial artery

• External compression for radial artery dissection • Emergency surgery • Stenting when dissection of right coronary ostium is caused by a coronary

• Multiple arterial punctures • Radial artery perforation • Distal compression band malposition

• Manual compression • Adjustment of compression band pressure • Reposition of compression band • Surgical evacuation of hematoma

Arteriovenous fistula <0.1%

• Multiple puncture attempts

• Long sheath or catheter tamponade • External compression • Surgical repair

Radial artery pseudoaneurysm

0.03–0.2%

• Multiple puncture attempts • Catheter infection • Aggressive anticoagulation • Large sheath size

• Compression • Ultrasound-guided thrombin injection • Surgical excision of pseudoaneurysm • Ligation of the radial artery

Compartment syndrome

<0.05%

• Unsuccessful hemostasis • Excess anticoagulation • Glycoprotein IIb/IIIa inhibitor • Low body surface area • Ulnar access

• Weight-based anticoagulation • Glycoprotein IIb/IIIa inhibitor dose adjustment with creatinine clearance or avoid

Radial artery spasm 4.3–16%

Non-coronary artery 0.05–0.4% dissection

Radial/brachial artery 0.07–0.9% perforation

Local hematoma

1.2–2.6%

catheter

• Intra-arterial antispasmolytic: verapamil 5 mg and/or nitroglycerine 100–200 µg • Smaller size sheath and catheters

catheter

• Tamponade of perforation by long radial sheath, catheter, or angioplasty balloon with prolonged inflation

• External compression • Surgical repair and hematoma evacuation

entirely

• Postprocedural close monitoring • Maintain high index of suspicion • Fasciotomy

Radial artery occlusion

3.9–8.1%

• Female • Diabetes • Low body mass index • Repeat entry of the artery • Small radial artery diameter (≤2.2 mm) • Radial artery:sheath ratio <1 • Multiple puncture attempts • Low dose of unfractionated heparin • Arterial spasm • Prolonged occlusive hemostasis

• Minimize size of sheath/catheters • Heparin during procedure (e.g. 5,000 units) • Maintenance of patent hemostasis • Ipsilateral ulnar artery compression • Anticoagulation to promote recanalization • Distal radial artery access

Hand ischemia

<0.1%

• Smoking • Peripheral artery disease • Hypercoagulable state,

• Close monitoring • Intra-arterial verapamil, IV heparin, IV diltiazem • Thrombectomy • Vein patch angioplasty • Radial artery reconstruction with interposition with cephalic vein

such as malignancy, HIT or DIC

• Raynaud’s disease • Shock with vasopressor use • Radial artery spasm

DIC = disseminated intravascular coagulation; HIT = heparin-induced thrombocytopenia.

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Vascular Complications of Transradial Access or in combination with 100–200 µg of nitroglycerine is the most effective antispasmolytic.15

Figure 1: Angiography of Radial Artery Spasm

Non-coronary Artery Dissection

A tear in the wall of a major non-coronary artery leading to the collection of blood within the layers of arterial wall is a rare complication of transradial cardiac catheterization with an incidence of 0.02–0.4%.11,12 The incidence is higher in acute coronary syndrome cases than in elective cases, and it is also higher in percutaneous coronary intervention than in diagnostic cardiac catheterization.21 Arterial dissection can be prevented by ensuring that the catheter is not passing through a radial loop or recurrent radial artery; if there is resistance to initial passage of the catheter, then angiography should be undertaken to ensure that the artery is large enough and straight enough to accommodate the catheter. Using a smaller guide within the diagnostic guide or balloon-assisted tracking with an angioplasty balloon can prevent dissection of tortuous radial or brachial arteries. The most common dissection site is the radial artery (Figure 2A).

Catheter dissections of the radial and brachial artery can usually be managed conservatively by proceeding with the procedure. The catheter itself usually seals the dissection. Arteriography at the conclusion of the procedure is advisable to document the final status of the dissected artery.

Iatrogenic ascending aortic dissection is a serious complication that can occur with either radial or femoral access. It is an immediate threat to life when it causes hemodynamic instability. In the majority of case reports, the ascending aortic dissection is caused by right coronary artery intervention causing retrograde dissection to the aorta.22 The risk of dissection is increased by aggressive catheter or guidewire manipulation, and by use of extra backup catheters.21 Occasionally, with transradial access, innominate tortuosity can render catheter passage difficult, leading to innominate dissection that extends into the ascending aorta. This occurred in our catheterization laboratory when a 66-year-old woman with a 5.2 × 5.2 cm ascending aortic aneurysm and severe aortic regurgitation underwent diagnostic transradial cardiac catheterization. Upon introduction of a Jacky diagnostic catheter over a 0.035 inch Terumo Glidewire into the ascending aorta, the patient complained of chest pain radiating to her neck. Cine images showed a large ascending aortic dissection involving the aortic root and proximal arch (Figure 2B). CT imaging showed that it extended into (and presumably started at) the innominate artery. The patient underwent emergent Bentall root replacement, aortic valve replacement, and coronary artery bypass of all coronary arteries with ligation of the native left main artery, and was discharged 1 month later.

Figure 2: Cine Images of Non‑coronary Artery Dissection

Radial Artery Perforation

Perforation of the arterial wall with blood extravasation may occur in the radial or brachial artery (Figure 3). It may also present as a hematoma formation proximal to the access site in the forearm. This is an uncommon complication, with an incidence of 0.07–0.9%.11,23,24 Although radial artery perforation is rare, it can lead to severe forearm hematoma and compartment syndrome if it is not managed promptly.

Radial artery perforation occurs most often in patients who are elderly, short, female, or have tortuous arteries. Many cases of perforation occur when a guidewire passes up a small recurrent radial artery that is too small to accept the catheter. Occasionally, a diagnostic catheter will pass, but when the diagnostic procedure is converted to an intervention, the guide catheter will be too large for the recurrent radial artery, and an

A: Angiography of radial artery dissection. The white arrow represents the dissection site.

B: Aortography showing aortic root dissection extending into ascending aorta. The tip of the Jacky catheter is in the left coronary cusp.

operator who pushes the catheter too hard can easily cause dissection and perforation. In any situation where resistance to catheter passage is noted, angiography is indicated to define the anatomy.

Intraprocedural recognition of radial artery perforation does not prohibit the continuation of the procedure if the wire can be passed proximally

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Vascular Complications of Transradial Access Figure 3: Angiography of Radial Artery Perforation

Hematoma

Hematoma is a local accumulation of blood within the soft tissues causing a swelling. It can extend proximally from the access site to the forearm and arm. Femoral access site bleeding is associated with increased mortality.27 Clinically significant transradial access-associated local hematoma incidence is 1.2–2.6%, which is 60% lower than in transfemoral access.1,10,12,28–30 However, in the radial and ulnar cohorts in the SPIRIT of ARTEMIS study, the overall rate of local hematoma after transradial diagnostic coronary angiography was 23% when postprocedural vascular ultrasonography was performed on every patient, although most of these were not clinically significant.16 Most hematomas in this cohort were <5 cm in size. In this study, there was no difference in the incidence of hematoma between standard-dose (50 IU/kg bodyweight) and high-dose (100 IU/kg bodyweight) intra-procedural unfractionated heparin.

The development of hematoma depends on the experience of the operator and cardiac catheterization laboratory team members. Multiple arterial puncture attempts, inadequately managed radial artery perforation, and misplacement of a radial artery compression device (TR Band or HemoBand) are associated with hematoma. Early recognition and treatment of local hematoma are crucial to prevent serious complications, such as compartment syndrome.

When a hematoma is noted, manual compression, adjustment of the compression band pressure, or repositioning of the compression band may be sufficient. However, if the hematoma progresses proximally in the forearm, and particularly if the forearm becomes tense and swollen, or if the patient complains of anesthesia or pain in the hand, compartment syndrome should be suspected, and emergent vascular surgical consultation should be obtained.

Figure 4: Angiography of Radial Artery Arteriovenous Fistula

Arteriovenous Fistula

Arteriovenous fistula is an abnormal connection between an artery and a vein (Figure 4). This is a rare complication with an incidence less than 1 in 1,500. Only 12 isolated cases out of 17,870 patients are reported in three different cohorts.11,16,23 It may be asymptomatic, or it may present with persistent pain and swelling at the puncture site with visibly dilated veins and a palpable thrill. Multiple punctures increase the risk of arteriovenous fistula, because the radial artery is surrounded by small veins.

Arteriovenous fistula can be managed conservatively, similar to radial side branch perforation, if it is recognized during procedure. If a J-tip wire can pass through the artery proximally, then place the long sheath or catheter across the damaged segment. The sheath or the catheter will seal the connection between the artery and the vein. Prolonged compressive bandage can be used as an adjunctive treatment. Indications for surgical repair are symptomatic arterial steal phenomenon, venous congestion of extremity, or high-output cardiac state.30 into the innominate artery, because the intraluminal long radial sheath or catheter can tamponade the perforated segment.24 At the end of the procedure, radial artery angiography should be obtained to document that the perforation has sealed. Prolonged inflation of a peripheral or coronary artery balloon can be used to seal the perforation if a persistent leak through the perforation is noted.25 External compression with an elastic bandage or blood pressure cuff inflation at the level of systolic blood pressure may also be utilized.26 A delay in making the diagnosis or inability to achieve hemostasis by conservative measures may lead to the need for surgical repair of the arterial perforation, evacuation of hematoma, and treatment of compartment syndrome if necessary.

Radial Artery Pseudoaneurysm

Pseudoaneurysm results from a penetrating injury of the arterial wall (e.g. catheter access to the artery) causing a pulsating extraluminal hematoma and contained hemorrhage that communicates with the arterial lumen.

The usual presentation is a pulsatile mass with or without tenderness several days after the catheterization procedure. The diagnosis is confirmed by a systolic murmur and Doppler ultrasound showing to-andfro flow from the radial artery. The incidence of radial artery pseudoaneurysm due to transradial access is 0.03–0.2%.1,16,23 Risk factors of pseudoaneurysm are multiple puncture attempts, catheter infection, aggressive anticoagulation therapy, and large sheath sizes.31

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Vascular Complications of Transradial Access Literature on radial artery pseudoaneurysm management is limited.

Treatment is occlusive compression using a pneumatic radial artery compression band applied against the radial artery proximal to pseudoaneurysm for 3–4 hours followed by semi-occlusive compression using an elastic bandage for 24 hours.32 If this fails, ultrasound-guided thrombin injection can be used, with the caveat that any thrombin escaping the pseudoaneurysm can cause distal limb ischemia. Indications for surgical excision of a pseudoaneurysm are pain, diameter >3 cm, and failure of more conservative treatments.33

Compartment Syndrome

Compartment syndrome is due to compression of nerves, veins, arteries, and muscles inside the forearm compartment, leading to ischemic necrosis of the tissue. Its sign is well known as the ‘five Ps,’ including pain, pallor, paresthesias, pulselessness, and paralysis. The incidence is reported at 0.004–0.05%, none of the 3,507 patients in the transradial access group in the RIVAL trial developed compartment syndrome.1,16,34 Risk factors for compartment syndrome include radial artery perforation, unsuccessful compression at the puncture site, excess anticoagulation, glycoprotein IIb/ IIIa inhibitor administration, and low body mass index.11 When ulnar access is used, entry of the artery more than 2 cm proximal to the wrist can lead to compartment syndrome, because the artery is deep and not easily compressed against underlying bone.

Prevention of compartment syndrome is critical, because its management is difficult. A high index of suspicion, early recognition, and urgent management of hematoma are of the utmost importance to prevent compartment syndrome and the need for fasciotomy. A specific postprocedural monitoring protocol should be established to ensure timely response and proper management to minor vascular complications before they evolve into compartment syndrome. Doses of anticoagulation and glycoprotein IIb/IIIa inhibitor during the procedure need to be adjusted for weight and creatinine clearance. If compartment syndrome is diagnosed, emergent vascular surgery consultation followed by fasciotomy is needed to prevent long-term consequences, such as limb loss or Volkmann contracture after fasciotomy.34

Radial Artery Occlusion

Radial artery occlusion is due to thrombus formation secondary to intimal injury. Radial artery occlusion is a benign condition and most patients who have intact collaterals from the ulnar artery are asymptomatic, because palmar circulations remain protected. The concern for interventional cardiologists is that radial artery occlusion precludes repeated intervention through the same access site. Sinha et al. found that radial artery occlusion was identified by color Doppler ultrasound in 17.4% of their patients on the first day after the transradial catheterization.3 However, 60–70% of these occluded cases later have spontaneous recanalization of their radial artery.35,36 At 6 months postprocedure, radial artery occlusion diagnosed

by Doppler was 5.1%; this incidence is consistent with other studies that report radial artery occlusion in 3.9–8.1% of patients8,14,16,35 Nonetheless, only 0.2% of radial access patients developed symptomatic radial occlusion needing medical attention.1 The symptoms of radial artery occlusion include hand or finger pain or discoloration, weakness, cold, or sensory deficit. Because of recruitment of ulnar artery collaterals, noninvasive tests for collateral hand circulation, such as the Allen or Barbeau test, do not predict the occurrence of radial artery occlusion and should not be used for access site selection.

Predisposing factors of radial artery occlusion are female sex, diabetes, lower BMI, repeat entry of radial artery, smaller arterial diameter at

baseline (2.2 mm or smaller), and radial artery:sheath ratio <1.35–38 Risk factors related to the procedure are multiple arterial puncture attempts, low unfractionated heparin dose, radial artery spasm, and prolonged occlusive hemostasis.16,23 Prolonged occlusive hemostasis is defined as prolonged compression and absent flow during postprocedural hemostasis, especially at the final assessment before radial band removal.

Various techniques have been developed to prevent radial artery occlusion. First, the SPIRIT of ARTEMIS study showed that high-dose heparin (100 IU/kg bodyweight) was associated with a lower rate of radial artery occlusion when compared with low-dose heparin (50 IU/kg bodyweight), with an OR of 0.35 (95% CI [0.22–0.55]; p<0.001). The number needed to treat with high-dose heparin to avoid one case of radial artery occlusion is 19.6.16 Second, the PROPHET Study shows that maintenance of patent hemostasis is effective in reducing the radial artery occlusion rate after transradial catheterization.39 After a radial artery compression band is secured around the wrist at the site of artery access, “patent hemostasis” is confirmed by a plethysmographic signal on pulse oximeter sensor over the index finger when the ipsilateral ulnar artery is occluded transiently. If there is no signal, the radial artery compression band should be loosened until plethysmographic signal returns or bleeding occurs. If the radial artery patency can be maintained and the hemostasis is achieved, the compression band should be left in place for 2 hours. The patency of the radial artery during compression should be checked at least every hour.37 Third, ipsilateral ulnar compression can be used for both prophylaxis and treatment of acute radial artery occlusion. For prophylaxis, occlusive ulnar artery compression is applied concomitantly with patent radial artery hemostasis.40 As multiple puncture attempts is one of the risk factors for radial artery occlusion, ultrasound guidance for transradial artery access should be used to reduce the number of forward attempts required for access and improve the first-pass success rate according to the RAUST.41 For acute radial artery occlusion that is identified by duplex ultrasound within 3–4 hours after radial artery compression band removal, immediate ulnar artery compression for 1 hour using the same compression band increases the peak velocity of blood flow into the radial artery on the repeat ultrasound assessment.42 Once radial artery occlusion is confirmed by ultrasound, another treatment option is administration of systemic anticoagulation, such as lowmolecular-weight heparin for 4 weeks. Low-molecular-weight heparin treatment increases the patency rate of the radial artery up to 86% after 4 weeks of treatment.43 If vascular access is needed in patients with radial artery occlusion, distal radial artery access can be used for the catheterization.

Distal radial artery access involves cannulation of the radial artery on the dorsum of the hand where it emerges from the anatomical snuffbox. Distal radial access improves patient comfort, reduces the risk of radial artery occlusion, and also can be used as a treatment for retrograde recanalization of the occluded radial arteries.44 Patients who have intact collaterals from the ulnar artery are asymptomatic despite radial occlusion, because the palmar circulation provides collateral flow. The occurrence of hand or finger pain, or discoloration, weakness, cold, or sensory deficit should prompt immediate evaluation and, if necessary, consultation with a vascular surgeon. If the diagnosis is confirmed, then aggressive treatment is indicated, as described above.

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Vascular Complications of Transradial Access Hand Ischemia

Hand ischemia is a rare complication of transradial access with an incidence less than one in 1,000.45 The symptoms of hand or finger ischemia are dusky appearance of the hand or finger, paresthesia, weakness, pain, and cyanosis. There is an absence of Doppler signals in the ipsilateral radial artery and palmar arch in conjunction with a compromised ulnar artery collateral flow on ultrasound. The etiology is assumed to have two concurrent events: embolization of radial artery thrombus and in situ thrombosis of collateral vessels from vasospasm.

The abnormal result of a non-invasive test for collateral hand circulation (Allen test) does not predict clinical hand ischemia sequelae after cardiac catheterization, because recruitment of ulnar artery circulation may occur acutely during catheterization and prevent hand ischemia. Only sporadic cases of hand or finger ischemia after transradial catheterization have been reported. The following risk factors were collected from case reports and extrapolated from the Valentine et al. cohort that included all patients presenting to vascular surgery after radial artery cannulation: smoking, peripheral artery disease, hypercoagulable state (e.g., malignancy, heparin-induced thrombocytopenia, disseminated intravascular coagulation), Raynaud’s disease, shock state with vasopressor use, and radial artery spasm.45 Management of hand ischemia requires close monitoring of hand circulation postprocedure. In mild cases, medical management with intraarterial verapamil in combination with 6 hours’ treatment with IV diltiazem 1. Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet 2011;377:1409–20. https://doi.org/10.1016/S01406736(11)60404-2; PMID: 21470671.

2. Sandhu K, Butler R, Nolan J. Expert Opinion: Transradial coronary artery procedures: Tips for success. Interv Cardiol 2017;12:18–24. https://doi.org/10.15420/icr.2017:2:2; PMID: 29588725.

3. Sachdeva S, Saha S. Transradial approach to cardiovascular interventions: an update. Int J Angiol 2014;23:77–84. https:// doi.org/10.1055/s-0034-1372243; PMID: 25075159.

4. Kolkailah AA, Alreshq RS, Muhammed AM, et al. Transradial versus transfemoral approach for diagnostic coronary angiography and percutaneous coronary intervention in people with coronary artery disease. Cochrane Database Syst Rev 2018;4:CD012318. https://doi.org/10.1002/14651858.

CD012318.pub2; PMID:29665617.

5. Al Halabi S, Burke L, Hussain F, et al. Radial versus femoral approach in women undergoing coronary angiography: A meta-analysis of randomized controlled trials. J Invas Cardiol 2019;31:335–40. PMID: 31416045.

6. Ferrante G, Rao SV, Juni P, et al. Radial versus femoral access for coronary interventions across the entire spectrum of patients with coronary artery disease: A metaanalysis of randomized trials. JACC Cardiovasc Interv 2016;9:1419–34. https://doi.org/10.1016/j.jcin.2016.04.014; PMID: 27372195.

7. Roffi M, Patrono C, Collet JP, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267–315. https://doi.org/10.1093/eurheartj/ehv320; PMID: 26320110.

8. Omede P, Bertaina M, Cerrato E, et al. Radial and femoral access for interventional fellows performing diagnostic coronary angiographies: the LEARN-Cardiogroup II, a prospective multicenter study. J Cardiovasc Med 2018;19:650–4. https://doi.org/10.2459/ JCM.0000000000000716; PMID: 30222662.

9. Riangwiwat T, Limpruttidham N, Mumtaz T, et al. Coronary angiography in patients with arteria lusoria via right radial access: a case series and literature review. Cardiovasc Revasc Med 2020;21:417–21. https://doi.org/10.1016/j. carrev.2019.06.001; PMID: 31257174.

10. Bernat I, Horak D, Stasek J, et al. ST-segment elevation

11.

12.

13.

14.

15.

16.

17.

18.

19.

and low-dose IV heparin has returned palpable radial and ulnar artery pulses. Severe cases causing ischemia of the entire hand and requiring surgical intervention generally have a poor outcome and 50% require finger amputation. Surgical management includes operative thrombectomy and arterial patch angioplasty or radial artery interposition with the cephalic vein. Radial reconstruction with interposition vein graft has a better success rate than a vein patch.45

Conclusion

Transradial access is becoming the favored access route for cardiac catheterization. Invasive cardiologists and cardiac catheterization team members should be familiar with the vascular complications. Early detection and treatment is vital, as delayed diagnosis leads to worse complications and the need for surgical intervention.

Radial artery spasm is the most common cause of access site crossover.

Radial spasm is prevented with adequate pain control, and treated with verapamil and/or nitroglycerine. Hemorrhagic complications, such as perforation, hematoma, arteriovenous fistula, and pseudoaneurysm, are generally treated by prolonged compression. Precise detection and management of hemorrhagic complications will prevent development of compartment syndrome, which can leave the patients with long-term morbidity after fasciotomy. Thrombotic complications, such as radial artery occlusion and hand ischemia, are treated with anticoagulation. Preventive strategies and vigilant postprocedural monitoring should be implemented in daily practice at every cardiac catheterization laboratory.

myocardial infarction treated by radial or femoral approach in a multicenter randomized clinical trial: the STEMI-RADIAL trial. J Am Coll Cardiol 2014;63:964–72. https://doi. org/10.1016/j.jacc.2013.08.1651; PMID: 24211309.

Burzotta F, Mariani L, Trani C, et al. Management and timing of access-site vascular complications occurring after transradial percutaneous coronary procedures. Int J Cardiol 2013;167:1973–8. https://doi.org/10.1016/j.ijcard.2012.05.017; PMID: 22633677.

Rathore S, Stables RH, Pauriah M, et al. Impact of length and hydrophilic coating of the introducer sheath on radial artery spasm during transradial coronary intervention: a randomized study. JACC Cardiovasc Interv 2010;3:475–83. https://doi.org/10.1016/j.jcin.2010.03.009; PMID: 20488402.

Riangwiwat T, Mumtaz T, Blankenship JC. Barriers to use of radial access for percutaneous coronary intervention.

Catheter Cardiovasc Interv 2019;96:268–23. https://doi. org/10.1002/ccd.28619; PMID: 31797564.

Doubell J, Kyriakakis C, Weich H, et al. Radial Artery Dilatation to Improve Access and Lower complication rates during coronary angiography (RADIAL): a randomized controlled trial. EuroIntervention 2019. https://doi.org/10.1093/ eurheartj/ehz746.1108; PMID: 31746742; epub ahead of press.

Kwok CS, Rashid M, Fraser D, et al. Intra-arterial vasodilators to prevent radial artery spasm: a systematic review and pooled analysis of clinical studies. Cardiovasc Revasc Med 2015;16:484–90. https://doi.org/10.1016/j. carrev.2015.08.008; PMID: 26365608.

Hahalis GN, Leopoulou M, Tsigkas G, et al. Multicenter randomized evaluation of high versus standard heparin dose on incident radial arterial occlusion after transradial coronary angiography: the SPIRIT OF ARTEMIS study. JACC Cardiovasc Interv 2018;11:2241–50. https://doi.org/10.1016/j. jcin.2018.08.009; PMID: 30391389.

Deftereos S, Giannopoulos G, Raisakis K, et al. Moderate procedural sedation and opioid analgesia during transradial coronary interventions to prevent spasm: a prospective randomized study. JACC Cardiovasc Interv 2013;6:267–73. https://doi.org/10.1016/j.jcin.2012.11.005; PMID:23517838.

Carvalho MS, Calé R, Goncalves Pde A, et al. Predictors of conversion from radial into femoral access in cardiac catheterization. Arq Bras Cardiol 2015;104:401–8. https://doi. org/10.5935/abc.20150017; PMID: 25789883.

Xanthopoulou I, Stavrou K, Davlouros P, et al. Randomised comparison of JUDkins vs. tiGEr catheter in coronary angiography via the right radial artery: the JUDGE study.

EuroIntervention 2018;13:1950–8. https://doi.org/10.4244/EIJD-17-00699; PMID: 29061547.

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Comparative study of the use of diltiazem as an antispasmodic drug in coronary angiography via the transradial approach. Arq Bras Cardiol 2003;81:59–63. https://doi.org/10.1590/S0066-782X2003000900005; PMID: 12908073.

21. Khan MZ, Guzman L, Gharai LR, et al. Dissection of ascending aorta: a complication of transradial artery access of coronary procedure. Heart Views 2018;19:63–6. https:// doi.org/10.4103/HEARTVIEWS.HEARTVIEWS_102_17; PMID: 30505397.

22. Elefteriades JA, Zafar MA, Ziganshin BA. Iatrogenic aortic dissection: review of the literature. Aorta 2016;4:240–3. https://doi.org/10.12945/j.aorta.2016.16.081; PMID: 28516102.

23. Sanmartin M, Cuevas D, Goicolea J, et al. Vascular complications associated with radial artery access for cardiac catheterization. Rev Esp Cardiol 2004;57:581–4 [in Spanish]. https://doi.org/10.1016/S1885-5857(06)60634-8; PMID: 15225506.

24. Calvino-Santos RA, Vazquez-Rodriguez JM, SalgadoFernandez J, et al. Management of iatrogenic radial artery perforation. Catheter Cardiovasc Interv 2004;61:74–8. https:// doi.org/10.1002/ccd.10698; PMID:14696163.

25. Rigatelli G, Dell’Avvocata F, Ronco F, et al. Successful coronary angioplasty via the radial approach after sealing a radial perforation. JACC Cardiovasc Interv 2009;2:1158–9. https://doi.org/10.1016/j.jcin.2009.05.026; PMID: 19926061.

26. Buturak A, Demirci Y, Dagdelen S. Management of an iatrogenic radial artery perforation: a case report. Turk Kardiyol Dern Ars 2013;41:332–5. https://doi.org/10.5543/ tkda.2013.56957; PMID: 23760121.

27. Rao SV, McCoy LA, Spertus JA, et al. An updated bleeding model to predict the risk of post-procedure bleeding among patients undergoing percutaneous coronary intervention: a report using an expanded bleeding definition from the National Cardiovascular Data Registry CathPCI Registry.

JACC Cardiovasc Interv 2013;6:897–904. https://doi. org/10.1016/j.jcin.2013.04.016; PMID: 24050858.

28. Romagnoli E, Biondi-Zoccai G, Sciahbasi A, et al. Radial versus femoral randomized investigation in ST-segment elevation acute coronary syndrome: the RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) study. J Am Coll Cardiol 2012;60:2481–9. https://doi.org/10.1016/j. jacc.2012.06.017; PMID: 22858390.

29. Mehta SR, Jolly SS, Cairns J, et al. Effects of radial versus femoral artery access in patients with acute coronary syndromes with or without ST-segment elevation. J Am Coll Cardiol 2012;60:2490–9. https://doi.org/10.1016/j.

Vascular Complications of Transradial Access jacc.2012.07.050; PMID: 23103036.

30. Mason PJ, Shah B, Tamis-Holland JE, et al. An update on radial artery access and best practices for transradial coronary angiography and intervention in acute coronary syndrome: a scientific statement from the American Heart Association. Circ Cardiovasc Interv 2018;11:e000035. https:// doi.org/10.1161/HCV.0000000000000035; PMID: 30354598.

31. Kanei Y, Kwan T, Nakra NC, et al. Transradial cardiac catheterization: a review of access site complications.

Catheter Cardiovasc Interv 2011;78:840–6. https://doi. org/10.1002/ccd.22978; PMID: 21567879.

32. Kongunattan V, Ganesh N. Radial artery pseudoaneurysm following cardiac catheterization: A nonsurgical conservative management approach. Heart Views 2018;19:67–70. https:// doi.org/10.4103/HEARTVIEWS.HEARTVIEWS_124_17; PMID: 30505398.

33. Tosti R, Özkan S, Schainfeld RM, Eberlin KR. Radial artery pseudoaneurysm. J Hand Surg Am 2017;42:295.e1–6. https:// doi.org/10.1016/j.jhsa.2017.01.024; PMID: 28258867.

34. Tizon-Marcos H, Barbeau GR. Incidence of compartment syndrome of the arm in a large series of transradial approach for coronary procedures. J Interv Cardiol 2008;21:380–4. https://doi.org/10.1111/j.1540-8183.

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35. Sinha SK, Jha MJ, Mishra V, et al. Radial Artery Occlusion – Incidence, Predictors and Long-term outcome after TRAnsradial Catheterization: clinico-Doppler ultrasound-

based study (RAIL-TRAC study). Acta Cardiol 2017;72:318–27. https://doi.org/10.1080/00015385.2017.1305158; PMID: 28636520.

36. Nagai S, Abe S, Sato T, et al. Ultrasonic assessment of vascular complications in coronary angiography and angioplasty after transradial approach. Am J Cardiol 1999;83:180–6. https://doi.org/10.1016/S00029149(98)00821-2; PMID: 10073818.

37. Sanmartin M, Gomez M, Rumoroso JR, et al. Interruption of blood flow during compression and radial artery occlusion after transradial catheterization. Catheter Cardiovasc Interv 2007;70:185–9. https://doi.org/10.1002/ccd.21058; PMID: 17203470.

38. Sakai H, Ikeda S, Harada T, et al. Limitations of successive transradial approach in the same arm: the Japanese experience. Catheter Cardiovasc Interv 2001;54:204–8. https:// doi.org/10.1002/ccd.1268; PMID: 11590685.

39. Pancholy S, Coppola J, Patel T, et al. Prevention of radial artery occlusion-patent hemostasis evaluation trial (PROPHET study): a randomized comparison of traditional versus patency documented hemostasis after transradial catheterization. Catheter Cardiovasc Interv 2008;72:335–40. https://doi.org/10.1002/ccd.21639; PMID: 18726956.

40. Pancholy SB, Bernat I, Bertrand OF, et al. Prevention of radial artery occlusion after transradial catheterization: the PROPHET-II randomized trial. JACC Cardiovasc Interv

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2016;9:1992–9. https://doi.org/10.1016/j.jcin.2016.07.020; PMID: 27712733.

41. Seto AH, Roberts JS, Abu-Fadel MS, et al. Real-time ultrasound guidance facilitates transradial access: RAUST (Radial Artery access with Ultrasound Trial). JACC Cardiovasc Interv 2015;8:283–91. https://doi.org/10.1016/j. jcin.2014.05.036; PMID: 25596790.

42. Bernat I, Bertrand OF, Rokyta R, et al. Efficacy and safety of transient ulnar artery compression to recanalize acute radial artery occlusion after transradial catheterization. Am J Cardiol 2011;107:1698–701. https://doi.org/10.1016/j. amjcard.2011.01.056; PMID: 21439528.

43. Zankl AR, Andrassy M, Volz C, et al. Radial artery thrombosis following transradial coronary angiography: incidence and rationale for treatment of symptomatic patients with lowmolecular-weight heparins. Clin Res Cardiol 2010;99:841–7. https://doi.org/10.1007/s00392-010-0197-8; PMID: 20625752.

44. Corcos T. Distal radial access for coronary angiography and percutaneous coronary intervention: a state-of-the-art review. Catheter Cardiovasc Interv 2019;93:639–44. https:// doi.org/10.1002/ccd.28016; PMiID: 30536709.

45. Valentine RJ, Modrall JG, Clagett GP. Hand ischemia after radial artery cannulation. J Am Coll Surg 2005;201:18–22. https://doi.org/10.1016/j.jamcollsurg.2005.01.011; PMID: 15978439.

COVID-19 and Medical Education

Cardiovascular Medical Education During the Coronavirus Disease 2019 Pandemic: Challenges, Adaptations, and Considerations for the Future Hilary Shapiro, MD,1 and Nosheen Reza , MD2 1. Division of Cardiovascular Medicine, Department of Medicine, University of California, Los Angeles Medical Center, Los Angeles, CA; 2. Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has greatly impacted graduate medical education for cardiovascular fellows in training.

During the initial case surge in the US in early 2020, most training programs reformatted didactic curricula, redeployed fellows in training to noncardiac services or furloughed fellows in training on non-essential services, reimagined procedural training in light of decreased case volumes, and balanced issues regarding trainee wellbeing and safety with occupational COVID-19 exposure risk. In this article, the authors review the educational challenges posed by the COVID-19 pandemic, and discuss opportunities to incorporate technological and curricular innovations spurred by the pandemic into cardiovascular fellowship training in the future.

Keywords

Cardiovascular, fellowship, training, medical education, COVID-19, telehealth, telemedicine, simulation, virtual Disclosure: NR is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001879. HS has no conflicts of interest to declare.

Received: October 26, 2020 Accepted: November 26, 2020 Citation: US Cardiology Review 2021;15:e05. DOI: https://doi.org/10.15420/usc.2020.25 Correspondence: Nosheen Reza, MD, Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 11 South Tower, Room 11-145, 3400 Civic Center Boulevard, Philadelphia, PA 19104. E: nosheen.reza@pennmedicine.upenn.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The coronavirus disease 2019 (COVID-19) pandemic has dramatically transformed the healthcare landscape around the world. In US medical education, students, residents, and fellows have experienced significant educational disruptions. Many trainees have been redeployed as frontline clinicians in regions with high COVID-19 case counts, experienced delays and interruptions in formal educational programs and licensing exams, and struggled with the psychological and emotional uncertainty of completing their education during a once-in-a-lifetime infectious pandemic.1 These disruptions have challenged traditional medical education structures to varying degrees at programs around the country, and have also spawned several novel innovations regarding the delivery of medical education and the practice of medicine. Radical curricular transformations, many of which have been received with enthusiasm, have occurred for fellows training in cardiovascular medicine in 2020 and 2021.

In this article, we describe the impact of the COVID-19 pandemic on education for cardiovascular fellows in training (FITs), provide an overview of the most common adaptations in medical education and care delivery that have occurred during this time, and highlight issues that cardiovascular training programs and FITs must navigate as the COVID-19 pandemic endures (Figure 1).

Impacts of COVID-19 on Cardiology Training

For US cardiovascular FITs, the demands and changes to healthcare delivery wrought by the COVID-19 pandemic have also upended their

cardiovascular educations. Across the country, coinciding with temporal COVID-19 case surges, fellows have reported significant and prolonged interruptions to their training pathways.1–5 To accommodate the clinical care of patients with COVID-19 being admitted to academic medical centers, the Accreditation Council for Graduate Medical Education allowed institutions to self-declare Pandemic Emergency Status and reassign trainees from across all disciplines, including cardiovascular FITs, and restructure inpatient care teams to care for patients with COVID-19 as locally necessary.

Under this plan, cardiovascular FITs are allowed, if needed, to spend up to 20% of each academic year functioning as critical care fellows or internal medicine attending physicians, provided hospitals still maintain policies to ensure trainee safety, supervision, and work hour restrictions.6 FITs have therefore traded cardiovascular training opportunities for rotations in pulmonology, infectious disease, critical care medicine, and palliative care through reassignment to intensive care unit and hospitalist roles.7

Cardiovascular Procedural Volumes

Even in programs where redeployment of cardiovascular FITs was not necessary, social distancing mandates, personal protective equipment (PPE) conservation efforts, and anticipatory staffing changes resulted in many FITs being furloughed from their cardiovascular rotations, especially from in-person echocardiography, electrophysiology, and catheterization

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Cardiovascular Medical Education During the COVID-19 Pandemic Figure 1: The Impact of COVID-19 on Cardiovascular Fellowship Training

COVID-19 impacts on cardiovascular training

Adaptations and innovations

Post-COVID-19 future of cardiovascular training

• Reassignment of fellows to COVID-19 ICUs and wards • Reduction in cardiovascular procedural and direct patient care experiences • Disruption of traditional didactic experiences • Cancelation of professional society meeting and scientific conferences • Changes in performing and promoting research and scholarship • Increased stress and uncertainty • Illumination of existing and worsening health inequities • Online didactics and educational materials • Increased incorporation of technological educational tools • Simulation training • Telehealth exposure • Acquisition of skills in critical care, leadership, communication, crisis management • Virtual fellowship recruitment • Incorporation of health disparities and social determinants of health education into traditional cardiovascular didactic curricula • Evolution of competency-based assessments • Accommodation of variable fellow skillsets and backgrounds • Resumption of in-person didactics while maintaining virtual education strategies • Incorporation of telehealth into standing curriculum • Exploration of simulation-based learning • Continued emphasis on trainee wellbeing

COVID-19 = coronavirus disease 2019; ICU = intensive care unit.

laboratory services. In a national survey of cardiovascular FITs, with almost 1,000 respondents from around the US, 88% of respondents reported decreased FIT staffing in their echocardiography laboratories and 90% reported decreased FIT staffing in their catheterization laboratories at the start of the pandemic.2 Additionally, many elective cardiovascular procedures and face-to-face clinic visits were canceled or rescheduled during the initial wave of the pandemic, to allow for staff redeployment, reduced COVID-19 exposure for patients and staff, and conservation of hospital resources.8,9 In a highly procedural specialty, such as cardiology, where competency is achieved through repeated practice, these changes significantly impacted the proficiency and confidence of FITs who graduated in 2020.

Senior fellows approaching graduation and sub-specialized fellows in interventional cardiology (IC) and electrophysiology were likely the most negatively affected by reductions in case volumes. Since these fellows work with increasing independence and mastery toward the end of their training, case cancelations or redeployment of fellows off of cardiac services entirely decreased the number of supervised cases these trainees were able to complete. In addition, for graduating fellows, there were no opportunities to recompense for missed training in subsequent years of fellowship. Currently, interventional cardiology fellows are required to perform 250 percutaneous interventions (PCIs) by the end of their year of training, as per the Fourth Core Cardiology Training Symposium (COCATS 4).10 In an early survey of 21 IC fellowship programs within the New York City metropolitan area, 95% of the responding IC fellows reported moderate (72%) or severe (24%) concern that the COVID-19 pandemic would have an adverse impact on their procedural training. Nearly 25% of IC fellows reported performing <250 PCIs by March 1, 2020, indicating concern that they would not achieve their COCATS 4 recommended PCI volume before the end of their IC fellowship year.3 Further, in a national survey of IC fellows and programs, only 43% of the responding 135 IC fellows reported performing >250 PCIs by March 2020, and 49% of IC fellows felt that their developing procedural skills were negatively impacted by the COVID-19 pandemic.10

Not unexpectedly, many fellows reported concerns that these reductions in case loads and direct care experiences would leave them underprepared for independent practice. In one study, 47% of surveyed IC FITs reported concerns that COVID-19-related alterations to their training programs would leave them less proficient independent operators by the end of training.10 This group of fellows also reported concerns about limited job opportunities after graduation, citing hiring freezes, inability to travel for in-person interviews, delayed employment start dates, and fewer available positions as other reasons for unstable postgraduation plans.10 In another study, fellows cited the cancellation of in-person national meetings and academic conferences, and the networking opportunities provided by these meetings as potential causes of fewer job prospects and advanced fellowship opportunities after graduation.2

Didactics and Academic Conferences

In addition to reductions in procedural case loads and exposure to patients, cardiovascular FITs also saw interruptions and changes to their protected didactic time. Based on the 2020 survey of US cardiovascular FITs, the vast majority of training programs canceled in-person didactic lectures entirely or transitioned their lecture series to online-only formats.2 All professional society conferences and academic meetings were similarly canceled or transitioned to an online-only format, leaving many without the opportunity to network in advance of their job searches or advanced training opportunities.11 Furthermore, many fellows also reported postponing planned learning of cardiovascular disease topics to stay up-to-date on the rapidly growing body of evidence in COVID-19 pathophysiology and treatments, hospital policies, and other COVID-19associated topics.5,6

Trainee Wellbeing and Safety

These rapid and drastic changes to learning environments, reduced opportunities for the development of cardiovascular competencies, illumination of health inequities and systemic racism in medicine, and new and unfamiliar patient care roles have caused many FITs understandable mental strain and personal stress.12 In addition, fellows have reported concern for the health of their families and loved ones, financial stressors and uncertainty, social isolation, and disruptions in childcare.12,13 Finally, PPE rationing, ethical dilemmas regarding allocation of limited healthcare resources, repeated exposure to COVID-19-related morbidity and mortality, and overall concerns about personal health and COVID-19 exposures have all added to the emotional burdens of FITs during the past year.13,14 In a national survey of almost 1,000 cardiovascular FITs, 81% reported concern about personally contracting COVID-19, and 87% were worried about exposing their family or roommates to COVID-19. A total of 74% of FITs reported reusing N95 masks due to PPE rationing, and almost onethird of respondents reported difficulty obtaining PPE at their training institutions.2 While medical training is itself a time of potential stress for FITs, the changes created as a result of the COVID-19 pandemic ushered in unprecedented challenges to FITs’ physical and mental health.

Research and Scholarships

The COVID-19 pandemic also disrupted FITs’ participation in research, scholarly activities, and journal clubs and conferences.12 With the sudden and mandatory closures of non-essential operations, basic and translational research efforts were suspended, and clinical research operations, such as in-person clinical trial enrollment visits and follow‑ups,

US CARDIOLOGY REVIEW Access at: www.USCjournal.com

Cardiovascular Medical Education During the COVID-19 Pandemic have similarly suffered.12,13 More generally, social distancing mandates have limited mentorship opportunities for FITs pursuing research, and significantly reduced their options for presenting academic research and networking at conferences and academic meetings.1

Adaptations to Cardiology Training During COVID-19

Despite these disruptions, cardiovascular FITs, cardiovascular training programs, and national organizations have reaffirmed the importance of protecting trainees from COVID-19 exposure, and continuing to provide cardiovascular FITs with sufficient education in cardiovascular topics and core tenets.13,15 In line with these missions, a majority of programs pivoted their didactic programs and lecture series to online formats, and others embraced simulation training to continue procedural education. Most programs are providing training and exposure to telehealth care delivery, and some have advocated for a temporary relaxation of the COCATS 4 certification recommendations.

Online Education

To comply with social distancing guidelines, many cardiovascular training programs transitioned their in-person didactic series into online educational formats. A report from cardiovascular FITs at one academic center described their program-specific efforts to transition to online education, using a combination of Zoom (Zoom Video Communications) and Microsoft Teams (Microsoft Corporation) to provide lectures and educational activities for their fellows. They noted that the new online format promoted participation, and could potentially improve access to teaching for fellows who were at home on leave or otherwise not able to attend an in-person lecture.16 Other platforms, such as WebEx (Cisco Webex) and BlueJeans (BlueJeans Network), are also being frequently used at training centers around the country.6 Cardiovascular fellowship program directors at many programs established protocols for remote reading of cardiovascular imaging studies and other laboratory-based learning opportunities with a supervising physician via online platforms.12 The transition to online learning has had many benefits. Virtual lectures allow FITs at multiple training sites and multiple institutions to participate, and involve furloughed and quarantined fellows from home.6 These online platforms facilitate recording and asynchronous access to lectures, permitting FITs to learn on their own schedules or revisit lectures as desired.

Embedded tools, such as polling, screen sharing, and screen annotation, also foster a collaborative and engaging learning environment, with some reporting improved fellow participation in lectures since transitioning to an online format.12,17 In the national survey of almost 1,000 FITs, 73% reported enjoying virtual learning and voiced interest in continuing with online lectures after the resolution of the COVID-19 pandemic and social distancing mandates.2 Professional societies have also had to adapt to the COVID-19 pandemic, and many of them have offered free or cost-reduced online conferences and training materials to supplement FIT education. The virtual American College of Cardiology/World Congress of Cardiology Scientific Sessions in March 2020 provided an opportunity for >38,000 attendees from >157 different countries to participate and learn from the conference, which highlighted the success of online education as an opportunity to promote diversity and inclusion, especially for trainees who would not

have been able to attend an in-person conference for logistical or financial reasons.7,18 In addition, the American College of Cardiology, the American Heart Association, the American Society of Nuclear Cardiology, and other cardiovascular professional societies have produced free training materials for FITs during the COVID-19 pandemic.19,20

Simulation-based Training

Simulation training is also being leveraged to continue procedural training in programs where case volumes have decreased or FITs are unable to achieve the recommended numbers of procedures. Task trainers in cardiac catheterization procedures and echocardiography, both transthoracic and transesophageal, are available and highly rated for both learner experience and also reduction in procedural complications, although they are expensive and not available at all institutions across the country.21,22 For those fellows that do have access, simulation trainers can be powerful tools to improve proficiency in technical skills in cardiology. The University of Texas Southwestern Medical Center recently detailed their success in using a simulation trainer to develop a training program for transthoracic echocardiography, noting that the program was successfully able to differentiate the skills of early FITs from experienced sonographers and allowed for easy and rapid feedback to trainees. This study concluded that simulation learning should be viewed as a powerful tool complementary to the traditional models of hands-on transthoracic echocardiography training.23 Some educators note that during the COVID-19 pandemic, simulation learning may be more useful for junior FITs who are still learning foundational procedural skills, as opposed to senior FITs who are hoping to refine their skills with the additional variables of patient-related differences, in-room distractions, PPE considerations, and other time pressures.13 In situations where live cases are limited, then, senior FITs could be assigned to in-person procedures and junior FITs to simulation sessions instead, so as to guarantee continued learning of fellows at different levels of competency.

Telehealth

With the conversion of much of ambulatory cardiology to telephone or video-based clinic visits, FITs have been able to hone their skills in the provision of remote care to patients.24 This transition has allowed FITs to continue their education in ambulatory cardiovascular medicine, but it also poses unique learning opportunities for FITs who must now also assess patient suitability for a telehealth, rather than in-person, visit. FITs must also conduct patient assessments without the aid of an in-person physical examination, and develop follow-up plans and testing recommendations while staying conscious of limited hospital resources.24 Supervising physicians are able to join FIT video conference or telephone call patient encounters to assess and provide feedback on FIT history gathering and communication skills immediately after a visit, an opportunity that is not as regularly available during normal in-person cardiovascular FIT clinics.6 Of note, prior to COVID-19, many fellowship programs did not provide formal telehealth training for their FITs, and so FITs’ experiences with and opinions of telehealth will likely be shaped by the amount of support or training they receive in this care modality moving forward.

Clinical Competency and Wellness

Although no formal changes have yet been made, to address concerns regarding clinical competency for graduating fellows, there have been some calls to temporarily relax the COCATS 4 procedural volume

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Cardiovascular Medical Education During the COVID-19 Pandemic recommendations prior to graduation to account for the disruptions in training experienced by FITs across the country.4,13 Extensions in training duration, left to the discretion of program directors and clinical competency committees, have also been raised as a strategy to support graduating FITs who may not be prepared for independent practice by the expected graduation date.7 These changes would have potential domino effects on future employers, who might have to delay start times to allow fellows to complete additional months of training or provide extended periods of supervision at the start of new graduates’ practice to ensure that they are competent to practice independently.3 In addition to addressing issues regarding clinical competency, fellowship programs and their trainees have openly discussed increased efforts to promote FIT wellbeing. In a statement in the Journal of the American College of Cardiology, 10 cardiovascular fellowship program directors (PDs) from around the US called on all cardiovascular PDs to acknowledge the psychological stressors their FITs have encountered throughout the pandemic and to encourage FITs to prioritize self-care activities, including regular exercise, a regular sleep schedule, and dedicate time to loved ones and hobbies.12 In response, many programs have opened forums for FITs to express their concerns about redeployment, and communicate directly with program and hospital leadership. Other programs have offered hazard pay to redeployed fellows, provided financial support for childcare and mental health counseling, and have prioritized securing sufficient PPE and instruction in infection control for their FITs.1 To combat issues of social isolation and to allow for the rapid transmission of useful information, FITs have been encouraged to connect over social media platforms, such as Twitter and WhatsApp (Facebook).6 Virtual happy hours and office hours have been scheduled at many training programs.12 FITs also report regular virtual meetings with PDs to discuss trainee wellbeing, develop new support networks, and involve FITs in program decisions that will directly affect them, all of which help to cultivate a supportive work environment in the midst of a period of significant personal and institutional stress.12

Development of New Skills and Interests

Other potential benefits of curricular changes for cardiovascular FITs are the abilities to hone new skills, collaborate in multidisciplinary teams, and learn non-clinical competencies of leadership and crisis management within a healthcare environment.1 As noted in one report on cardiology training during the COVID-19 pandemic, FITs are also learning to practice medicine within resource-limited settings, and are relying on limited physical examination and point-of-care ultrasound skills to make diagnoses in situations where more advanced diagnostics would have previously been obtained.1 FITs are also learning about the cardiovascular impacts of COVID-19 infection and its therapies in real time as the evidence base surrounding its diagnosis, management, and prognosis rapidly evolves.25 Although these skills and topics were not included in pre-pandemic cardiovascular training curricula, FITs are now being offered opportunities to develop skills and knowledge that may prove essential in their future careers.7 The rapid generation of knowledge relating to COVID-19 has created plentiful opportunities for interested FITs to become involved in new research projects, including many studies investigating the shortand long-term cardiovascular impacts of COVID-19.

Virtual Fellowship Recruitment

Cardiovascular fellowship programs have rapidly adapted and innovated to continue training their current FITs, efforts to recruit future generations

of cardiovascular FITs were also significantly revamped. In line with the Coalition for Physician Accountability’s Work Group on Medical Students in the Class of 2021 Moving Across Institutions for Post Graduate Training’s recommendation that all medical school and residency applications be conducted via online interviews and virtual visits, all US-based cardiology fellowship programs similarly transitioned to a fully online interview season.26,27 Programs and applicants alike adjusted to online interviews and virtual site visits. Anecdotal reports from PDs across the country in mid-2020 claimed that the number of applications to individual programs significantly increased for application year 2020 compared with prior years. These sentiments were ultimately corroborated by data released by the National Resident Matching Program which demonstrated that 1,575 individuals applied for 1,042 training slots in Cardiovascular Disease, a notable increase from the 1,395 applicants in 2020.

Programs and applicants faced new challenges, such as a higher volume of interviews over a shorter period of time, ensuring effective communication across electronic platforms, technological malfunctions, and, especially for applicants, limited understanding of a program’s physical location.28 However, for both interviewers and interviewees, an online-only format provided the benefits of avoiding unnecessary travel during the pandemic, decreased financial burden for applicants who otherwise would be responsible for travel and hotel costs, and fewer work days lost to travel.29 Enduring travel limitations may hinder newlymatched fellows who are unable to visit their new cities and secure housing ahead of matriculation.1

The Post-pandemic Future of Training in Cardiovascular Medicine

As much as cardiology training programs were faced with urgent decisions regarding how and when to alter their educational programs in the face of a novel and surging infectious disease pandemic, they will also lead the creation of new post-pandemic educational structures.

Core Cardiovascular Experiences

For procedural fellows, the reduction in COVID-19 cases locally has been accompanied by a resurgence of elective or less urgent cardiovascular procedures. Already, in regions that have experienced a reduced prevalence of patients with COVID-19, programs have managed relative resurgences in cardiac procedure volumes, as providers reschedule those cases that were previously delayed, provide care to those patients who delayed medical evaluation during prior COVID-19 surges, and also continue to provide care for patients who were already scheduled for routine care throughout 2020 and 2021.30 While fellows regain the ability to perform more cardiac procedures, if volume is far above normal capacity, providers should remain mindful of maintaining a balance of service and education for fellows.

Program directors should be alert to different learning needs for their incoming general cardiology fellows and new interests for their current FITs. First year fellows who matriculate into training programs from 2020 onward may have missed opportunities for cardiology electives or procedural experiences due to pandemic-related redeployments and changes to their residency educations. Additionally, cardiology programs may see an increased interest from cardiovascular FITs in additional training in critical care. While this additional exposure must be balanced against the issues of increased risk and proper access to PPE, for some FITs, this increased exposure to critical care concepts may spark interest in dedicated cardiac

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Cardiovascular Medical Education During the COVID-19 Pandemic critical care training.5 Cardiac critical care was an emerging stand-alone field within cardiology before the start of the pandemic, and it would be not unexpected if this field’s popularity continues to rise as cardiovascular FITs return from their redeployments from COVID-19 wards with a newfound interest in critical care training opportunities.31

pandemic use will likely still be variable. Programs that have had access to simulation training models and incorporated them into their sociallydistanced education plan may well choose to continue to use them, especially for junior fellows looking to develop and refine their foundational skills.

Remote Patient Care and Didactics

Conclusion

Similarly, for many FITs, the COVID-19 pandemic has provided novel opportunities for training and experience in telehealth. While reimbursement decisions will likely dictate the extent of telehealth’s continued use at the conclusion of the pandemic, the abilities to provide care to patients who live a long distance from hospitals and to closely monitor patients via remote monitoring devices may prove to be winning arguments for the continued support of telehealth clinics and focused training for FITs in telehealth skills and management.

Decisions about when and how to return to in-person lectures or inperson academic conferences should be led by local and national guidelines on social distancing and safe infection control practices. Prior to holding meetings in person, cardiology PDs could consider soliciting feedback from their FITs on the preferred methods of didactic delivery.

Online lectures have thus far proven to be well-liked by trainees and have provided the additional benefits of allowing FITs at satellite hospitals or at home, on non-clinical rotations, or on parental or personal leave to participate in the didactic curriculum. Most likely, some combination of online and in-person lectures, or in-person lectures that are live-streamed online, will be embraced by most programs. Training program leaders should consider conducting formal assessments of the effectiveness of education in such hybrid models to inform future graduate medical education strategies. The remote learning resources produced and promoted by cardiovascular professional societies have proven to be popular methods of instruction for FITs around the country, and these initiatives should be supported for future trainees.

Simulation Learning

Simulation learning, although it has previously been touted as useful and effective, is, for many reasons, still inconsistently used, and its post1. Hadley MB, Lampert J, Zhang C. Cardiology fellowship during the COVID-19 pandemic: lessons from New York City.

J Am Coll Cardiol 2020;76:878–82. https://doi.org/10.1016/j. jacc.2020.07.013; PMID: 32732122.

2. Rao P, Diamond J, Korjian S, et al. The impact of the COVID-19 pandemic on cardiovascular fellows-intraining: a national survey. J Am Coll Cardiol 2020;76:871–5. https://doi.org/10.1016/j.jacc.2020.06.027; PMID: 32561407.

3. Gupta T, Nazif TM, Vahl TP, et al. Impact of the COVID-19 pandemic on interventional cardiology fellowship training in the New York metropolitan area: a perspective from the United States epicenter. Catheter Cardiovasc Interv 2021;97:201–5. https://doi.org/10.1002/ccd.28977; PMID: 3241591.

4. Berookhim J, Correa A, Tamis-Holland JE. Notes from the eye of the storm: trainees at the frontlines of the COVID-19 pandemic. J Am Coll Cardiol 2020;76:218–20. https://doi.org/10.1016/j.jacc.2020.05.021; PMID: 32422181.

5. Narula N, Singh HS. New York City innocence lost: cardiology in the COVID-19 pandemic. Circulation 2020;141:2039–41. https://doi.org/10.1161/ CIRCULATIONAHA.120.047265; PMID: 32255370.

6. DeFilippis EM, Stefanescu Schmidt AC, Reza N. Adapting the educational environment for cardiovascular fellows-intraining during the COVID-19 pandemic. J Am Coll Cardiol 2020;75:2630–4. https://doi.org/10.1016/j.jacc.2020.04.013; PMID: 32304798.

7. Narula N, Singh HS. Cardiology practice and training postCOVID-19: achieving “normalcy” after disruption. J Am Coll

8.

9.

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14.

Whether any of the pandemic-associated changes to cardiology medical education are carried forward, FITs and educators have proven their willingness to adapt, quickly assimilate new technologies and learning platforms, and find new ways to maintain their own and their colleagues’ education during a time of significant upheaval, stress, and uncertainty.

There remains great opportunity for formal investigation into the effectiveness and durability of the novel educational strategies inspired by the COVID-19 pandemic. Cardiovascular medicine is a dynamic and innovative field, and both educators and trainees have aptly demonstrated their abilities to remain nimble in the face of crisis.

Clinical Perspective

• The cardiovascular education of current fellows in training was

impacted greatly by cancellation of in-person didactics and conferences, re-deployment of trainees to front line non-cardiac services, and decreases in cardiovascular case volumes during the coronavirus 2019 pandemic.

• Cardiology training programs have quickly adapted their educational structures, with most now offering online lectures, simulation learning opportunities, training in telehealth medicine, and consideration of relaxed procedural requirements prior to fellowship graduation.

• Moving forward, programs will have to safely and effectively coordinate the transitions back to in-person formats, and maintaining hybrid educational formats, such as online lectures and other methods of remote and asynchronous instruction, should be considered.

Cardiol 2020;76:476–9. https://doi.org/10.1016/j. jacc.2020.06.036; PMID: 32703519.

Goel S, Sharma A. COVID-19 pandemic and its impact on cardiology and its subspecialty training. Prog Cardiovasc Dis 2020;63:525–6. https://doi.org/10.1016/j.pcad.2020.05.004; PMID: 32422229.

Welt FGP, Shah PB, Aronow HD, et al. Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: from the ACC’s Interventional Council and SCAI. J Am Coll Cardiol 2020;75:2372–5. https://doi.org/10.1016/j. jacc.2020.03.021; PMID: 32199938.

Shah S, Castro-Dominguez Y, Gupta T, et al. Impact of the COVID-19 pandemic on interventional cardiology training in the United States. Catheter Cardiovasc Interv 2020;96:997– 1005. https://doi.org/10.1002/ccd.29198; PMID: 32767717.

Neale T. ACC, EHRA Cancel 2020 Meetings Over COVID-19.

2020. https://www.tctmd.com/news/acc-ehra-cancel-2020meetings-over-covid-19 (accessed October 7, 2020).

Weissman G, Arrighi JA, Botkin NF, et al. The impact of COVID-19 on cardiovascular training programs: challenges, responsibilities, and opportunities. J Am Coll Cardiol 2020;76:867–70. https://doi.org/10.1016/j.jacc.2020.06.026; PMID: 32561406.

Dineen EH, Hsu JJ, Saeed A. Reinforcing cardiology training during a pandemic: an open letter to our leaders. Circulation 2020;142:95–7. https://doi.org/10.1161/ CIRCULATIONAHA.120.047593; PMID: 32357070.

DeFilippis EM, Ranard LS, Berg DD. Cardiopulmonary resuscitation during the COVID-19 pandemic: a view from trainees on the front line. Circulation 2020;141:1833–5. https://doi.org/10.1161/CIRCULATIONAHA.120.047260;

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PMID: 32271616.

15. Harrington RA, Elkind MSV, Benjamin IJ. Protecting medical trainees on the COVID-19 frontlines saves us all. Circulation 2020;141:e775–7. https://doi.org/10.1161/ CIRCULATIONAHA.120.047454; PMID: 32250654.

16. Almarzooq ZI, Lopes M, Kochar A. Virtual learning during the COVID-19 pandemic: a disruptive technology in graduate medical education. J Am Coll Cardiol 2020;75:2635–8. https://doi.org/10.1016/j.jacc.2020.04.015; PMID: 32304797.

17. Sinha SS, Sharma G, Cullen MW. The crucible of crisis: responses of fellows-in-training and early career cardiologists to the COVID-19 pandemic. J Am Coll Cardiol 2020;75:2627–9. https://doi.org/10.1016/j.jacc.2020.04.012; PMID: 32439013.

18. American College of Cardiology. Virtual ACC.20/WCC: The Show Must Go On. May 7, 2020. https://www.acc.org/ membership/sections-and-councils/cardiovascular-teamsection/section-updates/2020/05/06/12/42/virtual-acc20wcc-the-show-must-go-on (accessed October 17, 2020).

19. American Society of Nuclear Cardiology. Nuclear Cardiology Virtual Boot Camp for Fellows-In-Training. 2020. https:// www.asnc.org/fellows (accessed October 17, 2020).

20. Alraies MC. Training and education: new strategies for new times. September 21, 2020. https://www.acc.org/latest-incardiology/articles/2020/09/21/01/42/training-and-educationnew-strategies-for-new-times-covid-19-coronavirusdisease-2019 (accessed October 17, 2020).

21. Westerdahl DE. The necessity of high-fidelity simulation in cardiology training programs. J Am Coll Cardiol 2016;67:1375–8. https://doi.org/10.1016/j.jacc.2016.02.004; PMID: 26988961.

Cardiovascular Medical Education During the COVID-19 Pandemic 22. Narang A, Velagapudi P, Rajagopalan B, et al. A new educational framework to improve lifelong learning for cardiologists. J Am Coll Cardiol 2018;71:454–62. https://doi.org/10.1016/j.jacc.2017.11.045; PMID: 29389363.

23. Singh K, Chandra A, Lonergan K, Bhatt A. Using simulation to assess cardiology fellow performance of transthoracic echocardiography: lessons for training in the COVID-19 pandemic. J Am Soc Echocardiogr 2020 33:1421–3. https://doi. org/10.1016/j.echo.2020.06.021; PMID: 32828626.

24. Chowdhury D, Hope KD, Arthur LC, et al. Telehealth for pediatric cardiology practitioners in the time of COVID-19.

Pediatr Cardiol 2020;41:1081–91. https://doi.org/10.1007/ s00246-020-02411-1; PMID: 32656626.

25. Nishiga M, Wang DW, Han Y, et al. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol 2020;17:543–58. https://doi.

org/10.1038/s41569-020-0413-9; PMID: 32690910.

26. The Coalition for Physician Accountability’s Work Group on Medical Students in the Class of 2021, Moving Across Institutions for Post Graduate Training. Final Report and Recommendations for Medical Education Institutions of LCMEAccredited, U.S. Osteopathic, and Non-U.S. Medical School Applicants. 2020. https://www.aamc.org/system/files/202005/covid19_Final_Recommendations_05112020.pdf (accessed October 17, 2020).

27. Reza N, Berlacher K, McPherson JA, Faza NN. A guide to navigating virtual cardiovascular disease fellowship interviews. Jacc Case Rep 2020;2:1828–32. https://doi. org/10.1016/j.jaccas.2020.08.005; PMID: 32954365.

28. Murphy B. Residency Match 2021: How COVID-19 is forcing major adjustments. American Medical Association. May 27, 2020. https://www.ama-assn.org/residents-students/match/ residency-match-2021-how-covid-19-forcing-major-

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adjustments (accessed October 17, 2020).

29. Prisco S. Residency and fellowship interviews during COVID19. The Early Career Voice. July 10, 2020. https:// earlycareervoice.professional.heart.org/residency-andfellowship-interviews-during-covid-19/ (accessed October 17, 2020).

30. O’Riordan M. Hospitals plan cautious restart to elective procedures as COVID-19 wanes. TCTMD May 12, 2020. https://www.tctmd.com/news/hospitals-plan-cautious-restartelective-procedures-covid-19-wanes (accessed October 7, 2020).

31. Miller PE, Kenigsberg BB, Wiley BM. Cardiac critical care: training pathways and transition to early career. J Am Coll Cardiol 2019;73:1726–30. https://doi.org/10.1016/j. jacc.2019.03.004; PMID: 30947926.

Complex Coronary Interventions

Novel Non-invasive Fractional Flow Reserve from Coronary CT Angiography to Determine Ischemic Coronary Stenosis Lavanya Cherukuri , MD,1 Divya Birudaraju , MD,1 and Matthew J Budoff , MD1,2 1. The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA; 2. Division of Cardiology, Harbor-UCLA Medical Center, Torrance, CA

Abstract

Coronary artery disease (CAD) patients may have an obstructive disease on invasive coronary angiography, but few of these patients have had flow-limiting obstructive disease diagnosed on invasive fractional flow reserve (FFR). FFR is infrequently performed because of its cost- and time-effectiveness. Advancement in non-invasive imaging has enabled FFR to be derived non-invasively using coronary CT angiography (CCTA), without the need for induction of hyperemia or modification of the standard CCTA acquisition protocol. FFR derived from CCTA (FFRCT) has been shown to have excellent correlation with invasive FFR, and remains an effective diagnostic tool in the presence of reduced signal-to-noise ratio, coronary calcification and motion artifact. The utility of FFRCT has also helped to deepen our understanding of hemodynamically significant CAD. Hence, there is now interest in exploring the possible interplay between these mechanistic forces and their effect on the development of coronary plaque and the vulnerability of these plaques.

Keywords

Hyperemia, coronary CT angiography, coronary stenosis, fractional flow reserve, coronary artery disease Disclosure: MJB declares work for the National Institutes of Health and General Electric Healthcare. All other authors have no conflicts of interest to declare.

Received: August 25, 2020 Accepted: January 17, 2021 Citation: US Cardiology Review 2021;15:e06. DOI: https://doi.org/10.15420/usc.2020.24 Correspondence: Lavanya Cherukuri, MD, The Lundquist Institute at Harbor-UCLA Medical Center, 1124 W Carson St, Torrance, CA 90502. E: lavanyacherukuri3@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Coronary CT angiography (CCTA) is a robust non-invasive method for direct visualization of the coronary arteries and atherosclerotic plaque burden. Recent advancements in cardiac CT and its clinical application have enabled the production of high-quality images with low radiation exposure. CCTA has a high sensitivity and high negative predictive value for the detection of coronary artery disease (CAD). The main limitations of CCTA are the low specificity and positive predictive value for determining the severity and hemodynamic significance of coronary stenosis.1,2 The functional significance of coronary stenosis dictates the prognosis and the need for coronary revascularization in patients with stable CAD.3 Functional ischemia was found in less than half of the patients referred for invasive coronary angiography (ICA) based on the angiographic severity of stenosis.4,5 Such limitations of CCTA have raised the concern that it could lead to unnecessary ICA or revascularization procedures for patients who do not have ischemia. This led to the introduction of fractional flow reserve (FFR) derived from conventional CCTA (FFRCT) to determine the physiologic significance of CAD, in order to reduce the false-positive rate and incidence of negative referrals to ICA. FFRCT, a noninvasive method, is the gold standard diagnostic method for guiding decision-making to identify stable CAD patients who would benefit from revascularization. In this article we review the role of FFRCT according to supporting evidence and describe the challenges in its widespread application for determining hemodynamically significant stenosis, based on the most significant research articles.

Real-world Experience With FFR

ICA has routinely been used to detect coronary artery plaques to determine the need for revascularization, independent of quantitative coronary angiographic modalities. However, the vast majority of patients referred for ICA have either been discharged with no evidence of CAD (54–62%) or have undergone revascularization of lesions that are not hemodynamically significant or that are not the true cause of the symptoms.6 Various methods have been developed and are now available in the catheterization laboratory to determine the functional significance of coronary lesions. The most acceptable measure of the hemodynamic pressure of coronary stenoses is FFR, which aids the interventionist to identify specific vessels and lesions that require appropriate revascularization. FFR is measured routinely in the catheterization laboratory using a pressure wire with an IC or IV vasodilator to produce maximal hyperemia. FFR represents the fraction of the normal maximal myocardial flow across the coronary stenotic lesion, and an FFR of 0.75 represents a stenosis causing a 25% drop in pressure across the lesion.

Deferral of percutaneous coronary intervention (PCI) has been shown to be safe in patients with >50% visual stenosis on ICA but an invasive FFR ≥0.75.7 Invasive FFR during PCI reduces the composite outcome of death, non-fatal MI, and revascularization in patients with stable multivessel CAD.8 However, FFR is not routinely measured in clinical practice due to the invasive nature of the FFR procedure, the added time, the use of radiation and contrast, the cost of adenosine needed during FFR

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Coronary CT Angiography-derived FFR Figure 1: Simple Algorithm for the Management of CAD Diagnosis of coronary atherosclerosis

In the case of high-risk patients with chronic kidney disease, it is prudent to proceed directly to the catheterization laboratory to avoid double doses of contrast, which may cause contrast-induced nephropathy.

Overview of Non-invasive FFRCT Known CAD

Suspected CAD

CCTA

Normal coronary arteries

All coronary artery lesions with <50% stenosis

Coronary artery lesions with ≥70% stenosis

Hemodynamically significant coronary lesions: FFRCT

Risk factor management

FFRCT 0.76–0.80

No ischemia or FFRCT >0.8

No additional testing; risk factor management and/or optimal medical therapy

●

● ●

Assess high-risk plaque features and plaque burden Number of vessels with stenosis Location of the stenosis (left main stem)

FFRCT ≤0.75

ICA

CAD = coronary artery disease; CCTA = coronary CT angiography; FFRCT = fractional flow reserve derived from CCTA; ICA = invasive coronary angiography.

measurement, the high cost of the pressure-sensing wires, and the limited reimbursement.8–11 For instance, invasive FFR was performed in only 6.1% of patients according to data from more than 60,000 ICA cases in the National Cardiovascular Data Registry. Of these 6.1%, FFR procedures were more likely to be performed in a university hospital setting than in private and community hospitals (p<0.0001).12 In studies on the use of CCTA in individuals with suspected CAD and the indications for ICA, the prevalence of significant CAD on CCTA was reported in only 23% (CAT-CAD study) and 53% (CONSERVE study) of the study populations.4,13 Given this superior performance of CCTA, prior knowledge of the functional significance of coronary artery lesions before angiography may reduce the need for invasive procedures and the healthcare cost. Non-invasive FFRCT fills that gap and provides the scores of hemodynamic pressure and flow across the entire coronary tree.

Invasive FFR, however, assesses only the pressure gradient in the targeted vessel chosen during ICA at the discretion of the interventionist.

There is great value in measuring FFRCT after stress testing. In the National Cardiovascular Data Registry, after abnormal functional test, only 47% were found to have obstructive CAD.14 Use of FFRCT can cut down on falsepositive stress tests by at least 80% (PLATFORM STUDY).15,16 Kim et al. reported that CT-derived computer modeling is feasible and helpful to predict functional outcome after coronary stenting.17 FFRCT had a 96% diagnostic accuracy in predicting or ruling out myocardial ischemia after stenting, with a mean difference of 0.02 ± 0.05 between FFR after stenting and FFRCT after virtual stenting. Here, we present a simple algorithm for the management of CAD (Figure 1).

FFRCT was first proposed by Charles Taylor and colleagues, and it involves the application of computational fluid dynamics to the available anatomical data from CCTA to produce a 3D model of coronary blood flow and pressures.18,19 A minimum of 64-slice CCTA is required to produce the data for FFRCT analysis, and the currently available method is marketed by HeartFlow. FFRCT enables calculation of rest and hyperemic pressure fields in coronary arteries without the use of additional medication (i.e. adenosine), additional imaging or radiation exposure, or changes to CCTA protocols.20 The steps involved in the computation of FFRCT are based on the Navier– Stokes equations, the physical laws that govern fluid dynamics, which have been previously published.3,21–23 The physiologic model is derived using the patient’s anatomical model and is based on three scientific principles. The first principle is that resting total coronary blood flow is proportional to myocardial mass from volumetric CCTA. The second principle is that the total coronary resistance is calculated from the inverse relationship between microcirculatory resistance at rest and vessel diameter. The third principle is that the vasodilatory response of the coronary microcirculation to adenosine is able to be predicted.

The precise interpretation of CCTA and FFRCT depends on image quality, especially in patients with high heart rate, arrhythmias and other artifacts.

Recent advances in CCTA and its clinical application, however, means that high image quality is now available, with temporal spatial resolution and software-based motion correction.

Diagnostic Accuracy of FFRCT

CCTA is reported to be only moderately predictive of abnormal invasive FFR, which has become the standard reference for the identification of clinically significant lesions of stenosis. The DEFER and FAME studies showed a low risk of adverse cardiovascular outcomes associated with the FFR-based revascularization procedure.5,24,25 FFR, the ratio of blood flow through a coronary artery with stenosis to that through a coronary artery without stenosis, is equal to 1.0 in a normal coronary artery, while FFR ≤ 0.80 identifies ischemia-causing coronary stenoses with >90% accuracy.25 FFRCT is a novel method that has been reported to reduce the need for ICA and the healthcare cost.26 Three major, prospective, multicenter studies have evaluated the diagnostic performance of FFRCT in patients with suspected or known CAD, using invasive FFR as the reference method. First, the DISCOVERFLOW (Diagnosis of Ischemia-causing Stenoses Obtained via Non-invasive Fractional Flow Reserve) study enrolled 103 patients, 56% of whom had ≥1 vessel with FFR ≤ 0.80.18 Using receiver operating characteristics (ROC) analysis, a higher area under the curve (AUC) was noted for FFRCT relative to CCTA (0.90 versus 0.75; p=0.001). Second, the DeFACTO (Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography) study demonstrated only 54% specificity on a per-patient basis, which did not meet the pre-specified primary endpoint for diagnostic accuracy of >70% for the lower boundary of the 95% CI.27 The specificity in the per-vessel analysis was improved to 61% with high sensitivity (80%), but this was still low compared with DISCOVER-FLOW.27 The DISCOVER-FLOW study showed good correlation with invasive FFR, but the DEFACTO study failed to achieve a similar accuracy. The third study was the NXT trial (Analysis of Coronary Blood Flow Using CT

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Coronary CT Angiography-derived FFR Angiography: Next Steps), which enrolled 254 patients who were clinically referred for ICA for suspected CAD.28 CCTA was performed before ICA. On a per-patient basis, the sensitivity and specificity to identify myocardial ischemia were 86% and 79% for FFRCT, versus 94% and 34% for coronary CTA, and 64% and 83% for ICA, respectively. In predicting functionally important CAD, FFRCT was found to have greater value than CCTA on a per-patient (AUC 0.9 versus 0.81; p=0.0008) and per-vessel level (AUC 0.93 versus 0.79; p=0.0001). FFRCT reclassified 68% of patients with falsepositive CCTA, 67% of whom were found to have true-negative results.28 In a meta-analysis by Gonzalez et al., FFRCT was observed to have a significantly higher specificity compared with CCTA (72% versus 43%; p=0.004) on a per-patient basis, with a high positive predictive value (70%).29 No improvement in the sensitivity was reported, however, and the per-vessel analysis did not show a significant correlation for either sensitivity or specificity between CCTA and FFRCT. However, when Xu et al. compared the integrated results from DISCOVER-FLOW and DeFACTO with the data from the NXT trial (which used a refined version of FFRCT), a significant improvement was seen in specificity on a per-patient basis with the upgraded FFRCT technology (62.2% versus 78.7%, p<0.001).30 Multiple studies have confirmed the superior diagnostic value of CCTA with the addition of FFR in identifying functionally significant lesions.25–30 FFR analysis further improves the specificity and positive predictive value of CCTA, with high sensitivity and negative predictive value. The accurate interpretation of FFRCT completely relies on the quality of the CCTA images, especially in patients with high heart rate, arrhythmias and other artifacts.

Even a large calcified lesion may pose a challenge for the 3D anatomical modeling required for FFRCT analysis. However, the discrepancies between FFRCT and invasive FFR due to CT image quality and use of sublingual nitroglycerin or β-blockers prior to CCTA, can be accounted for using CTAderived computational algorithms. Also, the recent advancements in CT technology with regard to enhanced spatial and temporal resolution and iterative image reconstruction, mean that improved image quality can be achieved even in the case of calcified lesions or motion artifacts. A DISCOVER-FLOW substudy assessed the effect of CT image quality on the accuracy of FFRCT and noted the superior accuracy of FFRCT over CCTA even in the presence of coronary calcification, motion artifacts and low signal-to-noise ratio.31 Leipsic et al. reported an improved diagnostic performance of FFRCT with the use of β-blockers and nitroglycerin prior to CCTA, however, the diagnostic accuracy of FFRCT was significantly reduced with misalignment artifact (accuracy, 56.0% versus 71.0%, p=0.03; sensitivity, 43.0% versus 86.0%, p=0.001).32 Furthermore, Nørgaard et al. showed that the diagnostic efficiency of FFRCT was not reduced compared with CCTA in patients with high coronary artery calcium score ≥400.33 The FFRCT technique uses computational fluid dynamics principles and image-based modeling from CCTA images to non-invasively determine the coronary flow and pressures along the length of the entire coronary tree. The evidence-based studies of the diagnostic performance of FFRCT are summarized in Supplementary Material Table 1. According to the evidence-based studies, FFRCT diagnostic accuracy ranges from 73% to 81%, and FFRCT has a sensitivity of 86–93% and a specificity of 54–79%. In summary, compared with invasively measured FFR, non-invasive FFRCT has a high diagnostic accuracy for the detection of ischemia-causing stenosis in stable patients with suspected or known CAD.

Impact on Clinical Decision-making and Prognostic Value of FFRCT

In addition to the enhanced prognostic value relative to CCTA stenosis, FFRCT may have a direct impact on therapeutic decision-making, which

further enhances the efficiency of ICA in patients with suspected CAD. The evidence-based studies are summarized in Supplementary Material Table 2. FFRCT may change the downstream management of patients by identifying individuals with stenosis and calcification.34,35 In the FFRCT RIPCORD study, 47% (n=94) of all the participants had significant obstructive CAD on CCTA and were later found to have no obstructive disease on ICA. Of these 94 patients, 57 (60.6%) had FFRCT >0.80 and 37 (39.4%) had FFRCT ≤0.80. This discrepancy between the physiological significance and visual assessment of stenosis severity resulted in a change in the allocated management plans for 72 (36%) of the patients.36 Similarly, PLATFORM (Prospective Longitudinal Trial of FFRCT: Outcome and Resource Impacts) found no obstructive CAD on ICA in 24 (12.4%) of the CTA/FFRCT arm or in 137 (73.3%) of the invasive arm participants (risk difference 60.8%; 95% CI [53.0–68.7]; p<0.0001).6 In the patients in the CTA/FFRCT arm who were scheduled for planned ICA, there were only two major adverse cardiac events (MACEs: all-cause mortality, MI, and unplanned hospitalization for chest pain leading to urgent revascularization) were reported, which was too low to determine the significance of the correlation. In the ADVANCE (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care) registry, 72.3% of the study population undergoing invasive angiography with FFRCT ≤0.80 underwent revascularization.15,16 Non-obstructive coronary disease (no stenoses >50%) was significantly lower in ICA patients with FFRCT ≤0.80 compared with patients with FFRCT >0.80 (OR 0.19; 95% CI [0.15–0.25]; p<0.001).

FFRCT enables assessment of the hemodynamic forces that play a role in the pathogenesis of atherosclerotic plaque.37,38 In order to select the appropriate treatment, it is essential to identify the number of vessels that need intervention in patients with multivessel CAD and to identify the location of the cause of lesion-specific ischemia. The anatomic SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score was proposed to determine the complexity of atherosclerotic lesions based on location, severity, bifurcation and calcification.39,40 The integration of anatomic, plaque and hemodynamic characteristics can aid in non-invasive risk prediction of acute coronary syndrome. The SYNTAX III study demonstrated that CCTA alone overestimated the anatomic SYNTAX scores compared with FFRCT, and that FFRCT had good diagnostic accuracy compared with invasive functional SYNTAX scores.7,8 Furthermore, the anatomic and functional information derived from FFRCT to calculate SYNTAX scores aids clinicians in deciding between optimal medical therapy and revascularization, and between PCI and coronary artery bypass graft surgery.9,40 There were no serious adverse cardiac events in patients who were deferred from ICA based on FFRCT.10 An appropriate revascularization strategy, involving planning and the selection of target lesion for revascularization, is possible with FFRCT, which can provide both anatomic and functional information prior to the invasive procedure.

FFRCT Versus Other Non-invasive Functional Tests

The use of FFRCT for the detection of lesion-specific ischemia was compared with that using other functional cardiac testing. The advantages and disadvantages of various non-invasive modalities used for the assessment of coronary ischemia have been previously published and are summarized in Table 1.41 In comparison with myocardial perfusion imaging, CCTA has the ability to detect, localize and exclude CAD accurately.42,43 CCTA, however, overestimates the severity of lesions and does not define their functional significance reliably. This gap in non-invasive testing could be resolved by integrating anatomic and physiologic data. Yang et al. demonstrated the increased diagnostic accuracy of CCTA when combined with FFRCT (AUC 0.856 versus 0.919; p=0.004), and showed that CT-

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Coronary CT Angiography-derived FFR Table 1: Comparison of Non-invasive Imaging Techniques Sensitivity45,46,50,58,59

Specificity45,46,50,58,59

Comments

Exercise ECG

60%

76%

• Limited to ambulatory patients

Stress echocardiography

Per patient: 77%

Per patient: 75%

• Echocardiography unable to evaluate the spatial extent of coronary artery stenosis and has a limited ability to assess posterior structures of heart

• Required trained technicians and readers, and good image quality to maintain diagnostic accuracy and reproducibility

MPI (SPECT/PET)

Per vessel: 57% Per patient: 70%

Per vessel: 75% Per patient: 78%

Cardiac MRI

Per vessel: 87% Per patient: 91%

Per vessel: 89% Per patient: 87%

CAC score

90%

85%

CCTA

Per vessel: 91% Per patient: 90%

Per vessel: 58% Per patient: 39%

• Image quality depends on body habitus • Limited spatial resolution and specificity due to attenuation artifacts, such as elevated diaphragm and breast

• False positives with multivessel disease and left main stem disease • FFRCT is superior to MPI for identifying patients with balanced ischemia, multivessel disease or complexity of atherosclerotic plaque

• Limited 3D quantification of ischemia • Contraindications (implantable devices, such as defibrillator or pacemaker) • Lack of direct visualization of extent of coronary artery stenosis • Able to use in combination with FFR to determine the lesion-specific ischemia • Assess coronary stenosis and plaque morphology • Excellent spatial resolution

CAC = coronary artery calcium; CAD = coronary artery disease; CCTA = coronary CT angiography; FFR = fractional flow reserve; FFRCT = fractional flow reserve derived from CCTA; ICA = invasive coronary angiography; MPI = myocardial perfusion imaging; SPECT = single-photon emission CT.

derived FFR significantly correlated with invasive FFR (r=0.671, p<0.001).44 Pontone et al. evaluated the diagnostic accuracy of CT perfusion plus CCTA compared with FFRCT plus CCTA and reported no significant difference in sensitivity, specificity or AUC (p=0.4).45 However, the diagnostic performance for the detection of lesion-specific ischemia was improved when CCTA was combined with CT perfusion plus FFRCT compared with CCTA plus CT perfusion (AUC 0.919 versus 0.876; p=0.016).45 A significant correlation of per-vessel FFRCT to invasive FFR was reported (Pearson’s correlation coefficient 0.69; p<0.001). FFRCT also provided additional value in terms of specificity, positive predictive value and diagnostic accuracy to detect flow-limiting stenosis (patient-based AUC 0.90 versus 0.94; vessel-based AUC 0.89 versus 0.93; p<0.001) compared with CCTA alone. Li et al. have demonstrated the low specificity (63% versus 91%; p<0.001) and AUC (0.79 versus 0.96, p<0.001) of machine learning-based FFRCT compared with myocardial blood flow derived from CT perfusion for detecting hemodynamically significant CAD.46 The investigators reported that CT perfusion delivered higher radiation doses compared with FFRCT (3.6 ± 1.1 mSv versus 2.7 ± 0.8 mSv).

Additionally, Nørgaard et al. investigated the association of moving from myocardial perfusion imaging to FFRCT testing with the downstream utilization of diagnostic and therapeutic ICA.47 In patients referred to ICA, the rate of non-obstructive CAD was reduced by 12.8% (95% CI [−22.2, −3.4]; p=0.008) and the rate of revascularization increased by 14.1% (95% CI [3.3–24.9]; p=0.01). Downstream ICA utilization (after adjusting for baseline risk factors) was also reduced by 4.2% (95% CI [−6.9, −1.6]; p=0.002) with an FFRCT strategy.

Sand et al. compared the per-patient diagnostic performance of FFRCT with that of single-photon emission CT (SPECT).48 FFRCT had a higher sensitivity than SPECT (91% versus 41%; p<0.001) and reclassified six patients with multivessel disease with false-negative SPECT. The specificity of FFRCT was low compared with SPECT (55% versus 86%; p<0.001), and the authors attributed this to the vasodilatory response due to the use of nitroglycerine tablets rather than spray in the CT image acquisition protocol. The post-hoc substudy of the PACIFIC (Prospective

comparison of cardiac PET/CT, SPECT/CT Perfusion Imaging and CCTA with ICA) trial included 208 patients and compared the accuracy of FFRCT to PET and SPECT.49 On a per-vessel level, FFRCT had a high sensitivity compared with CCTA (90% versus 68%, p<0.001), SPECT (90% versus 42%, p<0.001) and PET (90% versus 81%, p=0.03).49 The AUC for identifying ischemia-causing lesions was significantly greater for FFRCT compared with CCTA (p<0.01) and SPECT (p<0.01) on both per-vessel and per-patient analysis. PET had the highest per-patient and per-vessel AUC, followed by FFRCT in the intention-to-diagnose analysis (0.86 versus 0.83; p=0.157; and 0.90 versus 0.79; p=0.005, respectively). However, FFRCT has the superior clinical diagnostic ability to provide anatomically and functionally significant information on coronary lesions in patients with multivessel disease.49 In a meta-analysis of 23 studies, Danad et al. compared the accuracy of various non-invasive imaging modalities (cardiac MRI, echocardiography, SPECT, CCTA) to that of FFRCT using invasive FFR as the reference standard for ischemia.50 Forest plots at the per-patient level showed a high sensitivity for FFRCT (90%; 95% CI [85–93]), CCTA (90%; 95% CI [86–93]) and cardiac MRI (90%; 95% CI [75–97]) with a low sensitivity for SPECT (70%; 95% CI [59–80]) and ICA (69%; 95% CI [65–75]). The highest specificity was noted for cardiac MRI (94%; 95% CI [79–99]) and the lowest for CCTA (39%; 95% CI [34–44]), with intermediate specificity for SPECT, echocardiography, FFRCT, and ICA. On a per-vessel basis, low diagnostic performance was observed for SPECT, stress echocardiography and ICA, whereas CCTA and FFRCT yielded high diagnostic sensitivity, with low specificity for CCTA. Furthermore, cardiac MRI provided a superior performance in the diagnosis of ischemiacausing CAD on both a per-patient and per-vessel basis compared with the invasive FFR reference standard. Although the diagnostic superiority of cardiac MRI over non-invasive cardiac tests has been demonstrated, it has not been implemented as a standard imaging test to determine myocardial perfusion measurements. In summary, most of these studies comparing FFRCT and other cardiac non-invasive imaging modalities have used small samples, and further large randomized multicenter studies are required.

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Coronary CT Angiography-derived FFR Cost-effectiveness

The 2016 updated National Institute for Health and Care Excellence (NICE) clinical guidelines recommend CCTA as a first-line investigation for chest pain in patients without known CAD.51 The addition of FFRCT to standard CCTA can reduce the healthcare costs compared with that when combining CCTA with other non-invasive modalities for evaluating inconclusive coronary lesions, for which a functional assessment is needed.52 In 2017, the NICE medical technology guidelines proposed the use of HeartFlow FFRCT to determine the extent of CAD in patients with stable recent-onset chest pain, and concluded that FFRCT analysis could save approximately £214 per patient by reducing the need for unnecessary invasive tests and treatment.53 A substudy using the clinical data from 96 DISCOVER-FLOW patients found that a CCTA/FFRCT/ICA strategy (i.e. initial CCTA, with FFRCT for patients having ≥50% stenosis, and patients with FFRCT ≤0.80 undergoing ICA and PCI) reduced the medical costs to identify functionally significant CAD requiring invasive coronary intervention by 30% relative to an ICA/ visual strategy (i.e. initial invasive angiography, with PCI for stenoses ≥50% on visual assessment; $7,674 versus $10,702), and resulted in a 12% lower clinical event rate at 1 year.52 Similarly, Kimura et al. demonstrated that the CCTA/FFRCT approach (i.e. initial CCTA with FFRCT in patients with ≥50% stenosis and ICA only in those with FFRCT ≤0.80) saved 32% in medical costs and was associated with a 19% lower cardiac event rate compared with the ICA/visual strategy at 1 year.54 Additionally, the PLATFORM investigators reported a substantially lower mean cost for an FFRCT-guided strategy than the usual invasive strategy ($8,127 versus $12,145; p<0.0001).16 For FFRCT, the quality of life had been improved over a 90-day follow-up relative to the usual non-invasive testing.16 The mean costs at 90 days and at 1 year were lower in the FFRCT cohort compared with the usual care cohort in the subgroup of patients with planned ICA (90 days: $7,343 versus $10,734, p<0.0001; 1 year: $8,127 versus $12,145, p<0.0001). In a retrospective analysis of FFRCT addition, Rajani et al. showed a per-patient saving of £200 compared with myocardial perfusion scanning in patients with a pre-test likelihood of CAD of 10–90%.55 The NICE guidelines for chest pain reported an average saving of £159 per patient using the adapted pathway with HeartFlow FFRCT, and £214 per patient for FFRCT compared with the current treatment pathway for all functional imaging tests (SPECT, MRI and echocardiography).53 Most of the PCIs and surgical revascularizations were performed following ICA, and sometimes with an invasive FFR. Given that FFRCT and invasive FFR are significantly correlated, FFRCT may facilitate the planning of revascularization strategies in individual vessels and patients.53 1. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment

by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial.

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3. Ball C, Pontone G, Rabbat M. Fractional flow reserve derived from coronary computed tomography angiography datasets: the next frontier in noninvasive assessment of coronary artery disease. Biomed Res Int 2018;2018:2680430. https://doi.org/10.1155/2018/2680430; PMID: 30276202.

4. Moscariello A, Vliegenthart R, Schoepf UJ, et al. Coronary CT angiography versus conventional cardiac angiography for therapeutic decision making in patients with high likelihood of coronary artery disease. Radiology

Future Trials

The results from future multicenter studies will determine the role of FFRCT in evaluating symptomatic patients with stable chest pain.

The FORECAST trial is a multicenter, randomized trial that will assess the clinical and economic outcomes of using FFRCT as the primary test to evaluate patients presenting with stable chest pain. A total of 1,400 patients will be randomized to receive either FFRCT or standard treatment outlined in the NICE guidelines for stable chest pain. The primary endpoint is resource utilization, and the secondary endpoints include MACE and quality of life.56 The DECIDE-Gold (Dual-energy Computed Tomography for Ischemia Determination Compared to Gold Standard Non-invasive and Invasive techniques) is a prospective, multicenter study. The diagnostic accuracy of CCTA with FFRCT is being evaluated against dual-energy CT perfusion imaging for non-invasive assessment of the hemodynamic significant coronary stenosis in 156 patients, as compared with invasive FFR as the reference standard. Additionally, the performance of FFRCT and/or dualenergy CT will be determined compared with myocardial perfusion imaging.57

Conclusion

CCTA-derived non-invasive FFR is a novel approach with a high diagnostic yield for the detection and exclusion of flow-limiting coronary lesions. It plays a vital role, especially with regard to patients referred to ICA, and bridges the gap between anatomic imaging and clinical decision-making.

FFRCT correlates well with invasive FFR and provides high diagnostic accuracy and discrimination to identify hemodynamically significant CAD when compared with invasive FFR as the reference standard. FFRCT has the potential to overcome the major limitations of anatomic testing using CCTA, such as low specificity, and substantially improves the detection of obstructive CAD. Integrating FFR into CCTA not only helps to rule out obstructive CAD but also provides information on anatomic and lesionspecific stenosis to facilitate revascularization procedures. FFRCT >0.80 safely identifies patients with an excellent medium-term follow-up that could be managed with optimal medical therapy. In the next 5 years, the UK may be able to provide essential clinical experience by clinically implementing CCTA and FFRCT chest pain pathways according to the NICE guidelines. Future research should aim to collect prospective, randomized and long-term outcome data for clinical guidelines in the coming years.

The class and level of recommendation will depend on the prognostic information and cost-saving benefits in future clinical trials.

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34. Mrgan M, Nørgaard BL, Dey D, et al. Coronary flow impairment in asymptomatic patients with early stage type-2 diabetes: detection by FFRCT. Diab Vasc Dis Res 2020;17:1479164120958422. https://doi. org/10.1177/1479164120958422; PMID: 32985257.

35. Chaganti BT, Cherukuri L, Birudaraju D, et al. The evolving pandemic of COVID-19 and increasing role of cardiac computed tomography. Coron Artery Dis 2020. https://doi. org/10.1097/MCA.0000000000000962; PMID: 32897900; epub ahead of press.

36. Curzen NP, Nolan J, Zaman AG, et al. Does the routine availability of CT-derived FFR influence management of patients with stable chest pain compared to CT angiography alone? The FFRCT RIPCORD study. JACC Cardiovasc Imaging 2016;9:1188–94. https://doi.org/10.1016/j.jcmg.2015.12.026; PMID: 27568119.

37. Choi G, Lee JM, Kim HJ, et al. Coronary artery axial plaque stress and its relationship with lesion geometry: application of computational fluid dynamics to coronary CT angiography. JACC Cardiovasc Imaging 2015;8:1156–66. https://doi.org/10.1016/j.jcmg.2015.04.024; PMID: 26363834.

38. Nørgaard BL, Leipsic J, Koo B-K, et al. Coronary computed tomography angiography derived fractional flow reserve and plaque stress. Curr Cardiovasc Imaging Rep 2016;9:2. https://doi.org/10.1007/s12410-015-9366-5; PMID: 26941886.

39. Serruys PW, Onuma Y, Garg S, et al. Assessment of the SYNTAX score in the Syntax study. EuroIntervention 2009;5:50–6. https://doi.org/10.4244/EIJV5I1A9; PMID: 19577983.

40. Serruys PW, Morice M-C, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961–72. https://doi.org/10.1056/NEJMoa0804626; PMID: 19228612.

41. Shah NR, Pierce JD, Kikano EG, et al. CT coronary angiography fractional flow reserve: new advances in the diagnosis and treatment of coronary artery disease. Curr Probl Diagn Radiol 2020. https://doi.org/10.1067/j. cpradiol.2020.09.006; PMID: 33041159; epub ahead of press.

42. Budoff MJ, Mayrhofer T, Ferencik M, et al. Prognostic value of coronary artery calcium in the PROMISE study (Prospective Multicenter Imaging Study For Evaluation Of Chest Pain). Circulation 2017;136:1993–2005. https://doi. org/10.1161/CIRCULATIONAHA.117.030578; PMID: 28847895.

43. SCOT-HEART Investigators. CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial. Lancet 2015;385:2383–91. https://doi. org/10.1016/S0140-6736(15)60291-4; PMID: 25788230.

44. Yang DH, Kim YH, Roh JH, et al. Diagnostic performance of on-site CT-derived fractional flow reserve versus CT perfusion. Eur Heart J Cardiovasc Imaging 2017;18:432–40. https://doi.org/10.1093/ehjci/jew094; PMID: 27354345.

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45. Pontone G, Baggiano A, Andreini D, et al. Dynamic stress computed tomography perfusion with a whole-heart coverage scanner in addition to coronary computed tomography angiography and fractional flow reserve computed tomography derived. JACC Cardiovasc Imaging 2019;12:2460–71. https://doi.org/10.1016/j.jcmg.2019.02.015; PMID: 31005531.

46. Li Y, Yu M, Dai X, et al. Detection of hemodynamically significant coronary stenosis: CT myocardial perfusion versus machine learning CT fractional flow reserve.

Radiology 2019;293:305–14. https://doi.org/10.1148/ radiol.2019190098; PMID: 31549943.

47. Nørgaard BL, Gormsen LC, Bøtker HE, et al. Myocardial perfusion imaging versus computed tomography angiography-derived fractional flow reserve testing in stable patients with intermediate-range coronary lesions: influence on downstream diagnostic workflows and invasive angiography findings. J Am Heart Assoc 2017;6:e005587. https://doi.org/10.1161/JAHA.117.005587; PMID: 28862968.

48. Sand NPR, Veien KT, Nielsen SS, et al. Prospective comparison of FFR derived from coronary CT angiography with SPECT perfusion imaging in stable coronary artery disease: the ReASSESS study. JACC Cardiovasc Imaging 2018;11:1640–50. https://doi.org/10.1016/j.jcmg.2018.05.004; PMID: 29909103.

49. Driessen RS, Danad I, Stuijfzand WJ, et al. Comparison of coronary computed tomography angiography, fractional flow reserve, and perfusion imaging for ischemia diagnosis.

J Am Coll Cardiol 2019;73:161–73. https://doi.org/10.1016/j. jacc.2018.10.056; PMID: 30654888.

50. Danad I, Szymonifka J, Twisk JWR, et al. Diagnostic performance of cardiac imaging methods to diagnose ischaemia-causing coronary artery disease when directly compared with fractional flow reserve as a reference standard: a meta-analysis. Eur Heart J 2017;38:991–8. https://doi.org/10.1093/eurheartj/ehw095; PMID: 27141095.

51. National Institute for Health and Care Excellence. Recentonset chest pain of suspected cardiac origin: assessment and diagnosis. London: NICE, 2010. https://www.nice.org.uk/cg95 (accessed March 30, 2021).

52. Hlatky MA, Saxena A, Koo BK, et al. Projected costs and consequences of computed tomography-determined fractional flow reserve. Clin Cardiol 2013;36:743–8. https:// doi.org/10.1002/clc.22205; PMID: 24114863.

53. National Institute for Health and Care Excellence. HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography. London: NICE, 2017. https://www.nice.org.uk/ mtg32 (accessed November 29, 2020).

54. Kimura T, Shiomi H, Kuribayashi S, et al. Cost analysis of non-invasive fractional flow reserve derived from coronary computed tomographic angiography in Japan. Cardiovasc Interv Ther 2015;30:38–44. https://doi.org/10.1007/s12928014-0285-1; PMID: 25030180.

55. Rajani R, Webb J, Marciniak A, Preston R. Comparative efficacy testing: fractional flow reserve by coronary computed tomography for the evaluation of patients with stable chest pain. Int J Cardiol 2015;183:173–7. https://doi. org/10.1016/j.ijcard.2015.01.035; PMID: 25666127.

56. Mahmoudi M, Nicholas Z, Nuttall J, et al. Fractional flow reserve derived from computed tomography coronary angiography in the assessment and management of stable chest pain: rationale and design of the FORECAST trial.

Cardiovasc Revasc Med 2020;21:890–6. https://doi. org/10.1016/j.carrev.2019.12.009; PMID: 31932171.

57. Truong QA, Knaapen P, Pontone G, et al. Rationale and design of the dual-energy computed tomography for ischemia determination compared to “gold standard” noninvasive and invasive techniques (DECIDE-Gold): a multicenter international efficacy diagnostic study of reststress dual-energy computed tomography angiography with perfusion. J Nucl Cardiol 2015;22:1031–40. https://doi. org/10.1007/s12350-014-0035-x; PMID: 25549826.

58. Takx RAP, Blomberg BA, El Aidi H, et al. Diagnostic accuracy of stress myocardial perfusion imaging compared to invasive coronary angiography with fractional flow reserve meta-analysis. Circ Cardiovasc Imaging 2015;8:e002666. https://doi.org/10.1161/CIRCIMAGING.114.002666; PMID: 25596143.

59. Birudaraju D, Cherukuri L, Kinninger A, et al. Relationship between cardio-ankle vascular index and obstructive coronary artery disease. Coron Artery Dis 2020;31:550–5. https://doi.org/10.1097/MCA.0000000000000872; PMID: 32168051.

Heart Failure

Optimizing Guideline-directed Medical Therapies for Heart Failure with Reduced Ejection Fraction During Hospitalization Neal M Dixit, MD, MBA, 1 Shivani Shah, PharmD, APh,2 Boback Ziaeian, MD, PhD, Gregg C Fonarow, MD, 1,3 and Jeffrey J Hsu, MD, PhD, 1,3,4

1,3,4

1. Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA; 2. Department of Pharmacy Services, Olive View-UCLA Medical Center, Los Angeles, CA; 3. Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA; 4. Division of Cardiology, Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, CA

Abstract

Heart failure remains a huge societal concern despite medical advancement, with an annual direct cost of over $30 billion. While guidelinedirected medical therapy (GDMT) is proven to reduce morbidity and mortality, many eligible patients with heart failure with reduced ejection fraction (HFrEF) are not receiving one or more of the recommended medications, often due to suboptimal initiation and titration in the outpatient setting. Hospitalization serves as a key point to initiate and titrate GDMT. Four evidence-based therapies have clinical benefit within 30 days of initiation and form a crucial foundation for HFrEF therapy: renin-angiotensin-aldosterone system inhibitors with or without a neprilysin inhibitor, β-blockers, mineralocorticoid-receptor-antagonists, and sodium-glucose cotransporter-2 inhibitors. The authors present a practical guide for the implementation of these four pillars of GDMT during a hospitalization for acute heart failure.

Keywords

Clinical barriers, guideline-directed medical therapy, heart failure hospitalization, acute decompensated heart failure, heart failure with reduced ejection fraction.

Disclosure: GF has consulted for Abbott, Amgen, Bayer, Janssen, Medtronic, Merck, and Novartis. All other authors have no conflicts of interest to declare.

Received: November 23, 2020 Accepted: March 7, 2021 Citation: US Cardiology Review 2021;15:e07. DOI: https://doi.org/10.15420/usc.2020.29 Correspondence: Jeffrey J Hsu, UCLA Center for Health Sciences, A2-237, 650 Charles E Young Drive South, Los Angeles, CA 90095-1679. E: jjhsu@mednet.ucla.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In the US, the annual direct cost of heart failure (HF) is estimated at over $30 billion, largely driven by the >1 million hospitalizations in which HF is the primary discharge diagnosis.1–3 The subset of patients with HF with reduced ejection fraction (HFrEF) comprises about half of all patients with HF.4 Guideline-directed medical therapy (GDMT) is proven to reduce mortality and morbidity for patients with HFrEF. GDMT includes the following drug therapies: renin-angiotensin-aldosterone system inhibitors (RAAS-I), with or without a neprilysin inhibitor, β-blockers, and mineralocorticoid-receptor-antagonists (MRA).5 Recently, sodium-glucose cotransporter-2 inhibitors (SGLT2i) demonstrated efficacy as an important fourth pillar of GDMT.6 Together, this combination can add over six additional years of lifespan for HFrEF patients compared to the traditional approach of RAAS-I and β-blockers alone.7 However, studies highlight that many eligible HFrEF patients are not receiving one or more of the recommended medications, in the absence of contraindications or intolerance.8 Even among patients who are treated, less than half receive optimal doses of GDMT. Additionally, time to initiation and optimization of dosing may be exceedingly slow in the outpatient setting.

Analysis of the CHAMP registry showed that less than 1% of patients receive target doses of RAAS-I/angiotensin receptor–neprilysin inhibitor (ARNI), β-blockers, and MRA simultaneously over a 12-month period.8,9

Guideline recommendations for device therapy, such as ICD and cardiac resynchronization therapy (CRT), recommend consideration only after 3 months of GDMT optimization. Yet, target doses of GDMT are rarely achieved prior to device therapy implantation.5,10 Barriers to optimization include lack of access and coordination of care, gaps in provider knowledge, and patient-related factors such as renal function, perceived intolerance to medications, inadequate insurance coverage, out-ofpocket expenses, and adherence.11,12 Hospitalization provides an opportunity to initiate and titrate medical therapy with close monitoring in patients with new-onset or acute on chronic HFrEF.13 Medications provided at discharge are more likely to be adhered to, continued, and further titrated in the outpatient setting.14 An acute heart failure (AHF) hospitalization is an important opportunity to initiate and titrate all four pillars of GDMT (Figure 1), laying a complete foundation for further outpatient optimization. We present a practical guide for the initiation and titration of evidence-based chronic HFrEF therapies during hospitalization.

Renin-Angiotensin-Aldosterone-Inhibitor/ Angiotensin Receptor–Neprilysin Inhibitor

According to expert consensus, optimization of GDMT in an AHF hospitalization should occur once a positive clinical trajectory has been obtained.15 Although initially studied in the outpatient setting, angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers

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Optimizing GDMT for HFrEF During Hospitalization Figure 1: Shifting the Paradigm of Guideline-directed Medical Therapy Initiation

RAAS-I/ARNI β-blocker

Continued up-titration

MRA SGLT2i

Telehealth follow-up

In-person follow-up

Admission day

Approaching euvolemia

Oral diuretic trial

Discharge day

Laboratory monitoring

A suggested timeline of initiating guideline-directed medical therapy (GDMT) for patients admitted with heart failure with reduced ejection fraction during their hospitalization. ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; MRA = mineralocorticoid receptor antagonist; RAAS-I = renin-angiotensin-aldosterone system inhibitor; SGLT2i = sodium–glucose cotransporter-2 inhibitor.

(ARB) have been shown in multiple observational studies to be safely and effectively initiated during hospitalization for AHF, with associated reduction in rehospitalization and mortality.16,17 ARNI is preferred to RAAS-I alone given substantial mortality benefit, similar tolerability, and long-term cost-effectiveness compared to ACEi or ARB.18–20 The PARADIGM-HF trial showed a 16% all-cause death reduction and 21% hazard reduction for HF first hospitalization in the ARNI group compared to the ACEi group.21 Of the patients entering the ARNI ‘run-in’ phase of the trial, less than 5% dropped out as a result of hypotension, renal dysfunction, and hyperkalemia – the three most common reasons for pre-trial drop-out.22 Patients who were then randomized to ARNI actually had lower rates of discontinuation compared to those randomized to ACEi.21 Importantly, symptomatic hypotension is the most common adverse effect of ARNI initiation and occurs about 15% of the time; it is less commonly seen with ACEi or ARB.21,23 A detailed review by Sauer et al. provides further practical guidance on ARNI use.24 The PIONEER-HF trial suggested benefits of ARNI initiation during hospitalization greater than that achieved with ACEi.23 Analysis of the trial showed a 31% lower hazard for cardiovascular (CV) death or rehospitalization events for patients that were initiated on an ARNI during hospitalization versus those initiated on the ACEi, enalapril, in the first 8 weeks.25 PIONEER-HF showed that an ARNI can safely be initiated in patients with a systolic blood pressure (SBP) >100 mmHg for 6 hours, no use of vasodilators or increase in dose of intravenous diuretics in the preceding 6 hours, and no use of inotropes in the preceding 24 hours.23 Contrary to popular belief, RAAS-I/ARNI initiation is well tolerated in cases of mild renal dysfunction, for example, the interquartile range (IQR) of baseline estimated glomerular filtration rate (eGFR) in PIONEER-HF was 47.1–71.5 ml/ min/1.73m2.23,26,27 Acute kidney injury (AKI) after starting RAAS-I occurs in ~13% of HF patients but the long-term overall benefit of RAAS inhibition tends to outweigh any reduction in renal function, which is often transient.28

Experts agree that RAAS-I/ARNI should be continued if serum creatinine (SCr) increases <30% after initiation.29 For changes in SCr >30%, RAAS-I/ ARNI doses can be reduced or temporarily held to assess for improvement in renal function. Once renal function begins to improve, RAAS-I/ARNI should be re-trialed to assess maximally tolerated dose.

RAAS-I show modest dose responsiveness. High-dose RAAS-I (equivalent to lisinopril 20–40 mg daily) results in a 6% decrease in all-cause mortality compared to low-dose RAAS-I (equivalent to lisinopril 5–10 mg daily).30 This effect is similar for ARNI with maintained advantage over ACEi or ARB even at lower doses.31 Clinicians should aim to initiate a RAAS-I, preferably an ARNI, as soon as clinical stability has been obtained. Table 1 shows our proposed strategy of RAAS-I/ARNI initiation.

β-blockers

In three landmark trials, β-blockers demonstrated a reduction in all-cause mortality by 34–35%, even among patients with severe HF or recent decompensation.32–34 In-hospital initiation of β-blocker therapy for HFrEF has been shown to be safe, well tolerated, and associated with reduced mortality within the first 30 days of hospital discharge.35 This was observed even in patients with signs and symptoms of congestion. β-blockers show the clearest dose response relationship among GDMT.36 Initiating or uptitrating a β-blocker during hospitalization is an effective strategy to increase the likelihood of long-term target dose attainment.37 MartinezSellez et al. showed the safety of early initiation of carvedilol in AHF patients at a median 3 days after admission, achieving a mean discharge dose of 23 mg/day among those who tolerated in-hospital up-titration.38 No study has definitively shown the superiority of one evidence-based β-blocker versus another.39 Carvedilol may have a more potent blood pressure lowering effect versus metoprolol succinate in those with more elevated blood pressure.40 Although, for patients with lower blood pressure at baseline, β-blockers are hemodynamically well tolerated.41 In COPERNICUS, patients with a systolic blood pressure (SBP) of 85–95 mmHg at baseline had an increase in SBP with carvedilol greater than placebo.

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Optimizing GDMT for HFrEF During Hospitalization Table 1: Optimizing Guideline-directed Medical Therapies for Heart Failure with Reduced Ejection Fraction During Hospitalization Drug

RAAS-I/ARNI

β-blocker

MRA

SGLT2i*

Initiation criteria

ARNI initiation: • SBP >100 mmHg for 6 h • No use of IV VD or increase in dose of IV diuretics in the preceding 6 h • No use of inotropes in the preceding 24 h • eGFR >45 ml/min/1.73 m2 • K <5.0 mEq/l

• No hypoxia, symptomatic

• On at least minimum dose

• On at least minimum dose

hypotension, or evidence of shock

RAAS-I and β-blocker • SCr <2.5 mg/dl in men, <2.0 mg/dl in women • K <5.0 mEq/l • No symptomatic hypotension

RAAS-I and β-blocker

• eGFR >30 ml/min/1.73 m2 • No symptomatic hypotension

RAAS-I: See below Up-titration strategy

• Direct initiation of ARNI preferred • If SBP 90-120 mmHg or <85 kg strategy • If SBP 100–120 mmHg initiate sacubitril/valsartan 24/26 mg twice daily • If SBP >120 mmHg initiate sacubitril/valsartan 49/51 mg twice daily • Double dose every 1–2 days as tolerated until target dose reached or initiation of next pillar of GDMT

start equivalent of carvedilol 3.125 mg twice daily • If SBP >120 mmHg or >85 kg start equivalent of carvedilol 6.25 mg twice daily • Increase every 1–2 days as tolerated until target dose reached

Potential contraindications

K >5.5 mEq/l

HR <50 BPM

Clinical considerations

• Initiate at equivalent of

spironolactone 12.5 mg daily after the initiation of β-blockers and increase weekly

• Initiate before or after MRA, prior to discharge

• No dosage increase required

K >5.5 mEq/l, SCr >2.5 mg/dl in men, SCr >2.0 mg/dl in women

T1D, eGFR <30 ml/min/1.73 m2

• If SBP is <100 mmHg throughout • If shock, severe pulmonary hospitalization, prior to discharge, trial on equivalent of valsartan 20 mg twice daily or lisinopril 5 mg daily with intent to switch to ARNI when tolerated • No use of ACEi in preceding 36 h of ARNI initiation

edema or SBP <90 mmHg, hold β-blocker and reinitiate at lowest dose, per above • Always ensure patient is adherent to outpatient β-blocker before continuing dose • Younger and heavier patients may tolerate more aggressive dosing • Caution in patients with pulmonary disease

• Recheck of serum potassium

• Consider early initiation and

Relative risk reduction of all-cause mortality in meta-analysis32

RAAS-I 20% ARNI 28%†33

31%

25%

13%6

Relative risk reduction of HF hospitalization in meta-analysis

RAAS-I 33%34 ARNI 49%†33

37%35

23%36

25%6

Yes

Yes

Yes

Clinical benefits within 30 days Yes of initiation demonstrated?

Landmark trials

within 7 days and within 1–2 months31 • Consider addition of potassiumbinder if K >5.0 mEq/l

PIONEER-HF, PARADIGM-HF, CHARM, MERIT-HF, COPERNICUS, and CIBIS-II RALES, EMPHASIS-HF, EPHESUS Val-Heft, ELITE II, ATLAS, SOLVD-2, SOLVD

endocrinology consultation for patients with T2D on insulin or sulfonylurea. These patients may require reduced insulin doses and close glycemic monitoring • Consider submitting prior authorization, if required, early in hospitalization • Immediate reduction in eGFR by 4–6 ml/min/1.73m2 is expected and not harmful

DAPA-HF, EMPEROR-REDUCED, EMPA-REG

*No consensus guidelines for in-hospital initiation but in-hospital initiation preferred by authors. †Computed versus putative placebo in analysis of PARADIGM-HF Trial. ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; BNP = brain natriuretic peptide; CV = cardiovascular; eGFR = estimated glomerular filtration rate; HF = heart failure; HR = heart rate; MRA = mineralocorticoid receptor antagonist; RAAS-I = renin-angiotensin-aldosterone system inhibitor; SBP = systolic blood pressure; SCr = serum creatinine; SGLT2i = sodium glucose cotransporter-2 inhibitor; T1D = type 1 diabetes; T2D = type 2 diabetes; VD = vasodilator.

β-blockers should not routinely be discontinued on admission for AHF. Multiple studies have shown that discontinuation of β-blockers in AHF is associated with worsening short- and long-term mortality, although hypotension/shock or severe pulmonary edema may represent indications for temporary discontinuation.42 Otherwise, as long as the patient confirms

adherence prior to admission, β-blockers can be safely continued during hospitalization. β-blockers should be initiated or up-titrated so long as the patient is hemodynamically stable without marked volume overload, typically after

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Optimizing GDMT for HFrEF During Hospitalization Figure 2: Pre-discharge Checklist Medications

Follow-up

Patient Education

GDMT initiation: ACEi/ARB/ARNI, β-blocker, MRA, SGLT2i Assessment of oral diuretic efficacy Iron deficiency repletion Assess for potential drug–drug interactions

Telehealth/in-person visit within 1 week Heart failure clinic referral Labs: creatinine, electrolyte panel, glucose, BNP Cardiac rehabilitation referral

Medication education Nutrition counseling Physical exercise education Daily weight and blood pressure monitoring Substance use/tobacco cessation counseling

A suggested pre-discharge checklist to help clinicians ensure that patients who are hospitalized with heart failure with reduced ejection fraction receive optimal guideline-directed medical therapy (GDMT). ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; BNP = brain natriuretic peptide; MRA = mineralocorticoid receptor antagonist; SGLT2i = sodium glucose cotransporter-2 inhibitor.

the initiation of a RAAS-I/ARNI.43 Younger patients with higher BMI and without chronic obstructive pulmonary disease tend to tolerate higher doses and may be appropriate for a higher starting dose or more aggressive up-titration.44 Up-titration in patients may occur as tolerated toward target dose prior to discharge (Table 1).

Mineralocorticoid Receptor Antagonist

Only one-third of patients indicated for MRA receive them.8 Use of these agents has reduced CV death and HF hospitalization, with benefits observed within 30 days of initiation.45 Addition of MRA to RAAS-I and β-blockers has been shown to be safe during hospitalization.46 Further, long-term adherence is substantially improved with in-hospital initiation compared to delaying therapy to outpatient at clinician discretion.47 Hospitalization represents an opportunity to safely initiate an MRA under close monitoring, with provider fear of hyperkalemia and renal function often cited as barriers to initiation.48 Potassium binding drugs such as patiromer and sodium zirconium cyclosilicate have shown to be effective long-term options to maintain normokalemia in HF patients.49 While these agents do not confer mortality benefit on their own, they are beneficial in patients who would have otherwise been unable to tolerate MRA therapy.

Additionally, combined usage of MRA with SGLT2i or ARNI (versus ACEi) lowers the risk of hyperkalemia.50,51 At the dosages commonly used in trials, MRAs do not have any blood pressure lowering effect and can be safely initiated on borderline hypotensive patients.52 There is no clear dose response relationship with MRA, although the target dose in major trials was the equivalent of 25–50 mg/day of spironolactone.53 We suggest initiating an MRA after RAAS-I/ARNI and β-blocker initiation, but prior to discharge (Table 1).

Sodium-Glucose Cotransporter-2 Inhibitor

The DAPA-HF and EMPEROR-Reduced trials showed the significant benefits of SGLT2i in the treatment of patients with HFrEF, including reductions in all-cause mortality risk by 13% and recurrent CV hospitalizations by 25% in HFrEF patients with or without type 2 diabetes (T2DM).6 These clinical benefits can be seen within 12 days of initiation.54 Additionally, the DAPACKD trial showed a 44% decrease in the composite of a sustained decline in eGFR of at least 50%, end-stage kidney disease, or death from renal causes.55 Similar results were found in the CREDENCE trial.56 With an estimated 54% of HFrEF patients having concomitant CKD and declining renal function as one of the strongest predictors of mortality in HFrEF, SGLT2i hold substantial clinical promise as a vital fourth pillar of GDMT.57 The novelty of SGLT2i, along with their potential impact on glycemic control for patients with T2DM contribute to relatively low rates of prescription for HFrEF compared to more established pillars of GDMT.58,59 An eGFR <30 ml/min/1.73 m2 is one of a few exclusions to starting the medication at this time, but more than 80% of HFrEF patients are eligible

for treatment with SGLT2i.7 SGLT2i can be safely initiated during hospitalization and do not need to be up-titrated from its initial dosage.

Sotagliflozin, a dual SGLT-1 and -2 inhibitor, displayed benefits within 1 month of initiation when started during or shortly after hospitalization.60–62 SGLT2i do exhibit a modest BP lowering effect in HF patients (~1– 4mmHg).63,64 Additionally, attention should be paid to glycemic management when initiating SGLT-2i in patients on sulfonylureas or insulin due to risk of hypoglycemia and euglycemic diabetic ketoacidosis.64 Volume status of patients on diuretics should be reevaluated due to the risk of over-diuresis. Honigberg et al. previously described in detail the practical considerations for the initiation of SGLT2i. Given the rapid onset of clinical benefit, we favor in-hospital initiation of SGLT2i.65 A summary of the important points for in-hospital initiation are presented in Table 1.

Hydralazine/Nitrate

Although the hydralazine/nitrate combination was the first treatment to show mortality benefit in HFrEF, its usage varies widely.66,67 Current guidelines recommend a hydralazine/nitrate combination for New York Heart Association (NYHA) class III/IV self-described African-American patients who are optimized on RAAS-I and β-blockers.5 Because of modest mortality benefits and relatively larger blood pressure effects, the hydralazine/nitrate combination does not need to be prioritized for inhospital initiation and is not one of the critical four pillars of therapy.67,68 In patients who cannot take RAAS-I/ARNI due to renal dysfunction, hyperkalemia, or drug intolerance, the hydralazine/nitrate combination can be considered as alternate therapy, regardless of race.5 However, because of the demonstrated superiority of RAAS-I/ARNI, a repeat trial with a RAAS-I/ARNI should be attempted when deemed safe.68

Loop Diuretic

Diuretic optimization is an important aspect of chronic HF treatment for symptom management and reducing the likelihood of hospitalization for worsening HF.69 Three loop diuretics are commonly used for the treatment of HF: furosemide, bumetanide and torsemide.70 No trials have definitively shown superiority of one versus the other; however, furosemide is most commonly used in clinical practice and generally has the lowest acquisition cost.71,72 In a meta-analysis, torsemide has been shown to reduce hospitalizations, lower cardiac mortality, and improve functional status compared to furosemide.73 Torsemide also has the longest half-life and offers the advantage of consistent diuretic effect with once daily dosing.71 Both torsemide and bumetanide have superior bioavailability to furosemide. Guidelines recommend trialing an oral diuretic prior to discharge to verify dose effectiveness.5 In a study comparing patients observed on at least 24 hours of an oral diuretic regimen prior to discharge versus those not, 30-, 60-, and 90-day HF readmissions were reduced significantly.74 Fluid restriction should be liberalized for an oral diuretic trial to better match the diuretic dose with the patient’s unrestricted fluid intake.75 The lowest effective dose of loop diuretic should be used to maintain euvolemia, allowing for maximal up-titration of GDMT.71

Transition of Care

Although the average length of stay for an AHF admission is 5 days, an early focus on GDMT during the admission can increase the likelihood of initiation of all four agents, especially with increasing system pressures to reduce time in hospital.76,77 Following discharge, maintaining momentum and ensuring safety of in-hospital initiation and titration of GDMT is dependent on successful transition of care to the outpatient setting. A systematic review identified eight common components of successful programs: “telephone follow-up, education, self-management, weight

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Optimizing GDMT for HFrEF During Hospitalization Table 2: Overcoming Common Clinical Barriers to Guideline-directed Medical Therapies Optimization Barrier to Optimization

First-line Strategy

Second-line Strategy

Acute kidney injury

• Reduce dose or hold RAAS-I/ARNI. Retrial once renal function

• Switch RAAS-I/ARNI to combination of hydralazine/nitrate only after

Hyperkalemia

• Remove potassium supplementation • Reduce or hold doses of RAAS-I/ARNI or MRA. Retrial one at a time • Consider addition of potassium-binders and low potassium diet • Switch RAAS-I/ARNI to combination of hydralazine/nitrate only after multiple failed trials • Add SGLT2i • Retrial with ARNI (instead of ACEi or ARB) • Reduce or remove medications that lower BP and are not guideline • Prioritize β-blocker dosage recommended • Switch carvedilol to metoprolol succinate • Stagger doses of GDMT that lower BP (e.g. morning and evening • Reduce dosage of RAAS-I/ARNI doses) • Switch ARNI to ACEi/ARB and retrial with ARNI in future • Reduce GDMT dose based on symptoms of hypotension, not blood • Reduce SGLT2i dose and retrial at regular dose in future

Symptomatic hypotension

improves • Reduce diuretic dose to the lowest dose required to maintain euvolemia

multiple failed trials

pressure parameters alone

• Reduce diuretic dose to the lowest dose to required maintain euvolemia

Adherence Cost/insurance

• Medication reminders (e.g. pillboxes, smartphone apps, medication • Post-discharge telehealth. logs). Use once daily medications • Refer to HF-specific medication titration clinics • Submit prior authorization requests early in hospitalization • Periodically reassess availability of new/higher cost medications • Assess patient willingness and ability to pay and prescribe more • Perform institution specific cost-effectiveness analysis affordable medications, if necessary

ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; BP = blood pressure; GMDT = guideline-directed medical therapy; HF = heart failure; MRA = mineralocorticoid receptor antagonist; RAAS-I = renin-angiotensin-aldosterone system inhibitor; SBP = systolic blood pressure; SGLT2i = sodium glucose cotransporter-2 inhibitor.

monitoring, sodium restriction or dietary advice, exercise recommendations, medication review, and social and psychological support.”78 Supervised exercise training programs (cardiac rehabilitation) for at least 8 weeks following discharge reduce mortality and rehospitalization.79 Iron deficiency should be treated prior to discharge, with one dose of intravenous iron prior to discharge and additional doses as an outpatient shown to improve symptoms and reduce risk of rehospitalization.43,80 Additionally, laboratory values, particularly renal function markers, potassium, and glucose, should be monitored within 1–2 weeks of discharge to evaluate for adverse reactions to GDMT initiation.5 Brain natriuretic peptide (BNP) or N-terminal pro-hormone BNP (NT-proBNP) levels obtained at 1–2 months after GDMT initiation can be useful predictors of rehospitalization and response to therapy.18,81 An assessment of left ventricular systolic function by echocardiography should be performed ~3 months after optimal GDMT has been reached to assess response to therapy and indication for ICD implantation.43 Further, the coronavirus disease 2019 pandemic has highlighted the opportunities 1. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. https://doi.org/10.1161/ HHF.0b013e318291329a; PMID: 23616602.

2. Urbich M, Globe G, Pantiri K, et al. A systematic review of medical costs associated with heart failure in the USA (2014–2020). Pharmacoeconomics 2020;38:1219–36. https:// doi.org/10.1007/s40273-020-00952-0; PMID: 32812149.

3. Blecker S, Paul M, Taksler G, et al. Heart failure-associated hospitalizations in the United States. J Am Coll Cardiol 2013;61:1259–67. https://doi.org/10.1016/j/jacc.2012.12.038; PMID: 23500328.

4. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251–9. https://doi. org/10.1056/NEJMoa052256; PMID: 16855265.

5. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am

6.

7.

8.

9.

10.

to integrate telehealth to continue the aggressive up-titration of GDMT with the use of specialized nurses and pharmacists.82 A suggested predischarge checklist is presented in Figure 2 and strategies to overcome common clinical barriers are presented in Table 2.

Conclusion

Given the clinical benefits seen within 30 days of initiation of RAAS-I/ARNI, β-blockers, MRA, and SGLT2i, combined initiation of these four foundational therapies is preferable to the outdated paradigm of pursuing maximally tolerated β-blockers and RAAS-I prior to the addition of secondary agents. Additionally, due to the severe lack of optimization of GDMT in the outpatient setting, in-hospital initiation and titration of the four agents should be attempted in all patients admitted for AHF. The ability to closely monitor in the hospital setting allows for more aggressive up-titration and early recognition of adverse effects. Our strategy prioritizes the implementation of all four pillars of GDMT to meet the evolving standard of optimal treatment of HFrEF.

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Electrophysiology

Management of Long QT Syndrome in Women Before, During, and After Pregnancy Caroline Taylor, PA-C,

and Bruce S Stambler, MD

Cardiac Electrophysiology, Piedmont Heart Institute, Atlanta, GA

Abstract

Congenital long QT syndrome (LQTS) is a primary genetic and electrical disorder that increases risk for torsades de pointes, syncope, and sudden death. Post-pubertal women with LQTS require specialized multidisciplinary management before, during, and after pregnancy involving cardiology and obstetrics to reduce risk for cardiac events in themselves and their fetuses and babies. The risk of potentially life-threatening events is lower during pregnancy but increases significantly during the 9-month postpartum period. Treatment of women with LQTS with a preferred β-blocker at optimal doses along with close monitoring are indicated throughout pregnancy and during the high-risk postpartum period.

Keywords

Long QT syndrome, pregnancy, postpartum, torsades de pointes, β-blocker.

Disclosure: The authors have no conflicts of interest to declare.

Received: January 25, 2021 Accepted: March 14, 2021 Citation: US Cardiology Review 2021;15:e08. DOI: https://doi.org/10.15420/usc.2021.02 Correspondence: Bruce S Stambler, 275 Collier Rd NE, STE 500, Atlanta, GA 30309. E: bruce.stambler@piedmont.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Long QT syndrome (LQTS) is a primary genetic and electrical disorder that causes prolongation of ventricular repolarization and increases risk for ventricular arrhythmia-mediated syncope and sudden death.1,2 LQTS is more common in women than men, even after adjustment for the longer normal QT interval in women.3 An increased and unbalanced maternal transmission of deleterious LQTS gene mutations to daughters rather than to sons contributes to the preponderance of females with LQTS.4 Importantly, post-pubertal women with LQTS are at higher risk than men for serious cardiac events, including torsades de pointes (TdP).5,6 LQTS is not uncommon, occurring in about 1 in 2,000 live births.7 Therefore, most adult cardiologists are likely to encounter women in their clinical practice with LQTS contemplating pregnancy or who are pregnant.

However, there are only limited reviews guiding management of the pregnant woman with LQTS. This comprehensive review highlights important information to assist cardiologists in management of these women before, during, and after pregnancy. Substantial improvements in our understanding and knowledge regarding LQTS in areas of genetics, molecular biology and electrophysiology have made LQTS a highly manageable cardiovascular disorder. Pregnant women with LQTS benefit from multidisciplinary care from electrophysiologists, general adult cardiologists, obstetricians, maternal-fetal medicine specialists, fetal cardiologists, anesthesiologists, and genetic counselors.

Long QT Syndrome Diagnosis and Pathophysiology

After exclusion of secondary causes of QT prolongation, such as hypokalemia or drug-induced causes, a diagnosis of congenital LQTS is made on the basis of a prolonged QT interval on 12-lead ECG followed

by commercially available, genetic testing for established LQTS susceptibility genes. The diagnosis of LQTS is sex specific as the QT interval is longer in post-pubertal females than males.2 A prolonged QT (QTc >460 ms for for boys and girls <15 years of age; QTc >470 ms for females and >450 ms for males >15 years of age) along with unexplained syncope is sufficient to diagnose LQTS. Congenital LQTS should also be suspected in a person with a prolonged QT in association with a family history of recurrent syncope, seizures or unexplained cardiac arrest at a young age (<30 years).8 A carrier of an LQTS pathogenic variant who is asymptomatic or lacks QT interval prolongation can also be detected with clinical genetic testing.

Pathogenic variants in up to 17 genes have been associated with LQTS.9 However, the major and most important gene subtypes are LQT1 (KCNQ1 gene), LQT2 (KCNH2 gene), and LQT3 (SCN5A gene) known as LQTS types 1, 2, and 3, respectively. LQT1 results from a loss of function mutation in KCNQ1, the gene encoding the adrenergic-sensitive, slowly activating delayed rectifier potassium channels (IKs). Cardiac events typically occur at elevated hearts rates during emotional or physical stress. Diving and swimming have been identified as potent arrhythmia triggers of lethal events in LQT1. In some cases of LQT1 where the QT is normal at rest, QT prolongation may be provoked with exercise, typically at peak heart rates.

LQT2 arises from a loss of function mutation in KCNH2 (also known as the human ether-a-go-go-related gene – hERG), which encodes for rapidly activating delayed-rectifier potassium channels. The cardiac events in LQT2 are typically triggered by sudden bursts of catecholamines, such as in response to abrupt loud noises such as an alarm clock or the phone or doorbell ringing, or sudden excitement. LQT3 is due to a mutation in sodium channels (SCN5A), which disrupts fast inactivation of cardiac

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Pregnancy in Women with LQTS Table 1: β-blockers Used in Long QT Syndrome, Pregnancy, and While Breastfeeding Drug

Preferred in LQTS

Considered Safe in Pregnancy

Safety in Lactation

Nadolol

Yes (preferred)

Yes (limited data)

Caution (highly excreted in breastmilk)

Propranolol

Yes

Yes

Yes (preferred)

Bisoprolol

Yes

Yes (limited data)

Very limited data for safety

Labetalol

Yes (limited data)

Yes (preferred)

Limited data for safety

Carvedilol

Yes (limited data)

Yes

Unknown – may be safe

Atenolol

No (less effective)

Contraindicated

Caution (highly excreted in breastmilk)

Metoprolol

No (less effective)

Yes (preferred)

Yes (preferred)

sodium channels during early cardiac repolarization. Most adverse cardiac events occur in LQT3 during rest or sleep. Women with LQTS types 1 and 2 are at higher risk of TdP than men with the same mutation, whereas both sexes are equally vulnerable to clinical events with LQTS type 3.5,10

Physiological Changes During Pregnancy

The dramatic physiological changes that occur during pregnancy include increased cardiac output, decreased systemic vascular resistance and enhanced chronotropy and inotropy. The effect of pregnancy on cardiac electrophysiological characteristics is less well understood. It is speculated that myocardial stretch during pregnancy due to volume changes, altered sleep cycles and circulating hormones affect cardiac ion channel function. Sex hormones modulate the clinical course of women with LQTS throughout their lifetime, and pregnancy is an important modulator of outcome in LQTS. Alteration in sex hormone levels during pregnancy and the postpartum period influences cardiac repolarization and the likelihood of clinical events in LQTS. Most studies show that the risk of LQTS-related cardiac events decreases during pregnancy compared with the time period before a woman's first conception, but increases significantly in the 9-month postpartum period, and frequency of events returns to pre-pregnancy levels after this period.11–14 The hyperestrogenic state during pregnancy may provide protection against arrhythmias.14,15 Estrogen has been shown to downregulate expression of cardiac β-1 adrenergic receptors and reduces risk of TdP in LQTS animal models.16,17 The rapid decline in estrogen levels after parturition is needed for lactation. Estrogen withdrawal may increase adrenergic responsiveness and contribute to increased postpartum risk of cardiac events.

Prenatal Recommendations in Long QT Syndrome

Once pregnancy is confirmed in a woman with LQTS, a management plan for pregnancy and the 9-month postpartum period should be made in collaboration with the obstetrician and cardiologist with ongoing review and discussion throughout. Women should be educated and counseled on potential triggers of LQTS cardiac events including avoidance of hypokalemia and QT-prolonging drugs, which can be checked on the Credible Meds website (https://www.crediblemeds.org). Several recommendations regarding the management of pregnant patients with LQTS have been included in other guidelines.18 An ECG should be performed at each visit to evaluate the corrected QT interval. Electrolytes

and vitamin D levels should be monitored as mild hypomagnesemia and vitamin D deficiency are common during pregnancy and could put the mother and fetus at avoidable risk. Encouraging increased potassium and magnesium intake is reasonable. A maternal-fetal medicine specialist with expertise in the prenatal diagnosis and care of fetal LQTS can assist parents during the prenatal period. Likewise, early referral to a pediatric cardiologist familiar with LQTS will help expedite screening of the newborn and preventive therapy in the event that the baby is diagnosed with congenital LQTS.

Management of Women with Long QT Syndrome During Pregnancy

Treatment with a β-blocker is indicated to reduce risk of cardiac events and sudden cardiac death.14,18–20 Guidelines for management of ventricular arrhythmias and prevention of sudden cardiac death strongly recommend that in women with LQTS, a β-blocker should be continued during pregnancy and the postpartum period regardless of symptoms, including while breastfeeding.18 Arrhythmic events during pregnancy are not increased among women receiving β-blocker therapy.11,12,14,19 In contrast, in a case-control study, women with LQT1 who did not receive β-blockers during pregnancy were at increased risk of cardiac arrest or syncope.13 In at least one study, increased risk for cardiac events in the high-risk postpartum period was significantly reduced by β-blockers.14 Not all β-blockers are equally effective in LQTS (Table 1).21 In general, nonselective β-blockers, such as nadolol and propranolol, are preferred over the β1-selective agents, such as metoprolol. Documented evidence, however, is largely lacking comparing specific agents in LQTS during pregnancy and lactation. Most data are primarily limited to isolated small case reports. Nadolol titrated to a recommended dose of 1–1.5 mg/kg/day is prescribed for LQTS by the majority of electrophysiologists as it is the most effective β-blocker for the syndrome, especially in high-risk individuals.22,23 The longer half-life of nadolol compared with other β-blockers also gives it an advantage for LQTS. However, data supporting the use of nadolol in pregnancy are limited. Nadolol is highly excreted in breastmilk and infants exposed to nadolol via breast milk should be monitored for side-effects, such as bradycardia, lethargy, poor feeding or weight gain. Propranolol or bisoprolol appear to have acceptable efficacy and safety profiles in LQTS and during pregnancy and lactation.24,25 Metoprolol is not advised as it is less effective in LQTS than preferred β-blockers.21 Atenolol should be avoided as it is contraindicated in pregnancy (pregnancy risk category D), due to reports of intrauterine growth restriction, and is not effective in LQTS. β-blocker dosage should be individualized based on clinical status, tolerance, side-effects, symptoms, heart rate, blood pressure, and QT interval monitoring. The goal should be to minimize side-effects and maximize medication adherence recognizing that side-effects with higher doses may lead to non-adherence. Side-effects of β-blockers include hypotension, fatigue, and depression. However, symptoms reported during pregnancy may overlap with potential side-effects of β-blockers.

Dialogue between cardiology and obstetrics during prenatal maternal assessments may be warranted to interpret symptoms and adjust medications accordingly. The pharmacokinetics of drugs may change throughout gestation. For example, β-blocker dosage may need to be increased during the later stages of pregnancy due to increasing blood volume and drug excretion. The objective should be to aim for a resting heart rate between 50 and 100 BPM. Exercise testing may be helpful in selected cases to assess the adequacy of the β-blockade with physical activity or catecholamine surges.

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Pregnancy in Women with LQTS There are some safety concerns about the use of β-blockers during pregnancy with respect to the fetus. However, β-blockers are the most widely used cardiovascular medications and there has been a long clinical experience with these medications in pregnancy. In a large retrospective study, there was no significant increase in congenital cardiac abnormalities, after adjusting for maternal factors, among pregnant women exposed to β-blockers.26 Fetuses exposed to β‑blockers may have more bradycardia and hypoglycemia and be at risk for fetal intrauterine growth restriction resulting in newborns being small for their gestational age.19,27–30 If concern for fetal growth is identified at any stage of pregnancy, prompt communication between obstetrics and cardiology is warranted. An increased risk of preterm birth was observed in some studies. Use of β-blockers during labor does not prevent uterine contractions and vaginal delivery. Overall, β-blockers are safe in pregnancy and provide protection from sudden death and syncope in mothers affected by LQTS, especially in high-risk women who have a resting QTc >500 ms, previous cardiac arrest, a high burden of ventricular arrhythmias or an ICD in place.

Antiarrhythmic drugs are generally avoided in pregnancy unless absolutely necessary, as risk to the fetus with many of these drugs remains unknown or has been inadequately studied. β-blockers are less effective in LQT3 than in other LQTS variants and sometimes sodium channel-blockers, such as flecainide or mexiletine, are used in patients with this less common LQTS variant. Flecainide has a long history of safe clinical use in pregnancy for treating maternal or fetal supraventricular tachycardia and limited data similarly suggest that mexiletine is safe in pregnancy.

Management of Long QT Syndrome During Labor and Delivery

Appropriate medical management during labor and delivery for women with LQTS includes continuous telemetry ECG monitoring for ventricular arrhythmias. Electrolyte imbalance (hypokalemia and/or hypomagnesemia) should be corrected. A 12-lead ECG should be obtained as soon as possible in women with LQTS who are in labor. A QTc >500 ms should be discussed with cardiology or cardiac electrophysiology. β-blockers should be continued on admission as they reduce the risk of serious arrhythmias.

Most deliveries occur without serious arrhythmic events. However, resuscitation equipment including an external defibrillator should be easy to access during labor. Inactivating ICD therapy is not recommended in women with an ICD in place. A donut magnet should be placed over the ICD during cesarean section to avoid inappropriate shocks during electrocautery and external defibrillator pads should be placed on the thorax before preparing the patient for surgery.

QT-prolonging drugs, such as ondansetron, and certain anesthetics, such as sevoflurane, should be avoided.31–33 Oxytocin, used to induce labor and reduce bleeding, is on the list of drugs to avoid in LQTS.31 Safe vaginal delivery with use of oxytocin for the induction of labor has been reported in patients with LQTS, however cases of ventricular tachycardia developing immediately after administration of oxytocin have also been reported.34,35 In experimental models of LQT2, oxytocin and prolactin prolong QT by reducing IKs.36 Therefore, these drugs should be avoided wherever possible in high-risk LQTS women or used with due caution in the presence of telemetry ECG monitoring. If induction is performed, IV magnesium 2-4 g should be given prophylactically to reduce the risk of TdP even though magnesium can slow down labor.

Postpartum Management of Long QT Syndrome

Women with LQTS have an increased risk for cardiac events, including sudden cardiac death, in the first 9 months following delivery.11–14 In one

retrospective analysis of 111 probands with LQTS, 10% experienced their first cardiac event in the postpartum period and were more likely to have multiple events.11 Probands had a 40-fold increased risk of a serious cardiac event during the postpartum period, but treatment with βblockers was independently associated with a decrease in the risk for cardiac events. In another study, women treated with β-blockers experienced cardiac events at a rate of 0.8%, while women who were not treated with β-blockers experienced cardiac events at a rate of 3.7%.14 Therefore, it is essential for high-risk women with LQTS to continue taking β‑blockers throughout the postpartum period as first-line, protective therapy for which the benefits outweigh risks of treatment.

Mothers with LQTS should be seen by a cardiologist within the first few weeks postpartum and every month for the first 9 months to ensure adherence to β-blocker therapy and to review heart rates, QTc, and symptoms. Some women who required an increase in β-blocker dose during pregnancy may need a decrease in dose later (after 6–9 months postpartum). Adequacy of β-blockade can be assessed with exercise testing or event monitoring aiming to reduce peak exercise heart rates. β‑blockers are excreted in breast milk and there is potential for β‑blockade in nursing infants. Domperidone, used to stimulate lactation, is a QT‑prolonging drug and is contraindicated in LQTS patients.

Case Report One

A 28-year-old woman with genotyped LQT1 presented for routine cardiac evaluation. She was asymptomatic and was taking β-blocker therapy (nadolol 60 mg daily). She had a family history of LQTS and premature sudden death. Her QTC was 450 ms and in the past her QTc prolonged to more than 550 ms during stress testing at peak exercise. She was contemplating pregnancy, but in light of her cardiac history, she had concerns about the risks. She wanted to know if any precautions needed be taken to reduce the risk of adverse events and how likely it would be that her child would inherit LQTS and be at risk of cardiac events.

Preconception Counseling

Pregnancy is a major concern for women with LQTS. When a woman with LQTS is contemplating pregnancy, she and her family should be counseled and encouraged that it is likely that she will have an uneventful pregnancy and successful labor and delivery. Pregnancy will often provoke anxiety in women with LQTS and they will need support before, during and after pregnancy. Women should be reassured that LQTS is not a contraindication to pregnancy and the overwhelming majority of women with LQTS do not experience cardiac events while pregnant.

A woman with LQTS should be under the management of a cardiac electrophysiologist or cardiologist experienced in LQTS management.

The importance of continuing β-blocker therapy throughout pregnancy and the postpartum period should be stressed. Assessment should be made of the risk status and effectiveness of current management. Patients with LQT1 generally have a low risk for cardiac events throughout their lifetime including during and after pregnancy and in most cases will not require an ICD for primary prevention if appropriately managed with β-blockers. If an ICD is indicated in LQTS due to high-risk status, implantation should be performed prior to pregnancy or preferably after the first trimester.18 An ICD is not a contraindication to pregnancy and there are reports of women receiving ICD shocks during pregnancy without adverse fetal outcomes.37 Prenatal genetic counseling also may be considered to discuss and explain the risk of inheritance of a pathogenic gene variant. LQTS is

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Pregnancy in Women with LQTS Figure 1: Prolonged QTc Intervals in a Patient with LQT1 During Pregnancy and Postpartum

A: 508 ms (HR 60 BPM) at 21 weeks pregnancy prior to treatment with nadolol; B: 499 ms (HR 76 BPM) at 34 weeks pregnancy during treatment with nadolol 20 mg daily; C: 511 ms (HR 63 BPM) several hours after delivery; D: 499 ms (HR 66 BPM) on day one prior to hospital discharge on nadolol 20 mg daily; E: 507 ms (HR 55 BPM) at 2 weeks postpartum on nadolol 30 mg daily; F: 507 ms (HR 66 BPM) 1-year postpartum on nadolol 30 mg daily. HR = heart rate.

inherited in an autosomal dominant manner so there is a 50% chance that each child inherits the genetic variation. In rare situations where both parents have LQTS, the risk to each child is 75%. The genetic mutation does not skip generations. Families with LQTS variants should be referred to a maternal fetal specialist or pediatric cardiologist familiar with LQTS for further discussions regarding fetal LQTS diagnosis and management of LQTS in children.

Case Report Two

A 39-year-old woman with genotyped LQT1 was referred by her obstetrician at 21 weeks of pregnancy for cardiology evaluation. She was not taking any medications other than multivitamins and had never been prescribed β-blocker therapy. She was asymptomatic but had a family history of LQTS and sudden death in an uncle at age 40 and a sister with LQTS with an ICD implanted for aborted cardiac arrest. Her ECG showed a QT >500 ms (Figure 1). She was prescribed a β-blocker (nadolol at progressively increasing doses) with careful QT monitoring on repeated ECGs. Early referral was made to a pediatric electrophysiologist and genetic counselor to assist with screening the newborn for LQTS. She delivered a preterm baby boy with a normal birthweight just before 37 weeks. The newborn’s ECG showed a prolonged QT, which was confirmed by pediatric electrophysiology. Genetic testing identified a LQT1 mutation with the same pathogenic variant as the mother. The baby was started on oral propranolol and was later switched to nadolol. The mother had regular postpartum follow-up without any cardiac events. However, she returned after having a first trimester miscarriage the following year and also reported having had a miscarriage 10 years earlier.

Management of the Neonate in a Family with a History of Long QT Syndrome

Screening of the neonate is essential when a parent has LQTS. In an affected newborn, the risk of events including sudden infant death may

be as high as 4% during the first year of life.38 Preparations should be made for potential fetal distress or arrhythmias in labor and delivery. Fetal bradycardia may be the first indication and an important predictor of LQTS.39–42 LQTS can be diagnosed in the fetus with percutaneous umbilical blood sampling or non-invasively with fetal magnetocardiography.43 Ventricular tachycardia, TdP, bradycardia, and/or intermittent or sustained second degree atrioventricular block are hallmark arrhythmias in babies with LQTS, and 10% of cases of sudden infant death syndrome as well as childhood deaths may be attributed to LQTS, which highlights the need for comprehensive screening.44–46 Neonatal genetic screening can be performed on the infant’s blood sample or on cord blood obtained at birth for the specific parental pathogenic mutation. For all newborns with a parent with LQTS, a 12-lead ECG should be obtained on day one or before hospital discharge and evaluated by a pediatric cardiologist or electrophysiologist.47 Given the known variability of QT interval during the first week of life, screening ECGs should be repeated after 3 or 4 weeks.

Genetic testing evaluating for the known pathogenic variant in a family with LQTS should be performed on the baby regardless of ECG findings.

Miscarriage Risk in Women with Long QT Syndrome

Pregnant women with LQTS are at a higher risk of fetal death than the general population.48 A recent international study reported that when one parent had LQTS, miscarriages (fetal death at ≤20 weeks gestation) were twice as common (16% versus 8%) and stillbirths (fetal death at >20 weeks gestation) were 8 times more common (4.0% versus 0.5%) than the general population. Fetal death was significantly more frequent when the mother rather than the father had LQTS (24.4% versus 3.4%). In addition, mothers with LQTS delivered earlier and infants weighed less than infants of fathers with LQTS. Stillbirths were documented in fetuses without an LQTS mutation, which raises the possibility that an LQTS genetic mutation

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Pregnancy in Women with LQTS and ion channel variations in mothers may affect uterine or placental structures resulting in fetal death or growth restriction.

Case Report Three

A 37-year-old woman with a family history of LQTS was referred by obstetrics for cardiology evaluation at 32 weeks of pregnancy. Her mother and two sisters had genotype-positive LQT2. There was a family history of aborted cardiac arrest in a cousin. The woman had a previous miscarriage at 8 weeks gestation. She was asymptomatic without recent syncope. QTc at the initial visit was 486 ms and subsequent genetic testing confirmed the diagnosis of LQT2 (KCNH2 mutation). She was started on β-blocker therapy (nadolol). She presented at 40 weeks and 4 days for induction of labor and was started on oxytocin. Cardiac electrophysiology consultation was obtained and recommendations were to initiate telemetry monitoring, discontinue oxytocin, avoid ondansetron as an anti-emetic and prophylactically treat with IV magnesium. She had a successful vaginal delivery of a healthy baby girl.

The mother's QTc was 487 ms on postpartum ECG at hospital discharge, while continuing to receive nadolol.

Management of High-risk Long QT Syndrome Patients

The increased risk of cardiac events in LQTS in the 9-month postpartum period is highest in subjects with LQTS with a type 2 mutation.11,14 In one study, postpartum cardiac events, including life-threatening episodes, occurred in 16% of patients with LQT2 compared with <1% with LQT1. The early postpartum period is associated with changes in hormonal balance, 1. Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome: prospective longitudinal study of 328 families.

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4. Imboden M, Swan S, Denjoy I, et al. Female predominance and transmission distortion in the long-QT syndrome. N Engl J Med 2006;355:2744–51. https://doi.org/10.1056/ NEJMoa042786; PMID: 17192539.

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10. Zareba W, Moss AJ, Locati EH, et al. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J Am Coll Cardiol 2003;42:103–9. https://doi. org/10.1016/s0735-1097(03)00554-0; PMID: 12849668.

11. Rashba EJ, Zareba W, Moss AJ, et al. Influence of pregnancy on the risk for cardiac events in patients with hereditary

sleep deprivation, fatigue, stress, sudden auditory stimuli, such as a crying baby, that may be responsible for triggering and clustering of these events postpartum in LQT2. Close cardiac follow-up of women with LQT2 mutation during the postpartum period is recommended with serial ECGs every few weeks after delivery in consultation with a cardiologist experienced in LQTS management. Treatment with β-blockers at adequate doses is of paramount importance in LQT2 patients postpartum. An ICD should be considered in high-risk LQTS women who have had aborted cardiac arrest, syncope on β-blocker therapy or have a markedly prolonged QTc >500 ms with LQT2 or LQT3.18 In one study, two women with LQT2 required an ICD 4–8 weeks after delivery due to episodes of polymorphic ventricular tachycardia despite treatment with a β-blocker (metoprolol).49 Since the high-risk period might last only nine months in these patients with LQT2, another option to consider is a wearable defibrillator, but there is very limited experience with this approach during pregnancy and postpartum.

Conclusion

Women with congenital LQTS require a team approach involving cardiology and obstetrics before, during and after pregnancy to optimize care and reduce the risk of potentially life-threatening events in the mother, fetus, and baby. Cardiologists caring for women with LQTS need to be aware that the risk of cardiac events increases during the 9-month postpartum period. Treatment with a β-blocker, at an optimal dose, which is preferred in LQTS and considered safe in pregnancy along with close monitoring, is recommended during pregnancy and the high-risk postpartum period.

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13. Heradien MJ, Goosen A, Crotti L, et al. Does pregnancy increase cardiac risk for LQT1 patients with the KCNQ1A341V mutation? J Am Coll Cardiol 2006;48:1410–5. https:// doi.org/10.1016/j.jacc.2006.05.060; PMID: 17010804.

14. Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol 2007;49:1092–8. https://doi. org/10.1016/j.jacc.2006.09.054; PMID: 17349890.

15. Drici MD, Burklow TR, Haridasse V, et al. Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. Circulation 1996;94:1471–4. https://doi.org/10.1161/01.cir.94.6.1471; PMID: 8823008.

16. Kam KW, Qi JS, Chen M, et al. Estrogen reduces cardiac injury and expression of beta1-adrenoceptor upon ischemic insult in the rat heart. J Pharmacol Exp Ther 2004;309:8–15. https://doi.org/10.1124/jpet.103.058339; PMID: 14718598.

17. Nakajima T, Iwasawa K, Oonuma H, et al. Antiarrhythmic effect and its underlying ionic mechanism of 17β-estradiol in cardiac myocytes. Br J Pharmacol 1999;127:429–40. https:// doi.org/10.1038/sj.bjp.0702576; PMID: 10385243.

18. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2018;138:e272–391. https://doi. org/10.1016/j.jacc.2017.10.054; PMID: 29097296.

19. Ihibashi K , Aiba T, Kamiya C, et al. Arrhythmia risk and β-blocker therapy in pregnant women with long QT syndrome. Heart 2017;103:1374–9. https://doi.org/10.1136/ heartjnl-2016-310617; PMID: 28292826.

20. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013;34:3109-16. https://doi.org/10.1093/eurheartj/ eht089; PMID: 23509228.

21. Chockalingam P, Crotti L, Girardengo G, et al. Not all betablockers are equal in the management of long QT syndrome

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types 1 and 2: higher recurrence of events under metoprolol. J Am Coll Cardiol 2012;60:2092–9. https://doi. org/10.1016/j.jacc.2012.07.046; PMID: 23083782.

22. Abu-Zeitone A, Peterson DR, Polonsky B, et al. Efficacy of different beta-blockers in the treatment of long QT syndrome. J Am Coll Cardiol 2014;64:1352–8. https://doi. org/10.1016/j.jacc.2014.05.068; PMID: 25257637.

23. Ackerman MJ, Priori SG, Dubin AM, et al. Beta-blocker therapy for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia: are all beta-blockers equivalent? Heart Rhythm 2017;14:e41–4. https://doi. org/10.1016/j.hrthm.2016.09.012; PMID: 27659101.

24. Steinberg C, Padfield GJ, Al-Sabeq B, et al. Experience with bisoprolol in long-QT1 and long-QT2 syndrome. J Interv Card Electrophysiol 2016;47:163–70. https://doi.org/10.1007/s10840016-0161-2; PMID: 27394160.

25. Fazio G, Vernuccio F, Lo Re G, et al. Role of bisoprolol in patients with long QT syndrome. Ann Noninvasive Electrocardiol 2013;18:467–70. https://doi.org/10.1111/ anec.12047; PMID: 24047491.

26. Duan L, Ng A, Chen W, et al. Beta-blocker exposure in pregnancy and risk of fetal cardiac anomalies. JAMA Intern Med 2017;177:885–7. https://doi.org/10.1001/ jamainternmed.2017.0608; PMID: 28418448.

27. Bateman BT, Patorno E, Desai RJ, et al. Late pregnancy beta blocker exposure and risks of neonatal hypoglycemia and bradycardia. Pediatrics 2016;138:e20160731. https://doi. org/10.1542/peds.2016-0731; PMID: 27577580.

28. Tanaka K, Tanaka H, Kamiya C, et al. Beta-blockers and fetal growth restriction in pregnant women with cardiovascular disease. Circ J 2016;80:2221–6. https://doi.org/10.1253/circj.

CJ-15-0617; PMID: 27593227.

29. Lip GY, Beevers M, Churchill D, et al. Effect of atenolol on birth weight. Am J Cardiol 1997;79:1436–8. https://doi. org/10.1016/s0002-9149(97)00163-x; PMID: 9165181.

30. Ersbøll AS, Johansen M. Treatment with oral beta-blockers during pregnancy complicated by maternal heart disease increases the risk of fetal growth restriction. BJOG 2014;121:618–26. https://doi.org/10.1111/1471-0528.12522; PMID: 24400736.

31. CredibleMeds. https://www.crediblemeds.org (accessed March 9, 2021).

32. Drake E, Preston R, Douglas J. Brief review: anesthetic implications of long QT syndrome in pregnancy. Can J Anesthesia 2007;54:561–72. https://doi.org/10.1007/ BF03022321; PMID: 17602043.

33. Fazio G, Vernuccio F, Grutta G, et al. Drugs to be

Pregnancy in Women with LQTS avoided in patients with long QT syndrome: focus on the anaesthesiological management. World J Cardiol 2013;5:87–93. https://doi.org/10.4330/wjc.v5.i4.87; PMID: 23675554.

34. Martillotti G, Talajic M, Rey E, et al. Long QT syndrome in pregnancy: are vaginal delivery and use of oxytocin permitted? A case report. J Obstet Gynaecol Can 2012;34:1073–6. https://doi.org/10.1016/S17012163(16)35437-8; PMID: 23231845.

35. Liou SC, Chen C, Wong SY, et al. Ventricular tachycardia after oxytocin injection in patients with prolonged Q-T interval syndrome – report of two cases. Acta Anaesthesiol Sin 1998;36:49–52; PMID: 9807850.

36. Bodi I, Sorge J, Castiglione A, et al. Postpartum hormones oxytocin and prolactin cause pro-arrhythmic prolongation of cardiac repolarization in long QT syndrome type 2. Europace 2019;21:1126–38. https://doi.org/10.1093/europace/euz037; PMID: 30938413.

37. Boule, Ovart L, Marquié C, et al. Pregnancy in women with an implantable cardioverter-defibrillator: is it safe? Europace 2014;16:1587–94. https://doi.org/10.1093/europace/euu036; PMID: 24596396.

38. Schulze-Bahr E, Fenge H, Etzrodt D, et al. Long QT syndrome and life-threatening arrhythmia in a newborn: molecular diagnosis and treatment response. Heart 2004;90:13–6. https://doi.org/10.1136/heart.90.1.13;

PMID: 14676229.

39. Lupoglazoff JM, Denjoy I, Villain E, et al. Long QT syndrome in neonates: conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations. J Am Coll Cardiol 2004;43:826–30. https://doi.org/10.1016/j. jacc.2003.09.049; PMID: 14998624.

40. Horigome H, Nagashima M, Sumitomo N, et al.

Clinical characteristics and genetic background of congenital long-QT syndrome diagnosed in fetal, neonatal, and infantile life: a nationwide questionnaire survey in Japan. Circ Arrhythm Electrophysiol 2010;3:10–7. https://doi.org/10.1161/CIRCEP.109.882159; PMID: 19996378.

41. Beinder E, Grancay T, Menéndez T, et al. Fetal sinus bradycardia and the long QT syndrome. Am J Obstet Gynecol 2001;185:743–7. https://doi.org/10.1067/mob.2001.117973; PMID: 11568808.

42. Mitchell JL, Cuneo BF, Etheridge SP, et al. Fetal heart rate predictors of long QT syndrome. Circulation 2012;126:2688– 95. https://doi.org/10.1161/CIRCULATIONAHA.112.114132; PMID: 23124029.

43. Cuneo BF, Etheridge SP, Horigome H, et al. Arrhythmia phenotype during fetal life suggests long-QT syndrome genotype: risk stratification of perinatal long-QT syndrome.

Circ Arrhythm Electrophysiol 2013;6:946–51. https://doi. org/10.1161/CIRCEP.113.000618; PMID: 23995044.

US CARDIOLOGY REVIEW Access at: www.USCjournal.com

44. Schwartz PJ. Stillbirths, sudden infant deaths and long-QT syndrome: puzzle or mosaic, the pieces of the jigsaw are being fitted together. Circulation 2004;109:2930–2. https://doi.org/10.1161/01.CIR.0000133180.77213.43; PMID: 15210606.

45. Arnestad M, Crotti L, Rognum TO, et al. Prevalence of long QT syndrome gene variants in sudden infant death syndrome. Circulation 2007;115:361–7. https://doi.org/10.1161/ CIRCULATIONAHA.106.658021; PMID: 17210839.

46. Ackerman MJ, Siu BL, Sturner WQ, et al. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 2001;286:2264–9. https://doi.org/10.1001/ jama.286.18.2264; PMID: 11710892.

47. Saul JP, Schwartz PJ, Ackerman MJ, et al. Rationale and objectives for ECG screening in infancy. Heart Rhythm 2014;11:2316–21. https://doi.org/10.1016/j.hrthm.2014.09.047; PMID: 25239430.

48. Cuneo BF, Kaizer AM, Clur SA, et al. Mothers with long QT syndrome are at increased risk for fetal death: findings from a multicenter international study. Am J Obstet Gynecol 2020;222:263.e1–11. https://doi.org/10.1016/j. ajog.2019.09.004; PMID: 31520628.

49. Meregalli PG, Westendorp ICD, Tan HL, et al. Pregnancy and the risk of torsades de pointes in congenital long-QT syndrome. Neth Heart J 2008;16:422–5. https://doi.org/ 10.1007/BF03086191; PMID: 19127321.

Antithrombotics in High-risk PCI

Antithrombotic Therapy in Complex Percutaneous Coronary Intervention Patients Requiring Chronic Anticoagulation Despoina-Rafailia Benetou, MD, ,1 Panayotis K Vlachakis, MD, ,2 Charalampos Varlamos, MD, ,1 and Dimitrios Alexopoulos, MD, 1 1. Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece; 2. Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital, Athens, Greece

Abstract

The optimal antithrombotic treatment in patients receiving oral anticoagulation undergoing percutaneous coronary intervention (PCI) has been a field of intensive research. Although triple antithrombotic therapy had been, until lately, the strategy of choice, recent evidence points to the superiority of dual antithrombotic therapy regarding bleeding prevention, without significantly compromising efficacy. In the further challenging scenario of complex PCI, associated with a higher ischemic risk, the efficacy of an aspirin-free strategy, adopted shortly after the index event is under question, rendering decision-making a fairly difficult scenario for clinicians. Since patients with an indication for oral anticoagulation undergoing complex PCI are underrepresented in randomized trials, there are scarce data regarding the optimal treatment strategy in such patients. This review aims to analyze and compare different approaches regarding the type and duration of antithrombotic regimens, focusing on both safety and efficacy outcomes, as well as to discuss recent guidelines’ suggestions regarding the therapeutic approach in patients receiving oral anticoagulation undergoing PCI procedures of increased complexity.

Keywords

Percutaneous coronary intervention, complex percutaneous coronary intervention, antithrombotic therapy, anticoagulation, oral anticoagulation, dual antithrombotic therapy, triple antithrombotic therapy Disclosure: DA has received lecturing honoraria/advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Medtronic, Biotronik, and Chiesi Hellas. All other authors have no conflicts of interest to declare.

Received: November 24, 2020 Accepted: March 14, 2021 Citation: US Cardiology Review 2021;15:e09. DOI: https://doi.org/10.15420/usc.2020.31 Correspondence: Despoina-Rafailia Benetou, Second Department of Cardiology, Attikon University Hospital, Rimini 1, Chaidari 12462, Athens, Greece. E: benetoud@yahoo.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

During past decades, the percentage of patients with multiple comorbidities, as well as complex coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), has increased.1 With prevalence rates of AF reaching 1–3% of the general population, it comes as no surprise that up to 7.1% of patients undergoing PCI have AF.2–4 Thus, the probability of a patient undergoing complex PCI while requiring oral anticoagulation (OAC) is not negligible. Although there is not a universally adopted definition, complex PCI usually refers to procedures with implantation of three or more stents, treatment of three or more lesions, bifurcation with two stents implanted, total stent length >60 mm, or treatment of a chronic total occlusion.5 Complex PCI patients are at an increased risk for major adverse cardiovascular events, MI, stent thrombosis (ST), and ischemia-driven revascularization, while they also have a greater risk for major bleeding complications compared with noncomplex PCI patients.6

ischemic and thromboembolic events associated with stent implantation and AF, comes at the cost of an increased risk for major bleeding.

In contrast, patients with AF are at an increased risk for thromboembolic and bleeding events due to the prothrombotic milieu of AF, as well as concurrent anticoagulation therapy.7 Therapeutic management of such patients in everyday clinical practice represents a challenge for clinicians, as the combination of antiplatelet and anticoagulant therapy, to mitigate

Data regarding the optimal antithrombotic strategy in complex PCI patients with an indication for OAC are scarce. Although early hypothesisgenerating data regarding the optimal post-PCI treatment scheme in patients receiving OAC were presented in the WOEST study, most evidence dedicated to AF patients undergoing complex PCI procedures

Triple antithrombotic therapy (TAT), consisting of dual antiplatelet therapy (DAPT) plus an OAC agent, was until recently the treatment strategy of choice for AF patients undergoing PCI with stent implantation.8 However, emerging evidence points to the superiority of dual antithrombotic therapy (DAT), consisting of a single antiplatelet agent and OAC, regarding safety outcomes, without significantly compromising efficacy, although there is some concern regarding the risk of ST.9–11 Taking into account that such a risk is even higher in patients undergoing complex PCI compared with those undergoing non-complex PCI, the efficacy of DAT may be a more complex issue.

Triple Antithrombotic Therapy or Dual Antithrombotic Therapy?

© RADCLIFFE CARDIOLOGY 2021 Access at: www.USCjournal.com

Antithrombotic Therapy in Complex PCI Patients Under OAC Table 1: Major Randomized Controlled Trial Subgroup Analyses in Patients with AF Undergoing Complex Percutaneous Coronary Intervention Study

Size (n) Comparison

Endpoints

Results

PIONEER AF-PCI trial subgroup analysis by Kerneis et al. 201815

2,099

During a 12-month follow-up: • Clinically significant bleeding • Major adverse cardiovascular event

Group 1 versus 3: Safety outcome: DAT with rivaroxaban was associated with fewer bleeding events compared with TAT with VKA • 70% stenosis or thrombus: HR 0.57; 95% CI [0.44–0.75]; p<0.001, bifurcation lesions: HR 0.27; 95% CI [0.11–0.66]; p=0.002 • Stent length >40 mm: HR 0.57; 95% CI [0.33–0.98]; p=0.04, ≥2 stents implanted: HR 0.59; 95% CI [0.39–0.89]; p=0.01 Efficacy outcome: DAT with rivaroxaban had a similar rate of ischemic events compared with VKA • 70% stenosis or thrombus: HR 1.01; 95% CI [0.61–1.66]; p=0.97; bifurcation lesions: HR 3.05; 95% CI [0.81–11.48]; p=0.08 • Stent length >40 mm: HR 1.81; 95% CI [0.51–6.41]; p=0.35; ≥2 stents implanted: HR = 1.13; 95% CI [0.51–2.49]; p=0.76

During a mean follow-up of 14 months: • Time to first major bleeding or clinically relevant non-major bleeding event • Composite of death or thromboembolic event or unplanned revascularization

Safety outcome: DAT with dabigatran was associated with lower bleeding rates compared with TAT with warfarin in all categories of clinical or procedural complexity • Dabigatran 110 mg group: HR 0.56; 95% CI [0.40–0.78] for no complexity factor, HR 0.58; 95% CI [0.30–1.10] for procedural complexity alone, HR 0.48; 95% CI [0.35–0.65] for clinical complexity alone, HR 0.47; 95% CI [0.25–0.88] for both procedural and clinical complexity factors (p for interaction=0.90) • Dabigatran 150 mg: HR 0.85; 95% CI [0.60–1.20], HR 0.48; 95% CI [0.22–1.02], HR 0.63; 95% CI [0.46–0.86] and HR 0.92; 95% CI [0.48–1.77], respectively (p for interaction=0.37) Efficacy outcome: Efficacy seemed similar in both dabigatran DAT groups compared with warfarin TAT groups, irrespective of procedural and/or clinical complexity factors. (p for interaction=0.67 for dabigatran 110 mg and 0.54 for dabigatran 150 mg)

Group 1: DAT with rivaroxaban 15 mg once daily plus P2Y12 inhibitor Group 2: DAT with rivaroxaban 2.5 mg twice daily plus DAPT Group 3: triple therapy with VKA plus DAPT

REDUAL PCI trial subgroup analysis by Berry et al. 202016

2,725

DAT with dabigatran (110 mg or 150 mg twice daily) TAT with warfarin

DAPT = dual antiplatelet therapy; DAT = dual antithrombotic therapy; TAT = triple antithrombotic therapy; VKA = vitamin K antagonist.

comes from subgroup analyses of subsequent randomized trials, such as PIONEER AF-PCI and RE-DUAL PCI (Table 1).12–14 The PIONEER AF-PCI trial evaluated the use of rivaroxaban as part of DAT in 2,124 patients with AF undergoing PCI with stent implantation. Patients were randomized to receive rivaroxaban (15mg once daily) plus a P2Y12 receptor inhibitor (group 1), rivaroxaban (2.5mg twice daily) plus DAPT (group 2), or TAT with a vitamin K antagonist (VKA) plus DAPT (group 3).

Patients receiving DAT with rivaroxaban had lower rates of clinically significant bleeding compared with patients receiving TAT with VKA (HR 0.59; 95% CI [0.47–0.76]; p<0.001), while presenting a similar rate of ischemic events (HR 1.08; 95% CI [0.69–1.68]; p=0.75).13 Subgroup analysis showed that the treatment effect of rivaroxaban on major adverse cardiovascular events did not vary when stratified by the location of the culprit artery, presence of a bifurcation lesion, presence of thrombus, type and length of stent, or number of stents (p for interaction>0.05 for all subgroups), reaching the conclusion that there was not an interaction between the complexity of coronary lesions and the effect of rivaroxaban on efficacy outcomes (Figure 1).15 Additionally, regarding safety outcomes, in patients with 70% stenosis or thrombus, bifurcation lesions, stent length >40 mm, or two or more stents implanted,

DAT with rivaroxaban was associated with fewer bleeding events compared with TAT with VKA (HR 0.57; 95% CI [0.44–0.75]; p<0.001; HR 0.27; 95% CI [0.11–0.66], p=0.002; HR 0.57; 95% CI [0.33–0.98]; p=0.04; and HR 0.59; 95% CI [0.39 –0.89]; p=0.01, respectively; Figure 2). In brief, there was no effect modification by the presence of complex coronary lesions on the results of either bleeding or efficacy endpoints evaluated in the PIONEER AF-PCI trial.

The RE-DUAL PCI trial recruited 2,725 patients with AF who had undergone PCI, and randomized them to receive either TAT with warfarin plus DAPT or DAT with dabigatran (110 mg or 150 mg twice daily) plus a P2Y12 receptor inhibitor. Dual therapy with dabigatran was found to be superior to triple therapy regarding bleeding events, and non-inferior regarding thromboembolic events prevention in patients with AF undergoing PCI.14 A subgroup analysis of RE-DUAL PCI trial categorized patients according to the absence or presence of clinical and/or procedural complexity factors with the view to evaluate their effect on treatment outcomes.16 In detail, procedural complexity factors included more than two vessels treated, in-stent restenosis of a drug-eluting stent, prior brachytherapy, unprotected left main, more than two lesions per vessel, lesion length ≥30 mm, bifurcation lesion with a side branch ≥2.5 mm, vein bypass graft

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Antithrombotic Therapy in Complex PCI Patients Under OAC Figure 1: Comparison of Efficacy Outcomes Between Dual Antithrombotic Therapy with Rivaroxaban and Triple Antithrombotic Therapy with Vitamin K Antagonist Stratified by Procedure and Lesion Characteristics in the PIONEER AF-PCI Trial Population Group 1

Characteristics

Group 3

HR [95% CI]

15 mg rivaroxaban once daily Vitamin K antagonist

Overall

p-value Interaction p-value

41/696 (6.5)

36/697 (6.0)

1.08 [0.69–1.69]

0.74

Ischemia revascularization

Yes

23/376 (6.6)

24/379 (7.1)

0.94 [0.53–1.66]

0.82

No

18/320 (6.3)

12/318 (4.6)

1.35 [0.65–2.80]

0.42

Urgent revascularization

Yes No

19/279 (7.4)

21/253 (9.4)

0.77 [0.41–1.43]

15/444 (4.0)

1.47 [0.76–2.84]

0.40

22/417 (5.8)

Radial Femoral

24/430 (6.1)

25/453 (6.3)

0.96 [0.55–1.67]

17/163 (7.1)

11/241 (5.5)

LAD Cx

10/235 (4.7)

11/246 (4.9)

8/128 (7.0)

6/102 (7.2)

RCA MVD

6/172 (3.7) 13/130 (11.1)

12/185 (7.6) 6/131 (5.2) 30/560 (6.1)

Approach

Culprit lesion

1.33 [0.62–2.84]

0.24 0.87 0.46

0.91 [0.39–2.15]

0.84

1.00 [0.35–2.88]

0.99

0.49 [0.18–1.30]

0.14

2.16 [0.82–5.69]

0.97

70% stenosis or thrombus

Yes No

7/115 (7.0)

5/101 (6.2)

1.18 [0.37–3.71]

0.78

Bifurcation

Yes No

8/62 (14.1)

3/76 (4.7)

3.05 [0.81–11.48]

0.08

33/633 (5.7)

33/621 (6.1)

0.93 [0.57–1.50]

0.76

Thrombus

Yes No

3/44 (7.2)

5/43 (12.8)

0.54 [0.13–2.27]

0.40

37/651 (6.3)

31/653 (5.5)

1.13 [0.70–1.82]

0.61

15/230 (7.0)

13/221 (6.9)

1.03 [0.49–2.17]

0.93

23/452 (5.7)

23/463 (5.7)

0.97 [0.55–1.73]

0.92

6/112 (6.2)

4/135 (3.0)

1.81 [0.51–6.41]

0.35

7/95 (7.8)

4/81 (5.5)

1.45 [0.42–4.95]

0.55

10/201 (5.5)

11/179 (7.3)

0.74 [0.31–1.75]

0.49

1.03 [0.53–1.99]

0.94

DES BES

Stent length

>40 mm 31–40 mm 21–30 mm <20 mm

Number of stents Closure device

18/287 (6.8)

17/300 (6.8)

1 ≥2

27/454 (6.5)

25/475 (6.2)

1.05 [0.61–1.81]

14/242 (6.3)

11/221 (5.5)

1.13 [0.51–2.49]

0.86 0.76

Yes No

14/187 (8.3)

7/182 (4.6)

1.86 [0.75–4.60]

0.17

27/509 (5.8)

29/515 (6.5)

0.89 [0.52–1.50]

0.65

15 mg rivaroxaban once daily better 0.5

0.15 0.78

0.44

0.11

1.01 [0.61–1.66]

32/560 (6.2)

Type of stent

0.40

0.69

0.09

0.33

0.99

0.81

0.89

0.16

Vitamin K antagonist better 1

2

5

BES = biolimus-eluting stent; Cx = left circumflex coronary artery; DES = drug-eluting stent; LAD = left anterior descending coronary artery; MVD = multivessel disease; RCA = right coronary artery. Source: Kerneis et al. 2018.15 Reproduced with permission from Elsevier.

PCI, or a thrombus-containing lesion. Clinical complexity factors included acute coronary syndrome (ACS) presentation, acute ST-elevation MI, renal insufficiency/failure, and left ventricular ejection fraction <30%. In a total of 2,725 patients, 1,008 (37.0%) had no complexity factors, 1,174 (43.1%) had clinical complexity factors, 270 (10.0%) had procedural complexity factors, and 273 (9.9%) had both clinical and procedural factors. DAT with dabigatran was associated with lower rates of the primary bleeding endpoint compared with TAT with warfarin in all categories of clinical or procedural complexity. HRs for the dabigatran 110 mg group were 0.56 (95% CI [0.40–0.78]) for no complexity factors, 0.58 (95% CI [0.30–1.10]) for procedural complexity alone, 0.48 (95% CI [0.35–0.65]) for clinical complexity alone, and 0.47 (95% CI [0.25–0.88]) for both procedural and clinical complexity factors (p for interaction=0.90). In the 150 mg group, the respective HRs were 0.85 (95% CI [0.60– 1.20]) for no complexity factors, 0.48 (95% CI [0.22–1.02]) for procedural complexity alone, 0.63 (95% CI [0.46–0.86]) for clinical complexity alone, and 0.92 (95% CI [0.48– 1.77]) for both procedural and clinical complexity factors (p for interaction=0.37; Figure 3).

As far as efficacy outcomes are concerned, the risk of thromboembolic events seemed similar in both the dabigatran DAT groups compared with the TAT with warfarin groups, irrespective of procedural and/or clinical

complexity. (p for interaction=0.67 for dabigatran 110 mg and p for interaction=0.54 for dabigatran 150 mg). ST rates were low in all groups (1.2% for patients with clinical complexity alone, 0.4% for procedural complexity alone, 1.8% for both procedural and clinical complexity, and 1.0% for no complexity factors), hindering comparison of potential subgroup differences (Figure 4).

The aforementioned results underscore that the use of DAT with dabigatran may be of benefit even in patients with clinical or procedural complexity factors, as the risk of bleeding seemed to be reduced and the risk of atherothrombotic complications did not seem to be increased compared with TAT. The AUGUSTUS trial results showed apixaban superiority compared with VKA, as well as placebo superiority compared with aspirin administration regarding safety outcomes, and non-inferiority regarding efficacy outcomes in AF patients undergoing PCI.17 A subgroup analysis, dedicated to complex PCI patients, has not been released yet. The latter is also true for the ENTRUST-AF PCI trial, evaluating edoxaban, which reached the conclusion that DAT with edoxaban was non-inferior to TAT with VKA, regarding primary bleeding outcome, with similar rates of ischemic complications.18

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Antithrombotic Therapy in Complex PCI Patients Under OAC Figure 2: Comparison of Safety Outcomes Between Dual Antithrombotic Therapy with Rivaroxaban and Triple Antithrombotic Therapy with Vitamin K Antagonist Stratified by Procedure and Lesion Characteristics in the PIONEER AF-PCI Trial Population Characteristics

Group 1

HR [95% CI] p-value Interaction p-value

Group 3

15 mg rivaroxaban once daily Vitamin K antagonist

Overall

109/696 (16.8)

167/697 (26.7)

0.59 [0.47–0.76]

<0.001

Ischemia revascularization

Yes No

60/376 (17.1) 49/320 (16.5)

88/379 (25.7) 79/318 (28.0)

0.65 [0.47–0.90] 0.009 0.53 [0.37–0.76] <0.001

0.45

Urgent revascularization

Yes No

53/279 (20.5)

64/253 (28.7)

0.69 [0.48–0.99] 0.04

56/417 (14.4)

103/444 (25.6)

0.52 [0.38–0.72] <0.001

0.26

71/430 (17.7)

111/453 (26.9)

0.61 [0.45–0.82]

38/263 (15.6)

56/241 (26.9)

0.57 [0.37–0.85] 0.006

39/235 (17.7)

54/246 (24.1)

0.69 [0.46–1.05]

0.08

17/128 (15.5) 22 / 172 (15.9)

20/102 (22.0) 52 / 185 (31.2)

0.64 [0.34–1.23] 0.50 [0.31–0.79]

0.17 0.003

22 / 130 (18.8)

36 / 131 (30.5)

0.57 [0.33–0.96] 0.03

Radial Femoral

Approach

LAD Cx RCA MVD

Culprit lesion

0.001

70% stenosis or thrombus

Yes No

85/560 (16.3)

135/560 (26.6)

0.57 [0.44–0.75]

<0.001

21/115 (20.2)

18/101 (20.3)

0.97 [0.52–1.82]

0.92

Bifurcation

Yes No

6/62 (10.6)

23/76 (34.3)

0.27 [0.11–0.66]

0.002

103/633 (17.5)

144/621 (25.8)

0.64 [0.50–0.83] <0.001

Thrombus

Yes No

4/44 (10.2)

14/43 (37.6)

0.23 [0.08–0.71]

105/651 (17.3)

153/653 (26.1)

0.63 [0.49–0.80] <0.001

DES BES

37/230 (17.3)

59/221 (29.5)

0.54 [0.36–0.82] 0.003

71/452 (16.8)

104/463 (25.2)

0.64 [0.47–0.86] 0.003

>40 mm 31–40 mm 21–30 mm <20 mm

20/112 (19.8) 6/95 (6.9) 32/201 (16.6)

39/135 (31.2) 18/81 (24.2)

0.57 [0.33–0.98] 0.04 0.26 [0.10–0.65] 0.002

51/287 (19.2)

41/179 (26.0) 69/300 (26.0)

0.62 [0.39–0.99] 0.04 0.71 [0.49–1.02] 0.06

1 ≥2

71/454 (16.6)

113/475 (26.6)

0.60 [0.44–0.80] <0.001

38/242 (17.2)

54/221 (27.2)

0.59 [0.39–0.89] 0.01

Yes No

32/187 (19.2)

46/182 (29.6)

0.60 [0.38–0.94] 0.02

77/509 (16.0)

121/515 (25.8)

0.59 [0.44–0.79] <0.001

Type of stent

Stent length

Number of stents Closure device

15 mg rivaroxaban once daily better 0.5

0.005

0.96

0.76

0.14

0.07

0.10

0.49

0.39

0.95

0.94

Vitamin K antagonist better 1

2

BES = biolimus-eluting stent; Cx = left circumflex coronary artery; DES = drug-eluting stent; LAD = left anterior descending coronary artery; MVD = multivessel disease; RCA = right coronary artery.

Source: Kerneis et al. 2018.15 Reproduced with permission from Elsevier.

Nevertheless, Alkhalil et al., in their observational study including 256 patients under oral anticoagulation undergoing PCI with bioabsorbable polymer drug-eluting stent implantation, reported that patients with complex anatomy treated with DAT had a higher rate of major adverse cardiovascular events compared with TAT (HR 3.66; 95% CI [1.07–12.47]; p=0.038). Of note, the observed difference was mainly driven by rates of unplanned revascularizations (13.2% versus 0%, p<0.001), while there was also a numerically higher rate of spontaneous MI in patients receiving DAT (7.9% versus 1.4%, p=0.16) with no difference in rates of cardiovascular death.19 In summary, as patients with AF undergoing complex PCI are a high-risk subset of patients, carrying an increased thrombotic and bleeding risk, the aforementioned trials and subgroup analyses provide evidence regarding the safety and efficacy of DAT approach, with a non-vitamin K antagonist oral anticoagulant and P2Y12 inhibitor, compared with TAT. Nevertheless, it should be noted that both the PIONEER AF-PCI and REDUAL PCI trials were underpowered to identify small, but potentially important, differences in major adverse cardiovascular events rates, and especially to ascertain effects on rare events, such as ST. Even further, as trials were not focused solely on the subgroup of AF patients undergoing complex PCI, the analysis of results regarding efficacy endpoints should be interpreted with caution.

Thus, with the concern of a potentially numerically higher rate of ST or MI in patients receiving DAT, as observed in some trials, the administration of TAT for a short period after index PCI might provide a safer approach toward the prevention of short-term ischemic events, with the caveat of higher bleeding risk. Of importance, even if a DAT approach is adopted at discharge, it should be noted that in the aforementioned randomized trials, most, if not all, patients received TAT, with aspirin, in the periinterventional vulnerable phase and until randomization. Further studies are required to answer numerous considerations, as physicians have to find the optimal combined antithrombotic regimen, according to the clinical setting (ACS or elective PCI) and patients’ thrombotic–bleeding equilibrium, along with complexity of the disease.

Duration of Treatment

In the absence of specific guideline suggestions regarding patients receiving OAC undergoing complex PCI, decisions regarding the duration of antithrombotic treatment in AF patients undergoing complex procedures are based mostly on atherothrombotic and bleeding risk stratification, as in the cases of non-complex PCI. Although increased ischemic risk is well established in cases of complex PCI, the reckoning of bleeding risk is also an important factor in decision-making, as patients receiving OAC undergoing PCI are also at high bleeding risk, according to

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Antithrombotic Therapy in Complex PCI Patients Under OAC Figure 3: Comparison of Safety Outcomes Between Dual Antithrombotic Therapy with Dabigatran and Triple Antithrombotic Therapy with Vitamin K Antagonist Stratified by the Presence of Clinical and/or Procedural Complexity Factors in the REDUAL PCI Trial Population Subgroup

Patients

Patients with event, n (%)

HR [95% CI]

Interaction p-value

0.56 [0.40–0.78]

0.9023

0.85 [0.60–1.20]

0.3659

HR, 95% CI: dabigatran dual therapy versus warfarin triple therapy

Dual antiplatelet treatment factor No clinical procedure factor met Dabigatran 110 mg dual therapy Warfarin triple therapy Dabigatran 150 mg dual therapy Warfarin triple therapy*

353 381 274 305

55 (15.6) 98 (25.7) 58 (21.2) 71 (23.3)

Only procedural complexity factor met Dabigatran 110 mg dual therapy Warfarin triple therapy Dabigatran 150 mg dual therapy Warfarin triple therapy*

93 97 80 66

15 (16.1) 26 (26.8) 11 (13.8) 17 (25.8)

Only clinical complexity factor met Dabigatran 110 mg dual therapy Warfarin triple therapy Dabigatran 150 mg dual therapy Warfarin triple therapy*

425 414 335 326

64 (15.1) 115 (27.8) 67 (20.0) 90 (27.6)

Both complexty factors met Dabigatran 110 mg dual therapy Warfarin triple therapy Dabigatran 150 mg dual therapy Warfarin triple therapy*

110 89 74 67

17 (15.5) 25 (28.1) 18 (24.3) 18 (26.9)

0.58 [0.30–1.10] 0.48 [0.22–1.02]

0.48 [0.35–0.65] 0.63 [0.46–0.86]

0.47 [0.25–0.88] 0.92 [0.48–1.77] 0.1

Dabigatran 150 mg dual therapy versus warfarin triple therapy

Dabigatran 110 mg dual therapy versus warfarin triple therapy

Favors dabigatran dual therapy

1

Favors warfarin triple therapy

10

HRs and 95% CIs from Cox proportional hazards model; stratified by age (elderly versus nonelderly) for dabigatran 110 mg dual therapy versus warfarin triple therapy; unstratified for dabigatran 150 mg dual therapy versus warfarin triple therapy. *For the comparison with dabigatran 150 mg dual therapy, elderly patients outside the US are excluded. Source: Berry et al. 2020.16 Reproduced with permission from Wolters Kluwer Health.

Figure 4: Comparison of Efficacy Outcomes Between Dual Antithrombotic Therapy with Dabigatran and Triple Antithrombotic Therapy with Vitamin K Antagonist Stratified by the Presence of Clinical and/or Procedural Complexity Factors in the REDUAL PCI Trial Population Subgroup

Patients

Patients with event, n (%)

HR [95% CI]

Interaction p-value

HR, 95% CI: dabigatran dual therapy versus warfarin triple therapy

Dual antiplatelet treatment factor No clinical procedure factor met Dabigatran 110 mg dual therapy Warfarin triple therapy Dabigatran 150 mg dual therapy Warfarin triple therapy*

353 381 274 305

37 (10.5) 44 (11.5) 37 (13.5) 35 (11.5)

0.92 [0.59–1.43]

0.6673

1.17 [0.74–1.86]

0.5377

Only procedural complexity factor met Dabigatran 110 mg dual therapy Warfarin triple therapy Dabigatran 150 mg dual therapy Warfarin triple therapy*

93 97 80 66

14 (15.1) 14 (14.4) 8 (10.0) 9 (13.6)

1.01 [0.48–2.14]

Only clinical complexity factor met Dabigatran 110 mg dual therapy Warfarin triple therapy Dabigatran 150 mg dual therapy Warfarin triple therapy*

425 414 335 326

74 (17.4) 59 (14.3) 37 (11.0) 46 (14.1)

1.24 [0.88–1.74]

Both complexty factors met Dabigatran 110 mg dual therapy Warfarin triple therapy Dabigatran 150 mg dual therapy Warfarin triple therapy*

110 89 74 67

24 (21.8) 14 (15.7) 8 (10.8) 8 (11.9)

1.43 [0.74–2.77]

Dabigatran 110 mg dual therapy versus warfarin triple therapy

0.74 [0.29–1.93]

0.74 [0.48–1.14]

0.88 [0.33–2.36]

Dabigatran 150 mg dual therapy versus warfarin triple therapy

0.1

Favors dabigatran dual therapy

1

Favors warfarin triple therapy

10

HRs and 95% CIs from Cox proportional hazards model; stratified by age (elderly versus non-elderly) for dabigatran 110 mg dual therapy versus warfarin triple therapy; unstratified for dabigatran 150 mg dual therapy versus warfarin triple therapy. *For the comparison with dabigatran 150 mg dual therapy, elderly patients outside the US are excluded. Source: Berry et al. 2020.16 Reproduced with permission from Wolters Kluwer Health.

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Antithrombotic Therapy in Complex PCI Patients Under OAC Academic Research Consortium for High Bleeding Risk classification.20 Various risk scores, although not validated in our specified subgroup of patients, such as PRECISE-DAPT (PREdicting bleeding Complications in patients undergoing stent Implantation and SubsequEnt Dual AntiPlatelet Therapy) or HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio [INR], Elderly [>65 years], Drugs/alcohol concomitantly) may also guide decision-making regarding both the type and the duration of antithrombotic treatment regimens.21,22 North American guidelines highlight that, although DAT is suggested as the preferred antithrombotic therapy in most patients with AF undergoing PCI, TAT for up to 1 month after PCI should be considered in selected patients at high ischemic and low bleeding risk.23 Procedural factors, such as stent undersizing, stent underdeployment, small stent diameter, greater stent length, and bifurcation stents, are some of the factors considered to the increase risk for atherothrombotic complications, and thus, could favor a longer duration of TAT.24 As far as American College of Cardiology/American Heart Association guidelines are concerned, TAT, when used, is suggested for as short as possible, confined to a 4–6-week duration after index PCI, when the risk of ST is high, whereas DAT with clopidogrel or ticagrelor is an alternative option to reduce the risk of bleeding (class IIa recommendation).25 European guidelines regarding the management of patients with chronic coronary syndromes recommend TAT for 1–6 months in patients with high-risk features for ST, such as left main or proximal left anterior descending artery stenting, last remaining patent artery, suboptimal stent deployment, stent length >60 mm, diabetes, chronic kidney disease, bifurcation with two stents implanted, treatment of a chronic total occlusion, or previous ST on adequate antithrombotic therapy.26 However, in the recently published European guidelines regarding the management of ACS in patients presenting without persistent ST-segment elevation, TAT is recommended only for a short peri-interventional period up to 1 week post-index PCI (class Ia recommendation), whereas in patients at high ischemic risk, the extension of TAT up to 1 month should be considered (class IIa recommendation). Such cases include patients with complex CAD and at least one additional factor, either clinical (diabetes, history of recurrent MI, multivessel CAD, polyvascular disease, premature or accelerated CAD, concomitant systemic inflammatory disease, chronic kidney disease) or technical (implantation of ≥3 stents, treatment of ≥3 lesions, implanted stent length >60 mm, history of ST under antiplatelet treatment, left main stenting or bifurcation with two stents implanted, chronic total occlusion or stenting of last patent vessel).27 TAT for only a short peri-interventional period, followed by dual therapy with OAC and a P2Y12 inhibitor for 6 and 12 months in CCS and ACS patients, respectively, is also recommended in the 2020 ESC guidelines for the diagnosis and management of AF (class Ia recommendation).

Prolongation of TAT for up to 1 month is suggested in selected cases when the risk of ST outweighs the bleeding risk (class IIa recommendation), with PCI of the left main stem or last remaining patent artery, suboptimal stent deployment, stent length >60 mm, bifurcation PCI with two stents 1. Werner N, Nickenig G, Sinning JM. Complex PCI procedures: challenges for the interventional cardiologist. Clin Res Cardiol 2018;107(Suppl 2):64–73. https://doi.org/10.1007/s00392018-1316-1; PMID: 29978353.

2. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6:213–20. https://doi.org/10.2147/CLEP. S47385; PMID: 24966695.

implanted, treatment of chronic total occlusion, diabetes, chronic kidney disease, and previous ST on adequate antithrombotic therapy considered as risk factors for ST.28

P2Y12 Receptor Inhibitor of Choice

Potent P2Y12 receptor inhibitors, namely prasugrel and ticagrelor, are preferred over clopidogrel in the setting of an ACS when there are no contraindications.29 Additionally, they can be administered in specific high-risk situations of elective PCI, such as complex left main stem or multivessel PCI.26 However, in cases where there is a concomitant need for anticoagulation, clopidogrel is preferred as part of a triple therapy scheme, due to the lower risk of bleeding complications.25,30 Indeed, both ticagrelor and prasugrel as part of a TAT regimen have been associated with increased risk of bleeding compared with clopidogrel.31–33 A metaanalysis of three randomized controlled trials regarding the efficacy and safety of ticagrelor versus clopidogrel in more than 5,600 patients requiring treatment with antiplatelet plus OAC, demonstrated that patients on DAT with ticagrelor had an increased risk of clinically major bleeding compared with those on DAT with clopidogrel (OR 1.52; 95% CI [1.12–2.06] and OR 1.7; 95% CI [1.24–2.33], respectively).31 The increased bleeding risk of using a more potent P2Y12 inhibitor as part of DAT was also confirmed in a recent meta-analysis of more than 22,000 patients with AF on OAC undergoing PCI, where the use of ticagrelor (RR 1.36; 95% CI [1.18–1.57]) or prasugrel (RR 2.11; 95% CI [1.34–3.30]) was correlated with increased bleeding events compared with clopidogrel; of note, bleeding rates were similar between ticagrelor and prasugrel groups (RR 0.80; 95% CI [0.47–1.36]).32 According to current recommendations, European Society of Cardiology guidelines suggest that ticagrelor or prasugrel may be used as part of DAT, as an alternative to TAT with OAC, aspirin, and clopidogrel, in patients with moderate or high risk for ST (class IIb recommendation), whereas a North American expert consensus states that although clopidogrel is the P2Y12 receptor inhibitor of choice, ticagrelor may represent a reasonable treatment option in patients with low bleeding and high ischemic risk as part of a DAT regimen, as tested in the RE-DUAL PCI trial; the use of prasugrel is not encouraged.23,26,27

Conclusion

Population aging leads to an increasing prevalence of AF and complex PCI procedures in everyday clinical practice, emphasizing the imperative need to identify the optimal combination of antithrombotic drugs for the management of this high-risk subset of patients – those with AF undergoing complex PCI. With a view to maintain the subtle balance between ischemic and bleeding complications, DAT seems to be of benefit in terms of bleeding risk mitigation while not significantly compromising efficacy. Nevertheless, due to the increased ischemic risk associated with complex PCI cases, TAT of a short duration, confined to 4 weeks post-index procedure, could represent a more reasonable option, as supported by both European and US published guidelines, especially in cases where angiographic complexity coexists with clinical ischemic risk enhancers, such as diabetes, peripheral artery disease, or chronic kidney disease.

3. Zulkifly H, Lip GYH, Lane DA. Epidemiology of atrial fibrillation. Int J Clin Pract 2018;72:e13070. https://doi. org/10.1111/ijcp.13070; PMID: 29493854.

4. Choi HI, Ahn JM, Kang SH, et al. Prevalence, management, and long-term (6-year) outcomes of atrial fibrillation among patients receiving drug-eluting coronary stents. JACC Cardiovasc Interv 2017;10:1075–85. https://doi.org/10.1016/j. jcin.2017.02.028; PMID: 28527773.

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5. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. https://doi.org/10.1093/ eurheartj/ehx419; PMID: 28886622.

Antithrombotic Therapy in Complex PCI Patients Under OAC 6. Généreux P, Giustino G, Redfors B, et al. Impact of percutaneous coronary intervention extent, complexity and platelet reactivity on outcomes after drug eluting stent implantation. Int J Cardiol 2018;268:61–7. https://doi. org/10.1016/j.ijcard.2018.03.103; PMID: 30041804.

7. Wipf JE, Lipsky BA. Atrial fibrillation. Thromboembolic risk and indications for anticoagulation. Arch Intern Med 1990;150:1598–1603. https://doi.org/10.1001/ archinte.150.8.1598; PMID: 2200378.

8. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369–429. https://doi. org/10.1093/eurheartj/ehq278; PMID: 20802247.

9. Khan SU, Osman M, Khan MU, et al. Dual versus triple therapy for atrial fibrillation after percutaneous coronary intervention: a systematic review and meta-analysis. Ann Intern Med 2020;172:474–83. https://doi.org/10.7326/M193763; PMID: 32176890.

10. Capodanno D, Di Maio M, Greco A, et al. Safety and efficacy of double antithrombotic therapy with non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation undergoing percutaneous coronary intervention: a systematic review and meta-analysis. J Am Heart Assoc 2020;9:e017212. https://doi.org/10.1161/JAHA.120.017212; PMID: 32805186.

11. Lopes RD, Hong H, Harskamp RE, et al. Optimal antithrombotic regimens for patients with atrial fibrillation undergoing percutaneous coronary intervention: an updated network meta-analysis. JAMA Cardiol 2020;5:582– 9. https://doi.org/10.1001/jamacardio.2019.6175; PMID: 32101251.

12. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107–15. https://doi. org/10.1016/S0140-6736(12)62177-1; PMID: 23415013.

13. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375:2423–34. https://doi.org/10.1056/ NEJMoa1611594; PMID: 27959713.

14. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017;377:1513–24. https://doi.org/10.1056/ NEJMoa1708454; PMID: 28844193.

15. Kerneis M, Gibson CM, Chi G, et al. Effect of procedure and coronary lesion characteristics on clinical outcomes among atrial fibrillation patients undergoing percutaneous coronary intervention: insights from the PIONEER AF-PCI trial. JACC Cardiovasc Interv 2018;11:626–34. https://doi.org/10.1016/j.

jcin.2017.11.009; PMID: 29550085.

16. Berry NC, Mauri L, Steg PG, et al. Effect of lesion complexity and clinical risk factors on the efficacy and safety of dabigatran dual therapy versus warfarin triple therapy in atrial fibrillation after percutaneous coronary intervention: a subgroup analysis from the REDUAL PCI trial. Circ Cardiovasc Interv 2020;13:e008349. https://doi.org/10.1161/ CIRCINTERVENTIONS.119.008349; PMID: 32252548.

17. Lopes RD, Heizer G, Aronson R, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med 2019;380:1509–24. https://doi. org/10.1056/NEJMoa1817083; PMID: 30883055.

18. Vranckx P, Valgimigli M, Eckardt L, et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet 2019;394:1335–43. https://doi. org/10.1016/S0140-6736(19)31872-0; PMID: 31492505.

19. Alkhalil M, Shahmohammadi M, Spence MS, Owens CG. Aspirin discontinuation in patients requiring oral anticoagulation undergoing percutaneous coronary intervention, the role of procedural complexity. Cardiovasc Drugs Ther 2020;34:659–62. https://doi.org/10.1007/s10557020-07012-x; PMID: 32488426.

20. Urban P, Mehran R, Colleran R, et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention. Circulation 2019;140:240–61. https://doi. org/10.1161/CIRCULATIONAHA.119.040167; PMID: 31116032.

21. Costa F, van Klaveren D, James S, et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials.

Lancet 2017;389:1025–34. https://doi.org/10.1016/S01406736(17)30397-5; PMID: 28290994.

22. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138:1093–100. https://doi.org/10.1378/chest.10-0134; PMID: 20299623.

23. Angiolillo DJ, Goodman SG, Bhatt DL, et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention. Circulation 2018;138:527–36. https://doi. org/10.1161/CIRCULATIONAHA.118.034722; PMID: 30571525.

24. Angiolillo DJ, Goodman SG, Bhatt DL, et al. Antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention: a North American perspective – 2016 update. Circ Cardiovasc Interv 2016;9:e004395. https://doi.org/10.1161/ CIRCINTERVENTIONS.116.004395; PMID: 27803042.

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25. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019;74:104–32. https://doi.org/10.1016/j.jacc.2019.01.011; PMID: 30703431.

26. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504429.

27. Collet JP, Thiele H, Barbato E, et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2020;42:1289–367. https://doi.org/10.1093/eurheartj/ ehaa575; PMID: 32860058.

28. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021;42:373– 498. https://doi.org/10.1093/eurheartj/ehaa612; PMID: 32860505.

29. Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–77. https://doi.org/10.1093/eurheartj/ehx393; PMID: 28886621.

30. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/ EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437.

31. Andreou I, Briasoulis A, Pappas C, et al. Ticagrelor versus clopidogrel as part of dual or triple antithrombotic therapy: a systematic review and meta-analysis. Cardiovasc Drugs Ther 2018;32:287–94. https://doi.org/10.1007/s10557-018-6795-9; PMID: 29766335.

32. Lupercio F, Giancaterino S, Villablanca PA, et al. P2Y12 inhibitors with oral anticoagulation for percutaneous coronary intervention with atrial fibrillation: a systematic review and meta-analysis. Heart 2020;106:575–83. https:// doi.org/10.1136/heartjnl-2019-315963; PMID: 32034008.

33. Jackson LR, 2nd, Ju C, Zettler M, et al. Outcomes of patients with acute myocardial infarction undergoing percutaneous coronary intervention receiving an oral anticoagulant and dual antiplatelet therapy: a comparison of clopidogrel versus prasugrel from the TRANSLATE-ACS study. JACC Cardiovasc Interv 2015;8:1880–9. https://doi. org/10.1016/j.jcin.2015.08.018; PMID: 26718518.

Antithrombotics in High-risk PCI

Antithrombotic Therapy in Chronic Total Occlusion Interventions Iosif Xenogiannis, MD, PhD, , Charalambos Varlamos, MD, , Despoina-Rafailia Benetou, MD, , and Dimitrios Alexopoulos, MD, PhD, Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

Abstract

Chronic total occlusion (CTO) recanalization is among the most complex subsets of coronary interventions. Hence, optimum peri- and postprocedural anticoagulation and antiplatelet therapy is key for the achievement of successful revascularization and reduction of major adverse cardiovascular outcomes in patients undergoing CTO percutaneous coronary intervention (PCI). Unfractionated heparin is still considered the gold standard anticoagulant because its action can be reversed by protamine administration, with bivalirudin being reserved mainly for patients with heparin-induced thrombocytopenia. However, small studies comparing unfractionated heparin with bivalirudin in CTO interventions have shown similar outcomes. Glycoprotein IIb/IIIa inhibitors should, in general, be avoided. Aspirin in combination with clopidogrel for 6–12 months is the standard post CTO PCI dual antiplatelet regimen. For the most complex cases, clopidogrel can be substituted by a more potent P2Y12 inhibitor, namely ticagrelor or prasugrel.

Keywords

Chronic total occlusion, percutaneous coronary intervention, anticoagulation, antiplatelets, unfractionated heparin, bivalirudin, IIb/IIIa inhibitors, aspirin, clopidogrel, ticagrelor, prasugrel.

Disclosure: DA has received lecturing honoraria/advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Medtronic, Biotronik, and Chiesi Hellas. All other authors have no conflicts of interest to declare.

Received: November 28, 2020 Accepted: March 14, 2021 Citation: US Cardiology Review 2021;15:e10. DOI: https://doi.org/10.15420/usc.2020.37 Correspondence: Iosif Xenogiannis, Attikon University Hospital, Rimini 1, Chaidari 12461, Attika, Greece. E: iosifxeno@hotmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Chronic total occlusions (CTOs) are a common angiographic finding in patients with coronary artery disease (CAD). According to the findings of a Canadian multicenter registry, the prevalence of CTOs is approximately 18% in patients with CAD undergoing coronary angiography and 10% in those presenting with ST-elevation MI (STEMI), reaching levels as high as 89% in patients with prior coronary artery bypass grafting (CABG).1,2 Robust data, mainly from observational studies, but also randomized studies, have shown beneficial effects of successful percutaneous coronary intervention (PCI) in people with CTO in terms of symptom improvement – the main indication for CTO recanalization.3–7 Furthermore, multiple observational studies report successful CTO PCI to be associated with higher survival and lower mid- and long-term major adverse cardiovascular event (MACE) rates. However, survival benefit has not been replicated in randomized controlled trials.8–12 On the other hand, CTO interventions are considered to be high-risk procedures, having a substantial rate of acute and late complications. The insertion of a variety of devices in the coronary artery tree, such as the numerous microcatheters and guidewires frequently used during a long-lasting CTO PCI, predisposes to thrombus formation, with rates of acute stent thrombosis reported to be up to 2%.13 Likewise, the presence of extensive calcification – a common characteristic of CTO lesions – hinders stent expansion leading to both acute and late in-stent thrombosis.14 Hence, it is clearly understood that optimal antithrombotic therapy during the periand post-procedural period is a key component in achieving and maintaining a successful PCI outcome.

Periprocedural Intravenous Anticoagulation and Antiplatelet Therapy

According to the recent European guidelines on myocardial revascularization, unfractionated heparin (UFH) is the standard anticoagulant during elective PCI (70–100 U/kg) with bivalirudin (0.75 mg/ kg bolus, followed by 1.75 mg/kg/h for up to 4 hours after the procedure) mainly being used in cases of heparin-induced thrombocytopenia.

Enoxaparin (IV 0.5 mg/kg) should be considered as an alternative agent.15 Focusing on CTO interventions, in theory, UFH is the preferred anticoagulant agent having the advantage over bivalirudin that it can be reversed with the administration of protamine in cases of severe perforation. Moreover, there are unpublished cases in which guide catheter thrombosis occurred during long-lasting procedures when bivalirudin had been used.16 On the other hand, bivalirudin can be used as an alternative in patients with heparin-induced thrombocytopenia. Nevertheless, randomized data are encouraging regarding the perioperative administration of bivalirudin in CTO PCI. A single-center pilot study of 84 patients at high bleeding risk who underwent CTO PCI showed no difference in inhospital MACE (defined as the composite of all-cause mortality, cardiac death, stent thrombosis, periprocedural MI, or additional unplanned target lesion revascularization, or any other post-PCI ischemic event; 21.4% versus 14.3% for bivalirudin and heparin respectively; p=0.393) and major bleeding events (4.8% versus 9.5%; p=0.676). For both

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Antithrombotic Therapy in CTO Interventions Table 1: Comparison of Unfractionated Heparin Versus Bivalirudin Administration in Chronic Total Occlusion Interventions Study

n

Major Findings

Kong et al. 201819

74

No difference in MACE between UFH and bivalirudin at 1-year follow-up (21% versus 11%; p=0.246) Incidence of periprocedural bleeding was lower in the bivalirudin group (24% versus 6%; p=0.028)

Li et al. 201817

84

No difference in in-hospital (14% versus 21% for UFH and bivalirudin, respectively; p=0.393) and 1-year MACE (no events for both groups) between the two groups No difference in major bleeding (10% versus 5% for UFH and bivalirudin, respectively; p=0.676)

Wang et al. 201918

123

No difference in in-hospital (20% versus 18% for UFH and bivalirudin respectively; p=0.82) and 6-month (3.6% versus 1.5%; p=0.59) MACE between the two groups No BARC type 3–5 bleeding events or severe procedure (access)-related complications (subcutaneous hematoma >5 cm) occurred in either group

BARC = Bleeding Academic Research Consortium; MACE = major adverse cardiovascular events; UFH = unfractionated heparin.

Figure 1: Anticoagulation and Antiplatelet Therapy in Chronic Total Occlusion Interventions CTO PCI

ACS, CTO PCI (bystander lesion) during the index procedure

Stable coronary artery disease Anticoagulation IV heparin 70–100 U/kg Alternatively IV bivalirudin 0.75 mg/kg bolus, followed by 1.75 mg/kg/h for up to 4 hours

Follow ACS guidelines

Antiplatelet therapy Oral aspirin 150–300 mg followed by 80–100 mg/day Plus Oral clopidogrel 600 mg loading dose followed by 75 mg/day for 6–12 months (tailor duration according to ischemic/bleeding risk)

Avoid glycoprotein Ilb/Illa inhibitors

Aspirin should be continued indefinitely Consider ticagrelor or prasugrel as an alternative to clopidogrel in cases of stent underexpansion, left main CTO PCI, more than one CTO PCI, CTO plus non-CTO PCI

ACS = acute coronary syndromes; CTO = chronic total occlusion; PCI = percutaneous coronary intervention.

groups of the study the activated clotting time (ACT) was aimed to be ≥300 seconds.17 Likewise, another single-center prospective randomized controlled trial recruited 123 elderly CTO patients at high bleeding risk.

The in-hospital MACE rate was similar between bivalirudin and UFH (17.6% versus 20%; p=0.82), as well as Bleeding Academic Research Consortium (BARC) type 1–2 bleeding events (8.8% versus 10.9%, P=0.77) with no BARC type 3–5 bleeding events in either group.18 Mean ACT in the bivalirudin group was 356.6 seconds. It is worth noting that a glycoprotein IIb/IIIa receptor inhibitor was administered in 18.7% of the patients in the UFH group compared with none in the bivalirudin group.

In another randomized control trial that included 74 patients with CTO lesions, bivalirudin was associated with a lower incidence of perioperative bleeding (5.6% versus 23.7%; p=0.028) and slow-flow/noflow (0.0% versus 15.8%; p=0.025) suggesting that bivalirudin may even be safer than UFH for CTO interventions.19 Nevertheless, the studies described here had a small sample size and were likely underpowered, so their results should be interpreted with caution. Furthermore, the higher incidence of perioperative bleeding with heparin that was found in one study was potentially – at least partially – associated with the access site. The increase of radial usage in CTO interventions that has been observed over time may attenuate these differences.20 In addition, the significantly higher cost of bivalirudin is another factor that should be taken under consideration for the selection of anticoagulation therapy. Studies comparing UFH with bivalirudin administration in CTO interventions are summarized in Table 1.

The recommended ACTs are >300 seconds for antegrade CTO PCI and >350 seconds for retrograde CTO PCI, with some operators aiming for >300 seconds with frequent checking if it is in the low 300 seconds range. These recommendations are based mainly on expert opinion rather than data derived from studies. ACT should be checked every 20– 30 minutes depending on how high above the target ACT the most recent measurement was. Furthermore, some operators administer a heparin drip, in addition to the initial bolus, to avoid significant fluctuation in anticoagulation levels.16 Any contamination of the blood specimen with water, contrast agent, or drugs may strongly influence the result and thus should be strictly avoided.

Protamine can be used to reverse the action of heparin. To neutralize heparin, 1 to 1.5 mg of protamine is injected per 100 units of heparin (max dose 50 mg) administered at a rate not exceeding 5 mg per minute.

Follow-up doses of protamine of 0.5 mg per 100 units of heparin can be given if bleeding continues 4 hours later. Nevertheless, it should be highlighted that protamine is only used as a last resort in cases of perforation – and only after meticulous efforts to control extravasation by other means such as covered stents or coils/fat have failed – since it can cause thrombosis of the equipment that is still in the patient’s arterial tree.

Administration of glycoprotein IIb/IIIa inhibitors should be, in general, avoided during CTO PCI, even after successful crossing and stenting, as it may cause an unrecognized perforation to bleed, leading eventually to tamponade. Furthermore, their use has been independently associated with an increased risk for death (OR 32.29; 95% CI [6.03–172.75]) in a national registry.21 Interestingly, a case of recanalization of a bystander CTO at a subsequent angiography has been reported in a patient who was administered eptifibatide and dual antiplatelet therapy (DAPT) during primary PCI for a STEMI.22 The authors speculated that excessive antithrombotic and anticoagulant therapy aided the intrinsic fibrinolytic mechanism to dissolve the CTO lesion. Nevertheless, the administration of glycoprotein IIb/IIIa inhibitors may be needed in the presence of donor vessel thrombosis during a retrograde crossing attempt.

In the event of bleeding complications after abciximab administration, platelet transfusion can at least partially reverse inhibition of platelet aggregation.

Dual Antiplatelet Therapy

Aspirin (150–300 mg orally or 75–250 mg IV followed by 80–100 mg/ day) and clopidogrel (600 mg oral loading dose and 75 mg maintenance dose) administration for 6 months followed by indefinite administration of aspirin is considered the standard of care after PCI in the clinical context of stable CAD. Most of the time, CTO PCI is performed as a

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Antithrombotic Therapy in CTO Interventions Figure 2: Events in Patients Receiving Dual Antiplatelet Therapy for ≤12 Months Versus >12 Months ≤12 months

>12 months

Adjusted HR [CI 95%]

p-value

p for interaction 0.86

Acute coronary syndrome 0.97 [0.42–2.20]

0.95

234 No 151 CTO of left anterior descending artery

1.04 [0.64–1.68]

0.88

Yes

90

147

1.08 [0.57–2.02]

0.82

No

109

166

1.09 [0.62–1.90]

0.77

0.93 [0.39–2.26]

0.88

1.12 [0.70–1.79]

0.63

Yes

48

79

0.79

CTO of left circumflex artery Yes

52

80

No

147

233

0.87

CTO of right coronary artery Yes

82

141

0.90 [0.50–1.65]

0.74

No

117

172

1.42 [0.78–2.57]

0.25

205 108

1.27 [0.78–2.07] 0.68 [0.31–1.52]

0.35 0.35

0.34

168 145

1.22 [0.57–2.58] 0.98 [0.60–1.59]

0.61 0.93

0.41

0.36

Multivessel disease Yes No

134 65

Newer generation stent Yes No

66 133

0.1

1 Favors ≤12 months

10 Favors >12 months

Comparison of major adverse cardiac and cerebrovascular events in specific subgroups of patients treated with percutaneous coronary intervention for CTO receiving dual antiplatelet therapy for ≤12 months versus >12 months. CTO = chronic total occlusion. Source: Lee et al. 2017.28 Reproduced with permission from PLoS One.

scheduled non-ad hoc intervention in patients who present with symptoms related to stable CAD, such as walking angina or exertional dyspnea, thus aspirin and clopidogrel is the standard dual antiplatelet regimen initiated. In patients who present with an acute coronary event and also have a bystander CTO lesion that is recanalized during the index PCI of the culprit lesion or at a subsequent intervention, a more potent P2Y12 receptor inhibitor (prasugrel, ticagrelor) should be used instead of clopidogrel (Figure 1).

DAPT did not improve clinical outcomes in CTO patients. Similarly, in a retrospective analysis dedicated to CTO interventions by Lee et al., ≤12-month administration of aspirin plus clopidogrel was similar to >12-month administration with respect to major adverse cardiac and cerebrovascular events (MACCE; 19.4% versus 18.8%; p=0.88; Figure 2).28 In addition, moderate or severe bleeding according to BARC criteria (type 2, 3, or 5) was also similar between the ≤12-month and >12-month group (2.5% versus 1.9%; p=0.99).

The contemporary ISAR-REACT 5 trial showed benefit with prasugrel over ticagrelor in terms of fewer MIs, thus it seems reasonable to be the first option in the clinical context of acute coronary syndrome.23 In the clinical setting of stable CAD, the duration of DAPT can be tailored accordingly to less or more than 6 months after balancing ischemic and bleeding risk.

Optical coherence tomography (OCT) studies have shown that CTO PCI is related with delayed stent coverage and a high incidence of malapposition (both associated with stent thrombosis) justifying prolonged DAPT administration.24,25 In the 2017 European Society of Cardiology focused update on dual antiplatelet therapy in CAD, CTO PCI falls under the umbrella of complex PCI, thus prolonged (>6 months) DAPT therapy is recommended after CTO interventions (Class IIb, level of evidence B).26

A substantial percentage of patients, estimated to be up to 30%, has resistance to clopidogrel. Multiple intrinsic and extrinsic mechanisms such as drug–drug interactions involving cytochrome P450 3A4, polymorphisms of the P2Y12 receptor and increased release of adenosine diphosphate (ADP) have been implicated.29 Routine platelet function testing to adjust antiplatelet therapy is not recommended according to current guidelines.

However, high platelet reactivity (HPR) defined as ADP test ≥70% in patients with CTO lesions has been associated with lower survival. In a study by De Gregorio et al., which included 1,101 patients who underwent a CTO PCI attempt, HPR was found in 18% of the patients.30 Means for the ADP test by light transmission aggregometry were 44 ± 16% versus 77 ± 6%, respectively. Three-year survival was significantly higher in the optimal platelet reactivity (OPR) group compared with HPR patients (95.3 ± 0.8% versus 86.2 ± 2.8%; p<0.001). Interestingly, cardiac survival was similar in patients with OPR compared with those with HPR whose therapy had been escalated to either prasugrel or ticagrelor (95.3 ± 0.8% versus 90.7 ± 3.9%; p=0.172) suggesting that a tailored antiplatelet therapy in patients with high atherothrombotic burden, such as those with CTO lesions, based on platelet test, could lead to survival benefit.

Two recent studies failed to show any benefit from the extended DAPT administration in patients who underwent CTO PCI. Giustino et al. sought to investigate the optimal duration of aspirin and clopidogrel administration after complex PCI defined as an intervention that satisfies any of the following: three vessels treated, three or more stents implanted, three or more lesions treated, bifurcation with two stents implanted, total stent length >60 mm, or CTO.27 In their post hoc patient-level pooled analysis of six randomized control trials, long-term DAPT (≥12 months) yielded significant reductions in MACE (defined as the composite of cardiac death, MI, or stent thrombosis) compared with short-term DAPT (3 or 6 months) in the complex PCI group, (adjusted HR 0.56; 95% CI [0.35–0.89]) without an increase of major bleeding at adjusted analyses. However, long-term

The TIGER-BVS trial randomizes patients who receive CTO PCI with Absorb bioresorbable vascular scaffold (Abbott Vascular) implantation to receive ticagrelor or clopidogrel, focusing on the recovery of vascular function.31 The rationale behind this trial is that the worse CTO PCI outcomes compared with the non-CTO interventions might be partially associated

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Antithrombotic Therapy in CTO Interventions with impaired vasomotor function in the vessels post PCI. Ticagrelor increases local adenosine by blocking its uptake and through its vasodilating effect can potentially improve vessel vasomotor function.32 Prasugrel or ticagrelor may be considered as an alternative to clopidogrel, in specific high-risk situations of elective stenting (e.g. suboptimal stent deployment or other procedural characteristics associated with high risk of stent thrombosis, complex left main stem, or multivessel stenting), CTO PCI (left main CTO PCI, more than one CTO PCI, CTO plus non-CTO PCI) or if DAPT cannot be used because of aspirin intolerance.33 CTOs frequently have a high burden of calcific deposit predisposing to stent underexpansion. In such cases the selection of prasugrel or ticagrelor over clopidogrel is reasonable.

Wang et al. compared two different doses of ticagrelor (180 mg loading dose, 90 mg twice daily thereafter and 120-mg loading dose, 60 mg twice daily thereafter) with clopidogrel (300-mg loading dose, 75 mg daily thereafter) in East Asian patients with CTO undergoing PCI.34 At 1-year follow-up, both ticagrelor doses reduced the rate of MACCE (6.4% versus 7.3% versus 14.2%; p=0.023 for the ticagrelor 90 mg, ticagrelor 60 mg and clopidogrel 75 mg group respectively) and target vessel revascularization (2.3% versus 2.8% versus 7.4%, respectively; p=0.047). This was at the expense of higher major bleeding (4.1% versus 0.6% versus 0.6%, respectively; p=0.016) and minor bleeding (23.4% versus 12.4% versus 11.9%, respectively; p=0.004) with 90 mg of ticagrelor, leading the authors to conclude that in East Asian patients with CTO undergoing PCI, 60 mg ticagrelor was as effective as 90 mg 1. Fefer P, Knudtson ML, Cheema AN, et al. Current perspectives on coronary chronic total occlusions: the Canadian Multicenter Chronic Total Occlusions Registry.

J Am Coll Cardiol 2012;59:991–7. https://doi.org/10.1016/j. jacc.2011.12.007; PMID: 22402070.

2. Jeroudi OM, Alomar ME, Michael TT, et al. Prevalence and management of coronary chronic total occlusions in a tertiary Veterans Affairs hospital. Catheter Cardiovasc Interv 2014;84:637–43. https://doi.org/10.1002/ccd.25264; PMID: 24142769.

3. Obedinskiy AA, Kretov EI, Boukhris M, et al. The IMPACTORCTO Trial. JACC Cardiovasc Interv 2018;11:1309–11. https://doi. org/10.1016/j.jcin.2018.04.017; PMID: 29976368.

4. Sapontis J, Salisbury AC, Yeh RW, et al. Early procedural and health status outcomes after chronic total occlusion angioplasty: a report from the OPEN-CTO Registry (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures). JACC Cardiovasc Interv 2017;10:1523–34. https://doi.org/10.1016/j.jcin.2017.05.065; PMID: 28797429.

5. Werner GS, Martin-Yuste V, Hildick-Smith D, et al. A randomized multicentre trial to compare revascularization with optimal medical therapy for the treatment of chronic total coronary occlusions. Eur Heart J 2018;39:2484–93. https://doi.org/10.1093/eurheartj/ehy220; PMID: 29722796.

6. Xenogiannis I, Nikolakopoulos I, Krestyaninov O, et al.

Impact of successful chronic total occlusion percutaneous coronary interventions on subsequent clinical outcomes.

J Invasive Cardiol 2020;32:433–9. PMID: 32568095.

7. Brilakis ES, Mashayekhi K, Tsuchikane E, et al. Guiding principles for chronic total occlusion percutaneous coronary intervention. Circulation 2019;140:420–33. https://doi. org/10.1161/circulationaha.119.039797; PMID: 31356129.

8. Christakopoulos GE, Christopoulos G, Carlino M, et al. Metaanalysis of clinical outcomes of patients who underwent percutaneous coronary interventions for chronic total occlusions. Am J Card 2015;115:1367–75. https://doi. org/10.1016/j.amjcard.2015.02.038; PMID: 25784515.

9. George S, Cockburn J, Clayton TC, et al. Long-term followup of elective chronic total coronary occlusion angioplasty: analysis from the UK Central Cardiac Audit Database. J Am Coll Cardiol 2014;64:235–43. https://doi.org/10.1016/j. jacc.2014.04.040; PMID: 25034057.

10. Maeremans J, Avran A, Walsh S, et al. One-year clinical outcomes of the hybrid CTO revascularization strategy after hospital discharge: a subanalysis of the multicenter RECHARGE Registry. J Invasive Cardiol 2018;30:62–70; PMID: 29138365.

and at the same time significantly reduced risk of bleeding. Nevertheless, the patients included in the study were exclusively Asian and the results cannot be extrapolated to other populations. The reduction in MACCE should not be attributed exclusively to the effect of the more potent antiplatelet on CTOs but also to the more effective prevention of thrombotic events triggered by different unstable atheromatous plaques found in patients’ coronary trees.

Conclusion

Revascularization of CTO lesions is one of the most complex subsets of coronary interventions, posing often significant challenges to the interventional cardiologist. Choosing the optimum periprocedural anticoagulation and antiplatelet agent as well as long term DAPT regimen are of paramount importance. Although emerging data support that bivalirudin can be an effective and safe anticoagulant for CTO interventions, heparin is still the preferred option given the fact that its action can be reversed by protamine administration. Glycoprotein IIb/IIIa receptor inhibitors should be avoided in general, as they have been associated with increased mortality and they can increase bleeding due to an unrecognized minor perforation. Aspirin in combination with clopidogrel for 6–12 months is the standard DAPT in patients who have undergone CTO PCI. The duration of DAPT is individualized after balancing the ischemic and bleeding risk. Finally, in patients with stent underexpansion, left main CTO PCI and more than one CTO PCIs or CTO PCI plus non-CTO PCI during the same procedure, the administration of ticagrelor or prasugrel instead of clopidogrel seems reasonable.

11. Niccoli G, De Felice F, Belloni F, et al. Late (3 years) followup of successful versus unsuccessful revascularization in chronic total coronary occlusions treated by drug eluting stent. Am J Cardiol 2012;110:948–53. https://doi.org/10.1016/j. amjcard.2012.05.025; PMID: 22721573.

12. Wu KZ, Huang ZH, Zhong ZA, et al. Successful treatment of complex coronary chronic total occlusions improves midterm outcomes. Ann Transl Med 2019;7:194. https://doi. org/10.21037/atm.2019.05.09; PMID: 31205912.

13. Patel VG, Brayton KM, Tamayo A, et al. Angiographic success and procedural complications in patients undergoing percutaneous coronary chronic total occlusion interventions: a weighted meta-analysis of 18,061 patients from 65 studies. JACC Cardiovasc Interv 2013;6:128–36. https://doi.org/10.1016/j.jcin.2012.10.011; PMID: 23352817.

14. Karacsonyi J, Karmpaliotis D, Alaswad K, et al. Impact of calcium on chronic total occlusion percutaneous coronary interventions. Am J Cardiol 2017;120:40–6. https://doi. org/10.1016/j.amjcard.2017.03.263; PMID: 28499595.

15. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/ EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437.

16. Brilakis ES. Manual of chronic total occlusion interventions: a step-by-step approach. 2nd ed. London: Academic Press/ Elsevier, 2018.

17. Li C, Xu R, Shen Y, et al. Bivalirudin in percutaneous coronary intervention for chronic total occlusion: a singlecenter pilot study. Catheter Cardiovasc Interv 2018;91:679–85. https://doi.org/10.1002/ccd.27181; PMID: 28766879.

18. Wang Y, Zhao HW, Wang CF, et al. Efficacy and safety of bivalirudin during percutaneous coronary intervention in high-bleeding-risk elderly patients with chronic total occlusion: a prospective randomized controlled trial.

Catheter Cardiovasc Interv 2019;93:825–31. https://doi. org/10.1002/ccd.28087; PMID: 30724035.

19. Kong LD, Wang G, Han YL, et al. Efficacy of periprocedural bivalirudin infusion in patients with chronic total occlusion lesion undergoing percutaneous coronary intervention.

Zhonghua Xin Xue Guan Bing Za Zhi 2018;46:543–8 [in Chinese]. https://doi.org/10.3760/ cma.j.issn.0253-3758.2018.07.007; PMID: 30032545.

20. Tajti P Alaswad K, Karmpaliotis D, et al. Procedural outcomes of percutaneous coronary interventions for chronic total occlusions via the radial approach: insight from an international CTO registry. JACC Cardiovasc Interv 2019;12:346–58. https://doi.org/10.1016/j.jcin.2018.11.019; PMID: 30784639.

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21. de Medeiros J, Pintón F, Ybarra L. Brazilian registry of percutaneous coronary intervention in chronic total occlusions. J Transcat Intervent 2019;27:eA201810. https://doi. org/10.31160/JOTCI2019;27A201810.

22. Kos N, Radeljić V, Pavlović N, et al. Noninvasive recanalization of a coronary chronic total occlusion. Case Rep Cardiol 2019;2019:7979316. https://doi. org/10.1155/2019/7979316; PMID: 31093381.

23. Schüpke S, Neumann FJ, Menichelli M, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med 2019;381:1524–34. https://doi.org/10.1056/ NEJMoa1908973; PMID: 31475799.

24. Heeger CH, Busjahn A, Hildebrand L, et al. Delayed coverage of drug-eluting stents after interventional revascularisation of chronic total occlusions assessed by optical coherence tomography: the ALSTER-OCT-CTO registry. EuroIntervention 2016;11:1004–12. https://doi. org/10.4244/eijy14m10_01; PMID: 25287264.

25. Jia H, Hu S, Liu H, et al. Chronic total occlusion is associated with a higher incidence of malapposition and uncovered stent struts: OCT findings at 6 months following DES implantation. Catheter Cardiovasc Interv 2017;89:582–91. https://doi.org/10.1002/ccd.26969; PMID: 28318139.

26. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. https://doi.org/10.1093/ eurheartj/ehx419; PMID: 28886622.

27. Giustino G, Chieffo A, Palmerini T, et al. Efficacy and safety of dual antiplatelet therapy after complex PCI. J Am Coll Cardiol 2016;68:1851–64. https://doi.org/10.1016/j. jacc.2016.07.760; PMID: 27595509.

28. Lee SH, Yang JH, Choi SH, et al. Duration of dual antiplatelet therapy in patients treated with percutaneous coronary intervention for coronary chronic total occlusion.

PloS One 2017;12:e0176737. https://doi.org/10.1371/journal. pone.0176737; PMID: 28475584.

29. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 2005;45:1157–64. https://doi.org/10.1016/j.jacc.2005.01.034; PMID: 15837243.

30. De Gregorio MG, Marcucci R, Migliorini A, et al. Clinical implications of “tailored” antiplatelet therapy in patients with chronic total occlusion. J Am Heart Assoc 2020;9:e014676. https://doi.org/10.1161/jaha.119.014676;

Antithrombotic Therapy in CTO Interventions PMID: 32067582.

31. Brugaletta S, Gomez-Lara J, Caballero J, et al. TIcaGrEloR and Absorb bioresorbable vascular scaffold implantation for recovery of vascular function after successful chronic total occlusion recanalization (TIGER-BVS trial): rationale and study design. Catheter Cardiovasc Interv 2018;91:1–6. https:// doi.org/10.1002/ccd.27196; PMID: 28707316.

32. Shatila W, Krajcer Z. Chronic total occlusion: does antiplatelet choice impact outcomes? Catheter Cardiovasc Interv 2018;91:7–8. https://doi.org/10.1002/ccd.27456; PMID: 29314641.

33. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi.

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org/10.1093/eurheartj/ehz425; PMID: 31504439.

34. Wang Y, Zhao HW, Wang CF, et al. Efficacy and safety of standard and low dose ticagrelor versus clopidogrel in east Asian patients with chronic total occlusion undergoing percutaneous coronary intervention: a single center retrospective study. BMC Cardiovasc Dis 2020;20:109. https:// doi.org/10.1186/s12872-019-01307-0; PMID: 32138662.

Antithrombotics in High-risk PCI

Left Main Disease and Bifurcation Percutaneous Coronary Intervention: Focus on Antithrombotic Therapy Charalampos Varlamos, MD, , Ioannis Lianos, MD, , Despoina-Rafailia Benetou, MD, , and Dimitrios Alexopoulos, MD, Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

Abstract

Revascularization of both left main and bifurcation lesions is currently considered an important feature of complex percutaneous coronary intervention (PCI), whereas stenting distal left main bifurcation is fairly challenging. Recent evidence shows that such lesions are associated with an increased risk of ischemic events. There is no universal consensus on the optimal PCI strategy or the appropriate type and duration of antithrombotic therapy to mitigate the thrombotic risk. Prolonged dual antiplatelet therapy or use of more potent P2Y12 inhibitors have been investigated in the context of this high-risk subset of the population undergoing PCI. Thus, while complex PCI is a growing field in interventional cardiology, left main and bifurcation PCI constitutes a fair amount of the total complex procedures performed recently, and there is cumulative interest regarding antithrombotic therapy type and duration in this subset of patients, with decision-making mostly based on clinical presentation, baseline bleeding, and ischemic risk, as well as the performed stenting strategy.

Keywords

Complex percutaneous coronary intervention, left main disease, bifurcation lesion, antithrombotic therapy Disclosure: DA has received lecturing honoraria/advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Medtronic, Biotronik, and Chiesi Hellas. All other authors have no conflicts of interest to declare.

Received: November 24, 2020 Accepted: March 27, 2021 Citation: US Cardiology Review 2021;15:e11. DOI: https://doi.org/10.15420/usc.2020.34 Correspondence: Charalampos Varlamos, 2nd Department of Cardiology, Attikon University Hospital, Rimini 1, Chaidari 12462, Athens, Greece. E: chvar@yahoo.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Left main (LM) coronary artery disease (CAD) is a potentially fatal condition with poor prognosis as a result of a large myocardial territory at risk.1 Therefore, diagnosis, assessment, and treatment of LM-CAD are crucial to decrease the risk of future events.2,3 It is now well established that revascularization is recommended for any LM stenosis ≥50%, regardless of symptoms, ischemic burden, or concomitant CAD. The type of revascularization – coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) – depends on many factors, namely predicted surgical mortality, anatomical complexity of CAD, anticipated completeness of revascularization, patient comorbidities, and other technical aspects (Figure 1).4 PCI of the LM shaft is a procedure that has been associated with better clinical outcomes and a lower need for late repeat revascularization than PCI of the distal bifurcation, which is generally considered more challenging.5 The latter can partially explain why, until recently, some authors did not define PCI of the LM as a complex procedure, in contrast to the recently published European guidelines.6–8 Conversely, bifurcation PCI is considered complex when at least two stents are implanted according to the European Society of Cardiology focused update on dual antiplatelet therapy (DAPT).7 Nevertheless, there are studies where stenting bifurcation lesions with side branch diameter ≥2.5 mm is also considered of increased complexity, whereas in the DEFINITION study, the authors defined complex bifurcation lesions by high-risk angiographic features, as shown in Table 1.4,9

In the context of these high ischemic risk interventions, there is a growing interest regarding the optimal antithrombotic treatment type and duration, with decision-making based on the clinical presentation, the baseline risk of bleeding, and thrombotic events, as well as the chosen stenting strategy.

PCI Versus CABG for Left Main Coronary Artery Disease

Until recently, CABG was considered the most appropriate treatment of LM-CAD; however, recent knowledge suggests that PCI can be an alternative to CABG in specific subgroups of patients with lesser extent of atherosclerotic burden.10 There are six randomized control trials comparing PCI with CABG, but only two of them – EXCEL and NOBLE – were conducted in the era of second-generation stents.11,12 All but the NOBLE trial showed that PCI was non-inferior to CABG regarding major adverse cardiovascular events (MACE), while the rate of repeat revascularization was significantly higher in the PCI arm (Table 2).13–18 Therefore, a metaanalysis of five randomized clinical trials performed by Ahmad et al. showed no significant difference in all-cause death, cardiac mortality, stroke, or MI within a mean follow-up of 67.1 months. Unplanned revascularization was less common after CABG.19 In the light of the above findings, the European Society of Cardiology suggests PCI as an equivalent to CABG regarding mortality, MI, and stroke in patients with LM-CAD and low SYNTAX score (0–22), while PCI is not

© RADCLIFFE CARDIOLOGY 2021 Access at: www.USCjournal.com

Antithrombotics in LM and Bifurcation PCI Figure 1: Factors That Determine the Choice Between Percutaneous Coronary Intervention Left Main and Coronary Artery Bypass Grafting

techniques to offer a reliable alternative to CABG in patients with appropriate coronary anatomy.

Increased Thrombotic Risk of Left Main and Bifurcation Coronary Disease

Feasibility of both types of vascularization (heart team, proper PCI equipment) Patient preference

Concomitant CAD: 3 VD? Calculation of SYNTAX score Atherosclerotic burden: calcification, thrombus formation, severe narrowing of tortuosity Need for surgical intervention due to severe valve or aorta disease Assesement of available grafts and target vessels Evaluation of completeness of revascularization Calculate scores, e.g. STS score

Young age Good quality of life Good performance status Diabetes LVEF ≤30% LIMA graft availability Diffuse stent restenosis

Advanced age Short life expectancy Immobility, mental health disorder, frail patient Cancer, severe respiratory disease Prior chest radiotherapy, porcelain aorta Prior thoracic surgery Severe chest deformation

CABG

PCI

Multiple factors contributing to decision-making regarding revascularization of significant left main stenosis are shown. CABG = coronary artery bypass grafting; CAD = coronary artery disease; LIMA = left internal mammary artery; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; STS = Society of Thoracic Surgeons; VD = vessel disease.

Table 1: Definition of Complex Bifurcation Percutaneous Coronary Intervention According to the DEFINITION Study9 Criteria

Angiographic features

Complex

One major and any two minor criteria

Major

Distal LM bifurcation: SB-DS ≥70% and SB lesion length ≥10 mm Non-LM bifurcation: SB-DS ≥90% and SB lesion length ≥10 mm

Minor

Moderate-to-severe calcification Multiple lesions Bifurcation angle <45° Main vessel reference diameter <2.5 mm Thrombus-containing lesion Multivessel lesion length ≥25 mm

DS = diameter stenosis; LM = left main; SB = side branch.

favored in more anatomically complex lesions (SYNTAX score 23–32) and is contraindicated when the SYNTAX score exceeds 32.4 Regarding US guidelines, PCI is considered with a class IIa recommendation as an alternative to CABG if the coronary anatomy is associated with a low risk of procedural complications and a high likelihood of good long-term outcome (e.g. SYNTAX score ≤22, ostial or trunk LM-CAD), and the clinical characteristics predict a significantly increased risk of adverse surgical outcomes (e.g. Society of Thoracic Surgeons-predicted risk of operative mortality ≥5%).20 Overall, percutaneous revascularization of the LM demands an experienced operator, adequate preparation, and frequent use of newer

Complex PCI is generally associated with an increased risk of MACE and stent thrombosis (ST). PCI to unprotected LM-CAD is a demanding intervention that can occasionally lead to compromised final flow or side branch occlusion.3 From an autopsy registry regarding LM PCI, the most common cause of ST was malapposition, followed by uncovered strut, multiple stent techniques, and provisional stent technique without side branch dilatation.21 Stent deposition-related factors, such as malapposition or underexpansion, by delaying endothelization and enhancing the prothrombotic environment, are common triggers of adverse ischemic events.22 The latter has been associated with the chosen PCI technique performed, with the two-stent technique yielding numerically better results regarding cardiac death in patients with LM bifurcation disease compared with the one-stent technique.23 Moreover, the double-kissing (DK) crush technique compared with provisional stenting has been related with better outcomes, including a significantly lower composite endpoint of target lesion failure (TLF) and ST.24 Thus, proper planning of the procedure is pivotal in bifurcation LM-CAD, as the ‘bail-out’ placement of a second stent has been associated with a higher risk of ST than planned double stenting.25 However, stenting all types of bifurcation lesions has been widely recognized as a predisposing factor for thrombosis. Among all the spectrum of complex PCI procedures, bifurcation has been directly and more prominently associated with increased risk of ischemic outcomes, including coronary thrombotic events, ST, and MI within a 2-year followup.26 Interestingly, implantation of two stents was associated with an even higher incidence of ST in the ADAPT-DES study (2.8% at 2-year follow-up), as well as with a higher proportion of TLF in the recently published posthoc subanalysis of the e-Ultimaster registry (6.2% at 1-year follow-up).27,28 Of all bifurcations in the coronary circulation, those involving the left anterior descending artery and diagonal branches are the most frequently encountered in clinical trials.9 Regarding the background of thrombosis, anatomical factors, such as the fractal geometry of vascular bifurcations, increase the incidence of strut malapposition and stent underexpansion, leading to an increased ischemic risk. Except from excessive lesion calcification and inflammatory reaction, coronary artery bifurcation lesions exhibit localized turbulent flow and enhanced propensity for platelet aggregation, plaque rupture, and atherothrombosis.29 Of note, flow conditions vary in bifurcation lesion types according to the clinically oriented Medina classification, with Medina 1,0,1 more prone to atherosclerosis progression.30 In addition, shear stress plays an important role in the initiation and proliferation of coronary atherosclerosis.

A baseline low shear stress after bifurcation PCI, which decreases to its minimum value post-procedural, but eventually recovers to around its baseline level, could be the setting of in-stent restenosis.31 Last, but not least, stenting LM or bifurcation lesions usually require the use of a greater total stent length or higher volume of intravenous contrast, factors that could augment the thrombotic risk. Therefore, the implementation of individualized antithrombotic regimens to mitigate the ischemic risk, according to procedural complexity, is of utmost importance.

Stenting Techniques for Left Main Bifurcation and Antiplatelet Therapy Used in Major Trials

Regarding percutaneous LM bifurcation treatment options, the European Bifurcation Club recommends a provisional side branch approach in most

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Antithrombotics in LM and Bifurcation PCI Table 2: Randomized Trials Comparing Left Main Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting Study

Patients (n)

Follow-up

Endpoints

PCI Versus CABG

LEMANS 201613

105

10 years

LVEF Death MACE (death, MI, TVR, stroke)

54.9 ± 8.3% versus 49.8 ± 10.3%; p=0.07 21.6% versus 30.2%; p=0.41 51.1% versus 64.4%; p=0.28

SYNTAX 201914

1,800

5–10 years

MACE [all-cause death, MI, RR, stroke (LM subset)], mainly driven by: RR (LM subset)

36.9% versus 31%; p=0.12 26.7% versus 15.5%, p<0.01

Boudriot et al. 201115

201

12 months

MACE (all-cause death, MI, RR)

19% versus 13.9%; p=0.19

PRECOMBAT 2015

600

2 years

MACE (all-cause death, MI, TVR, stroke) Death MI TVR Stroke

12.2% versus 8.1%; p=0.12 2.4% versus 3.4%; p=0.45 1.7% versus 1%; p=0.49 9.0% versus 4.2%; p=0.02 0.4% versus 0.7%; p=0.56

EXCEL 201917

1,905

5 years

MACE (death, MI, stroke) TVR

22% versus 19.2%; p=0.13 16.9% versus 10%

NOBLE 202018

1,184

5 years

MACE (death, MI, RR, stroke), mainly driven by: • Non-procedural MI • RR

28.9% versus 19.1%; p=0.0066 8% versus 3%; p=0.0002 17% versus 10%; p=0.0009

16

LVEF = left ventricular ejection fraction; MACE = major adverse cardiovascular events; RR = repeat revascularization; TVR = target vessel revascularization.

Table 3: Major Trials Investigating Stenting Techniques and Antiplatelet Agents Used Trial

Population

Study Groups and Endpoints Results

Agent used

Gao et al. 201534

1,528 patients with distal LMCAD and low-mid SYNTAX score

One versus two stents Death, MI, TVR at 4 years

9.2% versus 11.6%, p=0.23

Clopidogrel 300 mg followed by 75 mg Aspirin 300 mg followed by 100 mg

Chen et al. 201724

482 patients with distal bifurcation LMCAD

DK crush versus provisional Cardiac death, TVMI, TVR at 1 year

5% versus 10.7%, HR 0.42; 95% CI [0.21–0.85]; p=0.02

Clopidogrel 300 mg followed by 75 mg Aspirin pretreatment followed by 100 mg

Chen et al. 201235

633 patients with bifurcation LMCAD

DK crush versus other two-stent technique versus one-stent Cardiac death, MI, TVR at 5 years

14.8% versus 37.0% versus 28.0%, p<0.001

Clopidogrel 300 mg followed by 75 mg Aspirin 300 mg for 1 month followed by 100 mg

Chen et al. 201536

419 patients with distal bifurcation LMCAD

DK crush versus Culotte technique Cardiac death, MI, TVR at 3 years

8.2% versus 23.7%, p<0.001

Clopidogrel 75 mg or 300 mg followed by 75 mg Aspirin 300 mg for 1 month followed by 100 mg

Koh et al. 201337

1,147 patients with non-LM true coronary bifurcation lesions

Two versus one stent Death, MI, TVR, TLR at 20 months

HR 0.911, 95% CI [0.614–1.351]; p=0.642

Clopidogrel 300–600 mg or ticlopidine 500 mg followed by maintenance dose Aspirin 300 mg followed by 100 mg

Takagi et al. 201638

937 patients with distal LMCAD

One versus two stents Death, MI, TLR at 1,592 days

HR 1.29, 95% CI [1.03–1.62]; p=0.03

Ticlopidine 200–250 mg twice daily or clopidogrel 75 mg once daily Aspirin 100 mg

DK = double kissing; LMCAD = left main coronary artery disease; TLR = target lesion revascularization; TVMI = target vessel MI; TVR = target vessel revascularization.

cases of distal disease.32 However, two-stent approaches, but mostly the DK crush technique, although technically challenging, have emerged as a preferred approach for true distal LM bifurcation lesions.33 Several observational studies and two randomized trials have already been published, while others are ongoing and the results are awaited with great interest (Table 3).3,24,34–38 Stenting LM bifurcation is feasible with one- or two-stent techniques. A large single-center study that enrolled patients with distal unprotected LM-CAD and a low-intermediate SYNTAX score found that the two techniques did not differ significantly regarding MACE at a mean followup of 4 years.34 Additionally, data collected from the Korea Coronary Bifurcation Stent registry found non-inferiority of the one-stent technique compared with the two-stent technique in patients with non-LM true coronary bifurcation disease.37 Of interest, the two-stent technique has been linked to a higher incidence of TLF, mainly caused by restenosis at

the ostial left circumflex artery.38 In contrast, there is cumulative evidence that the DK crush technique could be a favorable approach to true LM bifurcation PCI. The DK crush technique resulted in lower rates of a composite primary endpoint at 1-year follow-up compared with provisional stenting in patients with distal bifurcation LM-CAD.24 Moreover, the DK crush technique was associated with significantly lower rates of MACE and ST compared with the Culotte technique, mainly due to a decrease in MI (3.4 versus 8.2%, p=0.037) and target vessel revascularization (5.8 versus 18.8%, p<0.001), as well as significantly decreased rates of MACE at 5-year follow-up, compared with the other two-stent approaches or the one-stent approach, mainly driven by a reduction in target vessel revascularization (7.7 versus 30.5 versus 18.1%, p<0.001).35,36 Regarding antiplatelet agents of choice, clopidogrel at a loading dose of 300 mg and aspirin were administered in the majority of trials delineating stenting techniques (Table 2). Ticlopidine was another option, while potent P2Y12 inhibitors, such as prasugrel or ticagrelor,

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Antithrombotics in LM and Bifurcation PCI were not used in these studies’ populations. The duration of DAPT was mostly for 12 months.

Duration and Type of Antiplatelet Therapy in Left Main and/or Bifurcation PCI

The aforementioned findings point to the fact that patients undergoing PCI of LM bifurcation are at increased risk for thrombotic complications.

Therefore, intensification of antithrombotic pharmacotherapy might be beneficial towards ischemic risk mitigation in this subset of population, although data are scarce. In trials exploring the optimal antiplatelet treatment strategy in complex PCI patients, prolongation of DAPT seemed beneficial in terms of ischemic outcomes, with the caveat of a potential higher bleeding risk.

In patients undergoing complex PCI, the prolonged DAPT (≥12 months) group experienced a significant MACE reduction in comparison with short DAPT (3–6 months) group (adjusted HR 0.56; 95% CI [0.35–0.89]), although this was associated with a higher incidence of major bleeding (1.03 versus 0.52%; incidence rate difference 0.51%). The beneficial effect of long-term DAPT on MACE reduction was homogenous between the subsets of complex PCI; that is, patients with multivessel PCI and bifurcation PCI with two stents (incidence rate difference −8.31% and −0.42% for long-term versus short-term DAPT, respectively) were favored for this approach.26 Similarly, prolonged DAPT (≥12 months) was associated with a reduced incidence of all-cause death or MI and ST at 4-year followup compared with a short-term strategy (<12 months) among 2,082 patients undergoing bifurcation stenting (adjusted HR 0.21; 95% CI [0.13– 0.35]; p<0.001; and adjusted HR 0.08; 95% CI [0.01–0.43]; p=0.003, respectively). Interestingly, the beneficial role of prolonged DAPT was not significantly affected by lesion location (LM bifurcation) or stenting technique (one or two-stent technique).39 However, in a study by Rhee et al., extension of DAPT (≥12 months) seemed more beneficial to patients undergoing LM bifurcation PCI with implantation of two stents, as the selection of a two-stent strategy was related with higher rates of both TLF and thrombotic adverse cardiovascular events compared with a one-stent strategy in the subgroup of short-term DAPT (<12 months; HR 11.45; 95% CI [2.73–47.95]; p=0.001 for TLF; and HR 7.84; 95% CI [2.11–29.22]; p=0.002 for thrombotic adverse cardiovascular events).40 Similar conclusions regarding the optimal DAPT duration can be drawn from the multicenter Euro Bifurcation Club – P2BiTO – registry. In a 2-year follow-up period, an increased incidence of MACE was observed in the short-term DAPT group (<6 months) compared with the long-term (>12 months) and the intermediate groups (6–12 months; 14% versus 10% and 10% respectively, HR 0.72; 95% CI [0.64–0.82]; p<0.001). The difference in results remained unchanged after adjustment for clinical and angiographic characteristics (HR 0.66; 95% CI [0.58–0.77]; p<0.001). MACE-free survival was significantly lower in the group of DAPT duration <6 months (log-rank 29.5, p<0.001).41 Furthermore, results from the PRODIGY trial showed that 24-month DAPT was associated with lower occurrence of ST compared with the 6-month arm only in patients with LM or proximal LAD disease (2.8 versus 5.6%; HR 0.45; 95% CI [0.23–0.89]; p=0.02), but not in patients with other lesions, with a highly significant interaction testing (p for interaction=0.002).42 In a different approach, triple antiplatelet therapy by adding cilostazol to DAPT provided no additional long-term benefit in real-world patients undergoing bifurcation PCI. Patients on cilostazol had more comorbidities;

however, no statistically significant difference was observed regarding TLF (adjusted HR 0.86; 95% CI [0.53–1.39]; p=0.53) or other outcomes (death, cardiac death, MI, ST, TVR, or cerebrovascular accident).43 Novel P2Y12 receptor inhibitors provide more potent and consistent antiplatelet action, and may be useful in higher thrombotic burden procedures, including bifurcation PCI, at the expense of higher bleeding risk. In this context, there is a tendency in favor of ticagrelor and prasugrel over clopidogrel in patients with both high ischemic and low bleeding risk, although such an approach has not been established. D’Ascenzo et al. investigated the clinical outcomes following PCI with implantation of thin stents (<100 microns) in unprotected LM stenosis or main coronary bifurcation lesions in relation to DAPT duration. The primary endpoint included cardiovascular death, MI, TVR, and ST. Clopidogrel was the most common antiplatelet prescribed. Ticagrelor was administered in 31.3% of the total study population, while prasugrel was administered in 6.2% of the total study population. At a mean follow-up of 12.8 months, MACE occurred significantly more often in the short DAPT arm of ≤3 months, compared with the 3–12-month and 12-month groups (9.4 versus 4.0 versus 7.2%; p<0.001), a difference mainly driven by MI (4.4 versus 1.5 versus 3%; p<0.001) and overall ST (4.3 versus 1.5 versus 1.8%, p<0.001). Of note, in contrast to provisional stenting, a two-stent strategy was an independent predictor of MACE (OR 1.6; 95% CI [1.1–2.3]) at multivariate analysis and ST (OR 3.241; 95% CI [1.048–10.026]) after DAPT cessation. Regarding antiplatelets, the risk of ST was significantly higher in the 3-month group irrespective of the regimen used (clopidogrel, prasugrel, or ticagrelor).44 In contrast, the results from a smaller single-center retrospective cohort study argue in favor of ticagrelor as part of DAPT during the first year of post-bifurcation PCI. Among 584 patients treated for bifurcation lesions, a higher incidence of MACE was observed in patients on DAPT with clopidogrel (34/283 patients; 12.01%) in comparison with ticagrelor (22/270; 8.15%) with an adjusted HR of 0.488 (95% CI [0.277–0.861]; p=0.013) in favor of ticagrelor. Of interest, patients treated with ticagrelor tended to have a higher proportion of true bifurcation lesions, LM disease, and higher SYNTAX score. In contrast, clopidogrel was more commonly used in patients with LAD/diagonal PCI. As expected, ticagrelor was associated with a higher incidence of total bleeding events (adjusted HR 1.791; 95% CI [1.214–2.644], p=0.003), although major bleeding rates were similar between the two DAPT strategies (2.47% and 2.96% for the clopidogrel and ticagrelor groups, respectively; adjusted HR 0.972; 95% CI [0.321–2.941]; p=0.960).45 PROMETHEUS was an observational study that compared clopidogrel versus prasugrel in patients undergoing PCI in the setting of an acute coronary syndrome (ACS). The study population was divided into a noncomplex or complex PCI group; the latter including stenting LM (6.9%) or bifurcation lesions (20.1%). Prasugrel was used in almost one-fifth of the patients. Of note, its use declined with rising PCI complexity. In general, 1-year MACE rates were significantly higher in the complex PCI arm.

Compared with clopidogrel, prasugrel reduced the adjusted risk for 1-year MACE in the complex PCI group (HR 0.79; 95% CI [0.68–0.92]), but not in the non-complex PCI group (HR 0.91; 95% CI [0.77–1.08]), albeit there was no evidence of interaction (p interaction=0.281).46 Of note, bifurcation PCI was one of the main parameters associated with a greater absolute risk reduction of ST (3.2%) in the prasugrel arm compared with the clopidogrel arm in the TRITON-TIMI trial.47 In the context of the GLOBAL LEADERS trial, Kogame et al. compared the experimental treatment strategy of 1-month DAPT with ticagrelor and

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Antithrombotics in LM and Bifurcation PCI aspirin followed by 23 months of ticagrelor monotherapy with the standard antiplatelet treatment (12 months of DAPT followed by aspirin monotherapy), focusing on patients undergoing bifurcation PCI. The latter group presented similar incidence of the primary endpoint (all-cause death or new Q wave MI) compared with undergoing non-bifurcation PCI (4.7 versus 4.0%, p=0.083), although bifurcation stenting was related with an increased need for revascularization (11.21 versus 9.19; HR 1.24; 95% CI [1.09–1.41]; p=0.001). However, the experimental treatment failed to provide a significant benefit in terms of ischemic outcomes, while the presence or absence of a bifurcation lesion did not seem to impact on its effect regarding the primary endpoint (bifurcation: HR 0.74; 95% CI [0.51–1.07]; non-bifurcation: HR 0.90; 95% CI [0.76–1.07], p for interaction=0.343).48 Finally, in the TWILIGHT-COMPLEX study, patients were randomized to ticagrelor monotherapy or DAPT after 3 months of index MI. LM PCI and bifurcation with two stents implanted represented 15.1% and 21.4% of complex PCI patients (2,342 patients in total). Among the whole spectrum of patients undergoing complex PCI, ticagrelor monotherapy compared with ticagrelor plus aspirin resulted in lower rates of the primary endpoint of BARC type 2, 3, or 5 bleeding (4.2% versus 7.7%; absolute risk difference 3.5%; HR 0.54; 95% CI [0.38–0.76]) and BARC type 3 or 5 bleeding (1.1% versus 2.6%; absolute risk difference 1.5%; HR 0.41; 95% CI [0.21–0.80]), without compromising efficacy (3.8% versus 4.9%; HR 0.77; 95% CI [0.52– 1.15] for the composite of death, MI, or stroke; and 0.4% versus 0.8%; HR 0.56; 95% CI [0.19–1.67] for ST).49 The aforementioned trials highlight that the extension of DAPT beyond 12 months seems an appealing strategy toward reduction of thrombotic risk in this subset of patients provided a careful consideration of individual bleeding tendency. Regarding the antiplatelet agent of choice, there are some data supporting the use of more potent P2Y12 inhibitors instead of clopidogrel, although more evidence is required.

However, longer DAPT (12–24 months) or use of novel P2Y12 inhibitors seems more reasonable for patients with bifurcation disease treated with a two-stent technique.26,40,44,45 Recently, Zimarino et al. proposed an algorithm regarding antithrombotic treatment in patients undergoing bifurcation PCI. Clinical presentation, baseline bleeding risk, stenting strategy, and possible use of intracoronary imaging are among the factors that should be taken into account for decision-making in this high-risk population.29

High-bleeding-risk Patients

Although assessment of bleeding risk is a challenging task, it seems to significantly affect decision-making regarding the type and duration of antiplatelet therapy, even in patients undergoing PCI for LM/bifurcation disease, considered to be at higher ischemic risk. Validated scores estimating bleeding risk, such as the PRECISE-DAPT and PARIS score, can be used to tailor the treatment strategy, whereas a consensus document from the Academic Research Consortium for High Bleeding Risk (HBR) defined major and minor criteria to characterize a HBR patient undergoing PCI.50–52 Recently, two prognostic models were developed to evaluate the trade-off between high thrombotic and bleeding risk, aiding toward a more personalized treatment approach.53 Interestingly, in a study by Costa et al., HBR patients (defined as PRECISE-DAPT ≥25) undergoing a complex procedure, including bifurcation stenting, did not seem to benefit from long-term DAPT (12 or 24 months) in terms of ischemic or mortality risk reduction, a fact highlighting that in cases of both elevated ischemic and hemorrhagic risk, the latter should primarily guide treatment strategy.

Consequently, a DAPT of shorter duration (3 or 6 months) could be

Figure 2: Factors Affecting Antithrombotic Therapy in Patients Undergoing Left Main and/or Bifurcation Percutaneous Coronary Intervention Standard of care ACS: Prasugrel or ticagrelor plus aspirin for 12 months CCS: Clopidogrel plus aspirin for 6 months

Favors Prolonged DAPT (12–24 months) ± potent antiplatelets Clinical characteristics Diabetes Recurrent MI PAD Premature CAD <45 years of age Concomitant systemic inflammatory disease Moderate CKD (eGFR 30–59 ml/min/1.73m2) Angiographic aspects Bifurcation with two stents implanted Distal LM with SB-DS ≥70% Non-LM with SB-DS ≥90% SB lesion length ≥10 mm Main vessel reference diameter <2.5 mm Bifurcation angle <45° Multivessel CAD

Favors Standard of care or even shorter DAPT (3–6 months) Clinical characteristics Stable disease Age >75 years of age Anemia Concomitant medication* Chronic bleeding diathesis** Any history of hemorrhage Severe CKD (eGFR <30 ml/min/1.73m2) Angiographic aspects One stent implanted No kissing balloon (struts opening) Intravascular imaging used Main vessel reference diameter >3 mm Stent-to-artery ration 1:1 DES: Synergy, Xience, Onyx

*OAC, NSAID, steroids. **Thrombocytopenia, liver cirrhosis, active malignancy.

A figure to guide decision-making regarding the type and duration of antiplatelet therapy in the context of left main/bifurcation percutaneous coronary intervention, based on the clinical scenario and comorbidities, and also angiographic features and technical aspects regarding left main and bifurcation percutaneous coronary intervention. ACS = acute coronary syndrome; CAD = coronary artery disease; CCS = chronic coronary syndrome; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; DES = drug-eluting stents; DS = diameter stenosis; eGFR = estimated glomerular filtration rate; LM = left main; MI = myocardial infarction; NSAID, non-steroidal anti-inflammatory drug; OAC = oral anticoagulant; PAD = peripheral artery disease; SB = side branch.

appropriate, providing careful consideration of individual clinical and angiographic factors.54 Furthermore, recent evidence supports an even shortened DAPT duration (1–3 months) with newer-generation drug-eluting stents, such as Synergy (Boston Scientific) bioabsorbable polymer-coated everolimus-eluting stent or Resolute Onyx (Medtronic) zotarolimus-eluting stent, in the HBR population, without compromising efficacy.55,56 Of note, in the Onyx One study comparing Resolute Onyx with a polymer-free umirolimus-coated stent, the former was not inferior regarding safety and effectiveness in HBR patients receiving single antiplatelet therapy after 1 month of DAPT; notably, the majority of patients were treated for complex type B2/C lesions, while up to 16% of total patients had bifurcation PCI.57 Regarding the type of antiplatelet agents, potent P2Y12 inhibitors have been associated with a higher incidence of bleeding complications compared with clopidogrel; thus, their role in this subset of patients is limited.7,58

Perspectives

Both European and US guidelines include bifurcation with two stents implanted as a high-risk feature for ischemic events, among other characteristics of PCI complexity, suggesting that a longer duration of DAPT (≥ 6 months) may be considered in patients with chronic coronary syndromes.7,33,59 In recently published guidelines regarding ACS, a prolonged DAPT duration (≥12 months) is a class IIa recommendation in patients without increased risk of major or life-threatening bleeding.8

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Antithrombotics in LM and Bifurcation PCI Regarding the choice of antiplatelet agent in the setting of ACS, ticagrelor or prasugrel are recommended over clopidogrel due to their proven superior efficacy with a class I recommendation.7 In contrast, clopidogrel is still the preferred agent in patients with chronic coronary syndrome and PCI, while potent inhibitors may be considered with a class IIb recommendation at least as initial therapy, in specific high-risk situations of elective stenting, such as complex left main PCI or multivessel stenting.60 Interestingly, among patients who underwent complex PCI, a regimen of ticagrelor monotherapy (after an initial 3 months of DAPT with ticagrelor and aspirin) was associated with significantly lower clinically relevant bleeding rates without increasing the risk of ischemic events in comparison with the continuation of DAPT, providing an alternative strategy to double therapy extension.49 Regarding intravenous antiplatelet agents, experts suggest that patients, not pretreated with oral P2Y12 inhibitors, undergoing complex PCI could be ideal candidates for cangrelor administration during index MI.61 Glycoprotein IIb/IIIa inhibitors may still play an important therapeutic role in challenging clinical scenarios, such as revascularization of LM 1. Zalewska-Adamiec M, Bachórzewska-Gajewska H, Paweł K et al. Prognosis in patients with left main coronary artery disease managed surgically, percutaneously or medically: a long-term follow-up. Kardiol Pol 2013;71:787–95. https://doi. org/10.5603/KP.2013.0189; PMID: 24049017.

2. Collet C, Capodanno D, Onuma Y, et al. Left main coronary artery disease: pathophysiology, diagnosis, and treatment.

Nat Rev Cardiol 2018;15:321–31. https://doi.org/10.1038/ s41569-018-0001-4; PMID: 29599504.

3. Ramadan R, Boden WE, Kinlay S. Management of left main coronary artery disease. J Am Heart Assoc 2018;7:e008151. https://doi.org/10.1161/JAHA.117.008151; PMID: 29605817.

4. Staudacher DL, Schmitt C, Zirlik A, et al. Predictors of survival in patients with acute coronary syndrome undergoing percutaneous coronary intervention of unprotected left main coronary artery stenosis. Catheter Cardiovasc Interv 2020;96:E27–33. https://doi.org/10.1002/ ccd.28495; PMID: 31512392.

5. Naganuma T, Chieffo A, Meliga E, et al. Long-term clinical outcomes after percutaneous coronary intervention for ostial/mid-shaft lesions versus distal bifurcation lesions in unprotected left main coronary artery: the DELTA Registry (drug-eluting stent for left main coronary artery disease): a multicenter registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment. JACC Cardiovasc Interv 2013;6:1242–9. https://doi.org/10.1016/j.jcin.2013.08.005; PMID: 24355114.

6. Yeh RW, Kereiakes DJ, Steg PG, et al. Lesion complexity and outcomes of extended dual antiplatelet therapy after percutaneous coronary intervention. J Am Coll Cardiol 2017;70:2213–23. https://doi.org/10.1016/j.jacc.2017.09.011; PMID: 29073947.

7. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. https://doi.org/10.1093/ eurheartj/ehx419; PMID: 28886622.

8. Collet JP, Thiele H, Barbato E, et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021;42:1289–1367. https://doi.org/10.1093/eurheartj/ ehaa624; PMID: 32860058.

9. Chen SL, Sheiban I, Xu B, et al. Impact of the complexity of bifurcation lesions treated with drug-eluting stents: the DEFINITION study (Definitions and impact of complEx biFurcation lesIons on clinical outcomes after percutaNeous coronary IntervenTIOn using drug-eluting steNts). JACC Cardiovasc Interv 2014;7:1266–76. https://doi.org/10.1016/j. jcin.2014.04.026; PMID: 25326748.

10. Ragosta M. Left main coronary artery disease: importance, diagnosis, assessment, and management. Curr Probl Cardiol 2015;40:93–126. https://doi.org/10.1016/j. cpcardiol.2014.11.003; PMID: 25765453.

11. Stone GW, Sabik JF, Serruys PW, et al. Everolimus-eluting stents or bypass surgery for left main coronary artery

bifurcation, with the caveat of increased bleeding complications. Of note, the use of intracoronary bolus tirofiban may represent an effective and safe strategy to achieve rapid thrombus resolution in ACS patients with complex coronary anatomy.62 In summary, there is a particular interest regarding antithrombotic therapy type and duration in this subset of patients, with decision-making mostly based on clinical presentation, baseline bleeding, and ischemic risk, as well as the performed stenting strategy. Factors affecting antithrombotic treatment in patients undergoing LM and/or bifurcation PCI are shown in Figure 2.29,52,63

Conclusion

In the recent era of second-generation DES, PCI is gaining ground over CABG in revascularization of LM-CAD and complex bifurcation lesions.

Optimal antithrombotic treatment has yet to be defined, though; prolonged DAPT has shown some benefit regarding adverse cardiovascular events, with a caveat of potentially increased bleeding rates. Additionally, selecting a more potent P2Y12 inhibitor seems to be a reasonable choice in patients with low hemorrhagic risk, although more randomized studies and data are required to support their use in selected patients.

disease. N Engl J Med 2016;375:2223–35. https://doi. org/10.1056/NEJMoa1610227; PMID: 27797291.

12. Makikallio T, Holm NR, Lindsay M, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial.

Lancet 2016;388:2743–52. https://doi.org/10.1016/S01406736(16)32052-9; PMID: 27810312.

13. Buszman PE, Buszman PP, Banasiewicz-Szkróbka I, et al.

Left main stenting in comparison with surgical revascularization: 10-year outcomes of the (Left Main Coronary Artery Stenting) LE MANS Trial. JACC Cardiovasc Interv 2016;9:318–27. https://doi.org/10.1016/j. jcin.2015.10.044; PMID: 26892080.

14. Thuijs DJFM, Kappetein AP, Serruys PW, et al.

Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial. Lancet 2019 12;394:1325–34. https://doi.org/10.1016/S01406736(19)31997-X; PMID: 31488373.

15. Boudriot E, Thiele H, Walther T, et al. Randomized comparison of percutaneous coronary intervention with sirolimus-eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis. J Am Coll Cardiol 2011;57:538–45. https://doi.org/10.1016/j. jacc.2010.09.038; PMID: 21272743.

16. Ahn JM, Roh JH, Kim YH, et al. Randomized trial of stents versus bypass surgery for left main coronary artery disease: 5-year outcomes of the PRECOMBAT study. J Am Coll Cardiol 2015;65:2198–206. https://doi.org/10.1016/j. jacc.2015.03.033; PMID: 25787197.

17. Stone GW, Kappetein AP, Sabik JF, et al. Five-year outcomes after PCI or CABG for left main coronary disease. N Engl J Med 2019;381:1820–30. https://doi.org/10.1056/ NEJMoa1909406; PMID: 31562798.

18. Holm NR, Mäkikallio T, Lindsay MM, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial. Lancet 2020;395:191–9. https://doi.org/10.1016/ S0140-6736(19)32972-1; PMID: 31879028.

19. Ahmad Y, Howard JP, Arnold AD, et al. Mortality after drugeluting stents vs. coronary artery bypass grafting for left main coronary artery disease: a meta-analysis of randomized controlled trials. Eur Heart J 2020;41:3228–5. https://doi.org/10.1093/eurheartj/ehaa135; PMID: 32118272.

20. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/ AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease.

J Am Coll Cardiol 2012;60:e44–164. https://doi.org/10.1016/j. jacc.2012.07.013; PMID: 23182125.

21. Mori H, Kutys R, Torii S, et al. Pathological features of left main stent thrombosis. J Am Coll Cardiol 2017;6(11 Suppl 2)9:1151. https://doi.org/10.1016/S0735-1097(17)34540-0.

22. Hachinohe D, Mitomo S, Candilio L, et al. A practical approach to assessing stent results with IVUS or OCT. Methodist Debakey Cardiovasc J 2018;14:32–41. https://doi. org/10.14797/mdcj-14-1-32; PMID: 29623170.

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23. Wang J, Guan C, Chen J, et al. Validation of bifurcation DEFINITION criteria and comparison of stenting strategies in true left main bifurcation lesions. Sci Rep 2020;10:10461. https://doi.org/10.1038/s41598-020-67369-9; PMID: 32591602.

24. Chen SL, Zhang JJ, Han Y, et al. Double kissing crush versus provisional stenting for left main distal bifurcation lesions: DKCRUSH-V randomized trial. J Am Coll Cardiol 2017;70:2605–17. https://doi.org/10.1016/j.jacc.2017.09.1066; PMID: 29096915.

25. Zimarino M, Briguori C, Amat-Santos IJ, et al. Mid-term outcomes after percutaneous interventions in coronary bifurcations. Int J Cardiol 2019;283:78–83. https://doi. org/10.1016/j.ijcard.2018.11.139; PMID: 30528620.

26. Giustino G, Chieffo A, Palmerini T, et al. Efficacy and safety of dual antiplatelet therapy after complex PCI. J Am Coll Cardiol 25;68:1851–64. https://doi.org/10.1016/j. jacc.2016.07.760; PMID: 27595509.

27. Stone GW, Witzenbichler B, Weisz G, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013;382:614– 23. https://doi.org/10.1016/S0140-6736(13)61170-8; PMID: 23890998 28. Mohamed MO, Polad J, Hildick-Smith D, et al. Impact of coronary lesion complexity in percutaneous coronary intervention: one-year outcomes from the large, multicentre e-Ultimaster registry. EuroIntervention 2020;16:603–12. https://doi.org/10.4244/EIJ-D-20-00361; PMID: 32588821.

29. Zimarino M, Angiolillo DJ, Dangas G, et al. Antithrombotic therapy after percutaneous coronary intervention of bifurcation lesions. EuroIntervention 2021;17:59–66. https:// doi.org/10.4244/EIJ-D-20-00885; PMID: 32928716.

30. Zarandi MM, Mongrain R, Bertrand OF. Determination of flow conditions in coronary bifurcation lesions in the context of the medina classification. Modelling and Simulation in Engineering 2012;419087. https://doi.org/10.1155/2012/419087.

31. Hu ZY, Chen SL, Zhang JJ, et al. Distribution and magnitude of shear stress after coronary bifurcation lesions stenting with the classical crush technique: a new predictor for in-stent restenosis. J Interv Cardiol 2010;23:330–40. https:// doi.org/10.1111/j.1540-8183.2010.00571.x; PMID: 20642479.

32. Lassen JF, Burzotta F, Banning AP, et al. Percutaneous coronary intervention for the left main stem and other bifurcation lesions. The 12th consensus document from the European Bifurcation Club. EuroIntervention 2018;13:1540–53. https://doi.org/10.4244/EIJ-D-17-00622; PMID: 29061550.

33. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/ EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy855; PMID: 30615155.

34. Gao Z, Xu B, Yang Y, et al. Comparison between one-stent versus two-stent technique for treatment of left main bifurcation lesions: a large single-center data. Catheter Cardiovasc Interv 2015;85:1132–8. https://doi.org/10.1002/ ccd.25849; PMID: 25614097.

35. Chen SL, Zhang Y, Xu B, et al. Five-year clinical follow-up of unprotected left main bifurcation lesion stenting: one-stent versus two-stent techniques versus double-kissing crush

Antithrombotics in LM and Bifurcation PCI technique. EuroIntervention 2012;8:803–14. https://doi. org/10.4244/EIJV8I7A123; PMID: 23171801.

36. Chen SL, Xu B, Han YL, et al. Clinical outcome after DK crush versus culotte stenting of distal left main bifurcation lesions: the 3-year follow-up results of the DKCRUSH-III study. JACC Cardiovasc Interv 2015;8:1335–42. https://doi. org/10.1016/j.jcin.2015.05.017; PMID: 26315736.

37. Koh YS, Kim PJ, Chang K, et al. Long-term clinical outcomes of the one-stent technique versus the two-stent technique for non-left main true coronary bifurcation disease in the era of drug-eluting stents. J Interv Cardiol 2013;26:245–53. https://doi.org/10.1111/joic.12025; PMID: 23480867.

38. Takagi K, Naganuma T, Chieffo A, et al. Comparison between 1- and 2-stent strategies in unprotected distal left main disease: the Milan and New-Tokyo registry. Circ Cardiovasc Interv 2016;9:e003359. https://doi.org/10.1161/ CIRCINTERVENTIONS.116.003359; PMID: 27810964.

39. Jang WJ, Ahn SG, Song YB, et al. Benefit of prolonged dual anti- platelet therapy after implantation of drug-eluting stent for coronary bifurcation lesions: results from the Coronary Bifurcation Stenting Registry II. Circ Cardiovasc Interv 2018;11:e005849. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.005849; PMID: 30006330.

40. Rhee TM, Park KW, Kim CH, et al. Dual antiplatelet therapy duration determines outcome after 2- but not 1-stent strategy in left main bifurcation percutaneous coronary intervention. JACC Cardiovasc Interv 2018;11:2453–63. https:// doi.org/10.1016/j.jcin.2018.09.020; PMID: 30573055.

41. Di Serafino L, Gamra H, Cirillo P, et al. Impact of dual antiplatelet therapy duration on clinical outcome after stent implantation for coronary bifurcation lesions: results from the Euro Bifurcation Club – P2BiTO – registry. Eur Heart J 2019;40(Suppl 1):ehz748.0709. https://doi.org/10.1093/ eurheartj/ehz748.0709.

42. Costa F, Adamo M, Ariotti S, et al. Left main or proximal left anterior descending coronary artery disease location identifies high-risk patients deriving potentially greater benefit from prolonged dual antiplatelet therapy duration.

EuroIntervention 2016;11:e1222–30. https://doi.org/10.4244/ EIJY15M08_04; PMID: 26342472.

43. Song PS, Song YB, Yang JH, et al. Triple versus dual antiplatelet therapy after percutaneous coronary intervention for coronary bifurcation lesions: results from the COBIS (COronary BIfurcation Stent) II Registry. Heart Vessels 2015;30:458–68. https://doi.org/10.1007/s00380-0140500-0; PMID: 24682436.

44. D’Ascenzo F, Barbero U, Abdirashid M, et al. Incidence of adverse events at 3 months versus at 12 months after dual antiplatelet therapy cessation in patients treated with thin stents with unprotected left main or coronary bifurcations.

Am J Cardiol 2020;125:491–9. https://doi.org/10.1016/j.

amjcard.2019.10.058; PMID: 31889527.

45. Zheng W, Li Y, Tian J, et al. Effects of ticagrelor versus clopidogrel in patients with coronary bifurcation lesions undergoing percutaneous coronary intervention. Biomed Res Int 2019;20:3170957. https://doi.org/10.1155/2019/3170957; PMID: 31016189.

46. Chandrasekhar J, Baber U, Sartori S, et al. Associations between complex PCI and prasugrel or clopidogrel use in patients with acute coronary syndrome who undergo PCI: from the PROMETHEUS study. Can J Cardiol 2018;34:319–29. https://doi.org/10.1016/j.cjca.2017.12.023; PMID: 29475531.

47. Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008;371:1353–63. https://doi.org/10.1016/S0140-6736(08)60422-5; PMID: 18377975.

48. Kogame N, Chichareon P, De Wilder K, et al. Clinical relevance of ticagrelor monotherapy following 1-month dual antiplatelet therapy after bifurcation percutaneous coronary intervention: insight from GLOBAL LEADERS trial. Catheter Cardiovasc Interv 2020;96:100–11. https://doi.org/10.1002/ ccd.28428; PMID: 31410968.

49. Dangas G, Baber U, Sharma S, et al. Ticagrelor with or without aspirin after complex PCI. J Am Coll Cardiol 2020;75:2414–24. https://doi.org/10.1016/j.jacc.2020.03.011; PMID: 32240761.

50. Camarero TG, de la Torre Hernández JM. Antithrombotic treatment after coronary intervention: agreement and controversy. Eur Cardiol 2020;15:1–8. https://doi. org/10.15420/ecr.2019.25.2; PMID: 32180829.

51. Baber U, Mehran R, Giustino G, et al. Coronary thrombosis and major bleeding after PCI with drug-eluting stents: risk scores from PARIS. J Am Coll Cardiol 2016;67:2224–34. https://doi.org/10.1016/j.jacc.2016.02.064; PMID: 27079334.

52. Urban P, Mehran R, Colleran R, et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention. Circulation 2019;140:240–61. https://doi. org/10.1093/eurheartj/ehz372; PMID: 31116395.

53. Urban P, Gregson J, Owen R, et al. Assessing the risks of bleeding vs thrombotic events in patients at high bleeding risk after coronary stent implantation: the ARC-High Bleeding Risk Trade-off Model. JAMA Cardiol 2021;6:e206814. https://doi.org/10.1001/ jamacardio.2020.6814; PMID: 33404627.

54. Costa F, Van Klaveren D, Feres F, et al. Dual antiplatelet therapy duration based on ischemic and bleeding risks after coronary stenting. J Am Coll Cardiol 2019;73:741–54. https://doi.org/10.1016/j.jacc.2018.11.048; PMID: 30784667.

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55. Kirtane AJ, Stoler R, Feldman R, et al. Primary results of the EVOLVE Short DAPT study: evaluation of 3-month dual antiplatelet therapy in high bleeding risk patients treated with a bioabsorbable polymer-coated everolimus-eluting stent. Circ Cardiovasc Interv 2021;14:101044; https://doi. org/10.1161/CIRCINTERVENTIONS.120.010144; PMID: 33641374.

56. Kandzari DE, Kirtane AJ, Windecker S, et al. One-month dual antiplatelet therapy following percutaneous coronary intervention with zotarolimus-eluting stents in highbleeding-risk patients. Circ Cardiovasc Interv 2020;13:e009565. https://doi.org/10.1161/ CIRCINTERVENTIONS.120.009565; PMID: 33167705.

57. Windecker S, Latib A, Kedhi E, et al. Polymer-based or polymer-free stents in patients at high bleeding Risk. N Engl J Med 2020;382:1208–18. https://doi.org/10.1056/ NEJMoa1910021; PMID: 32050061.

58. Gragnano F, Moscarella E, Calabrò P, et al. Clopidogrel versus ticagrelor in high-bleeding risk patients presenting with acute coronary syndromes: insights from the multicenter START-ANTIPLATELET registry. Intern Emerg Med 2021;16:379–87. https://doi.org/10.1007/s11739-020-02404-1; PMID: 32557093.

59. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082–115. https://doi.org/10.1016/j.jacc.2016.03.513; PMID: 27036918.

60. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504439.

61. Capodanno D, Milluzzo RP, Angiolillo DJ. Intravenous antiplatelet therapies (glycoprotein IIb/IIIa receptor inhibitors and cangrelor) in percutaneous coronary intervention: from pharmacology to indications for clinical use. Ther Adv Cardiovasc Dis 2019;13:1753944719893274. https://doi. org/10.1177/1753944719893274; PMID: 31823688.

62. Wilmer CI. Intracoronary high-dose bolus tirofiban administration during complex coronary interventions: a United States-based case series. Cardiovasc Revasc Med 2018;19:112–6. https://doi.org/10.1016/j.carrev.2017.06.009; PMID: 28684062.

63. Schüpke S, Neumann FJ, Menichelli M, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med 2019;381:1524–34. https://doi.org/10.1056/ NEJMe1911207; PMID: 31618546.

Interventional Cardiology

Transcatheter Tricuspid Valve Intervention: Current Perspective Trevor J Simard, MD,

and Mackram F Eleid, MD

Department of Cardiovascular Medicine, Mayo Clinic School of Medicine, Rochester, MN

Abstract

Tricuspid regurgitation (TR) adversely impacts both quality of life and long-term survival, which generates interest in therapeutic approaches to mitigate these effects. Historically, therapeutic options for TR were limited to surgical approaches, which are often complicated by significant morbidity and mortality in elderly patients with multiple comorbidities. This gap in therapeutic options led to the rapid evolution of transcatheter tricuspid valve intervention (TTVI), with a wide variety of approaches pursued and early results suggesting that TTVI improves clinical outcomes.

Numerous strategies, including edge-to-edge repair, annular reduction, spacers, caval valve implantation, and transcatheter tricuspid valve replacement form the basis of TTVI today. In this review, the authors discuss the current state of each approach.

Keywords

Tricuspid regurgitation, transcatheter, TTVI, TTVR Disclosure: The authors have no conflicts of interest to declare.

Received: November 17, 2020 Accepted: March 14, 2021 Citation: US Cardiology Review 2021;15:e12. DOI: https://doi.org/10.15420/usc.2020.26 Correspondence: Mackram F Eleid, MD, Department of Cardiovascular Medicine, Mayo Clinic School of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

E: eleid.mackram@mayo.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The prevalence of tricuspid regurgitation (TR) increases with age, with up to 6% of individuals having moderate or greater TR over the age of 75, representing an ever-growing cohort.1,2 TR is known to adversely impact both quality of life and long-term survival, particularly in people with mitral regurgitation.1,3,4 Accordingly, an expanding population will stand to benefit from the development of dedicated transcatheter tricuspid valve intervention (TTVI) approaches to reduce morbidity and mortality.1,3 Mechanistically, TR mirrors mitral regurgitation (MR). Primary TR denotes abnormalities of the leaflet, chordae and papillary muscles, while secondary TR involves right ventricle (RV) dilation leading to leaflet tethering or annular dilation, and is often related to left-sided cardiac issues. Finally, isolated TR is a separate entity resulting from right atrium (RA) and tricuspid valve (TV) annulus dilation without left-sided heart disease and often presents in elderly patients with atrial fibrillation, akin to atrial MR as previously described.5–7 These differing mechanisms lend themselves to different interventional approaches.

TR quantification has proven considerably more challenging than MR quantification, with traditional scoring methods inadequately describing the magnitudes of regurgitation often encountered – an important consideration when standardizing intervention assessment. Accordingly, there is momentum to revise the TR quantification scale to better reflect the pathologies encountered by including the terms ‘massive’ and ‘torrential’, with specific criteria already proposed.8 Historically, therapeutic options for TR were limited, with guidelines supporting surgical intervention for even mild TR when present at the time of concomitant left-sided cardiac surgery.9 Interestingly, isolated TV surgery remains rare and continues to have a high mortality rate

of 8.8% – the highest risk of all surgical valve interventions.10,11 The noted morbidity and mortality of TR coupled with a lack of therapeutic approaches spurred rapid innovation with numerous approaches to TTVI as a result.

To ensure standardized assessment of this rapidly evolving field, the International Multisite Transcatheter Tricuspid Valve Therapies (TriValve Registry; NCT03416166) was recently established, enabling swift outcome monitoring regardless of device type.12 Early results suggest that TTVI has better survival rates and fewer admissions for heart failure (HF) than medical therapy for symptomatic TR.13,14 Reassuringly, even in patients with massive and torrential TR, who are known to have greater mortality and HF admissions than severe those with TR, studies suggest consistent benefit with improved outcomes following successful TTVI.15,16 Enhanced awareness coupled with considerable advancements in transcatheter technology have generated a marked expansion in the TTVI space, with numerous strategies approaching this pathologic state from different angles.11

Edge-to-edge Repair

Transcatheter edge-to-edge valve repair, modeled after the surgical Alfieri repair, was firmly established as a viable therapeutic approach for valve repair in patients with MR. This concept was then extended to the TV. In some instances, combined MV and TV clips are implanted in the same sitting, yielding promising results, although this remains an area of ongoing investigation.17,18 Nonetheless, using MV devices in the TV demonstrated the feasibility of edge-to-edge repair, laying the groundwork for dedicated TV devices, which continue to improve procedural efficiency and success.

© RADCLIFFE CARDIOLOGY 2021 Access at: www.USCjournal.com

Transcatheter Tricuspid Valve Intervention: Current Perspective However, the TV presents unique challenges for edge-to-edge repair that do not arise in the MV. First, the TV has a complex, nonplanar anatomy with a flattened oval configuration that alters in shape and size depending on the cardiac cycle, loading conditions and pathology.11 Indeed, this anatomy often results in substantial coaptation gaps coupled with tethered leaflets that render grasping to facilitate leaflet approximation challenging.19

PASCAL

Novel techniques including modified steering, grasp optimization, and 'zipping' the valve together (done by starting the intervention at the annular aspect and moving centrally) have proven helpful to achieving successful reductions within challenging anatomies.20,21

The first-in-human (FIH) compassionate patient series demonstrated a favorable procedural success rate of 86% with a 7% leaflet detachment rate. In follow-up, this translated to sustained reductions in TR in 75% of patients with improvements in New York Heart Association (NYHA) class and 6-minute walking distance (6MWD; Table 1).19

In addition, TV imaging is considerably more challenging than MV imaging. While transesophageal echocardiography (TEE) remains the foundation of TV imaging, it is often limited by the TV’s complex anatomy and its anterior position, distant from the TEE probe. Acoustic shadowing of TV anatomic structures during TEE imaging can be encountered in a variety of circumstances, including in the presence of a horizontal heart axis, a lipomatous atrial septum, prosthetic mitral and aortic valves, and device leads.

The advent of multimodality imaging, including the combination of fluoroscopy, 2D and 3D TEE, intracardiac echocardiography (ICE), and cardiac CT, have provided added benefit to TV procedural planning and execution.22 For edge-to-edge TV repair, we favor a complementary strategy that integrates TEE and ICE, alternating between the modalities intraprocedurally to achieve the necessary views to enable successful edge-to-edge repair.23 ICE will continue to evolve with upcoming 3D and mapping iterations that will further optimize imaging for TV interventions.24 While imaging modalities continue to evolve, so too do the devices designed for edgeto-edge repair of the TV (Table 1).

MitraClip in the Tricuspid Position and TriClip

The groundwork for TV edge-to-edge repair was laid by the early use of the MitraClip (Abbott) in the tricuspid position using modified steering approaches.21 Early compassionate use demonstrated successful deployment of the MitraClip in the TV position in 97% of cases, reducing the TR grade by one or more in 91% of patients, with sustained TR reductions up to moderate grade in 86% at 30 days.17 This was further supported to less than TriValve registry demonstrating successful reduction to TR grade up to 2+ in 77%, with long-term follow-up demonstrating excellent clinical and technical success (Table 1).25 While concomitant TV procedures performed at the time of MV interventions have acceptable safety, feasibility and learning curve profiles, dedicated studies are needed to identify the optimal approach in this cohort.18 The success of MitraClip in the TV position led to the development of the dedicated TriClip device (Abbott), which employed the same clip but with altered delivery system mechanics to optimize implantation in the TV.26 First studied in 85 patients as part of the TRILUMINATE single-arm trial, this device demonstrated 86% successful TR reduction by one grade or more, with 6-month follow-up showing sustained rates of major adverse cardiovascular events and mortality (Table 1).26 Currently, the TRILUMINATE pivotal randomized control trial (RCT) (NCT03904147) is under way to firmly establish the utility of dedicated TriClip-mediated edge-to-edge repair compared to conservative therapy.

The PASCAL repair system (Edwards Lifesciences) was initially developed for MR repair then extended for use in TR. The PASCAL implant, similar in design to the MitraClip, is composed of a central spacer with two adjacent paddles upon which clasps are deployed to secure the leaflets in a grasping position, offering a low-profile design to improve subvalvular manipulation (Figure 1).19

The CLASP TR EFS (NCT03745313) enrolled 34 patients (29 patients implanted) at multiple centers in the US and demonstrated that 85% of implanted patients achieved at least 1 grade of TR reduction, with 52% having moderate or less TR after the procedure.27 Major adverse event rates at 30 days were 5.9% and improvements in NYHA class, 6MWD and quality of life were all observed at 30 days.27 The CLASP TR II Pivotal Trial (NCT04097145) is randomizing patients to device or optimal medical therapy and will provide definitive evidence regarding the role of edge-toedge repair for TR.

Annular Reduction

Annular dilation plays a major role in many TR pathologies, with numerous surgical approaches focusing on annuloplasty as a primary approach, particularly in the early stages of TR.11 Accordingly, percutaneous annular reduction approaches aim to mimic surgical annuloplasty by reducing the size of the tricuspid annulus, reducing the coaptation gap, and restoring leaflet approximation.

Challenges with this approach include achieving successful annular reduction with a secure device implant while not impinging on the adjacent conduction system, right coronary artery, or aortic or coronary sinuses.11

Cardioband

The Cardioband tricuspid repair system (Edwards Lifesciences) was adapted from the mitral system and uses a sutureless, adjustable band attached to the atrial aspect of the TV annulus. The band is delivered via a 24 Fr venous access sheath and secured in position by multiple anchors.

Once the band is fixed in place, the size adjustment tool can then be used to adjust the annular size (Figure 2).28 This device showed promise in the TRI-REPAIR study, with sustained improvements in both clinical and echocardiographic results (TR grade) with an excellent safety profile sustained at both 1 and 2-year follow-up (Table 1).28–30 The Cardioband early feasibility study (EFS) in the US included 30 patients who underwent repair, and found a 13% reduction in septolateral diameter, and 35–40% reduction in TR severity by quantitative measures. In 85% of patients, TR decreased by one grade or more and the majority of patients experienced improvements in NYHA class and quality of life at 30 days.31,32 Ongoing device refinements are planned before pivotal studies commence.

Trialign

The Trialign system (Mitralign) was developed from the earlier Mitralign annular reduction systems. From a transjugular approach, this device achieves annular reduction by plicating the TV to create a bicuspid valve.

US CARDIOLOGY REVIEW Access at: www.USCjournal.com

Abbott

Edwards Lifesciences

TriClip

PASCAL

US CARDIOLOGY REVIEW Access at: www.USCjournal.com

Mitralign

4Tech Cardio

Trialign

TriCinch First generation

TriCinch Coil System Second generation

Edwards Lifesciences

Cardioband

Annular reduction

Abbott

MitraClip

Edge-to-edge repair

Company

• 8.3% hemopericardium • 16.7% late anchor detachment • Pericardial effusion • Dehiscence

• 75% deployment success • 94% TR reduction ≥1 grade • TR reduction ≥1 grade

Second generation – FIH36

PREVENT – FIH35 1

24

• 20% leaflet detachment 1 month • 7% unplanned surgery/reintervention rates

• 100% successfully device implant • 80% technical success

severity

15

SCOUT I – EFS

34

1 month

6 months

1 month

• 13% ↓ septolateral diameter • 85% TR reduction ≥1 grade • 35–40% ↓ quantitative TR

6 months

30

• 6.6% mortality • 3.3% stroke • 3.3% tamponade • 13.3% bleeding • 10% coronary complication • 6.7% anchor disengagement

1 month

1 month

6 months

1 year

EFS (Davidson et al. 202032)

• 100% technical success

deployment

• 85% successful device

• 20.3% mortality • 0.4% cardiac surgery • 0.8% stroke • 6% bleeding • 4% mortality • 6% MACE • 11% bleeding • 7% leaflet detachment • 9% TV stenosis • 7.1% mortality • 3.5% HF admission • 7.1% leaflet detachment • 0% mortality • 2.2% bleeding • 2.9% leaflet detachment

• 100% NYHA I/II • 53m ↑ 6MWD • 26.5 point ↓ MLHFQ • 75% NYHA class ≤II • ↑ 6MWD • Mild TR • NYHA I

• ↓ NYHA • ↑ QOL

• 88% NYHA I/II • 60m ↑ 6MWD • 24 point ↑ KCCQ

• 88% NYHA class ≤II • 95m ↑ 6MWD • 75% TR grade ≤2+ • 89% NYHA class ≤II • 85% ↓TR ≥1 grade • 71m ↑ 6MWD • 15 point ↑ KCCQ score

• 87% NYHA class ≤II • 20.7 point ↑ KCCQ score • 57% TR grade ≤2+

• 69.4% NYHA class ≤I • 72.4% TR grade ≤2+

Follow-up Outcomes

30

34

CLASP TR EFS27 (NCT03745313)

(device implanted + ↓TR grade ≤2+)

• 86% procedural success

• 77% ↓ TR ≤2+ • 86% ↓ TR ≥1 grade

• 77% ↓ TR ≤2+ • 89.2% ↓ TR ≥1 grade

Procedural Safety

TRI-REPAIR28

28

85

249

Size Procedural Success

FIH (Fam et al19)

TRILUMINATE – EFS (single arm)26

TriValve Registry25

Studies

Table 1: Summary of Devices for Transcatheter Valve Intervention

Device redesign and PREVENT-EFS

Device redesign and PREVENT-EFS

SCOUT II (NCT03225612)

Device refinements before pivotal studies

CLASP TR II Pivotal RCT (NCT04097145)

TRILUMINATE Pivotal RCT (NCT03904147)

TriValve Registry (NCT03416166)

Ongoing Studies

Transcatheter Tricuspid Valve Intervention: Current Perspective

Edwards Lifesciences

Company

US CARDIOLOGY REVIEW Access at: www.USCjournal.com

Cardiovalve (Valtech/ Edwards Lifesciences

VDYNE

Ningbo Jenscare Biotechnology

Medtronic

Edwards Lifesciences

Cardiovalve

VDYNE

LuX-Valve

Intrepid

EVOQUE

1

25

FIH multi-center experience (Fam et al. 2021)51

3

12

–

–

5

1

28

29

embolizations requiring cardiac surgery)

• 29% right-sided HF • 21% infection • Stable device position

• 14.3% device embolization • 7.1% cardiac tamponade • 7.1% device dislocation • 57% mortality (driven by device

• 7% RV perforation • 7% anchor detachment • 7% mortality • 10% device-related cardiac surgery • 21% bleeding • 3% vascular complications

Procedural safety

–

–

–

• 92% technical success • 92% ↓ TR ≤1+

• 12% bleeding • 4% reintervention

• Successful device deployment • Mild PVL • 8% pacemaker rate

• Successful device deployment

• 100% successful device implant • 8.3% bleeding requiring surgery • 100% ↓ TR grade • 8.3% mortality

–

–

• 100% successful device implant • 60% bleeding (chest wall) • 90.9% ↓ TR ≤2+ • 13-day average ICU LOS • 20% mortality

pressure

• Successful device deployment • Successful reduction in IVC

hepatic flow

• 100% device deployment • Successful reduction in IVC/

• 93% procedural success • 49% TR reduction ≥1 grade

Size Procedural Success

FIH (Fam et al. 202050)

FIH (Bapat, 202048)

FIH (direct transatrial access) (Lu et al. 2020)47

–

–

FIH (direct transatrial access) (Hahn et al. 201943)

FIH (Lauten et al. 201140 and 201441)

TRICAVAL RCT4

EFS (Perlman et al. 201838)

Studies

–

–

–

–

1 month

1 year

3 months

1 month

• NYHA I • 45 point ↓ MLHFQ • 200m ↑ 6MWD • 96% TR grade ≤2+ • 76% NYHA ≤II

–

• 90.9% ↓ TR ≤mild • 100m ↑ 6MWD • 54.5% NYHA II

–

–

• 100% TR grade ≤2+

• NYHA II • Right-sided HF resolved • 6MWD improved

improved by 1 class • 12.3 point ↓ MLHFQ • 21.7m ↑ 6MWD

• 63% NYHA class

• 94% NYHA class ≤II • 65m ↑ 6MWD • 15 point ↑ KCCQ

Follow-up Outcomes

TRISCEND II Pivotal RCT (NCT04482062)

TRISCEND-EFS (NCT04221490 )

TTVR Early Feasibility Study (NCT04433065)

EFS – TRAVEL trial (NCT04436653)

FIH pending

Early Feasibility Study of the Cardiovalve System for Tricuspid Regurgitation (NCT04100720)

EFS transcatheter device in progress

TRICUS EFS (NCT03723239) TRICUS Study Euro EFS (NCT04141137)

Study terminated early due to safety concerns related to device embolization

Device redesign given dislodgements with future studies to be decided

Ongoing Studies

6MWD = 6-minute walking distance; EFS = early feasibility study; FIH = first in human; HF = heart failure; ICU LOS = intensive care unit length of stay; IVC = inferior vena cava; KCCQ = Kansas City Cardiomyopathy Questionnaire; MACE = major adverse cardiovascular events; MLHFQ = Minnesota Living With Heart Failure Questionnaire; MV = mitral valve; NYHA = New York Heart Association; QOL = quality of life; PVL = paravalvular leak; RV = right ventricle; TR = tricuspid regurgitation; TV = tricuspid valve.

NaviGate Cardiac Structures

P&F Products and Features

GATE

Replacement

TricValve bicaval valves system (self-expandable)

Sapien in stent Edwards Lifesciences (balloon-expandable)

Caval valve implantation (CAVI )

FORMA

Spacer

Table 1: Cont.

Transcatheter Tricuspid Valve Intervention: Current Perspective

Transcatheter Tricuspid Valve Intervention: Current Perspective Figure 1: Edge-to-edge Tricuspid Repair with Pascal Device

A: Transesophageal echocardiogram (TEE) transgastric short-axis view of tricuspid valve reveals central coaptation gap between septal (S) and anterior (A) leaflets. B and C: Tricuspid inflow view on TEE (B) and apical 4 chamber TTE view (C) demonstrating severe TR by color Doppler assessment. D: right antero-oblique view demonstrating PASCAL device is released and intracardiac echo probe is seen inferiorly. E: Intracardiac echo facilitates enhanced leaflet visualization and grasping. F: Tricuspid regurgitation is reduced to moderate after implantation.

This is achieved via radiofrequency-mediated placement of pledgets at the posteroseptal and anteroposterior commissures, which are then drawn together to, essentially, remove the posterior TV leaflet and reduce TR.33 This approach was assessed in the SCOUT I EFS trial in 15 patients, which demonstrated overall excellent procedural success but was limited by 20% leaflet detachment rates for which device refinements were pursued.34 The SCOUT II trial (NCT03225612), now ongoing, is intended to improve the understanding of the role of this therapy in TR reduction (Table 1).

TriCinch

Another approach to annular remodeling is employed by the TriCinch device (4Tech Cardio) and intended for secondary TR. This device is delivered via the femoral approach with a 24 Fr sheath; a corkscrew is fixated supra-annularly into the anteroposterior TV annulus, with an anchor line connected to a stent placed within the inferior vena cava (IVC).

The PREVENT study examined this first-generation device with successful deployment in 75% of cases with a TR reduction of one grade or more in 94%.35 However, 8% of patients experienced hemopericardium and 16.7% late detachment of the annular anchor. This led to a device redesign yielding the TriCinch Coil System (4Tech Cardio), which uses an epicardial coil with two hemostatic seals placed by creating a carbon dioxide pneumopericardium to enable visibility of the anchor placement in the pericardial space.36 This device was limited by dehiscence and hemorrhagic pericardial effusions (Table 1).35 Ongoing EFS work on this technology is forthcoming and the role of this therapy remains to be defined.

Spacer FORMA

Physical filling of the coaptation defect is an alternative strategy pursued in so-called spacer therapies; rather than approximating the surrounding tissue to fill the defect, they physically fill the space themselves.

The FORMA device (Edwards Lifesciences) has been the primary device using this mechanism and is implanted via a 24 Fr sheath via either the left subclavian or axillary vein. The anchor is first implanted at the right ventricle (RV) apex and a foam-filled spacer balloon is then advanced and tethered to the apical rail, securing the device in position (Figure 3).

Early compassionate use of the FORMA device in 18 patients yielded an 89% procedural success rate with one RV perforation and one devicerelated thrombus; however, it provided 79% of patients with improvement to NYHA I/II and sustained reduction to less than moderate TR in 46%.37 The subsequent EFS in 29 patients yielded promising results as well, with a good efficacy profile, but RV perforation and late anchor dislodgement challenged this technology and prompted a redesign (Table 1).38 Accordingly, the future of the FORMA device is uncertain at present.

Caval Valve Implantation

A unique, outside-the-box strategy for dealing with the challenges of the TV was to move the device therapy outside the TV, with so-called heterotopic valve implantations. This strategy uses traditional valve replacement devices but deploys the valves in the caval vessels adjacent to the right atrium to mitigate the effects of TR on surrounding organs while not sparing

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Transcatheter Tricuspid Valve Intervention: Current Perspective Figure 2: Cardioband Tricuspid Annuloplasty Repair

Apical four-chamber view with color showing severe tricuspid regurgitation at baseline (A) being reducing to mild immediately after implantation (B). Left anterior oblique projection demonstrating the direct annuloplasty implanted before (C) and after (D) contraction with resulting decrease in the annular size (yellow arrows).

the RA. This caval valve implantation (CAVI) strategy has been approached with both balloon-expandable and self-expanding valves.

study Euro (NCT04141137) are enrolling to achieve CE mark status for the TricValve device.

The TRICAVAL RCT explored the use of a standard balloon-expandable Sapien valve (Edwards Lifesciences) implanted within a stent deployed within the IVC.4 This strategy raised significant safety concerns related to valve dislocations and procedural complications requiring surgical interventions, which prompted an early stop to the study for safety reasons.4

However, the CAVI strategy, if successful, would likely fill a niche role in those with end-stage right-sided HF experiencing significant annular dilation that precludes the use of other devices. In these circumstances, the effects of RA ventricularization and persistent overload remain to be explored. Taken together, while intriguing, it is unlikely that this approach will represent the primary modality of TTVI going forward.

An alternative strategy using a dedicated, self-expanding nitinol TricValve (P&F Products and Features) placed within the superior and/or inferior vena cava offered another approach, eliminating the need for pre-stenting and mitigating the radial forces applied to the caval structures with balloon-expandable valves.39 Early FIH work with this technology appeared promising, with symptomatic improvement and a favorable safety profile (Table 1).40,41 The TRICUS study (NCT03723239) and TRICUS

Replacement

Transcatheter tricuspid valve replacement (TTVR) is challenged by the anatomic complexities of the TV and annulus, which are often further deviated in the presence of significant TR. Indeed, the large annulus and lack of a supportive matrix for valve anchoring pose significant limitations for TTVR implantation. A single early report of TTVR in a native TV required pre-stenting the TV annulus with covered stents followed by

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Transcatheter Tricuspid Valve Intervention: Current Perspective implantation of two Sapien valves for positioning and was complicated by wire-induced pulmonary artery perforation, highlighting the significant challenges the TV presents for TTVR.42 However, dedicated valves designed for the mitral and tricuspid positions are now showing promise in ongoing investigations.

Figure 3: FORMA Spacer Therapy Baseline

6 months

A

B

C

D

E

F

GATE

The GATE bioprosthetic device (NaviGate Cardiac Structures) was one of the first TTVR devices available, although is was developed initially as a surgical implant. This device is advanced via a mini-thoracotomy approach using a 42 Fr introducer sheath to enable placement of the conical nitinol stent, which encompasses three pericardial leaflets that are secured in place by anchoring RA winglets and RV tines.43 Its use was first demonstrated in two patients, one of whom had an existing TV annuloplasty ring.44 The complete compassionate FIH experience demonstrated successful valve implantation in all patients with successful TR reduction to a grade up to 2+ in all patients, with sustained reduction in TR severity at 30-day follow-up.43 However, the direct atrial access resulted in significant bleeding complications and prolonged intensive care unit admissions, with a 20% mortality rate in the FIH experience (Table 1).43 Upcoming device iterations are expected to enable transjugular access, which will likely yield marked improvements in outcomes. Early feasibility studies are now under way to establish the safety and efficacy of this device.

Cardiovalve

The Cardiovalve (Cardiovalve) is a percutaneously delivered, low-profile (15 mm height), double-framed valve with tri-leaflet bovine pericardial leaflets. This valve showed early promise in FIH studies following MV implantation via a transseptal approach.45 Cardiovalve has now gained Food and Drug Administration (FDA) approval to proceed with an EFS study for TV implantation with enrollment expected shortly (NCT04100720).

VDYNE

The VDYNE valve (VDYNE) affords a unique approach based upon a 30 mm porcine inner valve encased in an outer annular ring; the outer rings offered vary in size to provide five valve sizes, providing an anatomic fit to the native annulus. The device is deployed through a single 28 Fr transfemoral sheath, employing a novel side delivery system, abrogating the need for hardware in the RV while allowing the operator to reposition and recapture the device. The device uniquely offers a pop-off mechanism in the event of afterload mismatch. The VDYNE valve will soon be undergoing FIH assessments.46

LuX-Valve

The LuX-Valve (Ningbo Jenscare Biotechnology) is a radial-force independent system with four components: a bovine pericardial valve; a self-expanding nitinol valve stent with an atrial disc; an interventricular septal anchor tab; and two graspers. This device is delivered via right thoracotomy with a 32 Fr system. The FIH study demonstrated promising results with 100% procedural success and no more than mild residual TR in 90.9% of patients.47 Ongoing assessment is being performed in a dedicated EFS study (TRAVEL trial; NCT04436653).

Intrepid

The Intrepid valve (Medtronic) was originally developed for transcatheter mitral valve repair, but adapted for the TV position. It provides three annular sizes, built around a single 29 mm bovine valve that is delivered

At baseline, the RV is moderately enlarged with a wide coaptation gap (A) and torrential tricuspid regurgitation (TR) (effective regurgitant orifice area (EROA): 0.91 cm2; regurgitant volume (RegVol): 80 ml) (C) and associated systolic flow reversals in the hepatic veins (E). Six months after spacer implantation (B), the TR is reduced (EROA 0.5 cm2; RegVol: 46 ml) (D) and systolic flow reversals are no longer present in the hepatic veins (F).

via transfemoral access, and has yielded promising FIH results and safety.48 This device received FDA breakthrough status in 2020 and is now actively enrolling in an EFS (NCT04433065).49

EVOQUE

Similarly, EVOQUE (Edwards Lifesciences) was initially developed for the MV position with considerable refinements employed to enable its use for the TV. This system enables 44 mm, 48 mm and 52 mm valves to be implanted via a 28 Fr delivery system.

The FIH implant was recently performed, with successful implantation being achieved with mild PVL. Follow-up yielded clinical improvement to NYHA class I, 6MWD increased by 200 meters and a 45-point improvement in Minnesota Living with Heart Failure Questionnaire score.

Echocardiographic follow-up showed stable mild paravalvular leak (PVL) and a mean gradient of 2 mmHg with reduced RV volumes (Table 1).50 The subsequent multicenter FIH experience was published shortly after; this included 25 patients with 92% technical success, and durable improvements in clinical and echocardiographic parameters at 30 days.51 Accordingly, the TRISCEND EFS (NCT04221490) and TRISCEND II Pivotal

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Transcatheter Tricuspid Valve Intervention: Current Perspective RCT (NCT04482062) are actively enrolling to establish this therapy as a viable TTVR approach.

Remaining Questions

Several important questions will be answered by ongoing device trials in the TTVI field, including whether reduction of TR leads to improved survival and other endpoints including hospitalizations, diuretic use and quality of life as compared to medical therapy.

No randomized studies to date, including both surgical and percutaneous approaches, have shown a survival benefit of TR treatment. Hence, the next phase of studies are critically important to establish our fundamental knowledge of this pathology while discerning the optimal population and patient anatomy that stand to benefit most from the specific therapies studied to improve clinical outcomes.

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The durability of the various TR therapies will need to be carefully studied to understand their role and potential application in a lower-risk population. Optimal strategies for the management of TR in combination with other valvular disease will also require dedicated evaluation.

Conclusion

The rising awareness of the importance of TR coupled with the rapid evolution of transcatheter technologies have yielded marked advances in TTVI development. While the TV poses many unique challenges, the breadth of technological approaches to this pathologic state remain diverse, with the future TTVI armamentarium likely to include multiple modalities with dedicated devices for specific pathology subtypes. While considerable work remains, TTVI, especially TTVR, are poised to rapidly become the standard therapeutic strategies for TR.

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50. Fam NP, Ong G, Deva DP, Latib A. Transfemoral transcatheter tricuspid valve replacement. JACC Cardiovasc Interv 2020;13:e93–4. https://doi.org/10.1016/j. jcin.2020.01.194; PMID: 32171717.

51. Fam NP, Von Bardeleben RS, Hensey M, et al. Transfemoral transcatheter tricuspid valve replacement with the EVOQUE system. JACC Cardiovasc Interv 2021;14:501–11. https://doi. org/10.1016/j.jcin.2020.11.045; PMID: 33582084.

COVID-19

Door-to-balloon Time for ST-elevation MI in the Coronavirus Disease 2019 Era Haytham Mously, MD, MPH, Nischay Shah, DO, Zachary Zuzek, MD, Ibrahim Alshaghdali, MD, Adham Karim, MD, Rahul Jaswaney, MD , Steven J Filby, MD, Daniel I Simon, MD, Mehdi H Shishehbor, DO, MPH, PhD, and Farshad Forouzandeh, MD, PhD Harrington Heart and Vascular Institute and Case Western Reserve University, Cleveland, OH

Abstract

In patients presenting with ST-elevation MI, prompt primary coronary intervention is the preferred treatment modality. Several studies have described improved outcomes in patients with door-to-balloon (D2B) and symptom onset-to-balloon (OTB) times of less than 2 hours, but the specific implications of the coronavirus disease 2019 (COVID-19) pandemic on D2B and OTB times are not well-known. This review aims to evaluate the impact of COVID-19 on D2B time and elucidate both the factors that delay D2B time and strategies to improve D2B time in the contemporary era. The search was directed to identify articles discussing the significance of D2B times before and during COVID-19, from the initialization of the database to December 1, 2020. The majority of studies found that onset-of-symptom to hospital arrival time increased in the COVID-19 era, whereas D2B time and mortality were unchanged in some studies and increased in others.

Keywords

Percutaneous coronary intervention, ST-elevation myocardial infarction, door-to-balloon time, healthcare outcome, door-to-balloon time, coronavirus disease 2019 Disclosure: The authors have no conflicts of interest to declare.

Received: February 23, 2021 Accepted: April 5, 2021 Citation: US Cardiology Review 2021;15:e13. DOI: https://doi.org/10.15420/usc.2021.05 Correspondence: Farshad Forouzandeh, Case Western Reserve University School of Medicine, 11100 Euclid Ave, Mailstop LKS 5038, Cleveland, OH 44106.

E: farshad.forouzandeh@case.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Reperfusion of blood flow in the infarct-related artery through percutaneous coronary intervention (PCI) or fibrinolysis is the standard of care for the treatment of patients with ST-elevation MI (STEMI). When performed promptly, PCI is the preferred approach for reperfusion therapy in most patients with STEMI. In a meta-analysis of 23 randomized trials comparing PCI with fibrinolytic therapy, there was a significantly lower risk of short-term death, stroke, or nonfatal MI in those who received PCI.1 In patients with suspected STEMI, several quality improvement measures have been undertaken to reduce the door-to-balloon (D2B) time, that is, the interval between patient arrival at the hospital to balloon angioplasty of the occluded coronary artery.

Outcomes such as myocardial blush grade, ST-elevation resolution, mortality at 1 year, and heart failure at 1 year were all significantly lower in patients with expedited symptom onset-to-balloon inflation (OTB) time and D2B time.2 This article aims to examine the impact of the coronavirus disease 2019 (COVID-19) pandemic on OTB time and D2B time, identify factors that delay both OTB and D2B times and strategies that can help decrease these times. Before the pandemic, shorter D2B and OTB times were associated with mortality benefits. It is important to determine if shorter ischemic time means mortality benefit in the COVID-19 era and to identify possible strategies to shorten the ischemic time during the on-going pandemic. We will discuss evidence showing improved outcomes with shorter D2B times and the impact of COVID-19 on OTB and D2B times.

Methods

This review was conducted based on an established literature review protocol that detailed our objectives, methods, and selection criteria.3 The criteria for the selection of studies allowed the inclusion of many study designs, types of participants, interventions and outcome measures. We conducted electronic searches of the MEDLINE/PubMed and EMBASE databases to identify all relevant and pertinent articles. The included keywords were ‘Strategies Improving Door-to-Balloon Time’ or ‘Door to Balloon Alliance,’ ‘Improving Door to Balloon Time’ in conjunction with ‘STEMI,’ ‘PCI,’ ‘COVID-19,’ ‘SARS-CoV-2’ and ‘Review.’ References from chosen articles were also reviewed for possible selection per our selection criteria. The search was directed to identify articles discussing the significance of D2B times in the COVID-19 era, pre-COVID-19 era, and factors that impacted D2B times. Finally, all authors participated in the search and review of search results with a qualitative summary of relevant full-text versions of selected articles. Articles chosen for inclusion were consistent with our search parameters and published from the initialization of the database to December 1, 2020. Our literature review was limited to articles published in English, but not limited by country of origin.

Results Evidence Supporting Benefits of Reducing Door-to-balloon Time

The significance of optimized management (angioplasty) of patients with STEMI and reduced D2B time has been well established. In 1999, Berger et al. showed that patients randomized to PCI in 60 minutes or less had

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Door-to-balloon Time in the COVID-19 Era the lowest rates of 30-day mortality, with rates progressively higher with an increased delay between diagnosis and balloon inflation.4 De Luca et al. expanded on this work, looking at 1,791 STEMI patients in a similar timeframe and concluded that for every minute of ischemic time until adequate reperfusion therapy, mortality at 1 year increased significantly.2 It is difficult to create objective guidelines about the timing of reperfusion therapy because there is great variability in total time from patient symptom onset to hospital arrival. Cannon et al. sought to address this issue and looked at the relationship between both OTB time and D2B time. Mortality in a cohort of 27,080 patients undergoing primary angioplasty was not related to OTB time, but there was a significant increase in mortality risk (by 41–62%) if D2B time exceeded 2 hours.5 Later studies that looked at the timeliness of reperfusion therapy found that when D2B time was <90 minutes, patients had significantly lower 30-day mortality and 1-year mortality.6,7 An analysis of 5,243 patients with documented STEMI from November 2011 to December 2015 indicated a lower risk of mortality associated with each 30-minute decrement in D2B time, with the greatest benefit seen in D2B times of <60 minutes.8 With the increased use of quality improvement initiatives such as the National Cardiovascular Data Registry (NCDR), there has been even greater scrutiny and analysis of outcomes after PCI. A study by Park et al. of 96,738 patients undergoing primary PCI for STEMI demonstrated a significant reduction in D2B time from 83 minutes to 67 minutes over 4 years, but did not demonstrate a significant reduction in in-hospital mortality (5.0% versus 4.7%, p=0.340).9 The discrepancies between these two analyses may be caused by multiple factors. Namely, the Park et al. study was a primarily Korean cohort, whereas the NCDR analysis was based on a US cohort. In the US cohort, the study population on average was older, had a higher BMI, and included a higher proportion of female patients.8,9 Furthermore, the reduction of D2B time in the NCDR analysis was only 16 minutes, whereas in the Park et al. study, outcomes were based on 30-minute increments.

Lastly, it is important to note that time from symptom onset to when the patient presented to the hospital was collected for each patient, but no specific analysis was performed regarding OTB time in the NCDR registry.

Hence, the NCDR data do not have the granularity of distinguishing OTB time compared with the Park et al. study.8,9 While there are conflicting data regarding the significance of OTB time compared with D2B time, it is important to minimize the ischemic time for a patient with STEMI.4,5 The D2B time appears to be a better quality-ofcare indicator because the OTB time includes variation in patient presentations, and possible recall bias that is present when a patient is describing the timing of onset of their symptoms. It is difficult to make empirical recommendations based on the literature, but there are sufficient data to suggest that mortality increases as the time to balloon angioplasty increases.10

National Quality Improvement

With the overwhelming evidence that reductions in D2B times improve long-term outcomes for patients presenting with STEMI, it became imperative to formulate a unifying initiative. In 2006, the D2B Alliance was formed by over 1,000 hospitals across the US, with the goal of achieving D2B times of <90 minutes in at least 75% of non-transferred patients with STEMI.11 The D2B Alliance represents the first national quality improvement initiative from the American College of Cardiology’s (ACC) Quality Improvement for Institutions Program. The program was based on the results of the Acute Myocardial Infarction Guidelines Applied in Practice

(AMI-GAP) initiative in Michigan, which was a systems-based approach to improving outcomes after AMI in a consortium of five hospitals in southeast Michigan.12 This project demonstrated that system-wide approaches to implement evidence-based medicine could improve outcomes. As a result, several of the strategies implemented in problem solving for the AMI-GAP project were used in the D2B initiative.

The D2B Alliance called for a multidisciplinary approach to quality improvement and needed buy-in from providers at all levels and in various settings. Specifically, five suggestions were outlined for hospitals to implement with the hope that addressing these bottlenecks could streamline activation of the cardiac catheterization laboratory (CCL) for patients with acute STEMI. These proposals included allowing for emergency department activation of the CCL without cardiologist approval, a single call activation of the CCL, CCL staff arriving on-site within 30 minutes of the call for activation, and rapid feedback that allowed for realtime performance measures and feedback to be given post-PCI. This, in conjunction with vocal support by senior management at the D2B Alliance hospitals, led to a significant reduction in D2B time, which is reflected in hospital reports of increased use of these measures.

Other suggestions included allowing for CCL activation using ECGs from the field, but adoption of this metric was optional.13,14 The D2B Alliance met its goal in 2008 and, since then, additional studies have begun calling for D2B times of under 60 minutes.8 Current ACC/American Heart Association guidelines suggest that when a STEMI patient is directly being transferred to a PCI-capable center, then first medical contact to the deployment of the device in the procedure should be accomplished in 90 minutes; and if the patient is being transferred from a non-PCI capable center, then it should be accomplished in 120 minutes.15 European Society of Cardiology (ESC) guidelines suggest identical timings for D2B time.16 According to the ESC, time from STEMI diagnosis to passing of wire should be within 60 minutes if the patient presented to a PCI-capable facility, 90 minutes for a patient getting transferred to a PCI-capable facility, and should not be delayed >120 minutes if PCI is the primary strategy for treatment of STEMI.

Impact of COVID-19 on Door-to-balloon Time

During the on-going COVID-19 pandemic, STEMI management deserves special scrutiny. It is an established phenomenon that severe acute respiratory syndrome coronavirus 2 has an impact on the heart, whether directly or indirectly. Early studies from China made it clear that patients who had pre-existing cardiovascular disease, diabetes and hypertension died most often or were most often admitted to the intensive care unit as a result of COVID-19 infection.17 Here we will review the impact of COVID-19 on timings of presentation in patients with STEMI (Table 1) who underwent PCI. An early paper from Yerasi et al. described the risks and benefits of PCI and fibrinolysis in STEMI patients during COVID-19 infection and proposed that PCI should still be the preferred modality in STEMI patients during the pandemic.18 As discussed earlier, there is sufficient evidence in the literature that reduction in D2B times improves long-term outcomes in STEMI patients. There has been concern about the impact of COVID-19 infection on D2B times in STEMI patients and the implication it will have on the prognosis of these patients.

In the literature, mixed results were found on the impact of COVID-19 infection on D2B times. A study from Ohio by Hammad et al. looked at 143 STEMI cases that presented from January to April 2020 in 18 hospitals.19

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Door-to-balloon Time in the COVID-19 Era Table 1: Studies Comparing Door-to-balloon Times Before and During the Coronavirus Disease 2019 Pandemic Study

Pre-COVID-19 Group and Time Period

Main Outcome

Important Result

p-value for Results

Hammad et al.

202119

108 STEMI cases pre-COVID-19 35 STEMI cases during (January 1–March 23, 2020) COVID-19 (March 23–April 15, 2020)

D2B times had no significant change

59 min pre-COVID-19 and 58 min during COVID-19

p=0.850

Tan et al.

202020

167 patients undergoing cardiac catheterization pre-COVID-19 (December 23, 2019–March 15, 2020)

37 patients undergoing cardiac D2B times had no catheterization during significant change COVID-19 (March 16–April 12, 2020)

80.6 min before COVID-19 and 79.3 min during COVID-19

p=0.470

Aldujeli et al.

202021

62 STEMI/NSTEMI cases pre-COVID-19 (March 11–April 20, 2019)

30 STEMI/NSTEMI cases during Compared median pandemic (March 11–April 20, pain-to-door time and 2020) showed significant increased time during pandemic

Average time of pain onset-to-door of 194 min before pandemic and 332 min during pandemic

p=0.030

Garcia et al.

202022

Pre-COVID-19 patients from 12 different sites (January 2019–February 2020)

Patients during COVID-19 from D2B time increased 12 different sites (March to April significantly during 2020) COVID-19 period

20% increase in D2B time

p=0.050 (95% CI [−2, 44])

Kwok et al.

202025

All PCI procedures recorded

by British Cardiovascular Intervention Society from January 1, 2017 to March 23, 2020

All PCI procedures from March D2B and symptom-to-door 23, 2020 to end of April 2020 time were longer during COVID-19 pandemic (April 2020)

D2B pre-pandemic was 37 min and during pandemic was 48 min Symptom-to-hospital time was 239 min during pandemic compared with 235 min pre- pandemic

D2B p<0.001

Turkish registry of 711 STEMI patients pre-pandemic (November 1–15, 2018)

485 STEMI patients who D2B was not changed presented during the pandemic significantly but symptom (April 17–May 2, 2020) onset-to-hospital arrival time increased significantly

D2B was 37 min before pandemic and 40 min after pandemic for all acute coronary syndrome patients

D2B p=0.448

Symptom onset to hospital arrival time was 150 min before pandemic versus 185 min after pandemic

MACE significantly increased during the pandemic period (4.9% versus 8.9% [p<0.001]) D2B p=0.187

Erol et al.

202030

COVID-19 Group and Time Period

Symptom-to-hospital time p=0.045 No difference in in-hospital mortality (p=0.670) and MACE during and before pandemic (p=0.280)

Symptom onset to hospital arrival time p< 0.001

Daoulah et al.

202031

1,785 patients from 16 different 500 STEMI patients during centers in Saudi Arabia pandemic (January 1– pre-pandemic (January 1 to April 30, 2020) April 30 in 2018 and 2019)

D2B times did not show any significant changes

D2B of <90 min achieved in 70.4% of patients before pandemic and in 73.1% of patients during pandemic

Fu et al.

202032

29 STEMI patients admitted to 24 STEMI patients admitted a center in China between during the pandemic (January January 20 and April 20, 20–April 20, 2020) 2019

Symptom onset to first medical contact times and D2B times were longer during the pandemic

D2B time in the pandemic D2B p=0.006 and pre-pandemic groups was 83.3 ± 29.7 min and Symptom-onset to first medical 61.1 ± 21.9 min, respectively contact p=0.049

No difference in in-hospital adverse events (p=0.377)

Average symptom onset to first medical contact time was 319.4 ± 89.5 min in the pandemic group and 261.5 ± 87.3 min before the pandemic Chew et al.

202133

208 STEMI patients in Singapore center from before the COVID-19 pandemic (October 1, 2019 to February 6, 2020)

95 STEMI patients in Singapore Fewer patients during center during the COVID-19 achieved D2B COVID-19 pandemic <90 min

80.9% achieved D2B <90 min D2B p=0.040 before the COVID-19 pandemic versus 71.4% during the COVID-19 pandemic

COVID-19 = coronavirus disease 2019; D2B = door-to-balloon time; MACE = major adverse cardiovascular events; NSTEMI = non-ST-elevation MI; PCI = percutaneous coronary intervention; STEMI = ST-elevation MI.

They found that, on average, D2B times were not different between the pre- and post-COVID-19 cohorts (59 minutes [44–84] versus 58 minutes [42–102]; p=0.84). However, they found that STEMI patients who presented 12 hours after the onset of symptoms had significantly high D2B time and peak troponins.

Similarly, a study from a single center in California by Tan et al. found that during the early months of the pandemic, patients did not seem to have delays in STEMI presentation or significant differences in all-cause mortality at their institution, compared with the pre-COVID-19 era.20 Another study from Texas by Aldujeli et al. that looked at 200 acute STEMI

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Door-to-balloon Time in the COVID-19 Era Figure 1: Factors Contributing to Delay in Door-to-balloon Time in the Coronavirus Disease 2019 Era • Fear of COVID-19 exposure • Lack of protocol for EMS staff regarding transfer of COVID19-positive STEMI patients transfer of COVID positive STEMI patients • Confusion between symptoms of STEMI and COVID-19

Onset of symptoms

Arrival to hospital

Balloon angioplasty

• Screening questions and test for COVID-19 • Difficulty diagnosing STEMI based on ECG in COVID-19 patients • Difficulty in procedure technique with PPE • Lack of trained nursing staff to facilitate transfer of COVID-19 patients to CCL • Lack of adequate number of CCLs for COVID-19 patients CCL = cardiac catheterization laboratory; EMS = emergency medical services; STEMI= ST-elevation MI; PPE = personal protective equipment.

cases found that there were significant delays in onset to reaching the hospital in the STEMI patients after COVID-19 but, once in the hospital, D2B time was no different from the pre-COVID-19 era.21 In contrast, a study of data about STEMI patients from 18 hospital systems across the US performed by Garcia et al. found opposite results.22 They compared STEMI patients before COVID-19 (from January 2019 to February 2020) with STEMI patients during the COVID-19 pandemic (from March and April 2020) and found that the average monthly D2B time during the COVID-19 pandemic was about 20% (95% CI [−0.2, 44.0]; p=0.052) higher.

Interestingly when they did monthly analysis, D2B times in March 2020 were increased by 27% (95% CI [6–52]; p=0.011), relative to pre-COVID-19 times, but no significant change was seen in D2B in April 2020.

Such mixed results of D2B times in the US are consistent with what has been seen in other countries. The OTB time delay has been reported across several European countries, including Italy, Spain, UK, Austria, Belgium, and Switzerland.23–27 Some studies have specifically also found delays in D2B times, while others have only found this with OTB times. For instance, Secco et al. carried out a study involving three high-volume centers in northern and central Italy and looked at all acute coronary syndrome cases in March 2019 compared with March 2020.28 In their STEMI subgroup they found that D2B (66 ± 17 minutes versus 40 ± 12 minutes, p<0.001) and OTB times (5.8 ± 3.1 hours versus 3.9 ± 2.2 hours, p<0.001) were significantly longer in March 2020 compared with 2019. They also found that patients who presented during the pandemic had high troponin values and lower residual left ventricular function on average, and higher predicated in-hospital and 6-month mortality values.28 A study from the UK by Kwok et al. found similar results.25 A large database of 34,127 patients with STEMI was studied. They compared patients who underwent primary PCI for STEMI in the years 2017 to 2019 with patients who had PCI for STEMI in the period from January 2020 to the end of April 2020. They found that, on average, after the lockdown period, D2B increased to 48 minutes from 37 minutes before the pandemic (48 minutes

[21–112] versus 37 minutes [16–94]; p<0.001). Time from symptom onset to presentation at hospital also showed longer delays (150 minutes [99–270] versus 135 minutes [89–250]; p<0.001).25 However, there were no differences in in-hospital mortality and major cardiovascular adverse events. All studies demonstrated a significantly longer time from symptom onset to arrival at the hospital.

Likewise, in Asian and Middle-Eastern countries, such as China, Singapore, Turkey and Saudi Arabia, consistent delay in D2B and symptom onset to PCI time were observed.29–33 A study by Fu et al. showed that D2B time in the COVID-19 era was 83.3 minutes, which is significantly longer than 61.1 minutes from pre-COVID-19 (p<0.050).32 Similarly, symptom onset to hospital time was delayed in the COVID-19 era to 319.4 minutes from 261.4 minutes in the pre-pandemic period.32 A study from Singapore by Chew et al. looked at 323 STEMI cases that presented to tertiary care hospitals.

They found that there were fewer patients who achieved D2B of <90 minutes during the COVID-19 outbreak, compared with patients from 2019 (71.4% versus 80.9%, p=0.042).33 Oddly enough, only patients with STEMI in South Korea (compared with other studies from all over the world) had better D2B during the COVID-19 outbreak. In the study by Lee et al., data about COVID-19 patients were analyzed over 20 weeks, starting January 26, 2020.34 All the patients with AMI who underwent PCI during the COVID-19 pandemic had longer D2B times (34.3 ± 11.3 minutes versus 22.7 ± 8.3 minutes; p<0.001) compared with patients pre-COVID-19. These data were from a single 560-bed hospital located in the Seoul metropolitan area. The authors of this study attributed these findings to smaller patient volume and increased availability of procedure rooms during the COVID-19 outbreak.

Discussion Factors Affecting Door-to-balloon Time in the COVID-19 Era

To the best of our knowledge, there are no studies from the US that have specifically focused on elucidating factors that impacted D2B times in STEMI patients. However, we can infer different factors affecting OTB time and D2B in the COVID-19 era from various studies.

There are many possible reasons for delay from the onset of symptoms to reaching the hospital in STEMI patients (Figure 1). Patients may have been afraid of exposure to COVID-19 infection if they went to the hospital.

Another possibility is that appropriate training of emergency medical services staff about how to appropriately triage or transfer patients with STEMI in the COVID-19 pandemic was lacking. Additionally, some patients may have confused symptoms of COVID-19 and STEMI. Delays could also have been a result of new requirements for screening questionnaires or performing tests, such as rapid COVID-19 test, transthoracic echocardiogram, or CT of the chest, to determine if a STEMI patient has COVID-19. Some possible reasons that led to delays specifically in D2B seen during pandemics are discussed here.

Some emergency department physicians faced difficulty in quickly diagnosing STEMI in patients with COVID-19 because of its presentation mimicking STEMI. If a hospital system was unprepared in advance to deal with a surge of COVID-19 cases and lacked a designated CCL for COVID-19 positive patients and trained staff that are specifically responsible for COVID-19 cases, it could delay D2B significantly. Another possibility is of hospitals only having one CCL for COVID-19 patients because, in such a case, a CCL would need proper sanitizing before the arrival of the next patient. Also, it is important to note that extra personal protective

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Door-to-balloon Time in the COVID-19 Era equipment on the operator can make performing angioplasty challenging.12,22,23,27,31

Strategies to Reduce Door-to-balloon Time in the COVID-19 Era

Education is key to reducing D2B, especially in the COVID-19 era.

Emergency medical services staff require proper training and the public must be aware of the need to seek prompt medical attention for signs or symptoms of a heart attack. Education campaigns in the local community, with the help of social media and education of patients by primary care physicians, can help in reducing the fear of contracting COVID-19 infection.

Some potential solutions (Figure 2) to reduce D2B time specifically in the COVID-19 era are:

Figure 2: Strategies to Achieve Lower Door-to-balloon and Symptom Onset-to-balloon Time in the Coronavirus Disease 2019 Era Develop algorithm Perform bedside echocardiogram

Cardiology telehealth

Factors that decrease D2B and OTB

Smartwatch ECG

• Develop an algorithm for the regional hospital network of how to

transfer STEMI patients suspected of having COVID-19 to the CCL.

• Assign teams that are specifically responsible for COVID-19 cases.

• Assign two or more CCLs for COVID-19 cases.

• Perform bedside echocardiography to quickly assess the patient and • • • •

reduce the exposure of the technician.

Consider bypassing COVID-19 tests in urgent cases.

Train nursing staff on how to safely transfer COVID-19 patients with STEMI to the CCL once they are in the hospital.

Where a standard 12-lead ECG might not always be available, a wearable smartwatch device with the capability to recognize STEMI with multiple-lead ECGs would be a great alternative.35 Develop an on-call telehealth cardiology team that specifically helps with timely diagnosis and CCL activation.17, 22,27,30,31

Limitations

One of the limitations of this review is the method used in the selection of the articles. To provide a concise review, some important articles were inevitably unable to be included. As the main topic involves a discussion about the impact of COVID-19 infection, most of the studies reviewed have a small population size and results cannot be extrapolated to longterm outcomes or any other topic.

1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials.

Lancet 2003;361:13–20. https://doi.org/10.1016/s01406736(03)12113-7; PMID: 12517460.

2. De Luca G, Suryapranata H, Ottervanger JP, Antman EM. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction. Circulation 2004;109:1223–5. https://doi.org/10.1161/01.cir.0000121424.76486.20; PMID: 15007008.

3. Pati D, Lorusso LN. How to write a systematic review of the literature. HERD 2018;11:15–30. https://doi.org/10.1177/ 1937586717747384; PMID: 29283007.

4. Berger PB, Ellis SG, Holmes DR, et al. Relationship between delay in performing direct coronary angioplasty and early clinical outcome in patients with acute myocardial infarction.

Circulation 1999;100:14–20. https://doi.org/10.1161/01. cir.100.1.14; PMID: 10393675.

5. Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000;283:2941–7. https://doi. org/10.1001/jama.283.22.2941; PMID: 10865271.

6. Antoniucci D, Valenti R, Migliorini A, et al. Relation of time to treatment and mortality in patients with acute myocardial infarction undergoing primary coronary angioplasty. Am J Cardiol 2002;89:1248–52. https://doi.org/10.1016/s00029149(02)02320-2; PMID: 12031722.

7. Lambert L, Brown K, Segal E, et al. Association between timeliness of reperfusion therapy and clinical outcomes in ST-elevation myocardial infarction. JAMA 2010;303:2148–55. https://doi.org/10.1001/jama.2010.712; PMID: 20516415.

8. Brodie BR, Gersh BJ, Stuckey T, et al. When is door-to-

9.

10.

11.

12.

13.

COVID-19-specific teams

Increase COVID-19 CCLs Skip COVID-19 screening CCL = cardiac catheterization laboratory; D2B = door-to-balloon time; OTB = onset-to-balloon time.

Icons by Coloripop, Healthcare Symbols, Delwar Hossain, Supalerk Laipawat, Jack Prams, John Salzarulo and Nithinan Tatah, from http://thenounproject.com.

Conclusion

For patients presenting with STEMI, PCI is the gold standard treatment modality. Studies have shown that reducing D2B and OTB times have significant mortality benefits. The COVID-19 pandemic has adversely affected OTB times, yet mixed results have been found concerning the D2B times and mortality in patients. Further studies with larger sample size and longer follow-up are needed. Given the known mortality benefit with low D2B times, it is imperative to continue to develop strategies to reduce ischemic time in the current era.

balloon time critical? Analysis from the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) and CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trials. J Am Coll Cardiol 2010;56:407–13. https://doi.org/10.1016/j.jacc.2010.04.020; PMID: 20650362.

Park J, Choi KH, Lee JM, et al. Prognostic implications of door-to-balloon time and onset-to-door time on mortality in patients with ST-segment-elevation myocardial infarction treated with primary percutaneous coronary intervention. J Am Heart Assoc 2019;8:e012188. https://doi.org/10.1161/ jaha.119.012188; PMID: 31041869.

Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) everything? Am J Cardiol 2003;92:824–6. https://doi.org/10.1016/s00029149(03)00891-9; PMID: 14516884.

Krumholz HM, Bradley EH, Nallamothu BK, et al. A campaign to improve the timeliness of primary percutaneous coronary intervention: Door-to-Balloon: An Alliance for Quality. JACC Cardiovasc Interv 2008;1:97–104. https://doi.org/10.1016/j. jcin.2007.10.006; PMID: 19393152.

Pinto DS, Kirtane AJ, Nallamothu BK, et al. Hospital delays in reperfusion for ST-elevation myocardial infarction. Circulation 2006;114:2019–25. https://doi. org/10.1161/circulationaha.106.638353; PMID: 17075010.

Eagle KA, Gallogly M, Mehta RH, et al. Taking the national guideline for care of acute myocardial infarction to the bedside: developing the Guideline Applied in Practice (GAP) Initiative in southeast Michigan. Jt Comm J Qual Improv 2002;28:5–19. https://doi.org/10.1016/s1070-3241(02)280025; PMID: 11787240.

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14. Bradley EH, Nallamothu BK, Stern AF, et al. Contemporary evidence: baseline data from the D2B Alliance. BMC Res Notes 2008;1:23. https://doi.org/10.1186/1756-0500-1-23; PMID: 18710480.

15. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 201329;127:e362–425. https://doi.org/10.1161/cir.0b013e3182742cf6; PMID: 23247304.

16. Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2018;39:119–77. https://doi.org/10.1093/eurheartij/ehx393; PMID: 28886621.

17. Nishiga M, Wang DW, Han Y, et al. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol 2020;17:543–58. https://doi. org/10.1038/s41569-020-0413-9; PMID: 32690910.

18. Yerasi C, Case BC, Forrestal BJ, et al. Treatment of ST-segment elevation myocardial infarction during COVID-19 pandemic. Cardiovasc Revasc Med 2020;21:1024–9. https://doi.org/10.1016/j.carrev.2020.05.027; PMID: 32471712.

19. Hammad TA, Parikh M, Tashtish N, et al. Impact of COVID-19 pandemic on ST-elevation myocardial infarction in a nonCOVID-19 epicenter. Catheter Cardiovasc Interv 2021;97:208– 14. https://doi.org/ 10.1002/ccd.28997; PMID: 32478961.

20. Tan W, Parikh RV, Chester R, et al. Single center trends in acute coronary syndrome volume and outcomes during the COVID-19 pandemic. Cardiol Res 2020;11:256–9. https://doi. org/10.14740/cr1096; PMID: 32595811.

21. Aldujeli A, Hamadeh A, Briedis K, et al. Delays in

Door-to-balloon Time in the COVID-19 Era presentation in patients with acute myocardial infarction during the COVID-19 pandemic. Cardiol Res 2020;11:386–91. https://doi.org/10.14740/cr1175; PMID: 33224384.

22. Garcia S, Stanberry L, Schmidt C, et al. Impact of COVID-19 pandemic on STEMI care: An expanded analysis from the United States. Catheter Cardiovasc Interv 2020. https://doi. org/10.1002/ccd.29154; PMID: 32767652; epub ahead of press.

23. Fileti L, Vecchio S, Moretti C, et al. Impact of the COVID-19 pandemic on coronary invasive procedures at two Italian high-volume referral centers. J Cardiovasc Med (Hagerstown) 2020;21:869–73. https://doi.org/10.2459/ JCM.0000000000001101; PMID: 33009170.

24. Roffi M, Guagliumi G, Ibanez B. The obstacle course of reperfusion for ST-segment-elevation myocardial infarction in the COVID-19 pandemic. Circulation 2020;141:1951–3. https://doi.org/10.1161/CIRCULATIONAHA.120.047523; PMID: 32315205.

25. Kwok CS, Gale CP, Kinnaird T, et al. Impact of COVID-19 on percutaneous coronary intervention for ST-elevation myocardial infarction. Heart 2020;106:1805–11. https://doi. org/10.1136/heartjnl-2020-317650; PMID: 32868280.

26. Reinstadler SJ, Reindl M, Lechner I, et al. Effect of the COVID-19 pandemic on treatment delays in patients with

ST-segment elevation myocardial infarction. J Clin Med 2020;9:2183. https://doi.org/10.3390/jcm9072183; PMID: 32664309.

27. Claeys MJ, Argacha JF, Collart P, et al. Impact of COVID-19related public containment measures on the ST elevation myocardial infarction epidemic in Belgium: a nationwide, serial, cross-sectional study. Acta Cardiol 2020:1–7. https:// doi.org/10.1080/00015385.2020.1796035; PMID: 32727305.

28. Secco GG, Zocchi C, Parisi R, et al. Decrease and delay in hospitalization for acute coronary syndromes during the 2020 SARS-CoV-2 pandemic. Can J Cardiol 2020;36:1152–5. https://doi.org/10.1016/j.cjca.2020.05.023; PMID: 32447060.

29. Çinier G, Hayıroğlu M, Pay L, et al. Effect of the COVID-19 pandemic on access to primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.

Turk Kardiyol Dern Ars 2020;48:640–5. https://doi. org/10.5543/tkda.2020.95845; PMID: 33034585.

30. Erol MK, Kayıkçıoğlu M, Kılıçkap M, et al. Treatment delays and in-hospital outcomes in acute myocardial infarction during the COVID-19 pandemic: a nationwide study. Anatol J Cardiol 2020;24:334–42. https://doi.org/10.14744/ AnatolJCardiol.2020.98607; PMID: 33122486.

31. Daoulah A, Hersi AS, Al-Faifi SM, et al. STEMI and COVID-19 pandemic in Saudi Arabia. Curr Probl Cardiol 2020:100656.

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https://doi.org/10.1016/j.cpcardiol.2020.100656; PMID: 32839042.

32. Fu XY, Shen XF, Cheng YR, et al. Effect of COVID-19 outbreak on the treatment time of patients with acute ST-segment elevation myocardial infarction. Am J Emerg Med 2021;44:192–7. https://doi.org/10.1016/j.ajem.2020.09.038; PMID: 33039221.

33. Chew NW, Sia CH, Wee HL, et al. Impact of the COVID-19 pandemic on door-to-balloon time for primary percutaneous coronary intervention – results from the Singapore Western STEMI network. Circ J 2021;85:139–49. https://doi. org/10.1253/circj.CJ-20-0800; PMID: 33162491.

34. Lee KD, Lee SB, Lim JK, et al. Providing essential clinical care for non-COVID-19 patients in a Seoul metropolitan acute care hospital amidst ongoing treatment of COVID-19 patients. J Hosp Infect 2020;106:673–7. https://doi. org/10.1016/j.jhin.2020.09.031; PMID: 33011308.

35. Spaccarotella CAM, Polimeni A, Migliarino S, et al.

Multichannel electrocardiograms obtained by a smartwatch for the diagnosis of ST-segment changes. JAMA Cardiol 2020;5:1176–80. https://doi.org/10.1001/ jamacardio.2020.3994; PMID: 32865545.

Antithrombotics in High-Risk PCI

Platelet Function Testing and Genotyping for Tailoring Treatment in Complex PCI Patients Athanasios Moulias, MD, PhD, ,1 Angeliki Papageorgiou, MD, ,1 and Dimitrios Alexopoulos, MD, PhD, FESC, FACC,

2

1. Department of Cardiology, General University Hospital of Patras, Patras, Greece; 2. Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

Abstract

Dual antiplatelet therapy (DAPT), comprising aspirin and a P2Y12 receptor inhibitor, is considered the cornerstone of treatment in patients who have undergone percutaneous coronary intervention (PCI). Patients with complex PCI (C-PCI) constitute a special PCI subpopulation, characterized by increased ischemic risk. Identifying the optimal DAPT strategy is often challenging and remains controversial in this setting. In an attempt to balance ischemic and bleeding risks in C-PCI patients receiving DAPT, treatment individualization regarding potency and duration has evolved as a feasible approach. Platelet function testing and genotyping have been evaluated in several trials with conflicting and mostly neutral results.

The aim of this review is to critically appreciate the role of these tools for antiplatelet treatment tailoring specifically in C-PCI patients. Because existing evidence is limited, dedicated future studies are warranted to elucidate the utility of platelet function testing and genotyping in C-PCI.

Keywords

Percutaneous coronary intervention, complex percutaneous coronary intervention, platelet function testing, genotyping, dual antiplatelet therapy, P2Y12 receptor inhibitors Disclosure: DA has received advisory board/lecturing fees from AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Biotronik, Medtronic, and Chiesi Hellas. AM and AP have no conflicts of interest to disclose.

Received: November 24, 2020 Accepted: April 5, 2021 Citation: US Cardiology Review 2021;15:e14. DOI: https://doi.org/10.15420/usc.2020.33 Correspondence: Athanasios Moulias, MD, PhD, Consultant Cardiologist, Department of Cardiology, General University Hospital of Patras, 26504 Patras, Greece.

E: dramoulias@live.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Dual antiplatelet therapy (DAPT), comprising aspirin and a P2Y12 receptor inhibitor, is the cornerstone of treatment in patients who have undergone percutaneous coronary intervention (PCI).1,2 Clopidogrel was the first broadly used P2Y12 receptor inhibitor and conferred a significant reduction in ischemic events after PCI.3,4 However, clopidogrel’s metabolic activation is unpredictable, leading to variability in response among patients.

Genetic polymorphisms, among other factors, have been implicated in ‘clopidogrel resistance’.5 Several studies have found an association between impaired response to clopidogrel (often termed high on-treatment platelet reactivity [HPR]) and adverse ischemic events.6–8 On the other hand, low platelet reactivity (LPR) has been recognized as a risk factor for bleeding events, which significantly influence the clinical outcome of patients with coronary artery disease (CAD) during and after myocardial revascularization.6,9 These observations, along with the advent of more potent P2Y12 inhibitors (prasugrel and ticagrelor), gave birth to the concept of antiplatelet treatment tailoring; this concerns the adaptation and individualization of antiplatelet therapy type and duration based on various factors, including clinical presentation, the patient’s clinical profile, ischemic/bleeding scores, and laboratory/point-of-care tests. More specifically, potential strategies involve upfront selection of a more potent P2Y12 inhibitor (such as prasugrel or ticagrelor) instead of clopidogrel based on genotyping,

and escalation (switching from clopidogrel to prasugrel or ticagrelor) or de-escalation (switching from prasugrel/ticagrelor to clopidogrel) of the initial antiplatelet treatment according to platelet function testing (PFT) results.10 Moreover, various scores – including the Predicting Bleeding Complications In Patients Undergoing Stent Implantation and Subsequent Dual Anti Platelet Therapy (PRECISE-DAPT) score, the DAPT score, ARCHBR trade-off risk model and PARIS – have been proposed for uncoupling bleeding and ischemic risks in patients undergoing PCI and, thus, guiding DAPT duration in this context.11–14 Patients with C-PCI constitute a special PCI subpopulation where antiplatelet treatment is challenging. Although no universal definition exists, C-PCI according to the European Society of Cardiology (ESC) involves at least one of the following procedural aspects: implantation of three or more stents; treatment of three or more lesions; bifurcation PCI with two stents; total stent length >60 mm; or chronic total occlusion (CTO) PCI.15 Additionally, left main (LM) or proximal left anterior descending (LAD) coronary artery PCI, saphenous vein graft PCI, bifurcation lesion with a side branch ≥2.5 mm, use of rotational atherectomy, lesion length ≥30 mm or the presence of thrombus in the coronary lesion have also been considered as procedural characteristics defining a coronary intervention as C-PCI.16

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Platelet Function Testing and Genotyping in Complex PCI Table 1: High Platelet Reactivity and Low Platelet Reactivity Cutoff Values for Available Platelet Function Testing Assays

been proposed as a potentially beneficial strategy for patients at a high risk of bleeding.25

PFT assay

HPR

LPR

VerifyNow P2Y12

208 PRU

85 PRU

Multiplate Analyzer

46 U

19 U

VASP

50% PRI

16% PRI

TEG platelet mapping

47 mm

31 mm

HPR: high platelet reactivity, LPR: low platelet reactivity, PFT: platelet function testing, PRI: platelet reactivity index, PRU: platelet reactivity units, VASP: vasodilator-stimulated phosphoprotein.

Adapted from: Tantry et al. 2013.26 Used with permission from Elsevier.

In addition to procedural complexity, patient complexity because of multiple comorbidities and high-risk clinical features (such as smoking, diabetes, chronic kidney disease, peripheral arterial disease, hypertension and/or poor left ventricular function) is increasing over time in patients presenting for PCI.17 C-PCI patients are at increased risk for ischemic events and this risk is greater as procedural complexity increases.18–19 It is noteworthy that C-PCI patients seem to be at a higher risk for major bleeding as well.20 DAPT of increased potency and duration might reduce adverse ischemic events but increase the risk of bleeding as well, which can compromise the clinical outcome.

The optimal antiplatelet treatment strategy in C-PCI remains a controversial and moving field. PFT and genotyping have been considered as potentially useful tools in individualizing antiplatelet treatment in attempts to balance ischemic and bleeding risks. The aim of this review is to summarize the existing evidence and critically appreciate the role of PFT and genotyping for antiplatelet treatment tailoring in C-PCI patients.

PFT and Genotyping in PCI

DAPT, comprising aspirin and a P2Y12 receptor inhibitor, has improved PCI clinical outcomes by reducing ischemic complications.3 The secondgeneration thienopyridine clopidogrel was the first broadly used P2Y12 receptor inhibitor, as it exhibited a better safety profile than the firstgeneration thienopyridine ticlopidine. However, platelet function measurements showed that the response to this regimen varied, with some patients exhibiting poor response, a condition often termed HPR or clopidogrel resistance, as mentioned above.21 Several factors have been implicated in the variation in response to clopidogrel, including diabetes, acute coronary syndrome, a high BMI, renal failure, older age, heart failure, inflammation, smoking, drug–drug interactions and genetic polymorphisms (mainly of CYP2C19).21–23 The results of multiple studies indicating a clear association between HPR and adverse ischemic events after PCI paved the way for research efforts investigating the role of treatment tailoring.6,21 This approach initially involved increasing clopidogrel dose but this failed to reduce the incidence of death from cardiovascular causes, nonfatal MI, or stent thrombosis in HPR patients after PCI, perhaps because of a modest pharmacodynamic effect.24 With the advent of the more potent P2Y12 inhibitors prasugrel and ticagrelor, escalation of antiplatelet treatment by switching clopidogrel to a novel agent became an additional option. On the other hand, an increased response to P2Y12 receptor inhibitor, leading to LPR, has been recognized as a risk factor for bleeding events, which compromise clinical outcomes after PCI.9 As a result, treatment de-escalation has also

Several methods of PFT are available for the ex vivo measurement of platelet reactivity to adenosine diphosphate, including point-of-care assays (e.g. the VerifyNow P2Y12 system [Werfen], the Multiplate analyzer [Roche], and thromboelastography [TEG] platelet mapping) and laboratorybased techniques (e.g. light transmission aggregometry [LTA] and vasodilator-stimulated phosphoprotein [VASP]).

There is a consensus that point-of-care assays should be preferred, and specific cut-off points for HPR and LPR have been defined for each assay (Table 1).8,26 Platelet reactivity assessed by a PFT assay in a P2Y12-treated patient should ideally be within the therapeutic window between LPR and HPR, which is associated with the lowest risk of ischemic and bleeding events according to observational data.27 Major randomized studies testing PFT-guided escalation of antiplatelet treatment in PCI patients failed to show clinical benefit, which calls its role in clinical practice into question.24,28–30 However, a PFT-guided de-escalation approach was found to be non-inferior for the primary endpoint of net clinical benefit (cardiovascular death, MI, stroke or bleeding grade ≥2 according to Bleeding Academic Research Consortium [BARC] criteria) compared with potent platelet inhibition for 12 months after PCI for acute coronary syndrome (ACS) in the TROPICAL-ACS randomized study (7% in the guided de-escalation group versus 9% in the control group; p for noninferiority=0.0004; HR 0.81; 95% CI [0.62–1.06]). It is noteworthy that there was no increase in the combined risk of cardiovascular death, MI, or stroke in the early de-escalation group.31 As already mentioned, HPR in clopidogrel-treated patients may be related to polymorphisms of genes that encode cytochromes responsible for clopidogrel’s metabolic activation. Research on genotyping has focused on polymorphisms of the CYP2C19 gene, the most common and relevant being CYP2C19*2 loss of function (LoF) polymorphism, causing CYP2C19 activity to be lost. The CYP2C19*3 allele is another LoF polymorphism, which has a low prevalence in white people.32 However, only 6–12% of the variability on clopidogrel response can be attributed to differences in genotype.5,33 It is reasonable to use genotyping only for clopidogreltreated patients and point-of-care assays are recommended over laboratory-based methods.8 Some randomized studies have shown efficacy of CYP2C19 genotyping in antiplatelet treatment tailoring for both elective and ACS PCI patients.34–37 However, the recently announced TAILOR-PCI study reported – though marginally – a non-significant (4% versus 5.9%; HR:0.66; p=0.056) reduction in major adverse cardiovascular events (MACE) (non-fatal myocardial infarction or stroke, cardiovascular death, severe recurrent ischemia or stent thrombosis) at 1 year in the genotyping compared with the non-genotyping group.38 Beyond the CYP2C19*2 LoF polymorphism, clinical factors are believed to have contributing roles in HPR and thrombotic complications. In this context, the ABCD-GENE (Age, Body mass index, Chronic kidney disease, Diabetes mellitus, and Genotyping) score was developed, which incorporates four clinical (age >75 years, BMI >30 kg/m2, chronic kidney disease [estimated glomerular filtration rate <60 ml/min/1.73m2], and diabetes) and one genetic (CYP2C19*2 LoF alleles) independent predictors of HPR. The ABCD-GENE score has been shown to independently correlate with all-cause death, as well as with the composite of all-cause death, stroke, or MI, both as a continuous variable and by using a cut-off point of ≥10.39

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Platelet Function Testing and Genotyping in Complex PCI Table 2: Studies Investigating Platelet Function Testing for Treatment Tailoring in Complex Percutaneous Coronary Intervention Patients Study

Population

Study Design

Main Endpoints

Main Results

Xu et al.

201455

384 ACS patients who received high-risk C-PCI

Randomized, single-center study Comparison of standard DAPT (conventional group) versus DAPT guided by modified TEG platelet mapping (PFT-guided group) • IPAAA < 50% → ↑ASA to 200 mg daily; • IPAADP < 30% → ↑clopidogrel to 150 mg daily

MI, emergency TVR, ST, and death at 6 months

No significant differences in the primary efficacy endpoint (4.7% in the conventional versus 5.2% in the PFT-guided group; HR 1.13; p=0.79)

Chen et al.

201956

334 Taiwanese patients with stable CAD and scheduled stent implantation for intermediate-to-highly complex coronary lesions (SYNTAX score >22)

Prospective, single-blind, randomized study ASA + clopidogrel (group standard) versus ASA + ticagrelor (group ticagrelor) versus ASA + clopidogrel + cilostazol (group cilostazol) for 6 months of treatment then switching to ASA only

PRU levels 24 h, 7 days, and 1 month after PRU levels decrease: in group ticagrelor > PCI in group cilostazol > in group standard MACE (death, MI, revascularization of the No significant difference in MACE between original lesion) at 2 years the three groups (group standard 12.1%, group cilostazol 8.7%, group ticagrelor 7.8%; p=NS)

De Gregorio 1,101 patients from the et al. 202057 Florence CTO- PCI registry with available PFT (LTA)

Retrospective Long- term cardiac survival (3 years) Patients stratified according to LTA results: optimal platelet reactivity (82%) and HPR (ADP test ≥70%) (18%) From 2011, escalation strategy applied: • HPR on clopidogrel → escalation to prasugrel or ticagrelor • HPR on new P2Y12 receptor antagonist → change between prasugrel and ticagrelor

Three-year survival was significantly higher in the optimal platelet reactivity group compared with HPR patients (95.3 ± 0.8% versus 86.2 ± 2.8%; p<0.001) HPR on clopidogrel ‘not switched’ associated with cardiac mortality (HR 2.37; p=0.003) after multivariable adjustment

ACS = acute coronary syndrome; ADP = adenosine diphosphate; ASA = acetylsalicylic acid; CAD = coronary artery disease; C-PCI = complex percutaneous coronary intervention; CTO = chronic total occlusion; DAPT = dual antiplatelet therapy; HPR = high on-treatment platelet reactivity; IPAAA = inhibition of platelet aggregation by arachidonic acid; IPAADP = inhibition of platelet aggregation by adenosine diphosphate; LTA = light transmission aggregometry; MACE = major adverse cardiac events; PCI = percutaneous coronary intervention; PFT = platelet function testing; PRU = platelet reactivity unit; ST = stent thrombosis; TEG = thromboelastography; TVR = target vessel revascularization.

Current guidelines on DAPT recommend against (class III) the routine use of PFT and genotyping as antiplatelet treatment modification guidance in the context of PCI.2,15 However, according to the recently published ESC guidelines on non-ST-segment elevation ACS: “De-escalation of P2Y12 receptor inhibitor treatment… may be considered as an alternative DAPT strategy, especially for ACS patients deemed unsuitable for potent platelet inhibition. De-escalation may be done unguided based on clinical judgment, or guided by platelet function testing, or CYP2C19 genotyping, depending on the patient’s risk profile and availability of respective assays.” (Class IIb, level of evidence A.)40 Moreover, experts agree that use of PFT/genotyping may be reasonable in specific high-risk clinical scenarios, including C-PCI.8

Rationale for Use of PFT and/or Genotyping in C-PCI

During the last decade, C-PCI procedures have been increasingly performed. Moreover, as mentioned before, a rise in the high-risk clinical features (smoking, diabetes, chronic kidney disease, peripheral arterial disease, hypertension, and poor left ventricular function) of treated patients has also been observed.41 C-PCI patients are at a higher risk of ischemic events, and this risk becomes greater as procedural complexity increases.18,19,42 DAPT of increased potency (with prasugrel or ticagrelor) might reduce adverse ischemic events.

On these grounds, ESC guidelines for myocardial revascularization offer the option of administering prasugrel or ticagrelor in specific high-risk situations of elective PCI; however, the level of evidence for this is weak (IIb, C).1 Moreover, prolonged DAPT has also been proposed as a potentially beneficial strategy for this high-risk group.19 Nevertheless, C-PCI patients seem to be at increased risk for major bleeding as well.20 Consequently, more potent and/or prolonged DAPT might compromise clinical outcome by increasing bleeding events.

As C-PCI procedures are performed more often and in sicker patients, optimization of DAPT strategies is imperative to optimize clinical outcomes. Here, antiplatelet treatment tailoring according to each patient’s ischemic and bleeding risk is a reasonable approach. PFT and genotyping may serve as tools to escalate or de-escalate DAPT to achieve the desired level of antiplatelet effect. Moreover, PFT could also be used to check compliance with treatment, which is crucial in this context.

Evidence Regarding Platelet Function Testing in Complex PCI

Numerous randomized and observational studies have investigated the potential role of PFT-guided antiplatelet treatment for the optimization of clinical outcomes of patients subjected to PCI.24,29–31,43–54 Supplementary Table 1 provides an overview of the relevant studies in this field. Smaller randomized and non-randomized studies suggest PFT-guided treatment tailoring improves clinical outcomes.51–54 Nonetheless, major randomized trials have failed to confirm a benefit from a PFT-guided treatment escalation approach whereas a PFT-guided de-escalation approach was found to be non-inferior regarding the primary endpoint of net clinical benefit (cardiovascular death, MI, stroke or BARC bleeding grade ≥2) compared with potent platelet inhibition for 12 months after PCI for ACS.24,28–31 C-PCI patients (e.g. those with multivessel PCI, LM PCI, saphenous vein graft PCI, bifurcation PCI, lesion type B2/C or three or more stents) are represented in these studies to varying degrees (mostly poorly), and relevant data are not reported in some of them (Supplementary Table 1).

Moreover, only a few studies have reported subgroup analyses of the primary endpoint for some procedural variables related to PCI complexity but not for the subgroup of C-PCI patients in total (Supplementary Table 1).

Consequently, extrapolation of the results of these studies to C-PCI patients is questionable.

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Platelet Function Testing and Genotyping in Complex PCI Table 3: Randomized Studies Investigating Genotyping for Antiplatelet Treatment Tailoring in Percutaneous Coronary Intervention Patients Study

Population Comparison

Main Endpoints

Main Results

C-PCI Patients

RAPIDGENE 201258

200 patients Standard group (clopidogrel scheduled for 75 mg daily) versus PCI genotyping-guided group (prasugrel 10 mg daily for CYP2C19*2 carriers, ACS: 37.4% clopidogrel 75 mg daily for non-carriers)

HPR (PRU>234) in CYP2C19*2 carriers after 7 days DAPT

Significant reduction of HPR in CYP2C19*2 carriers genotyping guided versus standard group (0 versus 30%, p=0.0092)

LM PCI 0 (0%) Vein graft PCI 2 (2%)

2 (2%) 4 (4%)

IAC-PCI 201337

600 ACS patients with successful PCI

MACE (all-cause death, MACE lower in the MI, stroke or TVR) at personalized than the 180 days after conventional group (2.66% intervention versus 9.03%; p=0.001)

LM PCI

17 (5.69%)

10 (3.32%)

LM lesion Multivessel disease

17 (5.3%)

15 (4.9%)

62 (19.4%)

69 (22.3%)

45 (10.6%) 112 (26.5%)

60 (13.8%) 119 (27.4%)

Shen et al. 628 CAD 201636 patients subjected to successful PCI

Conventional group: 300 mg clopidogrel LD/75 mg MD versus personalized group (CYP2C19 phenotype: EMs → standard dose of clopidogrel, IMs → double LD and MD of clopidogrel, PMs → double LD and MD of clopidogrel + cilostazol)

Routine group (75 mg clopidogrel MACE (death from any daily) versus individual group cause, MI, TVR) (CYP2C19 phenotype: EMs → clopidogrel 75 mg daily, IMs → clopidogrel 150 mg daily, PMs → ticagrelor 90 mg bid)

Lower MACE rate in individual group at 12 months after discharge compared with routine group (4.2% versus 9.4%; p=0.010)

Standard care versus pharmacogenomic (ABCB1, CYP2C19*2, and CYP2C19*17) guidance of P2Y12 receptor inhibitor administration

Significant reduction of the LM disease incidence of the primary 3-vessel endpoint in the disease pharmacogenomic compared with the standard-care arm (15.9% versus 25.9%; HR: 0.58; 95% CI: 0.43-0.78; p<0.001)

Conventional Genotyping Group, n (%) Guided Group, n (%)

ACS: rate not reported PHARMCLO 888 ACS 201835 patients PCI: 532 (62.2%)

Composite of CV death, MI, stroke, or BARC 3/5 bleeding at 12 months

Premature termination POPular Genetics 201934

ADAPTPCI trial 202059

2,488 STEMI P2Y12 inhibitor on the basis of early PCI patients CYP2C19 genetic testing (genotypeguided group) versus standard treatment with ticagrelor or prasugrel for 12 months

Net adverse clinical events (death from any cause, MI, ST, stroke, or PLATO major bleeding at 12 months)

Net adverse clinical events lower in genotype-guided group than standard group (5.1% versus 5.9%; pnoninf<0.001) Bleeding occurrence was lower in genotype-guided PLATO major/minor group bleeding at 12 months (9.8% versus 12.5%; HR 0.78; 95% CI [0.61–0.98]; p=0.04)

LM PCI Bypass graft PCI Ostial lesion Bifurcation lesion

9 (0.73%)

4 (0.3%)

6 (0.5%) 65 (5.5%)

5 (0.4%) 76 (6.4%)

239 (20.2%)

214 (18.1%)

504 PCI patients

Genotyping of CYP2C19 major alleles (*2, *3, *17) to guide antiplatelet drug selection (genotyped group) versus no genotyping (usual care)

Rate of prasugrel or Use of prasugrel or ticagrelor ticagrelor prescribing significantly higher in in each arm genotyped compared with usual care group (30% versus MACE endpoint: CV 21%; HR 1.60; 95% CI death, nonfatal MI, [1.07–2.42]; p=0.03) nonfatal stroke, No significant differences urgent in MACE in the genotyped revascularization, compared with the usual ST care group (13.7% versus 10.2%; p=0.27)

Stented vessels≥2

25 (10%)

27 (11%)

Non genotyping group (clopidogrel 75 mg MD) versus genotyping group (ticagrelor 90 mg twice a day for carriers, clopidogrel 75 mg daily for non-carriers)

Composite MACE Non-significant reduction of (non-fatal MI or stroke, MACE in the genotyping CV death, severe compared with the nonrecurrent ischemia, genotyping group (4% ST) at 1 year versus 5.9%; HR 0.66; TIMI major or minor p=0.056) bleeding No difference in bleeding (1.9% versus 1.6%)

LM PCI

21 (2%)

32 (4%)

ACS: 49.9%

TAILOR-PCI 5,302 202038 elective + ACS PCI patients

ACS = acute coronary syndrome; CAD = coronary artery disease; C-PCI = complex percutaneous coronary intervention; CV = cardiovascular; DAPT = dual antiplatelet treatment; EMs = extensive metabolizers; HPR = high on treatment platelet reactivity; IMs = intermediate metabolizers; LD = loading dose; LM = left main; MACE = major adverse cardiac events; MD = maintenance dose; PCI = percutaneous coronary intervention; PLATO = Platelet Inhibition and Patient Outcome; PMs = poor metabolizers; TVR = target vessel revascularization.

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Platelet Function Testing and Genotyping in Complex PCI Figure 1: Treatment with Platelet Function Testing Complex PCI Acute coronary syndrome

Thrombotic risk >bleeding risk PFT

'Mandatory' period of potent DAPT

Continuation of potent DAPT until 1 year after PCI Thrombotic risk >bleeding risk PFT

Continuation of potent DAPT beyond 1 year after PCI

Stable coronary artery disease

Bleeding risk >thrombotic risk PFT

De-escalation to moderate-intensity until 1 year after PCI

Bleeding risk >thrombotic risk Thrombotic risk >bleeding risk PFT PFT

De-escalation to moderate-intensity DAPT or SAPT beyond 1 year after PCI

Continuation of moderate-intensity DAPT beyond 1 year after PCI

Thrombotic risk >bleeding risk PFT

Genotyping

Guideline recommended moderate-intensity DAPT

Bleeding risk >thrombotic risk PFT Bleeding risk >thrombotic risk PFT SAPT beyond 1 year after PCI

De-escalation to SAPT beyond 6 months after PCI

Start with potent DAPT

Thrombotic risk >bleeding risk PFT

Prolonged DAPT >6 months

Potent DAPT: aspirin + ticagrelor or prasugrel; moderate-intensity DAPT: aspirin + clopidogrel. DAPT = dual antiplatelet therapy; PCI = percutaneous coronary intervention; PFT = platelet function testing; SAPT = single antiplatelet therapy.

Figure 2: Treatment with Genotyping Complex PCI Acute coronary syndrome

Stable coronary artery disease

'Mandatory' period of potent DAPT Thrombotic risk >bleeding risk

Bleeding risk >thrombotic risk Genotyping

Continuation of potent DAPT until 1 year after PCI

De-escalation to moderate-intensity until 1 year after PCI

Thrombotic risk >bleeding risk

Continuation of potent DAPT beyond 1 year after PCI

Bleeding risk >thrombotic risk Thrombotic risk >bleeding risk Genotyping

De-escalation to moderate-intensity DAPT or SAPT beyond 1 year after PCI

Continuation of moderate-intensity DAPT beyond 1 year after PCI

Genotyping

Guideline recommended moderate-intensity DAPT

Thrombotic risk >bleeding risk Genotyping

Start with potent DAPT

Bleeding risk >thrombotic risk Bleeding risk >thrombotic risk SAPT beyond 1 year after PCI

De-escalation to SAPT beyond 6 months after PCI

Thrombotic risk >bleeding risk

Prolonged DAPT >6 months

Potent DAPT is aspirin + ticagrelor or prasugrel; moderate-intensity DAPT is aspirin + clopidogrel. DAPT = dual antiplatelet therapy; PCI = percutaneous coronary intervention; PFT: platelet function testing, DAPT: dual antiplatelet therapy; SAPT = single antiplatelet therapy

To have more robust evidence regarding the role of PFT in C-PCI, dedicated clinical trials enrolling exclusively patients subjected to high-risk interventions are required. However, relevant studies to date are scarce and suffer the limitations of small sample size or non-randomized design.55–57 The design and main results of these studies are presented in Table 2.

In a randomized, single-center study, Xu et al. failed to show any improvement in the primary ischemic endpoint by using a guided DAPT escalation strategy, using modified TEG platelet mapping in ACS patients who underwent C-PCI.55 Similarly, no significant difference in MACE was reported by Chen et al. by the administration of more potent antiplatelet therapy (aspirin plus ticagrelor, or aspirin plus clopidogrel and cilostazol) compared with standard treatment (aspirin plus clopidogrel) in stable CAD patients scheduled for C-PCI, in spite of achieving a greater platelet reactivity unit decrease with the more intense antiplatelet treatment. This study did not investigate the guided strategy, but implies that more pronounced platelet inhibition does not confer additional benefit in stable CAD C-PCI patients.56 Finally, in a retrospective study including 1,101 patients from the Florence CTO-PCI registry, HPR on clopidogrel ‘not switched’ was associated with increased cardiac mortality (HR 2.37;

p=0.003) after multivariable adjustment, compared with an LTA-based treatment escalation strategy in HPR patients who underwent CTO PCI.57

Evidence Regarding Genotyping in Complex PCI

As with PFT, no studies regarding genotyping have been conducted exclusively for C-PCI. Table 3 contains a summary of the randomized studies investigating the role of genotyping (CYP2C19) for antiplatelet treatment tailoring in PCI patients.34–37,58,59 Although some small randomized studies have shown clinical benefit, the recent large-scale, randomized TAILOR- PCI study questioned the benefit from point-of-care, genotype-guided, anti-platelet therapy (ticagrelor 90mg twice daily for carriers and clopidogrel 75 mg daily for non-carriers) compared with routine care (clopidogrel 75 mg as directed) in patients undergoing PCI (electively or for ACS).34–38 The reduction of MACE (non-fatal MI or stroke, cardiovascular death, severe recurrent ischemia or stent thrombosis) at 1 year in the genotyping compared with the non-genotyping group was marginally non-significant (4% versus 5.9%; HR 0.66; p=0.056).

No significant difference in thrombolysis in MI (TIMI) major or minor bleeding classification was noted as well (1.9% versus 1.6%).

US CARDIOLOGY REVIEW Access at: www.USCjournal.com

Platelet Function Testing and Genotyping in Complex PCI Nevertheless, the results of this study show signs of benefit from the genetically guided antiplatelet therapy, since approximately one-third fewer adverse events occurred in the genetically guided treatment group compared with the standard treatment group. Notably, a prespecified sensitivity analysis allowing for multiple events per patient favored the use of genotype-guided therapy over the conventional approach in CYP2C19 LoF carriers (HR 0.60; 95% CI: 0.41–0.89; p=0.01).

Moreover, a post hoc analysis found a nearly 80% reduction in the rate of adverse events in the first 3 months of treatment among patients who received genetically guided therapy. This finding may be clinically relevant, considering that ischemic events are more frequent during the first 30 days after PCI in this population and potent P2Y12 inhibitor therapy may be beneficial during this early period. Bleeding is more pronounced during later period with potent P2Y12 inhibitors.

However, it should be noted that the representation of C-PCI in these studies was limited (Table 3). Therefore, it is not known to which extent their results are relevant to the C-PCI group of patients.

Conclusion

Taking into consideration the increasing performance of C-PCI procedures worldwide along with the associated high ischemic risk, refinement of antiplatelet treatment strategies is becoming imperative for this special group of patients.

Tailoring DAPT potency and duration is a reasonable approach and PFT/ genotyping may serve as valuable tools in this attempt (Figures 1 and 2).

To date, large-scale randomized clinical trials have failed to show any clinical benefit from routine monitoring of platelet function in PCI patients.

However, since C-PCI patients are mostly under-represented in these studies and subgroup analyses are limited, it remains unclear whether C-PCI patients would benefit from a tailored strategy guided by PFT. Similarly, results from randomized studies are not convincing so far regarding the utility of genotyping results for treatment escalation after 1. Neumann FJ, M Sousa-Uva, Ahlsson A et al. 2018 ESC/ EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437.

2. Levine GN, ER Bates, JA Bittl, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68:1082–115. https://doi.org/10.1016/j.jacc.2016.03.513; PMID: 27036918.

3. Yusuf S, F Zhao, SR Mehta, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. https://doi.org/10.1056/NEJMoa010746; PMID: 11519503.

4. Steinhubl SR, PB Berger, JT Mann 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411–20. https://doi. org/10.1001/jama.288.19.2411; PMID: 12435254.

5. Shuldiner AR, O’Connell JR , Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009;302:849–57. https://doi.org/10.1001/jama.2009.1232; PMID: 19706858.

6. Aradi D, A Kirtane, L Bonello, et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 2015;36:1762–71. https://doi.org/10.1093/eurheartj/ehv104; PMID: 25896078.

7. Stone GW, Witzenbichler B, Weisz G, et al. Platelet reactivity

8.

9.

10.

11.

12.

13.

PCI. However, as with PFT studies, it is not known to which extent these results can be extrapolated to C-PCI patients. A patient-level metaanalysis, including C-PCI patients enrolled in PFT/genotyping studies, could potentially provide further insights into this field of research.

Nonetheless, the heterogeneity in the design of conducted studies will definitely affect its reliability.

Dedicated randomized studies enrolling exclusively C-PCI patients in different clinical settings (such as stable CAD and ACS) are warranted and will elucidate the role of treatment tailoring based on PFT and genotyping in this group of patients. Notably, the establishment of a universal definition for C-PCI is required and will facilitate future research efforts.

Until more robust evidence becomes available in this controversial field, clinicians should follow the guidelines and adopt a PFT/genotypingguided approach for treatment tailoring selectively, according to their clinical judgement, in specific C-PCI patients where balancing ischemic and bleeding risks is challenging (Figures 1 and 2). Noteworthy, the results of PFT and/or genotyping should always be evaluated in combination with the patient’s clinical, procedural and socioeconomic parameters to optimize antiplatelet treatment planning.

Clinical Perspective

• Patients with complex percutaneous coronary intervention • • • •

(C-PCI) constitute a special PCI subpopulation at increased ischemic risk.

Antiplatelet treatment in C-PCI patients remains controversial.

Tailoring antiplatelet treatment in C-PCI patients is a reasonable approach and platelet function testing (PFT)/genotyping might serve as valuable tools in this.

Existing evidence from clinical studies in this field is limited.

Dedicated studies for C-PCI patients are warranted to elucidate the utility of antiplatelet treatment tailoring based on PFT and/or genotyping in this context.

and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013;382:614–23. https://doi. org/10.1016/S0140-6736(13)61170-8; PMID: 23890998.

Sibbing D, Aradi D, Alexopoulos D, et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv 2019;12:1521–37. https://doi.org/10.1016/j.jcin.2019.03.034; PMID: 31202949.

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Costa F, van Klaveren D, James S, et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials.

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Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur Heart J 2018;39:213–60. https://doi.org/10.1093/eurheartj/ehx419; PMID: 28886622.

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Giustino G, Chieffo A, Palmerini T, et al. Efficacy and safety of dual antiplatelet therapy after complex PCI. J Am Coll Cardiol 2016;68:1851–64. https://doi.org/10.1016/j.

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27. Sibbing D, Steinhubl SR, Schulz S, et al. Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window. J Am Coll Cardiol 2010;56:317–8. https:// doi.org/10.1016/j.jacc.2010.03.048; PMID: 20633826.

28. Collet JP, Cuisset T, Range G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012;367:2100–9. https://doi.org/10.1056/ NEJMoa1209979; PMID: 23121439.

29. Trenk D, Stone GW, Gawaz M, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012;59:2159–64. https://doi. org/10.1016/j.jacc.2012.02.026; PMID: 22520250.

30. Cayla G, T Cuisset, J Silvain, et al. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 2016;388:2015–22. https://doi. org/10.1016/S0140-6736(16)31323-X; PMID: 27581531.

31. Sibbing D, Aradi D, Jacobshagen C, et al. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017;390:1747–57. https://doi. org/10.1016/S0140-6736(17)32155-4; PMID: 28855078.

32. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354–62. https://doi.org/10.1056/NEJMoa0809171; PMID: 19106084.

33. Hochholzer W, Trenk D, Fromm MF, et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent

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34. Claassens DMF, Vos GJA , Bergmeijer TO, et al. A genotypeguided strategy for oral P2Y12 inhibitors in primary PCI. N Engl J Med 2019;381:1621–31. https://doi.org/10.1056/ NEJMoa1907096; PMID: 31479209.

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36. Shen DL, Wang B, Bai J, et al. Clinical value of CYP2C19 genetic testing for guiding the antiplatelet therapy in a Chinese population. J Cardiovasc Pharmacol 2016;67:232–6. https://doi.org/10.1097/FJC.0000000000000337; PMID: 26727381.

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38. Pereira NL, ME Farkouh, D So, et al. Effect of genotypeguided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial. JAMA 2020;324:761–71. https://doi. org/10.1001/jama.2020.12443; PMID: 32840598.

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Cardiogenic Shock

Describing and Classifying Shock: Recent Insights Ashleigh Long MD, PhD, ,1 Amin Yehya, MD, MSc, ,1,2 Kelly Stelling, RN, ,1 and David A Baran MD,

1.2

1. Sentara Heart Hospital, Norfolk, VA; 2. Eastern Virginia Medical School, Norfolk, VA

Abstract

Cardiogenic shock continues to present a daunting challenge to clinicians, despite an increasing array of percutaneous mechanical circulatory support devices. Mortality for cardiogenic shock has not changed meaningfully in more than 20 years. There have been many attempts to generate risk scores or frameworks to evaluate cardiogenic shock and optimize the use of resources and assist with prognostication. These include the Intra-Aortic Balloon Pump in Cardiogenic Shock (IABP-SHOCK) II risk score, the CardShock score and the new CLIP biomarker score.

This article reviews the Society for Cardiac Angiography and Interventions (SCAI) classification of cardiogenic shock and subsequent validation studies. The SCAI classification is simple for clinicians to use as it is based on readily available information and can be adapted depending on the data set that can be accessed. The authors consider the future of the field. Underlying all these efforts is the hope that a better understanding and classification of shock will lead to meaningful improvements in mortality rates.

Keywords

Cardiogenic shock, classification, scoring, shock stage schema, phenotypes Disclosure: AY has received speaking honoraria from CareDx, ZOLL, and Akcea Therapeutics; and is on the US Cardiology Review editorial board; this did not affect peer review.

DAB has received speaking honoraria from Pfizer and is a consultant for Abiomed, Getinge, LivaNova and Abbott. All other authors have no conflicts of interest to declare.

Received: March 24, 2021 Accepted: July 9, 2021 Citation: US Cardiology Review 2021;15:e15. DOI: https://doi.org/10.15420/usc.2021.09 Correspondence: David A Baran, Eastern Virginia Medical School, Sentara Heart Hospital, 600 Gresham Drive, Norfolk, VA 23507. E: docbaran@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Despite the availability of advanced medical management strategies, mechanical circulatory support (MCS), and culprit-vessel revascularization; cardiogenic shock (CS) continues to be associated with increased morbidity and mortality rates with an estimated 30-day mortality rate of 50%.1,2 Outcomes with CS have not improved over the previous three decades; possibly related to the heterogeneity of shock populations, which can make findings of clinical and retrospective trials difficult to apply globally.1,2 In this article, we will review selected major prognostication and risk scoring models for CS and discuss the recently published Society for Cardiac Angiography and Interventions (SCAI) CS classification schema.

Hemodynamic Correlate of Mortality: Cardiac Power Output

Cardiogenic Shock: Definitions, Hemodynamic Criteria, and Clinical Indicators

IABP-SHOCK II Trial Study and Risk Score

CS is a clinical syndrome associated with reduced cardiac output and a secondary reduction in end-organ perfusion.3 The landmark SHOCK trial defined CS in the following way: hemodynamic indicators of CS included persistent hypotension (systolic blood pressure <90 mmHg, or the addition of a vasopressor to maintain systolic pressure >90 mmHg), reduced cardiac output (CO) (<1.8 l/min/m2 without support or 2.0–2.2 l/ min/m2 with support), and concurrent elevation in left ventricular end diastolic pressure.3 Clinical signs of organ hypoperfusion from CS included cold extremities, reduced urine output, and altered mental status.3,4 Until recently, the stages of CS had not been well defined, though it was widely accepted patients requiring one or more inotropes had higher mortality.4 The topic of assessing risk in the setting of CS is quite broad and well covered elsewhere.5–7 The following are selected works but do not include all prior work.

An analysis from the original SHOCK trial demonstrated that cardiac power output (product of CO and mean arterial blood pressure divided by 451) is a potent predictor of outcome.3,8 The investigators from the Detroit Cardiogenic Shock Initiative have built upon this finding in the use of the Impella microaxial flow pump to address the hemodynamic disturbance of acute MI (AMI) shock.9,10 Using a protocolized approach to shock recognition and management with percutaneous MCS, they have demonstrated improved outcomes in multicenter findings, particularly for patients who achieve an increase in cardiac power output with MCS. The Intra-Aortic Balloon Pump in CS (IABP-SHOCK II) score was developed from the data set of the multicenter, open label, randomized IABP-SHOCK II trial.11,12 In this study, patients with AMI (with or without ST elevation), CS, and planned early revascularization (n=600), were randomized in a 1:1 ratio to IABP use versus no IABP use. The trial failed to show a difference in mortality between the groups. Using a stepwise multivariable Cox proportional hazards regression analysis, variables from this database significantly related to 30-day mortality (p<0.1) were identified and used as score parameters.13 These parameters included age >73 years; prior stroke; glucose at admission >10.6 mmol/l (191 mg/dl); creatinine at admission >132.6 μmol/l (1.5 mg/dl); Thrombolysis in MI flow grade <3 after percutaneous coronary intervention; and arterial blood lactate at admission >5 mmol/l. Level of risk for 30-day mortality was calculated by assigning either 1 or 2 points to each variable, leading to a score in three risk categories: low (0–2); intermediate (3 or 4); and high (5–9).13 In this

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Cardiogenic Shock Classification Figure 1: The SCAI Shock Pyramid and the Stages of Shock Extremis Arrest (A) Modifier: CPR, including defibrillation

A patient being supported by multiple interventions who may be experiencing cardiac arrest with ongoing CPR and/or ECMO.

E

Deteriorating Patient who fails to respond to initial interventions. Similar to stage C and getting worse.

D

Classic A patient presenting with hypoperfusion requiring intervention beyond volume resuscitation (inotrope, pressor, or mechanical support including ECMO). These patients typically present with relative hypotension.

C

Beginning A patient who has clinical evidence of relative hypotension or tachycardia without hypoperfusion.

B

At risk A patient with risk factors for cardiogenic shock who is not currently experiencing signs or symptoms.

For example, large acute MI, prior infarction, acute and/or acute on chronic heart failure.

A

CPR = cardiopulmonary resuscitation; ECMO = extracorporeal membrane oxygenation; SCAI = Society for Cardiovascular Angiography and Interventions. Source: Baran et al.19 Reproduced with permission from the Society for Cardiovascular Angiography and Interventions.

sub-study, the observed 30-day mortality rates were 23.8%, 49.2%, and 76.6%, respectively (p<0.0001). Validation in the IABP-SHOCK II registry population (patients not randomized, but seen contemporaneously with the trial) showed good discrimination, with an area under the curve (AUC) of 0.79.

CardShock Trial and Risk Score

The CardShock risk score was developed from the multicenter, prospective, observational CardShock study conducted between 2010 and 2012.14 In this study, patients with CS from either acute coronary syndrome (ACS) or non-ACS etiologies were enrolled within 6 hours from detection of severe hypotension with clinical signs of hypoperfusion and/ or serum lactate >2 mmol/l despite fluid resuscitation (n=219; mean age 67; 74% men).14 Data on clinical presentation, management, and biochemical variables were compared between different etiologies of shock to help stratify risk of short-term mortality. The CardShock risk score used seven variables that were associated with increased mortality: ACS etiology; age; previous MI; prior coronary artery bypass; confusion; low left ventricular ejection fraction, and blood lactate levels. The CardShock risk score was subsequently shown to predict in-hospital mortality as well (AUC 0.85).

Comparison of Risk Prediction Models

Two large studies have directly compared the prognostic accuracy of the IABP-SHOCK II and CardShock risk scores in real-world populations of patients with CS.15,16 Miller et al. looked at patients admitted to intensive care units (ICUs) in Alberta, Canada in 2015, focusing on 510 patients with CS from a registry of 3,021 patients.15 They applied the Acute Physiology and Chronic Health Evaluation-II (APACHE-II), CardShock, IABP-SHOCK II, and Sepsisrelated Organ Failure Assessment (SOFA) risk scores to each patient.

Scores were employed to predict in-hospital mortality with the following AUC values: APACHE-II AUC 0.72, (95% CI [0.66–0.76]), IABP-SHOCK II

AUC 0.73 (95% CI [0.68–0.77]), and CardShock AUC 0.76 (95% CI [0.72– 0.81]). The SOFA score was associated with an AUC of 0.76 (95% CI [0.72–0.81]).

Rivas-Lasarte et al. recently reported from the Red-Shock registry.16 Five tertiary Spanish centers collected data on all consecutive adult patients who were admitted to ICU with CS (n=696). The registry included patients with shock due to ACS as well as non-ischemic etiologies (referred to as heart failure shock). The authors applied the IABP-SHOCK II score and the CardShock score to each case. For non-ischemics, the Thrombolysis in MI (TIMI) grade needed for the IABP score was assumed to be normal flow.

They found that the AUC was 0.742 for the CardShock versus 0.752 for IABP-SHOCK II, and there was no difference in the predictive accuracy between scores in their population (p=0.65).

The team who performed the IABP-SHOCK II trial and the CULPRIT-SHOCK trial have applied sophisticated modeling to a selection of 58 candidate biomarkers from sub-studies of each of the two trials.17 Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis technique, the group selected four biomarkers which in combination are predictive of 30-day mortality in CS patients. The components are cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide (CLIP). The AUC was 0.82 (95% CI [0.78–0.86]) which was superior to CardShock or the IABP-SHOCK II score. Of note, the predictive value of the score was heavily driven by lactate. Other groups have applied the CLIP combination to a broad ICU population (including sepsis and non-cardiac disease) and the biomarker-based score also seems to be predictive of survival in these settings.18 Risk scores are still more useful in research than broad clinical use outside specialized centers. This set the stage for an alternative way to classify CS that would allow clinicians across the spectrum of care to assign categories to the information available, which is usually incomplete in real-world critical care settings.

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Cardiogenic Shock Classification Table 1: Studies of SCAI Cardiogenic Shock Stages Study

Study Type

Location

Study Size (n)

Key Endpoint

Main Findings

Jentzer et al.

201924

Retrospective

Single center

10,004

Mortality during index admission

SCAI shock stage at initial CICU admission accurately predicts hospital mortality

Jentzer et al.

202022

Retrospective

Single center

9,096

Mortality after hospital discharge at 30 days and 1 year

SCAI shock stage at CICU admission predicts mortality after hospital discharge at both 30 days and 1 year

Jentzer et al.

202023

Retrospective

Single center

9,898

Mortality following hospital admission when presenting with concomitant VF or CA

Patients with CA or non-VF CA at CICU admit had higher hospital mortality at each SCAI stage, except stage E

Pareek et al.

202026

Retrospective

Single center

393

Mortality at 30 days after OOHCA

Increasing SCAI shock grade after multifactorial OOHCA is associated with 30-day mortality

Thayer et al.

202028

Retrospective

Multicenter

1,414

Inpatient mortality in CS patients

An association between the proposed SCAI staging system and in-hospital mortality among patients with heart failure and MI

Schrage et al.

202027

Retrospective

Single center

1,007

Survival at 30 days

SCAI classification was significantly associated with 30-day survival

Padkins et al.

202025

Retrospective

Single center

10,004

The association between age and in-hospital mortality was analyzed using multivariable logistic regression and 1-year mortality was analyzed using Cox proportional hazards analysis

SCAI classification of CS predicts mortality inpatient and at 1 year. Age is an independent risk factor for mortality

Garan et al.

202020

Retrospective

Multicenter

1,414

In-hospital mortality

Mortality differed significantly between PAC groups at each SCAI stage sub-cohort assessed (stage C: p=0.03; stage D: p=0.05; stage E: p=0.02).

Hanson et al.

202021

Retrospective

Multicenter

300

Survival at 24 hours

In patients with acute MI-CS enrolled in NCSI, SCAI shock classification was reproducible, and predicted survival when applied at presentation and at 24 h

Baran et al.

202029

Prospective

Single center

166

Mortality at 30 days

Initial SCAI shock stage predicts survival with MCS interventions or medical therapy alone. The 24 h reassessment of shock stage further predicts prognosis

CA = cardiac arrest; CICU = cardiac intensive care unit; CS = cardiogenic shock; MCS = mechanical circulatory support; NCSI = National Cardiogenic Shock Initiative; OOHCA = out-of-hospital cardiac arrest; PAC = pulmonary artery catheter; SCAI = Society for Cardiac Angiography and Interventions.

SCAI Cardiogenic Shock Consensus Statement and Classification Scheme

The SCAI assembled a multidisciplinary group to address the need for a classification of CS and subsequently the SCAI clinical expert consensus statement on the classification of CS was published in 2019.19 An additional emphasis was placed upon the use of available clinical and hemodynamic data across the continuum of care, with the goal of creating criteria that delineated the stages of CS. This new schema of CS classification was also intended for use with patients regardless of ischemic or non-ischemic etiologies and to be usable across the care spectrum from pre-hospital and emergency department providers to the catheterization laboratory and ICU. Further, inherent in this novel classification scheme was the facilitation of communication between all members of a treatment team.

In addition, it was hoped that better classification of shock severity would allow therapeutic approaches to be examined across SCAI shock stages in an effort to improve the mortality rates for CS.

SCAI Cardiogenic Shock Stages

The expert consensus document was endorsed by the American College of Cardiology, the American Heart Association, the Society of Critical Care Medicine, and the Society of Thoracic Surgeons.19 There are five stages (A–E), with each increasing stage indicative of progressive deterioration in the patient’s clinical and hemodynamic status (Figure 1). The criteria are also meant to highlight changes in the patient’s clinical status for providers across the spectrum of care. The staging system was developed without

any preceding evidence that it would accurately predict outcomes or prove to be valid. Given the broad multidisciplinary representation, there was great hope that others would validate and examine the staging system and it might lead to improvements in the design of future trials.19 Fortunately, perhaps owing to its simplicity and the lack of similar classification constructs, the SCAI shock classification has been examined quickly, and there have been several large retrospective analyses and one prospective study since its original publication in 2019.20–29 The remainder of this review will focus on a summary of validation studies, assessments of feasibility, timing of early interventions, and a discussion of future directions of the SCAI shock classification. Table 1 summarizes the key features of the papers.

Validation of SCAI Shock Stage Schema

The SCAI CS staging criteria have been applied and validated in several large retrospective clinical cohorts.20–28 The first published validation involved a cohort of more than 10,000 patients admitted to a single cardiac ICU over an 8-year period. Patients were classified into SCAI CS stages A–E based on predefined vital sign and laboratory values.24 The authors set rules for translation of the SCAI shock classification into parameters that could be done by the computer or an electronic medical record (EMR). Table 2 summarizes the combinations of hypotension/ tachycardia, hypoperfusion, deterioration, and refractory shock that

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Cardiogenic Shock Classification Table 2: Defining SCAI Cardiogenic Shock Stages Using Electronic Medical Record Values Cardiogenic Shock Stage

Study Definition

Stage A: At Risk

Neither hypotension/tachycardia nor hypoperfusion

Stage B: Beginning

Hypotension/tachycardia without hypoperfusion

Stage C: Classic

Hypoperfusion WITHOUT deterioration

Stage D: Deteriorating

Hypoperfusion WITH deterioration NOT refractory shock

Stage E: Extremis

Hypoperfusion WITH deterioration AND refractory shock

SCAI = Society for Cardiovascular Angiography and Interventions. Source: Jentzer et al. 2019.24 Adapted with permission from Elsevier.

Table 3: Rules Applied to Define Hypotension/Tachycardia, Hypoperfusion, Deterioration and Refractory Shock Hypotension/tachycardia

Presence of any of the following criteria: • Admission systolic BP <90 mmHg • Minimum systolic BP <90 mmHg during first 1 h • Admission MAP <60 mmHg • Minimum MAP <60 mmHg during first 1 h • Admission HR >100 BPM • Maximum HR >100 BPM during first 1 h • Admission HR >admission systolic BP • Mean HR >mean systolic BP during first 1 h

Hypoperfusion

Presence of any of the following criteria: • Admission lactate >2 mmol/l • Urine output <720 ml during first 24 h • Creatinine increased by ≥0.3 mg/dl during first 24 h

Deterioration

Presence of any of the following criteria: • Maximum lactate >admission lactate • Number of vasoactives during first 24 h >number of vasoactives during first 1 h • Maximum VIS* during first 24 h >VIS during first 1 h • Maximum NEE† during first 24 h >NEE during first 1 h

Refractory shock

Presence of any of the following criteria: • Mean systolic BP during first 1 h <80 and on vasoactives • Mean systolic MAP during first 1 h <50 and on vasoactives • Number of vasoactives during first 1 h >2 • Number of vasoactives during first 1 h >1 and IABP during first 24 h • Admission lactate ≥10 mmol/l

*VIS is calculated using vasoactive drug doses (in µg/kg/min) as follows: VIS = dobutamine + dopamine +(10 × phenylephrine + milrinone) + (100 × [epinephrine + norepinephrine]) + (10,000 × units/kg/min vasopressin). †NEE is calculated using the dose equivalency as follows: 0.1 µg/kg/min norepinephrine = 0.1 µg/kg/ min epinephrine = 15 µg/kg/min dopamine = 1 µg/kg/min phenylephrine = 0.04 units/min vasopressin.

BP = blood pressure; HR = heart rate; IABP = intra-aortic balloon pump MAP = mean arterial pressure; NEE = norepinephrine-equivalent vasopressor dose; VIS = vasoactive-inotropic score.

Source: Jentzer et al. 2019.24 Reproduced with permission from Elsevier.

define the SCAI stages. Table 3 shows the specific hemodynamic definitions used, which were arbitrary but set a priori by the authors.24 Each successive shock stage was associated with an increase in unadjusted cardiac ICU and in-hospital mortality rate. The proportion of patients with SCAI shock stages A, B, C, D, and E were 46%, 30%, 16%, 7%, and 1%, respectively. SCAI shock stage was predictive of outcome regardless of the underlying etiology of CS. Of the study population, 43%

had ACS, 46% had heart failure (HF), and 12% had cardiac arrest.24 Additionally, each higher SCAI shock stage was associated with increased adjusted post-discharge mortality as compared to SCAI stage A (all p<0.001) and results were consistent among patients with ACS or HF.22 Further, in seeking to identify specific risk factors associated with increasing risk of mortality from CS, two separate studies employed multivariable logistic regression in this same clinical cohort. These studies demonstrated that both older age and out-of-hospital cardiac arrest were additional risk factors for mortality independent of SCAI CS stage, both during index hospitalization with CS and up to one year after.23,25 In a separate single-center study involving a cohort of 1,007 CS patients (ACS or non-ischemic shock), the SCAI classification was applied retrospectively looking at mortality.27 In this study, logistic regression demonstrated that a higher SCAI classification was significantly associated with lower 30-day survival (p<0.01); where survival probability was 96.4% (95% CI [93.7–99.0%]) in stage A, 66.1% (95% CI [50.2–87.1%]) in stage B, 46.1% (95% CI [40.6–52.4%]) in stage C, 33.1% (95% CI [26.6–41.1%]) in stage D, and 22.6% (95% CI [17.1–30.0%]) in stage E. The SCAI stages were also applied retrospectively to a subset of patients in the National Cardiogenic Shock Initiative database (NCSI). The NCSI is a multicenter, single arm prospective registry study which seeks to assess outcomes with early implementation of the Impella percutaneous MCS device and the use of invasive assessments for guiding shock management.21 With a sample size of 300 patients, SCAI shock stage was assigned retrospectively by two independent practitioners to patients who presented with AMI CS and needed MCS therapy. Patients were categorized as SCAI stages C–E in the first 24 hours after an initial CS diagnosis; survival to hospital discharge was seen in 76% of patients assigned to stage C or D, compared to those in stage E (58%; p=0.006).

Additionally, in patients who were initially assigned a lower SCAI stage (C or D) and who deteriorated to stage E over 24 hours, <20% survived to hospital discharge. In addition to further validating the use of the SCAI CS system, this study also showed that this schema of classifications could be applied with little inter-observer variability although it was done retrospectively.21 CS may result from many causes, and previous classification schemes have failed to adequately characterize discrete shock stages that could be used regardless of etiology. When the SCAI shock criteria were applied to a 5-year observational registry of 393 patients with CS in 2012–2017 following an out-of-hospital cardiac arrest (OHCA) of any cause, a stepwise and statistically significant increase in 30-day mortality was noted as shock stage increased (A: 28.9% versus B: 33.0% versus C: 54.5% versus D: 59.3% versus E: 82.9%; p<0.0001).26 There were 107 (27.2%) patients assigned to stage A, 94 (23.9%) in stage B, 66 (16.8%) in stage C, 91 (23.2%) in stage D, and 35 (8.9%) in stage E.10 Escalating SCAI shock stage was also associated with the need for renal replacement therapy, and death from multiorgan failure in addition to that resulting from cardiac causes.26 The Cardiogenic Shock Working Group (CSWG) reported on 1,414 CS patients with SCAI shock stage (assessed retrospectively) along with pulmonary artery catheter (PAC) data. The study cohort consisted of patients seen in 2016–2019 and were grouped into those with and without PACs placed prior to initiating MCS.20 PAC data was available for 598 (42%) patients and temporary MCS devices were used in 1,190 (84%) of those patients. SCAI stage predicted mortality as in other studies. The

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Cardiogenic Shock Classification PAC assessment group had the lowest in-hospital mortality across all SCAI stages. Patients without a PAC had a higher in-hospital mortality (adjusted OR: 1.57; 95% CI [1.06–2.33]).20

Figure 2: Utility of Shock Scores that Assist Clinician with Difficult Real-time Decisions About the Care of Complex Critically Ill Patients

In a separate study from the same registry, SCAI stages were applied to assess the risk of in-hospital mortality in patients with decompensated HF or MI.28 Risk for in-hospital mortality was associated with increasing SCAI stage (OR 95%; CI 3.25 [2.63–4.02]) in both MI patients (who made up 35% of the study registry) and decompensated HF cohorts (50% of the registry). Additionally, hemodynamic data was available in 1,116 patients (79%) in the registry, and while elevated biventricular filling pressures were common among patients with CS, elevated right atrial pressures were specifically associated with increased mortality and higher SCAI stage.28 The SCAI shock classification was also validated prospectively in a recent single center report.29 In this study, 166 patients were evaluated by a multidisciplinary shock team over the course of an 18-month period. The team could decide to implement MCS or defer as well as optimizing medical therapy. Importantly, the SCAI stage was assessed and recorded prospectively. Initial SCAI stage was highly predictive of survival, second only to the patient’s age. 30-day survival rates were 100%, 65.4%, 44.2%, and 60% for patients with initial SCAI stage B, C, D, and E, respectively (p=0.0004). Type of MCS or lack of such was not a predictor of outcome.

SCAI stage at 24 hours was also examined and change in SCAI stage was highly predictive of outcome. The best survival was noted for patients with an improvement in SCAI stage of three to four categories, but any improvement was better than either remaining at the same SCAI stage or deteriorating. The 30-day survival rates were noted to be 100%, 96.7%, 66.9%, 21.6%, and 6.2% for patients with three to four SCAI stage improvement, two-stage improvement, one-stage improvement, no change in SCAI stage and worsening of SCAI stage respectively, following initial evaluation by the shock team (p<0.0001).29

Future Directions

The purpose of risk scores or classification systems is to allow the clinician to quickly decide on a treatment strategy when confronted with a single patient (Figure 2). The best measurements can be made repetitively and will have sufficient significance to justify their assessment. Validated tools allow clinicians to focus maximal efforts where they have the best chance of success.

Several early studies have validated the use of the SCAI shock criteria in hemodynamically unstable patients regardless of etiology of CS, laying a foundation for future clinical trials. Additionally, these criteria have provided a validated risk stratification tool that serves to facilitate 1. Baran DA, Long A, Jentzer JC. The stages of CS: clinical and translational update. Curr Heart Fail Rep 2020;17:333–40. https://doi.org/10.1007/s11897-020-00496-6; PMID: 33188491.

2. Thiele H, Akin I, Sandri M, et al. One-year outcomes after PCI strategies in cardiogenic shock. N Engl J Med 2018;379:1699–710. https://doi.org/10.1056/NEJMoa1808788; PMID: 30145971.

3. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med 1999;341:625–34. https:// doi.org/10.1056/nejm199908263410901; PMID: 10460813.

4. Sleeper LA, Reynolds HR, White HD, et al. A severity scoring system for risk assessment of patients with cardiogenic shock: a report from the SHOCK trial and registry. Am Heart J 2010;160:443–50. https://doi.org/10.1016/j.ahj.2010.06.024; PMID: 20826251.

5. Sohail S, Fan E, Foroutan F, et al. Predictors of mortality in patients treated with veno-arterial ECMO for cardiogenic

Give up

Stay the course

Go for it!

Shock scores help you open the door

communication between all providers of a patient’s care team regarding clinical and hemodynamic status. In line with this important objective and widespread use of these criteria, future use of SCAI CS classification might be considered as part of the EMR given the definitions which lend themselves to simple determination. For example, the definitions set by Jentzer et al. could potentially be adapted to an EMR (Tables 2 and 3).24 Objective clinical information available from the EMR could be used in the calculation of a daily SCAI shock stage assessment and as part of the documentation of acute clinical changes. More studies are needed that examine the feasibility of SCAI CS criteria use in communications between pre-hospital providers, emergency department staff, nursing staff, and general cardiologists.

As SCAI stages are integrated into the lexicon of clinicians’ management of CS, it will be important to remember that the classification of a patient is dynamic. Depending on the care setting and local expertise, a patient with a particular SCAI stage may be appropriate for transfer or it may be appropriate to try initial interventions and reserve transfer for patients with stagnant or worsening shock stage (which indicates a poor prognosis). Clinical trials may well be designed to capture the initial SCAI stage either as an inclusion criterion or a prospective assessment at enrollment to allow effects of therapy to be assessed across the severity of illness.

Conclusion

CS remains an area of high interest with a stable incidence and no proven modality to reduce mortality beyond initial revascularization in ischemic patients. Various risk scores and more recently a classification system have been developed to categorize patients. Hopefully by carefully and prospectively ‘phenotyping’ shock patients, we will be able to develop effective therapies to target those patients who can be saved.

shock complicating acute myocardial infarction: a systematic review and meta-analysis. J Cardiovasc Transl Res 2021. https://doi.org/10.1007/s12265-021-10140-w; PMID: 34081255; epub ahead of press.

6. Iborra-Egea O, Montero S, Bayes-Genis A. An outlook on biomarkers in cardiogenic shock. Curr Opin Crit Care 2020;26:392–7. https://doi.org/10.1097/ mcc.0000000000000739. PMID: 32452847.

7. van Diepen S, Katz JN, Albert NM, et al. Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association. Circulation 2017;136:e232–68. https://doi.org/10.1161/ cir.0000000000000525; PMID: 28923988.

8. Fincke R, Hochman JS, Lowe AM, et al. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 2004;44:340–8. https://doi.org/10.1016/j. jacc.2004.03.060; PMID: 15261929.

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9. Basir MB, Kapur NK, Patel K, et al. Improved outcomes associated with the use of shock protocols: updates from the National Cardiogenic Shock Initiative. Catheter Cardiovasc Interv 2019;93:1173–83. https://doi.org/10.1002/ccd.28307; PMID: 31025538.

10. Basir MB, Schreiber T, Dixon S, et al. Feasibility of early mechanical circulatory support in acute myocardial infarction complicated by cardiogenic shock: the Detroit Cardiogenic Shock Initiative. Catheter Cardiovasc Interv 2018;91:454–61. https://doi.org/10.1002/ccd.27427; PMID: 29266676.

11. Thiele H, Zeymer U, Neumann FJ, et al. Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial. Lancet 2013;382:1638–45. https://doi.org/10.1016/s0140-6736(13)61783-3; PMID: 24011548.

12. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon

Cardiogenic Shock Classification

13.

14.

15.

16.

17.

support for myocardial infarction with cardiogenic shock.

N Engl J Med 2012;367:1287–96. https://doi.org/10.1056/ NEJMoa1208410; PMID: 22920912.

Pöss J, Köster J, Fuernau G, et al. Risk stratification for patients in cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 2017;69:1913–20. https://doi. org/10.1016/j.jacc.2017.02.027; PMID: 28408020.

Harjola VP, Lassus J, Sionis A, et al. Clinical picture and risk prediction of short-term mortality in cardiogenic shock. Eur J Heart Fail 2015;17:501–9. https://doi.org/10.1002/ejhf.260; PMID: 25820680.

Miller RJH, Southern D, Wilton SB, et al. Comparative prognostic accuracy of risk prediction models for cardiogenic shock. J Intensive Care Med 2020;35:1513–9. https://doi.org/10.1177/0885066619878125; PMID: 31610748.

Rivas-Lasarte M, Sans-Roselló J, Collado-Lledó E, et al.

External validation and comparison of the CardShock and IABP-SHOCK II risk scores in real-world cardiogenic shock patients. Eur Heart J Acute Cardiovasc Care 2020. https://doi. org/10.1177/2048872619895230; PMID: 33609101; epub ahead of press..

Ceglarek U, Schellong P, Rosolowski M, et al. The novel cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide (CLIP)-based mortality risk score in cardiogenic shock after acute myocardial infarction. Eur Heart J 2021;42:2344–52 https://doi.org/10.1093/eurheartj/ ehab110; PMID: 33647946.

18. Deniau B, Picod A, Azibani F, et al. The CLIP-based mortality score in cardiogenic shock: suitable only for cardiogenic shock? Eur J Heart Fail 2021;23:1240–2. https://doi. org/10.1002/ejhf.2208; PMID: 33932078.

19. Baran DA, Grines CL, Bailey S, et al. SCAI clinical expert consensus statement on the classification of cardiogenic shock. Catheter Cardiovasc Interv 2019;94:29–37. https://doi. org/10.1002/ccd.28329; PMID: 31104355.

20. Garan AR, Kanwar M, Thayer KL, et al. Complete hemodynamic profiling with pulmonary artery catheters in cardiogenic shock is associated with lower in-hospital mortality. JACC Heart Fail 2020;8:903–13. https://doi. org/10.1016/j.jchf.2020.08.012; PMID: 33121702.

21. Hanson ID, Tagami T, Mando R, et al. SCAI shock classification in acute myocardial infarction: insights from the National Cardiogenic Shock Initiative. Catheter Cardiovasc Interv 2020;96:1137–42. https://doi.org/10.1002/ccd.29139; PMID: 32672388.

22. Jentzer JC, Baran DA, van Diepen S, et al. Admission Society for Cardiovascular Angiography and Intervention shock stage stratifies post-discharge mortality risk in cardiac intensive care unit patients. Am Heart J 2020;219:37–46. https://doi.org/10.1016/j.ahj.2019.10.012; PMID: 31710843.

23. Jentzer JC, Henry TD, Barsness GW, et al. Influence of cardiac arrest and SCAI shock stage on cardiac intensive care unit mortality. Catheter Cardiovasc Interv 2020;96:1350– 9. https://doi.org/10.1002/ccd.28854; PMID: 32180344.

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24. Jentzer JC, van Diepen S, Barsness GW, et al. Cardiogenic shock classification to predict mortality in the cardiac intensive care unit. J Am Coll Cardiol 2019;74:2117–28. https:// doi.org/10.1016/j.jacc.2019.07.077; PMID: 31548097.

25. Padkins M, Breen T, Anavekar N, et al. Age and shock severity predict mortality in cardiac intensive care unit patients with and without heart failure. ESC Heart Fail 2020;7:3971–82. https://doi.org/10.1002/ehf2.12995; PMID: 32909377.

26. Pareek N, Dworakowski R, Webb I, et al. SCAI cardiogenic shock classification after out of hospital cardiac arrest and association with outcome. Catheter Cardiovasc Interv 2021;97:e288–97. https://doi.org/10.1002/ccd.28984; PMID: 32445610.

27. Schrage B, Dabboura S, Yan I, et al. Application of the SCAI classification in a cohort of patients with cardiogenic shock.

Catheter Cardiovasc Interv 2020;96:e213–9. https://doi. org/10.1002/ccd.28707; PMID: 31925996.

28. Thayer KL, Zweck E, Ayouty M, et al. Invasive hemodynamic assessment and classification of in-hospital mortality risk among patients with cardiogenic shock. Circ Heart Fail 2020;13:e007099. https://doi.org/10.1161/ circheartfailure.120.007099; PMID: 32900234.

29. Baran DA, Long A, Badiye AP, et al. Prospective validation of the SCAI shock classification: single center analysis. Catheter Cardiovasc Interv 2020;96:1339–47. https://doi.org/10.1002/ ccd.29319; PMID: 33026155.

Cardiogenic Shock

Heart Transplant and Ventricular Assist: Cardiac Surgery and Heart Failure Perspective Michael T Cain, MD ,1 Michael S Firstenberg, MD FACC FAIM,

,2 and Joseph C Cleveland Jr, MD

1

1. Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, CO; 2. William Novick Global Cardiac Alliance, Aurora, CO

Abstract

For nearly 60 years, there have been two surgical treatment options for individuals with severe advanced heart failure: heart transplantation or implantation of a left ventricular assist device. As these fields have advanced in parallel, improvements in surgical technique, device development, and patient selection have improved outcomes for both therapies. Development of a comprehensive approach to the management of the most severe forms of advanced heart failure requires a deep understanding of both heart transplantation and durable ventricular assistance, including recent advancements in both fields. This article will review the substantial progress in the fields of heart transplantation and mechanical left ventricular assistance, including recent changes to organ allocation prioritization and left ventricular assist device evaluation, both of which have dramatically influenced practice in these fields.

Keywords

Heart transplant, left ventricular assist device, frailty, minimally invasive cardiac surgery, heart allocation Disclosure: JCC discloses involvement with Abbott Medical as national co-principal investigator for the MOMENTUM 3 trial and membership on the Clinical Events Committee for ARIES. All other authors have no conflicts of interest to declare.

Acknowledgements: The authors thank Lyndsey Cain for her assistance in manuscript preparation.

Received: March 22, 2021 Accepted: June 2, 2021 Citation: US Cardiology Review 2021;15:e16. DOI: https://doi.org/10.15420/usc.2021.11 Correspondence: Michael T Cain, Division of Cardiothoracic Surgery, Department of Surgery, 12631 E 17th Ave, C-310, Aurora, CO 80045. E: Michael.Cain@ucdenver.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Advanced heart failure is a challenging condition to treat and has long been associated with significant morbidity for afflicted patients.1,2 Guideline-directed medical therapy has improved outcomes, helped prevent sudden death, and improved symptoms for these patients. But treatment of the most advanced forms of end-stage of heart failure requires one of two surgical treatment modalities: implantation of ventricular assist devices or orthotopic heart transplantation. First initiated in 1966 and 1967, respectively, the use of ventricular assist devices and heart transplantation have matured, evolved, and notably improved since their initial introductions. These two surgical treatments are intimately intertwined, often serving as complementary or stepwise therapies in the longitudinal management of end-stage heart failure.

New technological developments, improvements in surgical techniques, and the evolution of nationwide policies have driven and continue to drive both fields forward. Here we provide a historical perspective on the development of durable ventricular assistance and orthotopic heart transplantation, along with a focus on the recent evolutions, changes, and controversies in these fields that have significantly influenced practice.

Historical Perspective

The origins of ventricular assistance – and much of the early history of orthotopic heart transplantation – is inextricably linked to Houston, Texas.

Initial exploration into the field of left ventricular assistance by Michael DeBakey, William Kolff, Tetsuzo Akutsu and Domingo Liotta at Baylor

College of Medicine in the early 1960s focused on the development of a left ventricular assist device (LVAD), which would support the left ventricle temporarily to allow for recovery in patients who were experiencing significant difficulty weaning from cardiopulmonary bypass. The concept of ventricular rest to allow for recovery was developed in this era, and stemmed from the clinical observation that patients who had difficulty weaning cardiopulmonary bypass who were provided a more prolonged wean could occasionally recover.3 These observations stimulated future research into ventricular recovery, and culminated in the first successful use of what we would now call a bridge-to-recovery LVAD in September 1966 (Figure 1).

The motivation and these advancements in surgical support of ventricular function were paralleled by important advancements towards the successful implementation of heart transplantation. Pioneering canine research by Norman Shumway and Richard Lower at Stanford University on the successful use of hypothermia and the development of the orthotopic technique paved the way for human transplantation.4–6 Although much of the pioneering work on cardiac transplantation occurred in the US, the lack of clear ethical and legal guidelines outlining the definition of death in beating heart donation presented a significant obstacle for implementation in humans. However, in South Africa, opinions about the ethical nature of what would now be considered donation after neurological death were considerably more favorable at the time, thus

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Cardiac Transplant and Ventricular Assist in Heart Failure Figure 1: Pioneers in Ventricular Assist and Heart Transplantation

modern era, much as it was during its inception, and an understanding of the evolution of these surgical treatments remains critical to providing the best care for our heart failure patients.

Concomitant Procedures in Left Ventricular Assistance

Guidelines for the consideration for orthotopic heart transplantation or LVAD have been clearly outlined by international societies, and these guidelines form the foundation for evaluation of advanced heart failure patients at the authors’ institutions.11 As we expand the candidacy for patients receiving LVADs, it is inevitable that some patients with severe left ventricular dysfunction will also show concomitant cardiac pathologies that could be addressed at the time of LVAD implantation. A central question in considering these individuals as candidates for LVAD is the impact of addressing these pathologies concurrently with implantation of their durable LVAD. Left: Michael DeBakey with his first patient successfully bridged to recovery with a left ventricular assist device. Right: Christiaan Barnard with Louis Washkansky a few days after the first heart transplant. Source: DeBakey 1971 3 and Cooper 2001.8 Reproduced with permission from Elsevier.

cracking open the door of human-to-human cardiac transplantation just enough for an ambitious surgeon to walk through.7,8 Christiaan Barnard performed the first successful cardiac transplantation in Cape Town, South Africa in December 1967.9 Barnard achieved technical success, which was subsequently demonstrated reproducible in Denton Cooley’s numerous early heart transplants in Houston. But early transplantation was plagued with difficulty related to azathioprine-based immunosuppression and associated overwhelming sepsis. Prior to the introduction of cyclosporine and the eventual development of comprehensive and safe immunosuppression for heart transplantation, significant doubts continued to exist on the longevity of cardiac grafts, providing incentive for the further development of durable ventricular assist devices.10 Even today, the long-term consequences of chronic immunosuppression are not trivial and some patients – even when eligible and offered a transplant – may elect to continue with an LVAD. Development of left ventricular assistance over the subsequent decades initially focused on pulsatile pumps, although these devices were limited by their generally large size that precluded internal implantation in many patients and by the inevitable fatigue and critical failure of the flexing membranes that provided their pulsatile flow. These design challenges prompted development of more reliable continuous flow LVADs – devices that have become the predominant focus of the field since their introduction.

Although improved reliability and implantability of continuous-flow pumps eventually resulted in their more widespread use, continuous-flow LVADs were not without their own negative sequalae. Complications of red blood cell lysis from the pump speeds required to achieve flow, arteriovenous malformations as a result of continuous flow physiology, blood pressure lability related to baroreceptor dysregulation in the setting of decreased pulsatility, and device infection related to externalized LVAD drive lines are notable challenges. Significant improvements in design have mitigated many of these concerns, and continuous flow left ventricular assistance in the modern era has been established as a reliable therapy for alleviating heart failure symptoms and providing both quantity and quality of life for patients. The interplay between mechanical ventricular assistance and heart transplantation remains tight in the

A number of investigators have evaluated the impact of concurrent cardiac procedures on morbidity and mortality after LVAD implantation.12,13 Pal and colleagues investigated the impact of concomitant repairs on individuals undergoing implantation of a HeartMate II (HMII; Abbott) LVAD over a 2-year period. Concomitant coronary artery bypass grafting, intracardiac repair of a patent foramen ovale, or repair of the tricuspid or mitral valve were not shown to increase 30-day mortality for these patients.12 Patients who underwent an aortic valve procedure at the time of LVAD implantation were found to have a significantly increased 30-day mortality at 25% compared with 5.8% mortality for isolated HMII implantation.12 This work has been validated by later studies with respect to tricuspid valvular repair and closure of patent foramen ovale with longterm follow-up to 2 years, although the observed increased mortality associated with aortic procedures has been debated.13 Some studies have demonstrated an increased risk with aortic procedures.

However, it is important to note that aortic insufficiency that is moderate or greater on preoperative echocardiography may progress following LVAD implantation, creating a short recirculation loop that will decrease LVAD efficiency and worsen heart failure. As a result, aortic insufficiency should be treated aggressively.14,15 Multiple techniques exist for treatment of aortic insufficiency, ranging from a simple suture closure of the valve to traditional aortic valve replacement.16 Importantly, mechanical aortic valves increase the risk for embolic events in these patients, and should be avoided or explanted at time of LVAD implantation. Studies have suggested that aortic valve replacement may be superior to suture closure of the aortic valve in these patients. However, data have been conflicting, and aortic valve replacement undoubtedly increased aortic cross clamp time and ischemic time for these already dysfunctional ventricles.17,18 Suture closure of the aortic valve (or patch closure) is not without significant risk. Although there are immediate perioperative benefits to suture closure, permanent closure of the aortic valve will make the patient entirely LVAD-dependent for forward flow, and could result in sudden death in the setting of LVAD malfunction or failure.

Given the ever-expanding role of transcatheter aortic valve replacement (TAVR), the question arises whether TAVR may have a role in treating aortic insufficiency in patients receiving an LVAD. This is of particular interest in the setting of the late development of aortic insufficiency, which would require reoperative surgery with significant associated risk.

TAVR has generally been reserved for aortic stenosis due to the calcific nature of the disease, which affords annular stability against the expanded stent. Despite this, TAVR has been successfully used in insufficient aortic

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Cardiac Transplant and Ventricular Assist in Heart Failure valves, both with the self-expanding CoreValve (Medtronic), as well as the SAPIEN-3 (Edwards) balloon-expandable valve.19–21 One technique for employing TAVR in the setting of prior LVAD uses a combined deployment of a CoreValve into the aortic annulus, followed by valve-in-valve SAPIEN-3 deployment with balloon expansion into the reinforced annulus to prevent paravalvular leak.22 Although limited data exist with this technique, TAVR provides an interesting alternative to other endovascular techniques for treatment of late aortic insufficiency such as aortic valve closure with an Amplatzer Occluder (Abbott), and therefore would not create a potentially fatal condition in the event of LVAD mechanical failure.

The demonstration of the safety of concomitant procedures – particularly right heart procedures – during LVAD implantation is a significant finding, especially as we aim to improve the long-term function of the right ventricle after LVAD implantation. In their 2014 study, Milano et al. built upon prior work by again demonstrating the safety of concomitant valvular procedures by demonstrating comparable survival at 1 year following implantation of the HeartWare centrifugal-flow ventricular assist device system (HVAD; Medtronic) for both those patients who underwent additional procedures and those who did not. However, importantly, the study demonstrated that patients with severe preoperative tricuspid regurgitation were significantly more likely to have late right ventricular failure following HVAD implantation when compared with those who underwent concomitant repair at the time of HVAD implantation.23 Given the safety of concomitant repair, and its impact on right ventricular functional preservation, tricuspid valvular repair at the time of LVAD implantation has become well established.

Minimally Invasive Approaches to LVAD Implantation

A great deal of focus in the advancement of outcomes related to LVAD implantation has rightfully been given to the development of new iterations of assist devices. However, as the field has matured, significant advancements in the technical approach towards implantation have occurred as well. Traditionally, LVADs have been placed via a full median sternotomy with assistance of centrally cannulated cardiopulmonary bypass. With the introduction of new, smaller LVAD pumps, such as the HVAD and HeartMate 3 (HM3, Abbott), less invasive approaches to LVAD implantation have been developed.

One notable advancement in technique has been the introduction of a minimally invasive, or sternotomy-sparing approach to LVAD implantation.

Performed through the use of femoral cannulation for cardiopulmonary bypass, the apex of the left ventricle is approached through a left sided thoracotomy or subcostal incision to allow for left ventricular apical coring and implantation of the inflow portion of the LVAD (Figure 2).24 At the authors’ institution, the precise location of this limited thoracotomy is determined by intraoperative transthoracic ultrasound. The outflow graft is then tunneled through the pericardium and exits via either a right anterior thoracotomy or via an upper hemisternotomy to allow for access and grafting to the ascending aorta with assistance of a partial occlusion clamp. Careful attention to outflow graft placement location and angulation is critical to avoid kinking or compression of the RV. Outcomes following this approach to LVAD insertion have been evaluated by several authors and have been safe and reproducible.25–27 These early studies culminated in a multicenter clinical trial for the HVAD, the LATERAL trial.28 Having enrolled patients from 26 centers across the US and Canada, the LATERAL trial evaluated outcomes up to 180 days following HVAD implantation via thoracotomy and compared with historical

Figure 2: Surgical Approach to Minimally Invasive HeartWare Centrifugal-flow Ventricular Assist Device System Insertion

Source: McGee et al. 2019.28 Reproduced with permission from Elsevier.

sternotomy-based data. Patients who underwent thoracotomy experienced greater survival at 180 days (88.1% versus 77.5%), shorter mean hospital stay (18 versus 36.1 days), and significantly reduced bleeding requiring reoperation compared with sternotomy-based approaches at 30-days, 6 months and 1 year following implantation.25,28 Potential benefits observed with a thoracotomy-based approach are the potential for the preservation of right ventricular function, as well as preservation of renal function postoperatively.29,30 Postoperative right ventricular failure has remained a significant cause for morbidity and is the single greatest risk factor for early mortality following LVAD implantation.31 By quantitative and qualitative assessment of perioperative right ventricular function in these patients, lateral thoracotomy-based LVAD implantation has been shown to significantly reduce right ventricular dysfunction as evident by pulmonary artery pulsatility index, right ventricular stroke work index, and echocardiographic assessment. These results persisted when evaluating those at high risk for right ventricular dysfunction, as evident by a EUROMACS-RHF score >4.29 The etiology behind preservation of right ventricular function through a thoracotomy-based approach is thought to be multifactorial. Reduced manipulation of the heart, in addition to preservation of the native pericardial attachments and restraint over the right ventricle may result in less perturbed right ventricle following implantation.32,33 Additionally, the reduced incidence of bleeding requiring exploration suggest less postoperative blood product resuscitation is required in these individuals, resulting in less resuscitation-based right ventricular overload and subsequent dysfunction.

The recent withdrawal of the HVAD from the market has created a potential void for devices with FDA approval for non-sternotomy implantation; however, the groundwork laid by the LATERAL trial and HVAD experience has established non-sternotomy approaches as safe and effective. Ultimately this experience has allowed for other devices to move into this market, and this void has been filled by the HM3, which has been approved for non-sternotomy implantation by the FDA.

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Cardiac Transplant and Ventricular Assist in Heart Failure Table 1: Comparison of Allocation Status Criteria for Heart Transplantation Before and After the 2018 Allocation Policy Change

Figure 3: In Hospital Paradigm Shift for Patients Who May Be Candidates for Heart Transplantation Before October 2018

2006–2018 1A. Mechanical circulatory support with acute hemodynamic decompensation: ECMO, IABP, TAH, LVAD (within 30 days) MCS with device complication IV inotropes with hemodynamic monitoring Mechanical ventilation

Stabilize with LVAD and discharge

Await transplant as outpatient

Acute decompensated heart failure

1B. Stable LVAD Continuous IV inotropes

Orthotopic heart transplant After October 2018

Stabilize with temporary mechanical circulatory support

2. All other candidates

October 2018–Present 1. ECMO Nondischargeable BiVAD MCS with arrhythmias

Inpatient evaluation and optimization prior to heart transplant

LVAD = left ventricular assist device.

2. Dischargeable TAH, RVAD, BiVAD Nondischargable LVAD IABP/endovascular MCS MCS with device malfunction Sustained VT/VF

transplant survival (77.9 versus 93.4%, p<0.0001) in early studies evaluating the outcomes post-policy change, as the hemodynamic instability of patients prioritized for transplantation has increased, as expected.36

3. IV inotropes with hemodynamic monitoring LVAD (within 30 days) 4. Stable LVAD Continuous IV inotropes Congenital heart disease Restrictive cardiomyopathy Retransplantation 5. Multiorgan transplant 6. All other candidates BiVAD = biventricular assist device; ECMO = extracorporeal membrane oxygenation; IABP = intraaortic balloon pump; LVAD = left ventricular assist device; MCS = mechanical circulatory support; RVAD = right ventricular assist device; TAH = total artificial heart; VT = ventricular tachycardia.

United Network for Organ Sharing Allocation System Changes

One of the most wide-reaching and impactful recent changes in both the fields of mechanical ventricular support as well as orthotopic heart transplantation in the US has been the October 18, 2018 modification to the United Network for Organ Sharing allocation system for cardiac allograft donation. These changes aimed to reduce mortality for patients on the cardiac transplantation waiting list by prioritizing the sickest individuals for transplantation. The previous three-tier system for assessing priority for transplantation was deconstructed into six discrete categories (with ‘status 7’ reserved for temporary inactivation). This reorganization increased granularity in classifying the status of patients at the highest level of priority by separating the highest priority group from the previous allocation system into three distinct categories (Table 1).

These changes significantly reduce competition amongst the sickest individuals listed for heart transplantation, and patients with wellfunctioning LVADs are no longer prioritized to the same degree.

Early evidence has clearly shown that the changes have achieved the desired effect of reducing transplant wait times for the sickest individuals listed, with average transplant wait times reduced from 35 days for status 1a patients under the pre-2018 system to 15 days for status 1 or 2 patients since the allocation system change.34,35 Additionally, the updated allocation system resulted in improved 180-day survival on the wait list (96.1% versus 95.0%). However, this has been associated with reduced 180-day post-

In response to these allocation system changes, the use of temporary mechanical circulatory support (MCS) has significantly increased in the pre-transplantation setting, with 41% of patients currently undergoing transplantation from a temporary MCS device compared with 10% of patients prior to the change.35,36 The allocation system change has fundamentally changed the paradigm for the clinical treatment of acute decompensated heart failure for those patients who are candidates for heart transplantation. The previous conventional pathway for potential heart transplant candidates in acute decompensated heart failure typically consisted of inpatient stabilization followed by LVAD implantation. Patients subsequently underwent outpatient evaluation and listing for heart transplantation (Figure 3). Instead, inpatient stabilization for acute decompensated heart failure, often with the use of temporary MCS in conjunction with an expedited evaluation for heart transplantation has been adopted as a more viable pathway for transplantation in the current era.

Early data have confirmed these practice changes, showing a significantly reduced proportion of patients currently undergoing transplantation with a durable LVAD in place (42 versus 23%), an increased use of intra-aortic balloon pump prior to transplantation (45% versus 3%), and increased preoperative length of stay prior to transplantation (30% inpatient status versus 92%).35,36 Interestingly, these changes appear to be specific to the US. Evaluation the use of pre-transplant temporary MCS at US-designated transplant centers compared with Canadian centers has shown this increased use of support devices has been isolated to US-based centers, suggesting the change in organ allocation policy is driving the clinical behavior rather than a broad, physician-led adoption of temporary MCS prior to transplantation.37 These changes have also significantly impacted the approach to LVAD implantation. Prior to the 2018 allocation system change, destination therapy (DT) LVAD constituted a common, although not overwhelming, proportion of those patients receiving a durable LVAD when compared with the bridge-to-transplant (BTT) LVAD designation. However, following the allocation system change, DT LVAD indications at the time of implantation rose significantly, from 48–54% in the prior era to 70% following the policy change.38 As noted earlier, given the demotion of LVAD recipients to status 4 for heart transplantation, and the reduced

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Cardiac Transplant and Ventricular Assist in Heart Failure complication profile of modern LVADs that might increase an individual’s wait list status, a shift in the intention at the time of implantation is an expected change. In many ways, the allocation system changes are reactive to and reflective of success in the field of durable mechanical circulatory support. With steady improvements in long-term survival and morbidity profile of patients maintained on LVADs, the urgency to transition to heart transplantation has been reduced.

The impact of policy change on practice behaviors will continue to be substantial, and recent changes in the Centers for Medicare and Medicaid Services (CMS) National Coverage Determinants are poised to impact the field further. In the updated policy of December 1, 2020, the CMS made significant changes to requirements for reimbursement for durable left ventricular assist devices by removing the prior therapeutic intent-to-treat criteria of BTT and DT for LVADs.39 Specifically, this policy change removes the reimbursement requirement that patients receiving and LVAD be active on the waitlist maintained by the Organ Procurement and Transplantation Network, and removes the requirement that an implanting institution receive permission from a Medicare-approved transplant center prior to LVAD implantation if that center is not itself a heart transplant center. The decision further extends the evidence-based patient selection criteria, previously reserved for DT LVADs, to all LVAD recipients. These changes, in effect, eliminate the practical requirement for a transplant evaluation prior to LVAD implantation. This effectively uncouples the heart transplant and LVAD centers, and opens the door for non-transplant centers to establish LVAD programs without the need for BTT or DT determinations.

These changes to CMS reimbursement guidelines reflect the changing landscape of LVAD therapy, and, importantly, reflect what has been shown to be a somewhat arbitrary differentiation BTT and DT designations.

Advancements in LVAD technology and improved outcomes, specifically highlighted in the MOMENTUM 3 trial with respect to the HM3 LVAD, have demonstrated that in the current era, preoperative designation as BTT or DT has been unreliable. In their 2020 secondary analysis of the MOMENTUM 3 trial, Goldstein et al. observed significant crossover between BTT and DT therapeutic categories established at the time of HMII or HM3 implantation during a 2-year follow up period. Specifically, they observed a 13.5% orthotopic heart transplantation rate for patients initially deemed transplant ineligible by a DT categorization. They further demonstrated that 43% of patients categorized as BTT remained on their LVAD at the 2-year follow-up timepoint.40 The authors concluded that the use of categorizations based on patients’ current or future transplantation candidacy should be abandoned, and that adopting an implant-first strategy may improve survival and quality of life in these individuals.

Frailty in Patient Selection for LVAD and Transplantation

Frailty is complex syndrome associated with biological rather than chronological aging in patients, broadly characterized by progressive decline in functional reserves across multiple organ systems. Although multiple measures have been used, frailty is often measured using five clinically-measured domains of grip strength, exhaustion, unintended weight loss, slow gait speed, and low physical activity.41 Postoperative complications have been shown to be associated with markers of frailty, suggesting this is an important point of consideration prior to undergoing LVAD implantation or heart transplantation.42,43 Clinically frail patients have been shown to have increased time to extubation, increased hospital length of stay, and increased long-term mortality following LVAD implantation compared with non-frail individuals.44 Importantly, nevertheless, frailty appears to have little effect on short term mortality,

Figure 4: Frailty in the Context of LVAD Insertion A

Frailty Increased vulnerability to stress LVAD-responsive frailty Systolic and diastolic dysfunction ↑ PCWP and CVP ↓ Cardiac output

Post-operative complications Prolonged LOS Need for ICU care

B

LVAD-independent frailty Inflammation Anorexia Polypharmacy Deconditioning Sarcopenia Malnutrition Cognitive deficits Injurious falls

Aging COPD/lung disease Cancer Diabetes Osteoporosis Peripheral vascular disease Cirrhosis Neurologic disease

Impaired health status Disability Loss of ADLs Institutionalization

LVAD-responsive frailty

Reduced survival

LVAD-independent frailty

Patient A

Patient B

Patient C

Favorable outcome Lower risk for premature death or complications, with marked improvement in functional status

Intermediate outcome Moderate risk for premature death and complications with some persistent functional limitation

Unfavorable outcome High risk for premature death and complications with failure to improve functional status

Pre-LVAD frailty

Post-LVAD frailty

A: Breakdown of frailty into its underlying causes, manifestations, and clinical outcomes separated

by LVAD-responsive and LVAD-independent causes of frailty. In advanced heart failure with reduced left ventricular ejection fraction, a patient's heart failure contributes significantly to the frailty syndrome and is potentially reversible with LVAD (LVAD-responsive frailty). However, many patients with advanced heart failure may be frail due to illness unrelated to heart failure severity, which is not treatable with LVAD (LVAD-independent frailty).

B: Schematic representing patients undergoing DT LVAD with similar total baseline frailty but differing underlying causes of frailty. Patient A, with primarily LVAD-responsive frailty (ie, mostly heart failure-related illness), is likely to experience a good outcome if he or she survives the early postoperative period. Conversely, Patient C, with primarily LVAD-independent frailty (ie, mostly noncardiac-related illness), is at greater risk of death, complications and/or persistently poor functional status after LVAD placement. Many patients are best represented by Patient B with evidence of significant LV dysfunction warranting LVAD but also significant comorbidity and/or advanced age disqualifying them from transplantation.

ADL = activities of daily living; COPD = chronic obstructive pulmonary disease; CVP = central venous pressure; ICU = intensive care unit; LOS = length of stay; LVAD = left ventricular assist device; PCWP = pulmonary capillary wedge pressure. Source: Flint et al. 2012.46 Reproduced with permission from Wolters Kluwer.

and appears to have some reversibility with nearly half of patients having significant improvements in frailty indices after 3–6 months of LVAD support.42,44 Frailty in the setting of advanced heart failure should be conceptualized as frailty related to two separate conditions: LVADresponsive frailty, which may improve with ventricular assistance, and generalized, or LVAD-independent frailty, which may persist despite LVAD implantation (Figure 4).

Similar to patients receiving LVADs, orthotopic heart transplant recipients who demonstrate preoperative frailty have demonstrated significant increases in a variety of postoperative complications. Frail individuals have demonstrated significantly increased rates of post-transplant length

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Cardiac Transplant and Ventricular Assist in Heart Failure of stay, stroke, renal failure and mortality when compared to their non-frail counterparts at follow up extending up to 10 years post-transplant.45 The impact of frailty mechanistically on influencing outcomes following both LVAD and orthotopic heart transplantation is likely multifactorial. However, those individuals who exhibit frailty prior to major surgical procedures likely exhibit a significant depletion in physiological reserve resulting in a cumulative decline in the function of all physiologic systems. This depleted reserve and decline places them at unique risk for a lack of resiliency against stressors. The dramatic hemodynamic, immunologic, and inflammatory stressors associated with LVAD implantation and transplantation may exhaust this reserve, resulting in clinical decline.

Conclusion

Continued progress in both cardiac transplantation and LVAD have afforded patients with advanced, end-stage heart failure outstanding outcomes. These therapies have evolved in parallel and the future for 1. Chen J, Normand SL, Wang Y, Krumholz HM. National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998–2008. JAMA 2011;306:1669–78. https://doi.org/10.1001/jama.2011.1474; PMID: 22009099.

2. Roger VL. Epidemiology of heart failure. Circ Res 2013;113:646–59. https://doi.org/10.1161/ circresaha.113.300268; PMID: 23989710.

3. DeBakey ME. Left ventricular bypass pump for cardiac assistance. Clinical experience. Am J Cardiol 1971;27:3–11. https://doi.org/10.1016/0002-914990076-2; PMID: 5538711.

4. Lower RR, Shumway NE. Studies on orthotopic homotransplantation of the canine heart. Surg Forum 1960;11:18–9. PMID: 13763847.

5. Lower RR, Stofer RC, Hurley EJ, D et al. Successful homotransplantation of the canine heart after anoxic preservation for seven hours. Am J Surg 1962;104:302–6. https://doi.org/10.1016/0002-961090332-x; PMID: 14466957.

6. Shumway NE, Lower RR. Topical cardiac hypothermia for extended periods of anoxic arrest. Surg Forum 1960;10:563– 6. PMID: 14446329.

7. Hoffenberg R. Christiaan Barnard: his first transplants and their impact on concepts of death. BMJ 2001;323:1478–80. https://doi.org/10.1136/bmj.323.7327.1478; PMID: 11751363.

8. Cooper DK. Christiaan Barnard and his contributions to heart transplantation. J Heart Lung Transplant 2001;20:599– 610. https://doi.org/10.1016/s1053-249800245-x; PMID: 11404164.

9. Barnard CN. The operation. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. S Afr Med J 1967;41:1271–4. PMID: 4170370.

10. Cooley DA. Recollections of the early years of heart transplantation and the total artificial heart. Artif Organs 2011;35:353–7. https://doi.org/10.1111/j.1525-1594.

2011.01235.x; PMID: 21501184.

11. Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update. J Heart Lung Transplant 2016;35:1–23. https://doi.org/10.1016/j. healun.2015.10.023; PMID: 26776864.

12. Pal JD, Klodell CT, John R, et al. Low operative mortality with implantation of a continuous-flow left ventricular assist device and impact of concurrent cardiac procedures.

Circulation 2009;120(11 Suppl):S215–9. https://doi.org/10.1161/ circulationaha.108.844274; PMID: 19752370.

13. Morgan JA, Tsiouris A, Nemeh HW, et al. Impact of concomitant cardiac procedures performed during implantation of long-term left ventricular assist devices.

J Heart Lung Transplant 2013;32:1255–61. https://doi. org/10.1016/j.healun.2013.09.009; PMID: 24135274.

14. Rajagopal K, Daneshmand MA, Patel CB, et al. Natural history and clinical effect of aortic valve regurgitation after left ventricular assist device implantation. J Thorac Cardiovasc Surg 2013;145:1373–9. https://doi.org/10.1016/j. jtcvs.2012.11.066; PMID: 23312101.

15. Truby LK, Garan AR, Givens RC, et al. Aortic insufficiency during contemporary left ventricular assist device support: analysis of the INTERMACS Registry. JACC Heart Fail 2018;6:951–60. https://doi.org/10.1016/j.jchf.2018.07.012; PMID: 30384913.

16. McKellar SH, Deo S, Daly RC, et al. Durability of central aortic valve closure in patients with continuous flow left

both transplantation and LVADs remains bright. LVADs will continue to challenge the long-term success of transplantation, and this healthy competition is only expected to increase in intensity as the next generation of LVADs will be completely implantable and fully magnetically levitated.

The patient-derived benefit and acceptance of a totally implantable LVAD will has the potential to be truly transformative.

Transplantation, while mature, also has tremendous potential for growth.

Cellular-based therapies and the possibility of genetically modifying xenografts to an individual’s cell type (and therefore improving graft tolerance) have long been the holy grail in heart transplantation, and hold promise for alleviating the problem of donor heart scarcity. The community of providers who care for patients with advanced heart failure should remain poised to appropriately evaluate and test these new devices and potential therapies for the ever-growing patient population with advanced heart failure.

ventricular assist devices. J Thorac Cardiovasc Surg 2014;147:344–8. https://doi.org/10.1016/j.jtcvs.2012.09.098; PMID: 23246052.

17. Robertson JO, Naftel DC, Myers SL, et al. Concomitant aortic valve procedures in patients undergoing implantation of continuous-flow left ventricular assist devices: an INTERMACS database analysis. J Heart Lung Transplant 2015;34:797–805. https://doi.org/10.1016/j. healun.2014.11.008; PMID: 25511747.

18. Tang PC, Sarsour N, Haft JW, et al. Aortic valve repair versus replacement associated with durable left ventricular assist devices. Ann Thorac Surg 2020;110:1259–64. https://doi. org/10.1016/j.athoracsur.2020.01.015; PMID: 32105716.

19. Wilson W, Goldraich L, Parry D, et al. Cardiac arrest secondary to sudden LVAD failure in the setting of aortic valve fusion successfully managed with emergent transcatheter aortic valve replacement. Int J Cardiol 2014;171:e40–1. https://doi.org/10.1016/j.ijcard.2013.11.117; PMID: 24387895.

20. Kornberger A, Beiras-Fernandez A, Fichtlscherer S, et al.

Percutaneous SAPIEN S3 transcatheter valve implantation for post-left ventricular assist device aortic regurgitation.

Ann Thorac Surg 2015;100:e67–9. https://doi.org/10.1016/j. athoracsur.2015.06.089; PMID: 26434481.

21. D’Ancona G, Pasic M, Buz S, et al. TAVI for pure aortic valve insufficiency in a patient with a left ventricular assist device.

Ann Thorac Surg 2012;93:e89–91. https://doi.org/10.1016/j. athoracsur.2011.11.019; PMID: 22450111.

22. Pal JD, McCabe JM, Dardas T, et al. Transcatheter aortic valve repair for management of aortic insufficiency in patients supported with left ventricular assist devices. J Card Surg 2016;31:654–7. https://doi.org/10.1111/jocs.12814; PMID: 27487763.

23. Milano C, Pagani FD, Slaughter MS, et al. Clinical outcomes after implantation of a centrifugal flow left ventricular assist device and concurrent cardiac valve procedures. Circulation 2014;130(11 Suppl 1):S3–11. https://doi.org/10.1161/ circulationaha.113.007911; PMID: 25200052.

24. Maltais S, Danter MR, Haglund NA, et al. Nonsternotomy approaches for left ventricular assist device placement.

Operative Techniques 2014;19:276–91. https://doi.org/10.1053/ j.optechstcvs.2014.10.001.

25. Maltais S, Anwer LA, Tchantchaleishvili V, et al. Left lateral thoracotomy for centrifugal continuous-flow left ventricular assist device placement: An analysis from the mechanical circulatory support research network. ASAIO J 2018;64:715– 20. https://doi.org/10.1097/mat.0000000000000714; PMID: 29095733.

26. Wert L, Chatterjee A, Dogan G, et al. Minimally invasive surgery improves outcome of left ventricular assist device surgery in cardiogenic shock. J Thorac Dis 2018;10(Suppl 15):S1696–702. https://doi.org/10.21037/jtd.2018.01.27; PMID: 30034841.

27. Sileshi B, O’Hara BK, Davis ME, et al. Outcomes of patients implanted using a left thoracotomy technique for a miniaturized centrifugal continuous-flow pump. ASAIO J 2016;62:539–44. https://doi.org/10.1097/ mat.0000000000000407; PMID: 27347709.

28. McGee E, Jr., Danter M, Strueber M, et al. Evaluation of a lateral thoracotomy implant approach for a centrifugal-flow left ventricular assist device: the LATERAL clinical trial.

J Heart Lung Transplant 2019;38:344–51. https://doi. org/10.1016/j.healun.2019.02.002; PMID: 30945636.

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29. Pasrija C, Sawan MA, Sorensen E, et al. Less invasive left ventricular assist device implantation may reduce right ventricular failure. Interact Cardiovasc Thorac Surg 2019;29:592–8. https://doi.org/10.1093/icvts/ivz143; PMID: 31326991.

30. Ricklefs M, Heimeshoff J, Hanke JS, et al. The influence of less invasive ventricular assist device implantation on renal function. J Thorac Dis 2018;10(Suppl 15):S1737–42. https://doi. org/10.21037/jtd.2017.10.03; PMID: 30034846.

31. Kirklin JK, Naftel DC, Pagani FD, et al. Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transplant 2015;34:1495–504. https://doi.org/10.1016/j. healun.2015.10.003; PMID: 26520247.

32. Maniar HS, Prasad SM, Gaynor SL, et al. Impact of pericardial restraint on right atrial mechanics during acute right ventricular pressure load. Am J Physiol Heart Circ Physiol 2003;284:H350–7. https://doi.org/10.1152/ ajpheart.00444.2002; PMID: 12388317.

33. Zanobini M, Saccocci M, Tamborini G, et al. Postoperative echocardiographic reduction of right ventricular function: Is pericardial opening modality the main culprit? Biomed Res Int 2017;2017:4808757. https://doi.org/10.1155/2017/4808757; PMID: 28589141.

34. Huckaby LV, Seese LM, Mathier MA, et al. Intra-aortic balloon pump bridging to heart transplantation: Impact of the 2018 allocation change. Circ Heart Fail 2020;13:e006971. https://doi.org/10.1161/circheartfailure.120.006971; PMID: 32757643.

35. Liu J, Yang BQ, Itoh A, et al. Impact of new UNOS allocation criteria on heart transplant practices and outcomes.

Transplant Direct 2021;7:e642. https://doi.org/10.1097/ txd.0000000000001088; PMID: 33335981.

36. Cogswell R, John R, Estep JD, et al. An early investigation of outcomes with the new 2018 donor heart allocation system in the United States. J Heart Lung Transplant 2020;39:1–4. https://doi.org/10.1016/j.healun.2019.11.002; PMID: 31810767.

37. Varshney AS, Berg DD, Katz JN, et al. Use of temporary mechanical circulatory support for management of cardiogenic shock before and after the united network for organ sharing donor heart allocation system changes. JAMA Cardiol 2020;5:703–8. https://doi.org/10.1001/ jamacardio.2020.0692; PMID: 32293644.

38. Teuteberg JJ, Cleveland JC Jr, Cowger J, et al. The Society of Thoracic Surgeons Intermacs 2019 annual report: The changing landscape of devices and indications. Ann Thorac Surg 2020;109:649–60. https://doi.org/10.1016/j. athoracsur.2019.12.005; PMID: 32115073.

39. Centers for Medicare & Medicaid Services. Decision memo.

Artificial hearts and related devices, including ventricular assist devices for bridge-to-transplant and destination therapy (CAG-00453N). 2020. https://www.cms.gov/ medicare-coverage-database/details/nca-decision-memo. aspx?NCAId=298 (accessed June 21, 2021).

40. Goldstein DJ, Naka Y, Horstmanshof D, et al. Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: the multicenter study of maglev technology in patients undergoing mechanical circulatory support therapy with HeartMate 3 (MOMENTUM 3) randomized clinical trial. JAMA Cardiol 2020;5:411–9. https://doi.org/10.1001/ jamacardio.2019.5323; PMID: 31939996.

41. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci

2001;56:M146–56. https://doi.org/10.1093/gerona/56.3.m146; PMID: 11253156.

42. Maurer MS, Horn E, Reyentovich A, et al. Can a left ventricular assist device in individuals with advanced systolic heart failure improve or reverse frailty? J Am Geriatr Soc 2017;65:2383–90. https://doi.org/10.1111/jgs.15124; PMID: 28940248.

43. Chung CJ, Wu C, Jones M, et al. Reduced handgrip strength as a marker of frailty predicts clinical outcomes in patients

with heart failure undergoing ventricular assist device placement. J Card Fail 2014;20:310–5. https://doi. org/10.1016/j.cardfail.2014.02.008; PMID: 24569037.

44. Tse G, Gong M, Wong SH, et al. Frailty and clinical outcomes in advanced heart failure patients undergoing left ventricular assist device implantation: a systematic review and meta-analysis. J Am Med Dir Assoc 2018;19:255–61.e1. https://doi.org/10.1016/j.jamda.2017.09.022; PMID: 29129497.

45. Seese L, Hirji S, Sultan I, et al. Frailty screening tool for

patients undergoing orthotopic heart transplant. Ann Thorac Surg 2021;111:586–93. https://doi.org/10.1016/j. athoracsur.2020.05.072; PMID: 32622795.

46. Flint KM, Matlock DD, Lindenfeld J, Allen LA. Frailty and the selection of patients for destination therapy left ventricular assist device. Circ Heart Fail 2012;5:286–93. https://doi. org/10.1161/circheartfailure.111.963215; PMID: 22438521.

Antithrombotics in High-Risk PCI

Antithrombotics in Complex Percutaneous Coronary Interventions: Type and Duration of Treatment Despoina-Rafailia Benetou, MD, , Charalampos Varlamos, MD, , Christos Pappas, MD, Fotios Kolokathis, MD, and Dimitrios Alexopoulos, MD, Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

Abstract

Patients undergoing complex percutaneous coronary intervention (PCI) are at an increased risk of atherothrombotic complications. Although dual antiplatelet therapy is the mainstay of treatment for patients undergoing PCI with stent implantation, deciding its type and duration in complex PCI patients has long been considered a challenge for clinicians. This is because the beneficial effects of prolonged treatment and/or more potent antiplatelet agents’ use in preventing ischemic events are hindered by a concomitant increase in bleeding complications. The aim of this review is to highlight current evidence regarding the optimal antithrombotic therapy regimens used in complex PCI patients, focusing on the evaluation of both safety and efficacy outcomes as well as addressing future perspectives.

Keywords

Percutaneous coronary intervention, complex percutaneous coronary intervention, antiplatelet agents, dual antiplatelet therapy, P2Y12 inhibitors, antithrombotics, extended dual antiplatelet therapy Disclosure: DA has received lecturing honoraria/advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Medtronic, Biotronik, and Chiesi Hellas. All other authors have no conflicts of interest to declare.

Received: November 21, 2020 Accepted: June 4, 2021 Citation: US Cardiology Review 2021;15:e17. DOI: https://doi.org/10.15420/usc.2020.30 Correspondence: Despoina-Rafailia Benetou, Second Department of Cardiology, Attikon University Hospital, Rimini 1, Chaidari 12462, Athens, Greece.

E: benetoud@yahoo.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The presence of features commonly considered to characterize a complex percutaneous coronary intervention (PCI) procedure – such as treatment of three or more lesions, implantation of three or more stents, total stent length >60 mm, bifurcation lesion with two stents implanted or treatment of a chronic total occlusion (CTO) – has become increasingly frequent during the last decade.1–3 Additionally, other angiographic features, such as vein graft PCI, multivessel disease or thrombus-containing lesions have also been used to characterize a PCI procedure of increased complexity (Table 1).

Patients undergoing complex PCI are considered to have an elevated risk for ischemic complications since their rate of major adverse cardiovascular events (MACE) has been shown to be significantly higher than that of noncomplex PCI patients, especially when multiple complexity features are present.4–6 Dual antiplatelet therapy (DAPT) remains the cornerstone of treatment for patients undergoing PCI with stent implantation; this is intended to reduce atherothrombotic complications, although at the expense of increased bleeding complications. In the setting of complex PCI cases, the use of more potent agents and/or prolonged duration of antiplatelet therapy, although reasonable in terms of ischemic risk containment, raises safety issues, considering the increase of bleeding rates as well as the fact that complex PCI patients may be at an increased bleeding risk per se.7 In this review, we focus on the type and duration of antithrombotic regimens in patients undergoing complex PCI procedures.

Short- Versus Long-term Dual Anti-platelet Therapy

The optimal duration of DAPT in complex PCI patients has yet to be defined, since multiple factors, including patient, clinical and anatomical characteristics, should be taken into consideration before a decision is made.1,8 In the DAPT study, 3,730 patients were randomized to receive either prolonged (30-month) or standard (12-month) DAPT following a complex PCI procedure.9 Definition of complex PCI included unprotected left main, lesion length ≥30 mm, more than two lesions per vessel, bifurcation with side branch ≥2.5 mm, bypass vein graft PCI, or a thrombus-containing lesion. Clopidogrel was the P2Y12 inhibitor of choice in 65.6% while prasugrel was used in 34.4% of patients.

Regarding efficacy outcomes, analysis revealed that complex PCI patients in the prolonged DAPT group had a lower risk of major adverse cardiovascular and cerebrovascular events (MACCE) than those in the standard DAPT group (HR 0.72; 95% CI [0.55–0.96]; p=0.02). Additionally, MI and stent thrombosis (STh) rates were also lower in the prolonged DAPT group (HR 0.55; 95% CI [0.38–0.79]; p=0.001). On the other hand, as far as safety outcomes were concerned, prolonged DAPT was not significantly associated with an increase in moderate or severe bleeding events in complex PCI patients (HR 1.41; 95% CI [0.87–2.28]; p=0.16), although this was also evident in the non-complex PCI group (HR 1.78; 95% CI [1.27–2.50]; p<0.001; p for interaction=0.44).9

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Type and Duration of Antithrombotic Treatment in Complex PCI Table 1: Angiographic Features of Complex Percutaneous Coronary Intervention

new-generation DES. Concerning safety endpoints, via intention-to-treat analysis, there was a trend of higher major bleeding rates observed in the long-term DAPT arm, compared to short-term DAPT (1.03% versus 0.52%; incidence rate difference 0.51%; HR 1.81; 95% CI [0.67–4.91]).6

Angiographic feature Three or more lesions Two or more lesions per vessel Lesion length ≥30 mm Three or more stents Total stent length >60 mm Bifurcation lesion Left main or proximal left anterior descending lesion Multivessel disease Chronic total occlusion Vein graft percutaneous coronary intervention Use of atherectomy Thrombus Sources: Giustino et al. 2002;6 Yeh et al. 2007;9 Costa et al, 2009;10 Subhaharan et al. 2020;11 Bansilal et al. 2018;17 Serruys et al. 2019;18 Dangas et al. 2020;20 Bainey et al. 2020.22

In the study by Costa et al., high bleeding risk (HBR) status, defined as having a PRECISE-DAPT (PREdicting bleeding Complications in patients undergoing stent Implantation and SubsequEnt Dual AntiPlatelet Therapy) score >25, was evaluated as a potential treatment decision modifier, along with anatomical complexity.10 The study’s population included 3,118 complex PCI patients in total, pooled from eight randomized clinical trials.

Complex PCI was defined as three or more stents implanted, three or more lesions treated, three vessels treated, bifurcation with two stents implanted, total stent length >60 mm, and/or treatment of a CTO. Clopidogrel was used in most patients (79.5%), prasugrel in 10% and ticagrelor in only 8.5% of patients. Compared to short-term (3 or 6 months) DAPT, long-term DAPT (12 or 24 months) was associated with fewer ischemic events in non-HBR patients (absolute risk difference 3.86%; 95% CI [−7.71, 0.06%]; p=0.05) but not in HBR patients (absolute risk difference 1.30%; 95% CI [−6.99, 9.57%]; p=0.76). Regarding safety outcomes, there was a numerical but not statistically significant increase of bleeding rates in non-HBR patients (absolute risk difference 0.28%; 95% CI [−0.46, 1.26%]; p=0.57) as well as in HBR patients (absolute risk difference 3.04%; 95% CI [−2.97, 8.82%]; p=0.30) on long-term DAPT. Interestingly, though, complex PCI was not identified as a factor associated with increased bleeding rates per se.10 Similarly, in a pooled analysis of patient-level data from six randomized controlled trials involving 1,680 complex PCI patients, long-term (≥12 months) DAPT was associated with fewer MACE (adjusted HR 0.56; 95% CI [0.35–0.89]) and coronary thrombotic events (adjusted HR 0.57; 95% CI [0.33–0.97]) than short-term (3 or 6 months) DAPT; all patients were treated with clopidogrel.6 Complex PCI was defined as having three or more stents implanted, three or more lesions treated, three vessels treated, bifurcation with two stents implanted, total stent length >60 mm, or treatment of a CTO. Interestingly, the beneficial impact of long-term DAPT was progressively greater as the number of complex PCI variables increased, whereas the variable most consistently and strongly associated with elevated ischemic risk was bifurcation PCI with two stents implanted. Of note, all patients were treated with drug-eluting stent (DES) implantation and the effect of long-term DAPT on ischemic outcomes was uniform between early- and

Finally, the safety and efficacy of long-term (>12 months) DAPT was evaluated in a recent meta-analysis of five studies, including a total of 8,340 complex PCI patients. Complex PCI features included having more than three stents implanted, more than three lesions treated, three vessels treated, bifurcation lesions, total stent length >60 mm, left main or proximal left anterior descending lesion, a vein graft stent, or a CTO. Clopidogrel was the P2Y12 inhibitor of choice in all but one study, where prasugrel was also used.9 Compared to shorter DAPT duration, a DAPT regimen of >12 months was shown to reduce cardiac mortality (OR 0.57; 95% CI [0.35–0.92]; p=0.02) as well as MACE rates (OR 0.76; 95% CI [0.59–0.96]; p=0.02), with no statistically significant difference in STh rates (OR 0.54; 95% CI [0.21–1.38]; p=0.20). However, the anti-ischemic effects of prolonged DAPT came at the cost of an increased rate of bleeding events (OR 1.75; 95% CI [1.20–2.20], p=0.004), although there was no statistically significant difference in all-cause mortality (OR 0.86; 95% CI [0.61–1.22]; p=0.41).11 Apart from extending DAPT with clopidogrel, long-term treatment with ticagrelor (either 60 mg or 90 mg twice daily), on a background of lowdose aspirin, was also tested in PEGASUS-TIMI 54 trial, which included 21,162 patients who had experienced an MI 1–3 years earlier and had additional risk factors. Patients on long-term ticagrelor had a significantly lower risk of the primary efficacy endpoint – a composite of cardiovascular death, MI and stroke – although at a cost of a higher major bleeding risk.12 Ticagrelor effects on both efficacy and safety endpoints were consistent regardless of the presence of prior coronary stenting, although absolute risk reduction tended to be greater in patients without previous PCI because of the already increased baseline ischemic risk.13 Regarding high-risk patient subgroups, the PEGASUS-TIMI 54 subanalyses revealed a greater absolute risk reduction of MACE in patients with diabetes, renal dysfunction and peripheral artery disease (PAD) who were treated with ticagrelor. More specifically, patients with diabetes receiving ticagrelor had an absolute risk reduction of 1.5% compared to 1.1% in patients without diabetes (3-year number needed to treat: 67 versus 91) while, in diabetic patients, cardiovascular death as well as coronary heart disease death rates were reduced by 22% and 34%, respectively, with long-term ticagrelor therapy.14 Patients with renal dysfunction had a greater risk of MACE at 3 years after the index event and consequently experienced a higher absolute risk reduction with long-term treatment with ticagrelor, compared to those without (2.7% versus 0.63%).15 The latter was also observed in the highrisk subset of patients with PAD, who had a greater absolute risk reduction of MACE (4.1%) as well as a lower risk of major adverse limb events (HR 0.65; 95% CI [0.44–0.95; p=0.026]) with long-term ticagrelor.16 Regarding angiographic complexity, patients with multivessel disease had a similar relative risk reduction of MACE with ticagrelor (HR 0.82; 95% CI [0.72–0.94] for pooled ticagrelor versus placebo; p for interaction with patients without multivessel disease = 0.61). Once again, because of the increased baseline risk of MACE in patients with multivessel disease, the absolute risk reduction with ticagrelor tended to be greater than that in patients without (1.43% versus 0.97; 3-year number needed to treat: 70 versus 103).17

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Type and Duration of Antithrombotic Treatment in Complex PCI In short, prolongation of DAPT beyond 1 year following complex PCI seems a rational strategy towards ischemic risk mitigation in this high-risk subset of patients, although at the cost of a potentially higher risk of bleeding complications.

Alternative Strategies: Ticagrelor Monotherapy

Evaluating the role of potent P2Y12 receptor inhibitors and specifically ticagrelor, a post-hoc analysis of GLOBAL LEADERS trial compared the safety and efficacy of an experimental regimen consisting of a 23-month ticagrelor monotherapy after 1-month DAPT with a reference regimen (12-month aspirin monotherapy after 12-month DAPT – with aspirin and either ticagrelor for acute coronary syndrome (ACS) or clopidogrel for stable coronary artery disease (CAD).18 Complex PCI definition included multivessel PCI, three or more stents implanted, three or more lesions treated, bifurcation PCI with two or more stents, or total stent length >60 mm.

The study’s primary endpoint was the composite of all-cause death or new Q wave MI, whereas the secondary, safety endpoint was BARC (Bleeding Academic Research Consortium) type 3 or 5 bleeding. Out of a total 4,570 complex PCI patients, those following the experimental regimen were found to have a significantly lower risk of the primary endpoint (HR 0.64; 95% CI [0.48–0.85]; p=0.002) as well as the patientoriented composite endpoint (POCE) – a composite of all-cause death, stroke, MI or revascularization (HR 0.80; 95% CI [0.69–0.93]; p= 0.003) compared to patients under the reference regimen. Interestingly, the risk of bleeding was not statistically different between the two treatment arms (HR 0.97; 95% CI [0.67–1.40]; p=0.856), resulting in a significantly reduced risk of net adverse clinical events in patients under the experimental strategy (HR 0.80; 95% CI [0.69–0.92]; p=0.002).18 Once again, the benefit regarding ischemic events prevention associated with the experimental strategy tended to be greater as the number of complex PCI features increased. However, stratified analyses based on clinical presentation revealed that long-term ticagrelor monotherapy was of benefit mainly to patients with ACS, owing to reductions in both POCE and bleeding rates, resulting in a lower risk of net adverse clinical events (14.07% versus 18.71%; HR 0.73; 95% CI [0.59–0.90]; p=0.003; for interaction with stable CAD patients, p=0.010).18 This finding was also supported by the post-hoc analysis of the GLOBAL LEADERS study, which was dedicated to 3,576 patients undergoing multivessel PCI. Results showed that patients with ACS following the experimental strategy had a lower risk of the primary endpoint (2.95% versus 5.26%; HR 0.55; 95% CI [0.35–0.89]; p=0.014; p for interaction with stable CAD patients = 0.032), driven by a lower risk of all-cause mortality (2.19% versus 4.28%; HR 0.51; 95% CI [0.30–0.87]; p=0.013; p for interaction with stable CAD patients = 0.021), as well as a marginally significant reduced risk of bleeding (HR 0.58; 95% CI [0.33–1.01]; p=0.053; p for interaction with stable CAD patients = 0.334) compared with patients receiving the reference regimen.19 In the same direction, the TWILIGHT-COMPLEX study, a post-hoc analysis of the TWILIGHT trial, evaluated the effects of ticagrelor monotherapy compared to DAPT with aspirin plus ticagrelor in 2,342 event-free patients who had completed 3 months of DAPT. Complex PCI features included three or more lesions treated, three vessels treated, stent length >60 mm, bifurcation with two stents implanted, use of atherectomy device, left main PCI, surgical bypass graft or CTO PCI. Regarding ischemic endpoints, the two treatment regimens had similar

results, in terms of both the composite of death, MI or stroke (3.8% versus 4.9%; absolute risk difference 1.1%; HR 0.77; 95% CI [0.52–1.15]) and STh (0.4% versus 0.8%; absolute risk difference −0.4%; HR 0.56; 95% CI [0.19–1.67]) rates. Nevertheless, patients under the ticagrelor monotherapy regimen were found to have a lower risk of a BARC type 2, 3, or 5 bleeding during the first year after the index PCI (4.2% versus 7.7%; absolute risk difference −3.5%; HR 0.54; 95% CI [0.38–0.76]), and severe or fatal bleeding rates were also significantly lower than in patients in the DAPT arm (1.1% versus 2.6%; absolute risk difference −1.5%; HR 0.41; 95% CI [0.21–0.80]). Of note, the effect of ticagrelor monotherapy versus DAPT for the endpoint of death, MI, or stroke was consistent across all variables of complex PCI as well as after stratification based on the presence of progressive number of complex PCI features.20 To sum up, recent evidence points to the superiority of long-term ticagrelor monotherapy following a short course of DAPT concerning safety outcomes with no evidence of reduced efficacy, providing an alternative strategy towards bleeding risk mitigation in the high-risk population of complex PCI patients.

Alternative Strategies: Rivaroxaban

Another strategy of antithrombotic treatment extension involves the addition of an anticoagulant to aspirin for long-term prevention of atherothrombotic events. The COMPASS trial investigated the safety and efficacy of rivaroxaban 2.5 mg twice daily on top of aspirin in patients with stable CAD or PAD. Patients receiving rivaroxaban plus aspirin had a lower rate of MACE (HR 0.76; 95% CI [0.66–0.86]; p<0.001) than those on aspirin alone, although at the expense of an increase in major bleeding events (HR 1.70; 95% CI [1.40–2.05]; p<0.001).21 In a prespecified subgroup analysis of COMPASS, similar to non-PCI patients, stable CAD patients treated with PCI had a reduced rate of MACE when treated with rivaroxaban plus aspirin versus aspirin alone (4.0% versus 5.5%; HR 0.74; 95% CI [0.61–0.88]) as well as lower rates of mortality (2.5% versus 3.5%; HR 0.73; 95% CI [[0.58–0.92]) and stroke (0.9% versus 1.4%; HR 0.66; 95% CI [0.45–0.96]).22 There was also a modest trend toward lower MI rates in PCI patients under rivaroxaban plus aspirin in comparison with aspirin alone, although statistical significance was not reached (2.2% versus 2.7%; HR 0.79; 95% CI [0.61– 1.02]). Of interest, the results were consistent in patients with previous single-vessel and multivessel PCI (for interaction, p=0.73).

Regarding safety, the combination of rivaroxaban plus aspirin was associated with a higher rate of major bleeding events compared to aspirin alone (3.3% versus 2.0%; HR 1.72; 95% CI [1.34–2.21]), with no difference in intracranial bleeding, fatal bleeding or bleeding into a critical organ. Therefore, the risk of the composite net clinical benefit outcome (cardiovascular death, stroke, MI, fatal bleeding, or symptomatic bleeding into a critical organ) was lower in the rivaroxaban plus aspirin versus aspirin-alone arm (4.6% versus 5.9%; HR 0.78; 95% CI [0.65–0.93]). Of note, 62.8% of patients had undergone a PCI performed three or more years ago and 32.3% had undergone PCI 1–3 years before randomization.

Interestingly, though, the benefit of rivaroxaban plus aspirin on MACE reduction among PCI-treated patients was consistent irrespective of the time PCI was performed (1­ –10 years before randomization) or the presence or absence of previous MI.22 Detailed presentation of studies investigating antithrombotic regimens of different type and duration are presented in Table 2.

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Type and Duration of Antithrombotic Treatment in Complex PCI Table 2: Options for Extended Antithrombotic Therapy Study

Size (n) Complex PCI Definition

P2Y12 Inhibitor

Results

Comparison of Short Versus Long-term DAPT Regimens Yeh et al. 20179

3,730

Unprotected LM, lesion length ≥30 mm Two or more lesions per vessel Bifurcation with side branch ≥2.5 mm Vein graft PCI Lesion with thrombus

Clopidogrel (65.6%) Prasugrel (34.4%)

30-month versus 12-month DAPT MI or STh: HR 0.55 (95% CI [0.38–0.79]; p=0.001) MACCE: HR 0.72 (95% CI [0.55–0.96]; p=0.02) Moderate/severe bleeding: HR 1.41 (95% CI [0.87–2.28]; p=0.16)

Costa et al. 201910

3,118

Three or more stents implanted Three or more lesions treated Three vessels treated, bifurcation with two stents implanted Stent length >60mm CTO PCI

Clopidogrel (79.5%) Prasugrel (10%) Ticagrelor (8.5%)

12/24 months versus 3/6 months DAPT MI, definite STh, stroke or TVR: ARD: −3.86% (p=0.05) for non-HBR; and 1.30% (p=0.76) for HBR patients Bleeding: ARD: 0.28% (p=0.57) for non-HBR, and 3.04% (p=0.30) for HBR patients for TIMI Net clinical benefit: ARD: −4.05% (p=0.04) for non-HBR and 1.68% (p=0.73) for HBR patients

Giustino et al. 20166

1,680

Three or more stents implanted Three or more lesions treated Three vessels treated bifurcation with two stents implanted, stent length >60 mm CTO PCI

Clopidogrel

Long-term (≥12 months) versus short-term (3/6 months) DAPT MACE: HR 0.56 (95% CI [0.35–0.89]) CTE: HR 0.57 (95% CI [0.33-0.97]) Major bleeding: IRD 0.51% (HR 1.81; 95% CI [0.67–4.91])

Subhaharan et al. 202011

8,340

Three or more stents implanted Three or more lesions treated Three vessels treated Bifurcation lesions Stent length >60 mm LM/pLAD lesion Vein graft PCI CTO PCI

Clopidogrel (5/5 studies) Prasugrel (1/5 studies)

≥12 months versus shorter DAPT Cardiac mortality: OR 0.57 (95% CI: 0.35–0.92; p=0.02) MACE: OR 0.76 (95% CI [0.59–0.96; p=0.02) STh rates: OR 0.54 (95% CI [0.21–1.38; p=0.20) Bleeding: OR 1.75 (95% CI [1.20–2.20]; p=0.004) All-cause mortality: OR 0.86 (95% CI [0.61–1.22]; p=0.41)

Bansilal et al. 201817

12,558

Multivessel disease

Ticagrelor 90 mg/60 mg (against a background of aspirin)

Ticagrelor plus aspirin versus aspirin alone (1–3 years after MI) MACE: HR 0.82 (95% CI [0.72–0.94]) Coronary events: HR 0.76 (95% CI [0.66–0.88]) Coronary death: HR 0.64 (95% CI [0.48–0.85]) STh: HR 0.59 (95% CI [0.37–0.94]) Major bleeding: HR 2.67 (95% CI [1.81–3.93])

Alternative Strategies: Ticagrelor Monotherapy Serruys et al. 201918

4,570

Multivessel PCI Three or more stents implanted Three or more lesions treated Bifurcation PCI with two or more stents Stent length >60mm

Ticagrelor

23-month ticagrelor monotherapy after 1-month DAPT versus. 12-month aspirin alone after 12-month DAPT All-cause death or new Q-wave MI: HR 0.64 (95% CI [0.48–0.85]; p=0.002) POCE: HR 0.80 (95% CI [0.69–0.93]; p=0.003) Bleeding: HR 0.97 (95% CI [0.67–1.40]; p=0.856) Net adverse clinical events: HR 0.80; 95% CI [0.69–0.92]; p=0.002

Dangas et al. 202020

2,342

Three or more lesions treated Three vessels treated Stent length >60 mm bifurcation with two stents implanted Use of atherectomy LM PCI Bypass graft PCI CTO PCI

Ticagrelor

Ticagrelor monotherapy versus DAPT with ticagrelor plus aspirin following 3-month uneventful DAPT All-cause death, MI or stroke: HR 0.77 (95% CI [0.52–1.15]) STh: HR 0.56 (95% CI [0.19–1.67]) Bleeding: HR 0.54 (95% CI [0.38–0.76]) Severe/fatal bleeding: HR 0.41 (95% CI [0.21–0.80])

Alternative Strategies: Rivaroxaban Bainey et al. 202022

9,862

3,775 patients (38.3%) with multivessel PCI Rivaroxaban

Rivaroxaban plus aspirin versus aspirin alone in CCS patients with prior PCI treatment MACE: HR 0.74 (95% CI [0.61–0.88]) Mortality: HR 0.73 (95% CI [0.58–0.92]) Stroke: HR 0.66 (95% CI [0.45–0.96]) MI: HR 0.79 (95% CI [0.61–1.02]) Bleeding: HR 1.72 (95% CI [1.34–2.21]) Net clinical benefit outcome: HR 0.78 (95% CI [0.65–0.93])

ARD = absolute risk difference; CCS = chronic coronary syndrome; DAPT = dual antiplatelet therapy; HBR = high bleeding risk; IRD = incidence rate difference; LM = left main; MACE = major adverse cardiovascular events; PCI = percutaneous coronary intervention; pLAD = proximal left anterior descending artery; POCE = patient-oriented composite endpoint; STh = stent thrombosis; TVR = target vessel revascularization.

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Type and Duration of Antithrombotic Treatment in Complex PCI Figure 1: Treatment Options for Extended Antithrombotic Therapy

Figure 2: Treatment Algorithm for Patients Undergoing High-risk Percutaneous Coronary Intervention Patient undergoing PCI with high-risk angiographic features

Options for extended antithrombotic therapy (on top of aspirin)

Post-MI in patients who have tolerated DAPT for 1 year

Ticagrelor 60/90 mg twice daily

Evaluation of bleeding risk

Patients with CAD at high risk of ischaemic events

If ticagrelor is contraindicated

Rivaroxaban 2.5 mg twice daily

↑ Thrombotic risk ↓ Bleeding risk

Prolonged antithrombotic therapy*

Clopidogrel 75 mg once a day Prasugrel 10/5 mg once a day* *Prasugrel 5 mg once a day if body weight <60 kg or age >75 years. CAD = coronary artery disease; DAPT = dual antiplatelet therapy; PCI = percutaneous coronary intervention.

Guideline Recommendations and Future Considerations

Although not specifically defining complex PCI, American College of Cardiology/American Heart Association guidelines consider some procedural and anatomical features, such as greater stent length or bifurcation lesions, as high ischemic risk factors that could potentially advocate for a prolonged DAPT regimen; this would be for an additional 18–36 months after an initial 6–12 months of DAPT.8 On the other hand, European Society of Cardiology (ESC) guidelines propose that prolonged DAPT (>6 months) may be considered (class IIb recommendation) for patients undergoing complex PCI, defined as treatment of three or more lesions, three or more stents implanted, stent length >60 mm, bifurcation PCI with two stents implanted or treatment of a CTO.1 However, guidelines on chronic coronary syndromes suggest extension of antithrombotic therapy in patients with high ischemic risk (defined as diffuse multivessel CAD plus at least one of the following: diabetes requiring medication; recurrent MI, PAD, or chronic kidney dysfunction) and without high bleeding risk (class IIa recommendation).23 Recently published European guidelines regarding the management of ACS in patients presenting without persistent ST-segment elevation also recommend extended treatment (>12 months) with a second antithrombotic agent on top of aspirin, either rivaroxaban 2.5 mg or ticagrelor (or clopidogrel or prasugrel in cases of contraindication to ticagrelor) in patients at a high risk of ischemic events and without an increased risk of bleeding (class IIa recommendation). High-risk cases include patients with complex CAD undergoing PCI with implantation of three or more stents, treatment of three or more lesions, stent length >60 mm, history of left main or bifurcation stenting with two stents, treatment of a CTO or stenting of the last patent vessel, as well as patients with multivessel CAD or history of stent thrombosis under antiplatelet therapy, among others.24 Treatment options for extended antithrombotic therapy are presented in Figure 1.23,24 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology guidelines also consider the prolongation of DAPT beyond 6 months in stable CAD patients with high-risk clinical or angiographic features who are not at a high risk of bleeding (weak recommendation; moderate-quality evidence). High-risk angiographic features include three or more stents implanted, three or more lesions stented, use of a

↑ Thrombotic risk ↑ Bleeding risk

Standard DAPT (6/12 months)

Ticagrelor monotherapy after short-term DAPT (1/3 months)

*American College of Cardiology/American Heart Association guidelines (class IIb recommendation). European Society of Cardiology guidelines (class IIb recommendation/class IIa recommendation). Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology guidelines (weak recommendation; moderate-quality evidence).

DAPT = dual antiplatelet therapy; PCI = percutaneous coronary intervention.

biodegradable vascular scaffold, total stent length >60 mm, bifurcation treated with two stents, CTO PCI, left main or proximal left anterior descending artery stenting as well as multivessel PCI.25 A concise algorithm regarding potential treatment strategies in patients undergoing high-risk PCI procedures is presented in Figure 2.

The use of potent P2Y12 receptor inhibitor in patients undergoing complex PCI, although a potentially promising strategy towards ischemic risk mitigation, has not been evaluated thoroughly since in most published studies clopidogrel was the P2Y12 receptor inhibitor of choice.

Nevertheless, the 2018 ESC/European Association for Cardio-Thoracic Surgery guidelines on myocardial revascularization state that prasugrel or ticagrelor may be used in high-risk elective PCI, such as left main stenting and CTO procedures (class IIb recommendation).26 Additionally, the 2019 ESC guidelines on chronic coronary syndromes suggest the use of prasugrel or ticagrelor, at least as initial therapy, in specific high-risk situations of elective stenting – such as suboptimal stent deployment or other procedural characteristics associated with high risk of STh, complex left main stem, or multivessel stenting – or if DAPT cannot be used because of aspirin intolerance.23 However, an analysis of the PROMETHEUS study comparing prasugrel with clopidogrel in 9,735 patients undergoing complex PCI for ACS showed that prasugrel administration was inversely proportional to procedural complexity, revealing the hesitancy of physicians to prescribe potent P2Y12 inhibitors in high-risk situations. Nevertheless, the use of prasugrel was associated with a significantly lower risk of MACE at 1 year (HR 0.79; 95% CI [0.68–0.92]; p=0.002), compared to clopidogrel.27 In the same spirit, the ongoing SMART-ATTEMPT trial (NCT04014803) is evaluating the use of potent P2Y12 inhibitors in elective complex PCI patients.

Conclusion

The increasing prevalence along with the elevated atherothrombotic risk of complex PCI cases in everyday clinical practice dictate the need to identify the optimal antithrombotic treatment strategy for this high-risk

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Type and Duration of Antithrombotic Treatment in Complex PCI patient population, through an individualized approach that would result in a balanced thrombotic/bleeding risk prevention.

Although prolonged DAPT duration seems to reduce ischemic complications, the associated potentially elevated bleeding risk hinders a universal adoption of extended DAPT regimens in complex PCI patients.

On the other hand, a regimen consisting of long-term ticagrelor monotherapy after a short course of DAPT seems promising, especially in patients with a high bleeding risk.

1. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur Heart J 2018;39:213–60. https://doi.org/10.1093/eurheartj/ehx419; PMID: 28886622 2. Bortnick AE, Epps KC, Selzer F, et al. Five-year follow-up of patients treated for coronary artery disease in the face of an increasing burden of co-morbidity and disease complexity (from the NHLBI Dynamic Registry). Am J Cardiol 2014;113:573–9. https://doi.org/10.1016/j.amjcard.2013.10.039; PMID: 24388624.

3. Werner N, Nickenig G, Sinning JM. Complex PCI procedures: challenges for the interventional cardiologist. Clin Res Cardiol 2018;107(Suppl 2):64–73. https://doi.org/10.1007/s00392018-1316-1; PMID: 29978353.

4. Stefanini GG, Serruys PW, Silber S, et al. The impact of patient and lesion complexity on clinical and angiographic outcomes after revascularization with zotarolimus- and everolimus eluting stents: a substudy of the RESOLUTE All Comers Trial (a randomized comparison of a zotarolimuseluting stent with an everolimus-eluting stent for percutaneous coronary intervention). J Am Coll Cardiol 2011;57:2221–32. https://doi.org/10.1016/j.jacc.2011.01.036; PMID: 21616282.

5. Wilensky RL, Selzer F, Johnston J, et al. Relation of percutaneous coronary intervention of complex lesions to clinical outcomes (from the NHLBI Dynamic Registry). Am J Cardiol 2002;90:216–21. https://doi.org/10.1016/S00029149(02)02457-8; PMID: 12127606.

6. Giustino G, Chieffo A, Palmerini T, et al. Efficacy and safety of dual antiplatelet therapy after complex PCI. J Am Coll Cardiol 2016;68:1851–64. https://doi.org/10.1016/j. jacc.2016.07.760; PMID: 27595509.

7. Généreux P, Giustino G, Redfors B, et al. Impact of percutaneous coronary intervention extent, complexity and platelet reactivity on outcomes after drug eluting stent implantation. Int J Cardiol. 2018;268:61–7. https://doi. org/10.1016/j.ijcard.2018.03.103; PMID: 30041804.

8. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. J Am Coll Cardiol 2016;68:1082–115. https://doi.org/10.1016/j.jacc.2016.03.513; PMID: 27036918.

9. Yeh RW, Kereiakes DJ, Steg PG, et al. Lesion complexity and outcomes of extended dual antiplatelet therapy after

10.

11.

12.

13.

14.

15.

16.

17.

18.

Therefore, the role of potent P2Y12 receptor inhibitors in the management of complex PCI patients needs to be further evaluated as part of antiplatelet treatment regimens of various combinations and durations.

Finally, the addition of low-dose anticoagulant on top of aspirin has shown promising results in the long-term prevention of ischemic events in selected stable CAD patients with a history of PCI, even several years after the index procedure.

percutaneous coronary intervention. J Am Coll Cardiol 2017;70:2213–23. https://doi.org/10.1016/j.jacc.2017.09.011; PMID: 29073947.

Costa F, Van Klaveren D, Feres F, et al. Dual antiplatelet therapy duration based on ischemic and bleeding risks after coronary stenting. J Am Coll Cardiol 2019;73:741–54. https:// doi.org/10.1016/j.jacc.2018.11.048; PMID: 30784667.

Subhaharan D, Mridha N, Singh K. Clinical benefits of prolonged dual antiplatelet therapy following complex percutaneous coronary intervention. Coron Artery Dis 2020;31:273–8. https://doi.org/10.1097/ MCA.0000000000000827; PMID: 31658148.

Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791–800. https://doi.org/10.1056/ NEJMoa1500857; PMID: 25773268.

Furtado RHM, Nicolau JC, Magnani G, et al. Long-term ticagrelor for secondary prevention in patients with prior myocardial infarction and no history of coronary stenting: insights from PEGASUS-TIMI 54. Eur Heart J 2020;41:1625– 32. https://doi.org/10.1093/eurheartj/ehz821; PMID: 31811715.

Bhatt DL, Bonaca MP, Bansilal S, et al. Reduction in ischemic events with ticagrelor in diabetic patients with prior myocardial infarction in PEGASUS-TIMI 54. J Am Coll Cardiol 2016;67:2732–40. https://doi.org/10.1016/j.jacc.2016.03.529; PMID: 27046160.

Magnani G, Storey RF, Steg G, et al. Efficacy and safety of ticagrelor for long-term secondary prevention of atherothrombotic events in relation to renal function: insights from the PEGASUS-TIMI 54 trial. Eur Heart J 2016;37:400–8. https://doi.org/10.1093/eurheartj/ehv482; PMID: 26443023.

Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease. J Am Coll Cardiol 2016;67:2719–28. https://doi.org/10.1016/S07351097(16)32267-7; PMID: 27046162.

Bansilal S, Bonaca MP, Cornel JH, et al. Ticagrelor for secondary prevention of atherothrombotic events in patients with multivessel coronary disease. J Am Coll Cardiol 2018;71:489–96. https://doi.org/10.1016/j.jacc.2017.11.050.

PMID: 29406853.

Serruys PW, Takahashi K, Chichareon P, et al. Impact of long-term ticagrelor monotherapy following 1-month dual antiplatelet therapy in patients who underwent complex

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percutaneous coronary intervention: insights from the Global Leaders trial. Eur Heart J 2019;40:2595–604. https://doi.org/10.1093/eurheartj/ehz453; PMID: 31397487.

19. Takahashi K, Serruys PW, Chichareon P, et al. Efficacy and safety of ticagrelor monotherapy in patients undergoing multivessel PCI. J Am Coll Cardiol 2019;74:2015–27. https:// doi.org/10.1016/j.jacc.2019.08.997; PMID: 31623758.

20. Dangas G, Baber U, Sharma S, et al. Ticagrelor with or without aspirin after complex PCI. J Am Coll Cardiol 2020;75:2414–24. https://doi.org/10.1016/j.jacc.2020.03.011; PMID: 32240761.

21. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319–30. https://doi.org/10.1056/ NEJMoa1709118; PMID: 28844192.

22. Bainey KR, Welsh RC, Connolly SJ, et al. Rivaroxaban plus aspirin versus aspirin alone in patients with prior percutaneous coronary intervention (COMPASS-PCI).

Circulation 2020;141:1141–51. https://doi.org/10.1161/10.1161/ CIRCULATIONAHA.119.044598; PMID: 32178526.

23. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504439.

24. Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021;42:289–1367. https://doi. org/10.1093/eurheartj/ehaa575; PMID: 32860058.

25. Mehta SR, Bainey KR, Cantor WJ, et al. 2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology focused update of the guidelines for the use of antiplatelet therapy. Can J Cardiol 2018;34:214–33. https://doi.org/10.1016/j.cjca.2017.12.012; PMID: 29475527.

26. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/ EACTS Guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437.

27. Chandrasekhar J, Baber U, Sartori S, et al. Associations between complex PCI and prasugrel or clopidogrel use in patients with acute coronary syndrome who undergo PCI: from the PROMETHEUS study. Can J Cardiol 2018;34:319–29. https://doi.org/10.1016/j.cjca.2017.12.023; PMID: 29475531.

Cardiogenic Shock

Cardiogenic Shock: Protocols, Teams, Centers, and Networks Alex F Warren, MD, ,1,2 Carolyn Rosner, NP,3 Raghav Gattani, MD, ,3 Alex G Truesdell, MD, FSCAI, ,3,4 and Alastair G Proudfoot, MD, PhD, 5,6,7,8 1. South-East Scotland School of Anaesthesia, Edinburgh, UK; 2. Anaesthesia, Critical Care and Pain, University of Edinburgh, Edinburgh, UK; 3. Inova Heart and Vascular Institute, Falls Church, VA; 4. Virginia Heart, Falls Church, VA; 5. Department of Perioperative Medicine, Barts Heart Centre, London, UK; 6. Clinic for Anaesthesiology and Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany; 7. Department of Anaesthesiology and Intensive Care, German Heart Centre Berlin, Berlin, Germany; 8. Queen Mary University of London, London, UK

Abstract

The mortality of cardiogenic shock (CS) remains unacceptably high. Delays in the recognition of CS and access to disease-modifying or hemodynamically stabilizing interventions likely contribute to poor outcomes. In parallel to successful initiatives in other disease states, such as acute ST-elevation MI and major trauma, institutions are increasingly advocating the use of a multidisciplinary ‘shock team’ approach to CS management. A volume–outcome relationship exists in CS, as with many other acute cardiovascular conditions, and the emergence of ‘shock hubs’ as experienced facilities with an interest in improving CS outcomes through a hub-and-spoke ‘shock network’ approach provides another opportunity to deliver improved CS care as widely and equitably as possible. This narrative review outlines improvements from a networked approach to care, discusses a team-based and protocolized approach to CS management, reviews the available evidence and discusses the potential benefits, challenges, and opportunities of such systems of care.

Keywords

Cardiogenic shock, shock teams, acute MI, percutaneous coronary intervention, shock networks Disclosure: AGT is a consultant for Abiomed and serves on the speakers bureau for Abiomed. AGP declares an unrestricted educational grant from Abbott Vascular. AGT is a Guest Editor for US Cardiology Review; this did not influence peer review. All other authors have no conflicts of interest to declare.

Received: March 22, 2021 Accepted: June 14, 2021 Citation: US Cardiology Review 2021;15:e18. DOI: https://doi.org/10.15420/usc.2021.10 Correspondence: Alastair Proudfoot, Barts Heart Centre, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK. E: alastair.proudfoot1@nhs.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Cardiogenic shock (CS) can be defined as a syndrome of low cardiac output with resultant organ hypoperfusion and continues to have a high mortality.1–3 CS typically occurs in the setting of acute MI (AMI) or acute decompensated heart failure (ADHF), with or without prior cardiac arrest, and presently accounts for approximately 15% of all cardiac intensive care unit (CICU) admissions.4,5 Despite recent consensus efforts to standardize definitions, the complex hemodynamics and variable clinical phenotypes of the CS syndrome mean that the diagnosis and management of CS remain challenging and often require expertise across a range of specialties.1,6,7 Depending on the clinical phenotype of CS, a wide array of interventions, from coronary revascularization, percutaneous or surgical correction of structural heart disease through to mechanical circulatory support (MCS) adjunctive to critical care management, may be required to maintain lifesustaining physiology. Delays in recognition of CS and access to diseasemodifying or hemodynamically stabilizing interventions likely contribute to the significant lethality of CS. This may be compounded by heterogeneity of practice within and between hospitals, reflecting a limited evidence base, as well as logistical factors that can delay patient transfer to an experienced center for definitive intervention or hemodynamic assessment and support. These human factor elements are well recognized in other fields of acute care.8 The ideal service would deliver evidence-based or best-practice care efficiently, effectively, and reliably, with equity of access

for patients and referrers alike. Care would be multidisciplinary and ideally longitudinal, from resuscitation through to rehabilitation.

As a move towards this model, and in parallel with other time-critical clinical scenarios that have seen quantitative and qualitative improvements in care and process, regional networks of CS care are emerging.9–22 Referrers from regional hospitals are supported by a central shock hub staffed with a designated multiprofessional shock team and acute cardiac care specialists, with all the requisite technologies for diagnostics and patient management.12,14,15 The reliability of escalation to definitive care is ensured by locally developed protocols, with integration of consensusguideline best practices to ensure timely and appropriate escalation and de-escalation of care, specifically relating to the use of MCS technologies, and mitigation of complications. In an era of increasing incidence of CS with mortality rates that remain between 30% and 40% in contemporary randomized trials and cohort studies, it is hoped that these systems of care will impact primarily on patient-centered outcomes, as well as on the quality and reliability of care and potentially cost-effectiveness.5,23–26 This narrative review outlines improvements from a networked approach to care, discusses a team-based and protocolized approach to CS, reviews the available evidence and discusses the potential benefits, challenges, and opportunities of such systems of care.

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Cardiogenic Shock: Protocols, Teams, Centers, and Networks Learning from Other Systems

CS patients form a heterogeneous cohort at the thin end of the wedge of those presenting with heart failure or MI. In other groups of critically ill patients, network-based care has led to improved outcomes.9–11 Coordination of ST-elevation MI (STEMI) care is perhaps the exemplar of network-based care. Emergency medical and ambulance services, community hospitals, and tertiary referral centers seamlessly interact to form standardized ‘hub-and-spoke’ STEMI networks to ensure timely reperfusion.9 These networks are supported in the US and UK by societal programs, such as the American Heart Association (AHA) and British Cardiac Intervention Society, to provide quality assurance metrics and mechanisms for quality improvement.

In major trauma, the Advanced Trauma Life Support (ATLS) paradigm emphasizes the need for all centers to be able to provide life-saving initial resuscitation and diagnostics, but also the requirement for the sickest patients to be triaged to tertiary ‘hub’ centers for definitive care. Similarly, the ATLS program incorporates research and injury prevention education.

Transitioning to this model in major trauma has resulted in both qualitative service improvements and increased survival.10 Although these systems can result in improved patient outcomes, a key issue in translating these improvements to CS patients is their heterogeneity.9–11 Although STEMI and major trauma are relatively easy to classify and triage, the lack of clear consensus as to what constitutes CS and the difficulty in identifying the CS patient prior to manifestations of multiorgan failure provide particular challenges to introducing streamlined systems of care.

intervention and cardiac surgery centers.24 Another likely contributor to the volume–outcome effect in CS is a ‘failure to rescue’ the sickest CS patients who present to resource-limited, lower-volume centers. Systems of care that foster collaboration between larger and smaller academic and community centers to facilitate the early identification, stabilization, and escalation of CS patients with expedited transfer for definitive management remain an unmet need.

Team-based Care in Cardiogenic Shock

The concept of team-based cardiovascular care is not novel, and heart teams currently support decision making in a range of elective cardiac interventions.34,42,43 A critical element of the management of CS is efficient and reliable alerting of a range of specialists to allow collaborative and streamlined decision making in highly complex and potentially highresource-utilizing patients, particularly where there is a limited evidence base to drive practice.13–17 A core team of specialists, the shock team, is essential for time-critical decision making, supported by a wider team to ensure holistic follow-on care. The optimal composition of the shock team will depend on local resources, but contemporary shock teams typically comprise an interventional cardiologist, a cardiac critical care physician, cardiac critical care nurses, an advanced heart failure cardiologist, and a cardiac surgeon. Experience and knowledge in the management of CS is vital given the acuity and heterogeneity of presentation.

Cardiovascular procedural volumes have been consistently and positively associated with improved clinical outcomes, including survival.28–32 International practice guidelines recommend minimum procedural volumes for hospitals and operators for the maintenance of both accreditation and competency.33,34 In addition to procedural volumes, increased hospital volumes of CS patients are positively associated with improved outcomes in CS.35–38 An analysis of a US payer healthcare database including more than 500,000 CS patients demonstrated that hospitals treating <27 cases of CS each year had an absolute in-hospital mortality increase of 5%, compared with hospitals treating ≥107 cases/ year.35 A similar effect was seen in a large sample of AMI CS.36 Mortality in centers with durable left ventricular assist device (LVAD) capability, a likely surrogate of existing experience and expertise in the treatment of CS, was lower than in non-LVAD centers, even after accounting for revascularization rates and the use of mechanical support devices.37 Similarly, data from the greater Paris area showed a relative risk reduction in intensive care unit (ICU) mortality of 24% in CS patients managed in a university hospital compared with a non-university facility.38

Although any given shock team may have leadership with overall responsibility for the patient, decisions should be made by consensus with due regard for the expertise and experience of the team members.

Ideally the shock team should be capable of providing a response 24 hours a day, 365 days a year, regardless of patient location: emergency department, ICU, catheter laboratory, operating theatre, or off-site hospital. This reliability and resilience can be supported by technology solutions that allow real-time alerts and conference calling with first responders.44 The role of the shock team is to facilitate specific interventions tailored to the etiology of CS and real-time patient physiology, provide expertise that supports locally approved escalation protocols for MCS, and efficiently triage patients to an appropriate care location. Although the evidence base for MCS in cardiogenic shock is incomplete, both European Society of Cardiology and American Heart Association guidelines recommend that patients with CS refractory to first-line therapies undergo evaluation for temporary MCS by a clinical team with experience in MCS technologies.45–47 Therefore, the shock team should have the capability to facilitate emergency institution of MCS where deemed appropriate. This underpins the need for the team to consist of clinicians from interventional cardiology, advanced heart failure cardiology, and cardiac surgery.

Although these volume–outcome relationships will be influenced by confounders, they may also reflect increased access to therapies that may improve outcomes in CS. In the US payer healthcare dataset, CS patients in high-volume centers received higher rates of early revascularization in AMI CS and more frequent escalation to MCS.35 In CS patients undergoing percutaneous coronary intervention, intra-aortic balloon pump (IABP) or MCS use was more common in larger hospitals (>600 beds) and university and teaching hospitals than in community hospitals.39 Similarly, the use of invasive hemodynamic monitoring, which may aid in the identification, management, and prognostication of CS, is almost three time more frequent in urban teaching hospitals than in smaller hospitals.35,40,41 Despite this, 90% of AMI CS patients in a US registry were managed in community hospitals, with 43% treated in low-volume coronary

Finally, it must be remembered that CS is a condition with an exceptionally high mortality. Even when treatment is optimal and best practices are followed, patients may not survive and survivors may suffer complications and unacceptable functional limitation. The time critical nature of CS requires rapid decision making, often with incomplete premorbid information and an incapacitated patient. As such, it is incumbent on the shock team to ensure that, even when decisions are time critical, the ethical considerations of aggressive, often highly interventional treatments are borne in mind. Routine involvement of palliative care specialists in decision making has been advocated.47 The inclusion of critical care nursing staff and early recourse to palliative care specialists where futility is likely or evident would seem advisable, and consideration of patient or family wishes should be at the forefront of all decision-making.

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Cardiogenic Shock: Protocols, Teams, Centers, and Networks Table 1: Summary of Contemporary Studies of Cardiogenic Shock Teams and Protocols Study

Location

Population

Composition

Methodology

No. Patients

Single-center before–after 64 (shock team), non-randomized study 36 (control)

Outcomes

Studies of Multidisciplinary CS Team Lee et al.16

Ottawa, Canada

All CS etiologies

Smartphone-based team activation (ICU, IC, CTS, HF) with mobile MCS capability

8-month mortality: 67% versus 43%, control versus shock team

Tehrani et al.15

Inova Heart and Vascular Institute, VA, US

All CS etiologies

Telephone-based ‘shock line’ Single-center before–after 204 (shock team); (ICU, IC, CTS, HF) with mobile non-randomized study no. for control not MCS capability reported

30-day mortality: 53% versus 39%, control versus shock team

Taleb et al.17

Salt Lake City, UT, US

All CS etiologies, MCS only

Shock team with mobile MCS Single-center before–after 123 (shock team), capability (ICU, IC, CTS, HF) non-randomized study 121 (control)

In-hospital mortality: 52% versus 39%, control versus shock team

Mannino et al.19*

WellStar Health System, AMI-CS, Impella GA, US only

Hub-and-spoke shock team with mobile MCS capability (ICU, IC)

Single-center before–after 37 (control), non-randomized study 156 (shock team + Impella)

In-hospital mortality: 46% versus 29%, control versus shock team

AMI-CS, Impella only

Defined cardiogenic shock protocol including Impella

Multicenter observational cohort study

172

In-hospital mortality: 28%

Single-center 22† observational cohort study

In-hospital mortality: 55%

Studies of CS Protocols Basir et al.18

National Cardiogenic Shock Initiative, 35 US centers

Studies of Mobile MCS Teams Jaroszewski et al.20

Mayo Clinic, AZ, US

All CS etiologies, MCS only

Mobile shock team (CTS/HF, perfusion, nursing)

Beurtheret et al.21

Greater Paris area, France

All CS etiologies, VA-ECMO only‡

Mobile shock team (ICU, CTS, Single-center 87 perfusion, nursing) observational cohort study

In-hospital mortality: 63%

Ali et al.22

Royal Papworth Hospital, Cambridge, UK

All CS etiologies, VA-ECMO only

Mobile shock team (ICU, CTS, Single-center 24 HF, perfusion, nursing) observational cohort study

1-year mortality: 40%

*Non peer-reviewed study. †Cardiogenic shock (CS) patients only reported in this table. The original report contained five patients supported with mechanical cardiac support (MCS; here including intra-aortic balloon pump counterpulsation, veno-arterial extracorporeal membrane oxygenation [VA-ECMO] and the Impella microaxial left ventricular assist device [Abiomed]) for acute respiratory failure who are not included here. ‡Included patients with VA-ECMO instituted with ongoing cardiopulmonary resuscitation. ICU = intensive care; IC = interventional cardiology; CTS = cardiothoracic surgery; HF = heart failure cardiology.

Protocolized Care in Cardiogenic Shock

A number of healthcare systems in North America have described the development of shock teams and associated escalation protocols to streamline care and improve outcomes in patients with CS (Table 1). To date, there are no randomized studies on the use of CS teams, and comparisons are limited to historical controls from before–after studies.

The three largest reported studies to date included a total of 391 CS patients treated by multidisciplinary shock teams.15–17 The introduction of a telephone-activated multidisciplinary shock team at the Inova Heart and Vascular Institute in Virginia, accompanied by an institutional protocol for CS management, was associated with a reduction in 30-day mortality from 53% to 23%.14,15 A longer-term survival benefit was also reported from the introduction of a smartphone-activated shock team at the University of Ottawa, which was associated with a reduction in 8-month mortality from 67% to 43%.16 Both these studies introduced multidisciplinary shock teams comprising at least clinicians from critical care, heart failure cardiology, interventional cardiology, and cardiac surgery.

Although the majority of clinical decision making may be conducted by the core team, the involvement of the wider patient care team cannot be underestimated. Care is improved when bedside nursing staff and allied health professionals (including physiotherapy, occupational therapy, pharmacy, nutrition and dietetics, and perfusion staff) have experience of treating CS patients, including those on MCS. Because CS patients often develop multiorgan dysfunction and a systemic inflammatory response

syndrome, other available specialist physicians with an interest and experience in CS, including, but not limited to, nephrology, hematology, electrophysiology, anesthesia, and stroke medicine, also form part of the wider circle of individuals involved in the care of CS patients.

Other studies of shock teams have similarly reported the outcomes of CS patients treated with MCS as part of a multidisciplinary team approach. A study from the University of Utah compared 123 patients treated with short-term MCS by a shock team to a historical cohort of consecutive MCS patients without a team-based approach, reporting a reduction in inhospital mortality from 52% to 39%.17 The National Cardiogenic Shock Initiative included 172 patients with AMI CS managed at 35 US centers with a protocol emphasizing early revascularization supported by prepercutaneous coronary intervention (PCI) MCS, with a percutaneous microaxial flow left ventricular device (Impella, Abiomed) guided by hemodynamic data.18 This approach improved survival from 50% in a historical cohort to 72%, although the use of a shock team to support decision-making was not specified.16 A single-center study from the WellStar Health System in Georgia reported before and after hospital mortality of 46% and 29%, respectively, in a non-peer-reviewed study of a hub-and-spoke CS network in 156 patients treated with Impella.19 Although caution must be exercised in drawing conclusions from observational before–after studies, there is both a compelling rationale for the role of shock teams and a growing body of data to support patientlevel benefit. Which specific aspects of shock protocols are likely to be

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Cardiogenic Shock: Protocols, Teams, Centers, and Networks Figure 1: Example of a Hub-and-Spoke Cardiogenic Shock Network Showing Possible Patient Pathways Within the System Shock hub: experienced, high-volume centers with 24/7 interventional/HF cardiology, MCS capability, and cardiac surgery, with CS team on call

A

Spoke facility: PCI ± MCS capability Spoke facility: initial resuscitation only

E F B D

C

A: The patient is transferred directly to the shock hub as the nearest suitable hospital. B: The patient presents to a spoke hospital. CS is identified, the shock team is activated, and the patient is transferred to the shock hub for ongoing care. C: The patient presents to a spoke hospital. The shock team is activated and deploys a mobile mechanical circulatory support (MCS) team to retrieve the patient to the shock hub and provide on-site MCS at the local hospital if required. D: The patient presents to a spoke hospital. Discussions within the shock team lead to a consensus decision that advanced therapy is inappropriate. Palliative care is instituted at the local hospital. E: A patient is streamed by emergency medical services (EMS) to a percutaneous coronary intervention (PCI)-capable spoke hospital, receives revascularization but develops CS and is transferred to a shock hub for ongoing care. F: A patient develops CS at a PCI-capable spoke hospital. The patient is discussed with shock team, which advises on care, but transfer to a shock hub is not required. HF = heart failure; CS = cardiogenic shock; MCS = mechanical circulatory support.

Table 2: Definitions of Key Components of a Network-based Approach for Cardiogenic Shock Shock Team A core group of medical specialists collaborating in the multidisciplinary management of CS to include: rapid diagnosis; identification of specific CS phenotypes; recommendation and facilitation of definitive interventions, including MCS; recognition of futility and engagement of palliative care; triage of patients to the appropriate clinical care environment, including transfer to the network shock hub; and identification of patients suitable for clinical trial enrollment

Shock Hub A facility with core service components that allow high-quality, reliable, and longitudinal care, with evidence-based interventions or locally established best practices. This includes an established shock team, the use of escalation algorithms and protocols, information technology solutions to support real-time communication between the shock team and referrers, infrastructure for data collection for quality and research purposes, and enrollment of patients in clinical trials. Typically, hubs will have a range of MCS options and would usually have access to durable MCS and the capability to evaluate and list for heart transplantation

Shock Network A formal or informal community of hospitals within a geographic region committed to high-quality clinical care, education, uniform data collection, quality improvement, and evidence generation through clinical trials CS = cardiogenic shock; MCS = mechanical circulatory support.

essential and affect mortality remains unclear. Protocols may standardize clinical approach within and across institutions. However, they may fail to address complex issues in real-world settings or allow individualization of patient care. Despite recent advances in classification, CS remains illdefined and incorporates a range of phenotypes that cannot be

encapsulated by limited physiological and biochemical parameters alone.6,48,49 The role of early, pre-revascularization MCS in AMI CS remains unproven in randomized trials, as does the role of right heart catheter data to guide decision making and escalation to MCS, despite supportive observational data.45,50,51 Given the burden of complications of MCS and their effects on mortality, protocols pertaining to large-bore vascular access, anticoagulation, and MCS weaning and removal would seem prudent. Therefore, the role of shock teams may be to synthesize and analyze a locally (or regionally) defined minimum dataset of clinical, biochemical, imaging, and physiological parameters to guide the optimal timing of escalation to MCS, as well as device and patient selection.

Shock Hubs Within Networks of Cardiogenic Shock Care: Towards a 21st Century System of Care

The development and maturation of shock teams within high-volume cardiac centers is an intuitive first step. However, the extension of this expertise throughout a more formative network of CS care is required to deliver care equitably for both patients and referrers, and to improve patient-level outcomes at scale. This approach to CS care level has been advocated by societal guidelines and consensus statements.47,50,52 Proposed definitions of the requisite components of a network are outlined in Table 2. Given the prevalence of AMI CS within the cohort of CS patients as a whole, existing pathways to prioritize primary PCI in STEMI are a natural starting point, while also recognizing that non-AMI-related CS patients will have discrete needs, and may present through different pathways throughout the network. The outline of a potential regional shock network is shown in Figure 1, with key clinical logistical and organizational elements outlined in Table 3. Peripheral-spoke hospitals

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Cardiogenic Shock: Protocols, Teams, Centers, and Networks Table 3: Criteria for the Ideal Cardiogenic Shock Network

Table 4: Key Performance Indicators for Shock Centers of Excellence

Clinical

Door-to-balloon time for AMI CS

24/7 availability of multidisciplinary shock team comprising at least interventional cardiology (including structural heart interventions), advanced heart failure cardiology, cardiac critical care, and cardiac surgery to both discuss patient management and accept for rapid triage and transfer to a shock hub Availability to provide MCS 24/7, with experience and expertise in the use of these devices (including medical, nursing, and perfusion staff) Locally agreed escalation protocols based on clinical, hemodynamic, biochemical, and imaging data that are iterated as new evidence or data evolve Inpatient acute care provided on a dedicated CICU with multidisciplinary expertise in acute cardiac care and MCS Nurse:patient ratio of 1:1 for CS patients in the intensive care unit Provision of, or ability to rapidly refer and transfer to, a durable LVAD and cardiac transplantation service

Logistical A rapid and accessible call-out system to facilitate real-time discussion between the shock team and referring clinicians Ability to safely and rapidly transfer CS patients from referring facilities to shock hubs, including the use of mobile MCS when required

Organizational A commitment to leading and improving the management of CS patients, with dedicated time for key individuals Incorporation of evidence-based practice and identification of best practices where limited high-quality evidence exists with protocolized escalation of care Open culture of learning and a multifacility, multidisciplinary governance process including regular case reviews to ensure identification and discussion of quality improvement initiatives Embedded routine collection of referral and outcome data with patient follow-up and patient-centered outcomes Multidisciplinary education program with associated nursing and trainee education within acute cardiac critical care training programs Research infrastructure and collaboration with other CS networks, and willingness to incorporate randomized and observational trials into clinical practice CICU = cardiac intensive care unit; CS = cardiogenic shock; LVAD = left ventricular assist device; MCS = mechanical cardiac support.

may provide a range of services, including primary PCI and/or percutaneous MCS therapies, but many will only have the facility to provide initial assessment and resuscitation of patients. Because most CS patients will not present to a shock hub, the approach should be collaborative, with representatives from all types of facilities involved in all aspects of networked care delivery from inception.24,35 For the sickest CS patients (Society for Cardiovascular Angiography and Interventions stage D or E6), survival may depend on rapid access to MCS to sustain physiology; when such patients present at spoke centers without the ability to institute MCS locally, they will often also be too unstable to safely transfer to definitive care. A number of single-center studies have described mobile MCS teams set up to retrieve patients from off-site hospitals after institution of MCS.20–22 These cohorts, although small, report higher mortality than studies of systems where patients are moved to an MCS center and escalated according to local protocols.

Whether this reflects a selection bias, the benefit of care in an experienced center, or the role of local protocols in patient selection is unclear.

Nonetheless, based on these data, mobile MCS is safe and feasible.20–22 The need for transport infrastructure within a CS network will depend on local geography and healthcare organization. The key standard is that the

Door-to-shock team activation time Full complement of multispecialty shock team on each alert Shock team mustered and available within 5–10 min of activation Access to coronary revascularization in all eligible patients Adherence to locally agreed escalation protocols, including use of right heart catheterization Comparable outcomes between patients presenting to a shock hub and those who are transferred in from an outlying ‘spoke’ center Regular assessment and reassessment by the shock team on CICU All eligible patients discussed with the regional advanced heart failure service to determine eligibility for durable MCS or heart transplantation Engagement of palliative care services where futility is recognized and end-of-life care proposed After action, review of all cases where concern regarding ‘failure to rescue’ and learning documented and implemented Use of a nationalized and harmonized CS case report form for data collection Registry data validity and quality control Minimum quarterly clinical and governance meeting between hub and spoke clinicians to discuss outcomes, quality metrics, critical incidents, and research enrollment/ opportunities AMI = acute MI; CICU = cardiac intensive care unit; CS = cardiogenic shock; LVAD = left ventricular assist device; MCS = mechanical cardiac support.

patients throughout a network have equitable and timely access to specialist support and associated interventions such as MCS. Given the overlap between CS and cardiac arrest, and the emerging evidence base for extracorporeal membrane oxygenation in the treatment of refractory sudden cardiac arrest, extracorporeal cardiopulmonary resuscitation (eCPR) capability is likely to become a prerequisite for shock hubs.53,54 Although much of the infrastructure required for CS systems overlaps with that required for eCPR, eCPR demands 24/7 on-site expertise for patient selection and cannulation that may require the triage of patients to select geographical hubs or even mobilization of cannulation teams to the patient in the field. The resource implications of eCPR service provision are significant and should be balanced with the provision of optimal CS care at scale within shock hubs.

As CS systems of care evolve, it is vital to ensure continued stakeholder engagement, integration, and quality improvement inclusive across the entire patient journey. Clear pathways and protocols should be developed for referral, acceptance, transfer, and repatriation. Reimbursement will vary across healthcare systems, but an analysis of cost and the costeffectiveness of the shock team and a networked approach have not been adequately described. Despite the challenges of clinical governance across different institutions, the limited evidence base to guide interventions and high complication rates with MCS should mandate an open culture of learning across the network to ensure that ‘failure to rescue’ scenarios are identified and mitigated and that protocols and best practices are iterated as local experience and published data evolve, complications are minimized, and outcomes are optimized.

These quality improvement efforts require routine and robust data collection. Networked data collection and integration would also facilitate longer-term follow-up data analysis, including post-discharge healthcare

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Cardiogenic Shock: Protocols, Teams, Centers, and Networks utilization and quality of life metrics, and a shift towards a holistic model of CS care from resuscitation to recovery. Nonetheless, although local registries provide valuable information about participating network sites, simple comparisons between hospitals are not sufficiently reliable for reporting trends in demographics, access to interventions, and patient outcomes. Ultimately, data collection and analysis at scale could be achieved via a harmonized national case report form. This model has been adopted by the American Heart Association through the Get With the Guidelines initiative, which has led to transformation across several facets of acute cardiac care and could be a template for development of a nationalized CS registry given the overlap with existing programs in AMI and out-of-hospital cardiac arrest.55–57 This model may assist in validated designation of CS ‘centers of excellence’ using putative key performance metrics (Table 4).

Beyond quality improvement, research infrastructure and efficient approaches to informed consent should be a defining criterion of shock hubs. Given the historical challenges of patient recruitment to CS trials, it is imperative that with centralization of the sickest CS patients to shock hubs, the opportunity for clinical trial enrolment is leveraged.58 Research activity is associated with better clinical outcomes in acute care and should form part of shock network activity.59 1. Chioncel O, Parissis J, Mebazaa A, et al. Epidemiology, pathophysiology and contemporary management of cardiogenic shock – a position statement from the Heart Failure Association of the European Society of Cardiology.

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2. Stead EA Jr, Ebert RV. Shock syndrome produced by failure of the heart. Arch Intern Med 1942;69:369–83. https://doi. org/10.1001/archinte.1942.00200150002001.

3. Vahdatpour C, Collins D, Goldberg S. Cardiogenic shock.

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4. Bohula EA, Katz JN, van Diepen S, et al. Demographics, care patterns, and outcomes of patients admitted to cardiac intensive care units. JAMA Cardiol 2019;4:928–35. https://doi. org/10.1001/jamacardio.2019.2467; PMID: 31339509.

5. Berg DD, Bohula EA, van Diepen S, et al. Epidemiology of shock in contemporary cardiac intensive care units. Circ Cardiovasc Qual Outcomes 2019;12:e005618. https://doi. org/10.1161/CIRCOUTCOMES.119.005618; PMID: 30879324.

6. Baran DA, Grines CL, Bailey S, et al. SCAI clinical expert consensus statement on the classification of cardiogenic shock. Catheter Cardiovasc Interv 2019;94:29–37. https://doi. org/10.1002/ccd.28329; PMID: 31104355.

7. Samsky M, Krucoff M, Althouse AD, et al. Clinical and regulatory landscape for cardiogenic shock: a report from the Cardiac Safety Research Consortium ThinkTank on cardiogenic shock. Am Heart J 2020;219:1–8. https://doi. org/10.1016/j.ahj.2019.10.006; PMID: 31707323.

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Indeed, it should be remembered that with the exception of early revascularization in AMI CS, none of the interventions likely to be instituted

by CS teams, systems, or shock hubs (e.g. MCS, invasive hemodynamic monitoring, or protocolized care) have been shown to improve outcomes in randomized trials.60 Given the clear need to improve the evidence base for CS, the authors suggest that a key role of the shock team should be identification of eligible patients for future observational and randomized, intervention-based trials.

Conclusion

Mortality in cardiogenic shock remains unacceptably high. As has been demonstrated in other diseases, a multidisciplinary protocolized teambased approach with regional hub-and-spoke networks of care built around high-volume, experienced centers is likely to improve outcomes.

The existing data, although incomplete, support this approach. The development of processes to ensure equitable access to CS care across geographical and institutional boundaries requires a consensus approach with a robust educational and governance structure alongside clinical pathways. As the clinical care of CS patients continues to improve, the creation of CS networks provides a unique opportunity to replicate the success of other acute cardiovascular care pathways and realize improved outcomes for this disease, as well as engagement in future clinical trials.

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org/10.1007/s00134-018-5064-5; PMID: 29450594.

53. Yannopoulos D, Bartos J, Raveendran G, et al. Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial. Lancet 2020;396:1807–16. https://doi.org/10.1016/ S0140-6736(20)32338-2; PMID: 33197396.

54. Bělohlávek J. Hyperinvasive approach in refractory out-ofhospital cardiac arrest. Prague OHCA study. A randomized clinical trial. Presented at American College of Cardiology’s 70th Annual Scientific Session, May 17, 2021. https://www. crtonline.org/presentation-detail/hyperinvasive-approach-inrefractory-out-of-hospit (accessed August 24, 2021).

55. Ellrodt AG, Fonarow GC, Schwamm LH, et al. Synthesizing lessons learned from Get With The Guidelines. Circulation 2013;128:2447–60. https://doi.org/10.1161/01. cir.0000435779.48007.5c; PMID: 24166574.

56. Lewis WR, Ellrodt AG, Peterson E, et al. Trends in the use of evidence-based treatments for coronary artery disease among women and the elderly. Circ Cardiovasc Qual Outcomes 2009;2:633–41. https://doi.org/10.1161/ CIRCOUTCOMES.108.824763; PMID: 20031902.

57. Starks MA, Dai D, Nichol G, et al. The association of duration of participation in Get With The Guidelines-resuscitation with quality of care for in-hospital cardiac arrest. Am Heart J 2018;204:156–62. https://doi.org/10.1016/j.ahj.2018.04.018; PMID: 30121017.

58. Shaffer A, Sheikh O, Prasad A. Cardiogenic shock: a systemic review of clinical trials registered with ClinicalTrials.gov. J Invasive Cardiol 2020;32:e86–96.

PMID: 32240097.

59. Ozdemir BA, Karthikesalingam A, Sinha S, et al. Research activity and the association with mortality. PLoS One 2015;10:e0118253. https://doi.org/10.1371/journal. pone.0118253; PMID: 25719608.

60. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med 1999;341:625–34. https:// doi.org/10.1056/nejm199908263410901; PMID: 10460813.

Electrophysiology

The Role of Subcutaneous ICDs in the Prevention of Sudden Cardiac Death Leah A John, MD, MBA, , Ahmadreza Karimianpour, DO, and Michael R Gold, MD, PhD, Division of Cardiology, Medical University of South Carolina, Charleston, SC

Abstract

The ICD is an important therapy in the prevention of sudden cardiac death. The transvenous-ICD (TV-ICD) has been the primary device used for this purpose. However, mechanical and infectious complications occur with traditional TV-ICDs increasing morbidity and mortality. The subcutaneous-ICD (S-ICD) system was developed to circumvent some of these complications, but S-ICDs have their inherent set of limitations as well. These include inappropriate shock delivery, lack of bradycardia, antitachycardia or CRT pacing therapy and shorter device longevity. The S-ICD is now included in guidelines as an acceptable alternative to TV-ICDs among patients without pacing indications. This review discusses the rationale for S-ICDs by reviewing studies including the PRAETORIAN, PAS, and UNTOUCHED trials.

Keywords

Inappropriate shock, subcutaneous ICD, sudden cardiac death, transvenous ICD Disclosure: MRG is a consultant and receives research support from Medtronic and Boston Scientific, and is on the US Cardiology Review editorial board; this did not influence peer review. All other authors have no conflicts of interest to declare.

Received: January 9, 2021 Accepted: May 26, 2021 Citation: US Cardiology Review 2021;15:e19. DOI: https://doi.org/10.15420/usc.2021.01 Correspondence: Michael R Gold, Division of Cardiology, Medical University of South Carolina, 30 Courtenay Drive, MSC 592, Charleston, SC 29425-5920.

E: goldmr@musc.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

ICDs were developed more than 40 years ago and approved for use by the Food and Drug Administration (FDA) in 1985. They have remained a cornerstone of treatment in the prevention of sudden cardiac death ever since. Early ICDs were larger in size than those used now, and were placed subcutaneously in the abdomen. With the development of the transvenous-ICD (TV-ICD) system, the smaller pulse generator size and transvenous leads have allowed for placement of the device subcutaneously within the pre-pectoral space.

Despite the progression in ICD technology, there are still important risks and complications associated with traditional TV-ICDs. Some of the more serious complications include systemic infection (often lead related), pneumothorax, lead perforation or malfunction. To minimize such risks, the subcutaneous ICD (S-ICD) has emerged as a potential alternative therapy in the prevention of sudden cardiac death, with increasing use in the US. Studies of the first-generation S-ICDs showed high inappropriate shock rates but low complication rates, with high success for terminating ventricular arrhythmias.1 S-ICDs have been studied in multicenter clinical trials for more than a decade. Data have shown high complication-free rates and high shock efficacy for S-ICDs. Despite these apparent advantages, S-ICDs have limitations and potential risks too, including inappropriate shock delivery, lack of pacing and CRT therapy, and shorter device longevity. For instance, a recent report from Boston Scientific identified that its EMBLEM S-ICD Subcutaneous Electrode (Model 3501) body fractures just distal to the proximal sense ring, with an occurrence rate of 0.2% at 41 months.2

This review will summarize the rationale for S-ICDs in the appropriate patient population, in the context of the most relevant literature.

Subcutaneous ICD Leads

A significant limitation of conventional ICDs is the implantation of transvenous leads, which lend themselves to a variety of potential complications.3 Implant complications include pneumothorax, hemothorax, and cardiac tamponade.4 More chronic complications of TVICDs include infection and lead malfunction caused by insulation breaks or fracture, often exposing patients to inappropriate ICD shocks. Such shocks can also occur as a result of myopotentials and T wave oversensing.3–11 Lead failure often requires revision and/or extraction, and there are significant complications associated with these procedures.4 In contrast to TV-ICDs, vascular access is preserved with S-ICD implants, because the leads are placed subcutaneously. This eliminates many of the potential risks previously outlined. Furthermore, fluoroscopy is not required during the procedure because insertion of the S-ICD system is guided by anatomical landmarks only.4,5 The S-ICD pulse generator is placed in a lower left lateral thorax position, between the anterior and mid-axillary lines near the apex of the left ventricle.3 Attached to the generator is a single lead with a shock coil, which is tunneled from the lateral pocket medially to the xiphoid process and positioned 1–2 cm left of the sternum, with the distal tip close to the manubriosternal junction.3,12 The structure of S-ICD leads also allows for enhanced durability in comparison with transvenous leads. S-ICD leads do not require a stylet for

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Subcutaneous ICD for Sudden Cardiac Death Prevention placement and have no central lumen, which allows for higher tensile strength.3 Longer follow-up is still needed to adequately to assess longevity of S-ICD leads.3 Currently, the longest follow-up reported is 5.8 years, according to the European Registry Trial, during which no lead malfunctions or failures were noted.3,13 However, as highlighted above, a unique fracture point of the lead has been noted, leading to an FDA recall.14

Infection

Device infection is a problem associated with TV-ICDs and S-ICDs. However, it is important note that S-ICD infections are not associated with endocarditis and bacteremia.15,16 The EFFORTLESS registry and IDE trials reported no S-ICD infections associated with bacteremia.10,17 In a study by Bardy et al., the authors designed and tested an entirely S-ICD system evaluating four S-ICD configurations in 78 patients. They reported pocket infections in two of 55 patients enrolled in the European clinical trial.4 Higher infection rates have been reported in other studies, such as the IDE trial. Among the 330 patients in the IDE trial, 18 (5.5%) had suspected or confirmed infections reported by principal investigators.

Four of these infections required explant, and the remaining 14 were considered superficial or incisional infections (4.4%).10 Reported infection rates have varied considerably between retrospective analyses. There were higher rates noted in studies by Jarman et al. and Olde Nordkamp et al., reporting infection in 11 of 111 (9.9%) and in seven of 118 implants (5.9%), respectively.3,6,8 However, other studies, such as

by Abenkari et al., report lower infection rates of 3.2%.5 Part of the wide variability in reported events is the lack of consensus on the classification of infection events. Nevertheless, American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines recommend S-ICD over TV-ICDs for those at higher risk of infection.18 S-ICD remains a class I recommendation for patients at high risk of infection or without adequate venous access, without an indication for pacing or antitachycardia pacing (ATP).18,19

Site Complications

Achieving venous access can often prolong procedure times during TVICD placement. Venous access is not used for S-ICD implantation but site complications such as hematoma and device erosion can still occur, although they are rare.3,4 In a study by Köbe et al., one out of 69 patients (1.4%) reported hematomas.9 Most other studies, including the combined IDE and EFFORTLESS S-ICD registries, had much lower rates at 0.4% and 0.2%, respectively.3,17,20 With regard to the risk of device erosion, large pulse generator size and implant location have been problematic. First-generation S-ICDs, in particular, were significantly larger than TV-ICDs. The highest rates of device erosion have been reported by Jaman et al., noting an erosion rate of 18.8%.3,11 Most of the other early studies reported much lower rates at 1.4% and 0.8%.17,20 Others have reported no device erosions in their study cohort.4–7,9,10 The erosion rate was <0.2% with the small second- and thirdgeneration devices.11 Moreover, erosion rates may be reduced further with newer implant techniques placing the device partially intermuscularly.21 In addition to this approach, the less invasive two-incision technique, as described by Knops et al., is a safe and efficacious alternative for S-ICD implantation as it avoids a third, superior parasternal incision.22

Efficacy

Trials have reported high success rates for tachyarrhythmia detection and shock efficacy for S-ICDs. Bardy et al. demonstrated successful detection

and treatment of all 12 episodes of spontaneous, sustained ventricular tachyarrhythmias.4 Induced VF was detected in 100% of 137 induced episodes. VF was converted in 58 out of 59 patients (98%) with delivery of 65 J shocks in two consecutive tests.4 Other trials also demonstrate accurate ventricular tachycardia (VT)/VF detection and high rates of conversion, with first shock efficacy of 95.2% for monomorphic VT and 86.7% for polymorphic VT.23,24 S-ICD shocks for spontaneous arrhythmias are non-programmable at 80J, but reverse polarity with successive shocks if additional shocks are required for successful defibrillation.25 Failure of conversion with the first shock is predicted by patient height and BMI.26 As noted by Bardy et al., defibrillation threshold energy of S-ICDs is roughly three times higher than TV-ICDs (11.1 J versus 36.6 J).4 Despite this, the 80 J shock delivery of S-ICDs allows for a greater defibrillation threshold (DFT) safety margin.

In their retrospective analysis, Do et al. also noted that higher BMI and body surface area, and increased posterior and septal wall thickness, are associated with elevated S-ICD DFTs.27 It has been shown that patients with hypertrophic cardiomyopathy (HCM) have higher DFTs, and a higher percentage of HCM patients have DFTs >20 J with transvenous devices, which increases as left ventricular (LV) wall thickness increases, although other studies have shown high success rates in patients with HCM.28,29 In a large analysis from multicenter trials, S-ICD patients with HCM have comparable outcomes to non-HCM patients. Specifically, in a cohort of 99 HCM patients versus 773 non-HCM patients, successful defibrillation at >80J was achieved in 98.9% of HCM and 98.5% of nonHCM patients. Overall shock conversion efficacy was 100% in HCM versus 98% in non-HCM patients (p=not significant).30 These data suggest that S-ICD can be safe and effective for patients with HCM. This was further supported in the study by Francia et al., which showed that contemporary ICDs are safe and effective in HCM patients independent from LV hypertrophy.31 In addition to body habitus, S-ICD implant strategy and position are important determinants of S-ICD efficacy. Posterior generator and coil positioning have been associated with lower DFTs. High impedance is also associated with inadequate coil depth and lower rate of defibrillator success.32,33 Brouwer et al. compared various implantation techniques and found that the two-incision technique was a feasible alternative to the three-implantation technique and associated with shorter procedure times.34 In the IDE study, chronic conversion testing (>150 days post implant) was performed as a secondary endpoint as a surrogate to examine postimplant effectiveness. A 96% success rate with 65 J shock and 100% with 80 J shock were reported.10 In addition, S-ICDs demonstrated a 92.1% first shock success rate with 100.0% overall conversion rate among 119 spontaneous ventricular arrhythmia episodes in 21 patients, which is similar to rates noted in transvenous studies.10,35

Inappropriate Shocks

Inappropriate shocks as a result of oversensing or errors in arrhythmia discrimination had been one of the main drawbacks of S-ICDs with early generations of the device and programming. Jarman et al. reported inappropriate shocks in 17 of 22 patients. However, not all studies describe rates that high. Rates of 2.5% and 4.0% have been reported by Burke et al. and Köbe et al., respectively.9,20 In general, rates have ranged from 5% to 25% in early S-ICD trials.4–11 In contrast, TV-ICDs rates of inappropriate shock delivery with contemporary programming are <5%.3,36

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Subcutaneous ICD for Sudden Cardiac Death Prevention Table 1: Comparison of Patient Characteristics in the Three Major Trials S-ICD PAS26

PRAETORIAN47

UNTOUCHED45

Region

US

US, Europe

North America, EU

Number of patients (n)

1,637

426 (S-ICD only)

1,116

Age (years)

53 ± 15

63 (median)

56 ± 12

Female sex (%)

31

21

26

Ejection fraction (%)

32 ± 15

30 (median)

26 ± 6

Primary prevention (%)

77

81

100

Heart failure (NYHA class II or higher; %)

74

65

88

BMI (kg/m2)

29.8 ± 7.6

27

30.2 ± 7.3

Hypertension (%)

62

54

71

Diabetes (%)

34

26

33

AF (%)

16

27

13

NYHA = New York Heart Association; S-ICD = subcutaneous ICD.

High shock rates in early S-ICD trials were often a result of T wave oversensing, lead migration, or supraventricular tachycardias (SVTs) at rates in the shock zone where discrimination algorithms are inactive. In a comparison of TV-ICD and S-ICD sensing algorithms for discrimination of arrhythmias induced at implant, the START trial demonstrated equivalent S-ICD detection of ventricular arrhythmias and improved discrimination of supraventricular arrhythmias.25 Two strategies to mitigate inappropriate S-ICD shock occurrence have been the software update with enhanced SVT discrimination and device reprogramming.

Earlier generations of S-ICDs were often programmed with a shock only zone at a rate of 180 BPM. However, the use of a conditional zone, where discriminators are active, in addition to a higher rate shock zone, improved discrimination. The importance of the conditional zone for discrimination was apparent in analyses of prospective trials and is now the standard programming used.37 Developments in programming of both S-ICDs and TV-ICDs have led to reduction in inappropriate shock rates. Studies, such as ADVANCE III and MADIT-RIT, have shown that prolonging detection reduces shock rates in TV-ICDs.36,38 Although detection duration is not programmable in S-ICDs, the charge time of the device and the discrimination algorithms inherently prolong detection. Moreover, improved filtering of electrograms, known as SMART Pass, was developed. This technology has been shown to reduce first inappropriate shock rates by 50%, and risk for all inappropriate shocks by 68%.39 Earlier studies, such as EFFORTLESS and IDE, enrolled younger, healthier patients and demonstrated higher inappropriate shock rates. One of the first studies to enroll a sicker patient cohort with more comorbidities was the Subcutaneous ICD PAS study. This was an FDA-mandated registry of US S-ICD patients. This study demonstrated a complication free rate of 92.0% and an appropriate shock rate of 5.3%.24 Along with the subsequent trials, UNTOUCHED and PRAETORIAN, the PAS study illustrates low complication rates and high success rates of ICD therapy in patients without a pacing indication.24 Furthermore, the inappropriate shock rate has progressively declined from the PRAETORIAN to PAS to the UNTOUCHED trial, which reported the lowest rate of any prior multicenter S-ICD trials. This has been largely because of the development of improved programming and the SMART Pass filter.24,39 Table 1 shows the comparison of baseline characteristics among three of the major clinical trials. Figure 1 shows the comparison of annual inappropriate shock rates between some of the major trials.

Figure 1: Annual Inappropriate Shock Rate Comparison UNTOUCHED45 MADIT-RIT36 PAS24 EFFORTLESS17 PRAETORIAN34 0

2

4

6

8

10

12

Annual IAS rate IAS = inappropriate shock.

Lack of Pacing Ability

One of the major limitations of S-ICDs is the lack of pacemaker capability.

Unfortunately, this limits its use in the advanced heart failure population, as QRS prolongation, which may benefit from CRT, is an important component of therapy for this cohort. According to data from the European Regulatory Trial cohort, one of 55 patients (1.8%) developed an indication for bradycardia pacing over a 5.8-year follow-up period, thus requiring S-ICD explant.40 In this same cohort, two of 55 patients (3.6%) developed symptomatic heart failure and underwent explant of their S-ICD in exchange for a transvenous CRT.40 Pacing in transvenous devices is also used for painless termination of VT. Such ATP is not available in the S-ICD, but explant of the device for this indication is uncommon, probably because of exclusion of patients with known monomorphic VT at rates likely to be pace terminated. This confirms that proper patient selection can minimize the need for subsequent device upgrade for pacing. In contrast, retrospective studies have suggested that many patients with TV-ICDs would be appropriate for S-ICDs.41 Of note, even when bradycardia cardiac pacing requirements develop, there have been small case series which have successfully implemented concurrent use of S-ICDs and transvenous pacemakers, as opposed to S-ICD explant.3 However, this requires careful assessment of crosstalk between devices.42,43 To date, there have not been any large-scale studies to evaluate the safety and efficacy of this approach.

Preoperative Screening

In contrast to TV-ICDs the S-ICD requires preoperative EKG screening, which is largely designed to assess the ratio of R wave and T wave

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Subcutaneous ICD for Sudden Cardiac Death Prevention amplitudes to reduce the incidence of T wave oversensing. This was initially performed manually and could be time consuming. An automated programmer based screening tool has now been developed, which has similar performance to manual screening.44 However, there are little prospective data on the use of this tool in multicenter studies. For instance, only 28% of subjects in the UNTOUCHED study underwent automated screening.45

UNTOUCHED Trial

The UNTOUCHED trial was designed as a multinational, prospective trial to investigate limitations of S-ICDs in a higher-risk population of patients.

Study subjects across 110 sites (>1,110 patients) were enrolled. Those with LV ejection fractions (LVEF) ≤35%, as a result of either ischemic or nonischemic etiologies, were included in the study. Patients with pacing or cardiac resynchronization therapy indications, history of sustained ventricular arrhythmias or New York Heart Association classification.

Patients underwent standard pre-implant screening and the programming of therapy zones was mandated. Specifically, the conditional zone was programmed at 200 BPM and the shock zone at 250 BPM. The primary endpoint for the study was the inappropriate shock free rate at 540 days (18 months), compared with a performance goal of 91.6% derived from the MADIT-RIT cohort.45,46 The performance goal was developed based on results of ICD patients in the active arms of the MADIT-RIT TV-ICD study excluding CRT devices.45,46 At 18 months, the inappropriate shock-free rate was 95.9%, meeting the performance goal of 91.6%. In multivariate models, patients with history of AF (paroxysmal, persistent or permanent), non-ischemic etiology, and those with a lower EF had higher risk of inappropriate shocks. According to regression analysis, predictors of inappropriate shock included history of AF and two-incision implant technique (as opposed to three-incision implant). Moreover, the complication-free rate was 95.8% at 30 days, compared with the performance goal of 93.8%. Despite a cohort with higher LV dysfunction and heart failure, the UNTOUCHED trial outcomes demonstrated the lowest ever inappropriate shock rate compared with prior S-ICD and ICD trials.45,46

PRAETORIAN Trial

The PRAETORIAN trial was a randomized, controlled, multicenter, prospective two-arm trial comparing safety and efficacy of S-ICDs with 1. Freidman D, Parzynski C, Varosy P, et al. Trends and in-hospital outcomes associated with adoption of the subcutaneous implantable cardioverter defibrillator in the United States. JAMA Cardiol 2016;8:900–11. https://doi. org/10.1001/jamacardio.2016.2782; PMID: 27603935.

2. Boston Scientific. Important Medical Device Advisory. 2020. https://www.bostonscientific.com/content/dam/ bostonscientific/quality/dlt/reg-code-228/2020Dec_BSC_ EmblemElectrode3501_PhysLtr_Final.pdf (accessed August 9, 2021).

3. Lewis, G, Gold M. Safety and efficacy of the subcutaneous implantable defibrillator. J Am Coll Cardiol 2016;67:445–54. https://doi.org/10.1016/j.jacc.2015.11.026; PMID: 26821634.

4. Bardy G, Smith W, Hood M. An entirely subcutaneous implantable cardioverter-defibrillator. N Engl J Med 2010;363:36–44. https://doi.org/10.1056/NEJMoa0909545; PMID: 20463331.

5. Abkenari D, Theuns D, Valk S, et al. Clinical experience with a novel subcutaneous implantable defibrillator system in a single center. Clin Res Cardiol 2011;100:737–44. https://doi. org/10.1007/s00392-011-0303-6; PMID: 21416191.

6. Olde Nordkamp L, Abkenair D, Boersma L, et al. The entirely subcutaneous implantable cardioverter-defibrillator: initial clinical experience in a large Dutch cohort. J Am Coll Cardiol 2012;60:1933–9. https://doi.org/10.1016/j.jacc.2012.06.053; PMID: 23062537.

7. Aydin A, Hartel F, Schlüter M, et al. Shock efficacy of

8.

9.

10.

11.

12.

13.

TV-ICDs. The main objective was to assess noninferiority of the S-ICD compared with TV-ICD in terms of inappropriate shocks and major complications among patients with a class I or IIa indication for an ICD and without a pacing indication.47 The study spanned approximately 7 years and included 876 patients. The study population had a median LVEF of 30%. Over a 50-month follow-up period, the incidence of inappropriate shock was higher in the S-ICD group, which was primarily a result of cardiac oversensing. However, this difference was not statistically significant. The rate of complications was higher in the TV-ICD group but again this did not achieve statistical significance so noninferiority was established for the two arms of the study. Lead complications were higher with TV-ICDs. Notably, appropriate ICD shocks were higher in the S-ICD group, as the system is not capable of delivering ATP. In the TV-ICD group, the rate of ATP was higher, and successfully terminated 55% of all treated ventricular arrhythmias.47 With regard to the safety endpoint, lead complications were significantly more common in the TV-ICD arm.

Conclusion

Studies such as PRAETORIAN and UNTOUCHED demonstrate favorable outcomes of S-ICD in a traditional, higher-risk patient population, comparable to that of typical TV-ICD cohorts. The S-ICD was developed to reduce potential complications often associated with TV-ICDs and this was observed in these trials.48–50 Moreover, inappropriate shock rates are now much lower with later generation devices.

Despite the promising results of S-ICD trials, S-ICDs have their own limitations and potential complications. One limitation of S-ICD is the lack of pacing functionality, thus limiting its use in patients with bradycardia, CRT or ATPneeds. Trials of an extravascular ICD with pacing capabilities or leadless pacemakers to communicate with S-ICDs to address these limitations are ongoing. However, battery life is still shorter than for single chamber TV-ICDs. Large prospective trials of the S-ICD show that this device remains safe and effective among more traditional ICD patients for both primary and secondary prevention. The studies support the use of all ICD indicated patients in the absence of pacing indications. In this regard, clinical studies have recently reported a new device capable of pacing the heart from a substernal location, and the use of a leadless pacemaker combined with an S-ICD.51,52

subcutaneous implantable cardioverter-defibrillator for prevention of sudden cardiac death: initial multicenter experience. Circ Arrhythm Electrophysiol 2012;5:913–9. https:// doi.org/10.1161/CIRCEP.112.973339; PMID: 22923274.

Jarman J, Lascelles K, Wong T, et al. Clinical experience of entirely subcutaneous implantable cardioverter-defibrillators in children and adults: cause for caution. Eur Heart J 2012;33:1351–9. https://doi.org/10.1093/eurheartj/ehs017; PMID: 22408031.

Köbe J, Reinke F, Meyer C, et al. Implantation and follow-up of totally subcutaneous versus conventional implantable cardioverter-defibrillators: a multicenter case-control study.

Heart Rhythm 2013;10:29–36. https://doi.org/10.1016/j. hrthm.2012.09.126; PMID: 23032867.

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Circulation 2013;128:944–53. https://doi.org/10.1161/ CIRCULATIONAHA.113.003042; PMID: 23979626.

Jarman J, Todd D. United Kingdom national experience of entirely subcutaneous implantable cardioverter-defibrillator technology: important lessons to learn. Europace 2013;15:1158–65. https://doi.org/10.1093/europace/eut016; PMID: 23449924.

Rowley C, Gold M. Subcutaneous implantable cardioverter defibrillator. Circulation Arrhythm Electrophysiol 2012;5:587–93. https://doi.org/10.1161/CIRCEP.111.964676; PMID: 22715237.

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Food and Drug Administration. Boston Scientific recalls EMBLEM S-ICD Subcutaneous Electrode (Model 3501) due to risk of fractures. https://www.fda.gov/medical-devices/ medical-device-recalls/boston-scientific-recalls-emblem-sicd-subcutaneous-electrode-model-3501-due-risk-fractures (accessed October 1, 2021).

Athan E, Chu V, Tattevin P, et al. Clinical characteristics and outcome of infective endocarditis involving implantable cardiac devices. JAMA 2012;307:1727–35. https://doi. org/10.1001/jama.2012.497; PMID: 22535857.

Wilkoff B, Hess, M, Young J, et al. Differences in tachyarrythmia detection and implantable cardioverter defibrillator therapy by primary or secondary prevention indication in cardiac resynchronization therapy patients.

J Cardiovasc Electrophysiol 2004;15:1002–9. https://doi. org/10.1046/j.1540-8167.2004.03625.x; PMID: 15363071.

Lambiase P, Barr D, Theuns D, et al. Worldwide experience with a totally subcutaneous implantable defibrillator: early results from the EFFORTLESS S-ICD Registry. Eur Heart J 2014;35:1657–65. https://doi.org/10.1093/eurheartj/ehu112; PMID: 24670710.

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Subcutaneous ICD for Sudden Cardiac Death Prevention ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 2018;138:e272–391. https://doi. org/10.1161/CIR.0000000000000549; PMID: 29084731.

19. Baalman S, Quast A, Brouwer T, Knops RE. An overview of clinical outcomes in transvenous and subcutaneous ICD patients. Curr Cardiol Rep 2018;20:72. https://doi.org/10.1007/ s11886-018-1021-8; PMID: 29992422.

20. Burke M, Gold M, Knight B, et al. Safety and efficacy of the totally subcutaneous implantable defibrillator: 2 year results from a pooled analysis of the IDE study and EFFORTLESS registry. J Am Coll Cariol 2015;65:1605–15. https://doi. org/10.1016/j.jacc.2015.02.047; PMID: 25908064.

21. Winter J, Siekiera M, Shin D, et al. Intermuscular technique for implantation of the subcutaneous implantable cardioverter defibrillator: long-term performance and complications. Europace 2017;19:2036–41. https://doi. org/10.1093/europace/euw297; PMID: 28007749.

22. Knops RE, Olde Nordkamp LRA, Groot JR, et al. Two-incision technique for implantation of subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2013;10:1240–3. https://doi.org/10.1016/j.hrthm.2013.05016; PMID: 23707489.

23. Friedman D, Parzynski C, Heist E, et al. Ventricular fibrillation conversion testing after implantation of a subcutaneous implantable cardioverter defibrillator. Circulation 2018;137:2463–77. https://doi.org/10.1161/ circulationaha.117.032167; PMID: 29463509.

24. Burke, M, Aasbo, J, El-Chami M, et al. 1-year prospective evaluation of clinical outcomes and shocks: the subcutaneous ICD post approval study. JACC Clin Electrophysiol 2020;6:1537–50. https://doi.org/10.1016/j. jacep.2020.05.036; PMID: 33213814.

25. Gold, M, Theuns, D, Knight B, et al. Head-to-head comparison of arrhythmia discrimination performance of subcutaneous and transvenous ICD arrhythmia detection algorithms: the START study. J Cardiovasc Electrophysiol 2012;23:359–66. https://doi.org/10.1111/j.1540-8167.

2011.02199.x; PMID: 22035049.

26. Gold M, Aasbo J, El-Chami M, et al. Subcutaneous implantable cardioverter-defibrillator post-approval study: clinical characteristics and perioperative results. Heart Rhythm 2017;14:1456–63. https://doi.org/10.1016/j. hrthm.2017.05.016; PMID: 28502872.

27. Do K, Chang P, Konecny T, et al. Predictors of elevated defibrillation threshold with the subcutaneous implantable cardioverter-defibrillator. J Innov Card Rhythm Manag 2017;12:2920–9. https://doi.org/10.19102/icrm.2017.081203; PMID: 32494435.

28. Roberts B, Hood R, Saba M, et al. Defibrillation threshold testing in patients with hypertrophic cardiomyopathy. Pacing Clin Electrophysiol 2010;33:1342–6. https://doi.org/10.1111/ j.1540-8159.2010.02843.x; PMID: 20663074.

29. Quin EM, Cuoco FA, Forcina MS, et al. Defibrillation thresholds in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2011;22:569–72. https://doi.org/10.1111/ j.1540-8167.2010.01943.x; PMID: 21091965.

30. Lambiase P, Gold M, Hood M, et al. Evaluation of subcutaneous ICD early performance in hypertrophic

cardiomyopathy from the pooled EFFORTLESS and IDE cohorts. Heart Rhythm 2016;13:1066–74. https://doi. org/10.1016/j.hrthm.2016.01.001; PMID: 26767422.

31. Francia P, Adduci C, Semprini L, et al. Prognostic implications of defibrillation threshold testing in patients with hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2017;28:103–8. https://doi.org/10.1111/jce.131121; PMID: 27862589.

32. Heist EK, Belalcazar A, Stahl W, et al. Determinants of subcutaneous implantable cardioverter-defibrillator efficacy: a computer modeling study. JACC Clin Electrophysiol 2017;4:405–14. https://doi.org/10.1016/j.jacep.2016.10.016; PMID: 29759454.

33. Amin AK, Gold MR, Burke M, et al. Factors associated with high voltage impedance and subcutaneous implantable defibrillator ventricular fibrillation conversion success.

Circulation Arrhythm Electrophysiol 2019;12:e006665. https:// doi.org/10.1161/CIRCEP.118.006665; PMID: 30917689.

34. Francia P, Biffi M, Adduci C, et al. Implantation technique and optimal subcutaneous defibrillator chest position: a PRAETORIAN score-based study. Europace 2020;12:1822–9. https://doi.org/10.1093/europace/euaa231; PMID: 33118017.

35. Gold M, Higgins S, Klein R, et al. Efficacy and temporal stability of reduced safety margins for ventricular defibrillation. Primary results from the Low Energy Safety Study (LESS). Circulation 2002;105:2043–8. https://doi. org/10.1161/01.cir.0000015508.59749.f5; PMID: 11980683.

36. Moss A, Schuger C, Beck C, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl Med 2012;367:2275–83. https://doi.org/10.1056/NEJMoa1211107; PMID: 23131066.

37. Gold M, Weiss R, Theuns D, et al. Use of a discrimination algorithm to reduce inappropriate shocks with a subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2014;11:1352–8. https://doi.org/10.1016/j. hrthm.2014.04.012; PMID: 24732366.

38. Gasparini M, Proclemer A, Klersy C, et al. Effect of longdetection interval vs standard detection interval for implantable cardioverter-defibrillators on antitachycardia pacing and shock delivery: the ADVANCE III randomized clinical trial. JAMA 2013;309:1903–11. https://doi.org/10.1001/ jama.2013.4598; PMID: 23652522.

39. Theuns D, Brouwer T, Jones P, et al. Prospective blinded evaluation of a novel sensing methodology designed to reduce inappropriate shocks by the subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2018;15:1515–22. https://doi.org/10.1016/j.hrthm.2018.05.011; PMID: 29758404.

40. Theuns D, Crozier I, Barr C, et al. Longevity of the subcutaneous implantable defibrillator: long term follow up of the European Regulatory Trial Cohort. Circ Arrhythm Electrophysiol 2015;8:1159–63. https://doi.org/10.1161/ CIRCEP.115.002953; PMID: 26148819.

41. De Bie MK, Thijssen J, van Rees JB, et al. Suitability for subcutaneous defibrillator implantation: results based on data from routine clinical practice. Heart 2013;99:1018–23. https://doi.org/10.1136/heartjnl-2012-303349; PMID: 23704324.

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42. Porterfield D, DiMarco J, Mason P. Effectiveness of implantation of a subcutaneous implantable cardioverterdefibrillator in a patient with complete heart block and a pacemaker. Am J Cardiol 2015;115:276–8. https://doi. org/10.1016/j.amjcard.2014.10.036; PMID: 25465940.

43. Kuschyk J, Stach K, Tülümen E, et al. Subcutaneous implantable cardioverter-defibrillator: first single-center experience with other cardiac implantable electronic devices. Heart Rhythm 2015;12:2230–8. https://doi. org/10.1016/j.hrthm.2015.06.022; PMID: 26073595.

44. Sakhi R, Yap SC, Michels M, et al. Evaluation of a novel automatic screening tool for determining eligibility for a subcutaneous implantable cardioverter-defibrillator. Intl J Cardiology 2018;272:97–101. https://doi.org/10.1016/j. ijcard.2018.07.037; PMID: 30005832.

45. Gold M, Pier L Mikhael F, et al. Primary results from understanding outcomes with S-ICD in primary prevention patients with low ejection fraction (UNTOUCHED) trial.

Circulation 2021;143:7–17. https://doi.org/10.1161/ CIRCULATIONAHA.120.048748; PMID: 33073614.

46. Gold M, Knops R, Burke M, et al. The design of the understanding outcomes with the S-ICD in primary prevention patients with low EF study (UNTOUCHED). Pacing Clin Eletrophysiol 2017;40:1–8. https://doi.org/10.1111/ pace.12994; PMID: 27943348.

47. Olde Nordkamp L, Knops R, Bardy G, et al. Rational and design of the PRAETORIAN trial: a Prospective, RAndomizEd comparison of subcutaneous and tRansvenous ImplANtable cardioverter-defibrillator therapy. Am Heart J 2012;163:753– 60. https://doi.org/10.1016/j.ahj.2012.02.012; PMID: 22607851.

48. Van Rees J, de Bie M, Thijssen J, et al. Implantation-related complications of implantable cardioverter-defibrillators and cardiac resynchronization therapy devices: a systematic review of randomized clinical trials. J Am Coll Cariol 2011;58:995–1000. https://doi.org/10.1016/j.jacc.2011.06.007; PMID: 21867832.

49. Ezzat V, Lee V, Ahsan S, et al. A systematic review of ICD complications in randomized controlled trials versus registries: is our ‘real-world’ data an underestimation? Open Heart 2015;2:e000198. https://doi.org/10.1136/ openhrt-2014-000198; PMID: 25745566.

50. Kleemann T, Becker T, Doenges K, et al. Annual rate of transvenous defibrillation lead defects in implantable cardioverter-defibrillators over a period of >10 years.

Circulation 2007;115:2474–80. https://doi.org/10.1161/ CIRCULATIONAHA.106.663807; PMID: 17470696.

51. Crozier I, Haqqani H, Kotschet E, et al. First-in-human chronic implant experience of substernal extravascular implantable cardioverter defibrillator. J Am Coll Cardiol EP 2020;6:1537–50. https://doi.org/10.1016/j.jacep.2020.

05.029; PMID: 33213813.

52. Tjong F, Brouwer T, Koop B, et al. Acute and 3-month performance of a communicating leadless antitachycardia pacemaker and subcutaneous implantable defibrillator. J Am Coll Cardiol EP 2019;3:1487–98. https://doi.org/10.1016/j. jacep.2017.04.002; PMID: 29759829.

Structural Intervention

How Old is Too Old? Closure of Patent Foramen Ovale in Older Patients Carlos Vazquez-Sosa, MD,1 Stacey D Clegg, MD, FACC, FSCAI,1,2 and James C Blankenship, MD, MHCM, MACC, MSCAI,

1

1. University of New Mexico Health Science Center, Albuquerque, NM; 2. New Mexico Veterans Administration Medical Center, Albuquerque, NM

Abstract

Percutaneous closure of a patent foramen ovale (PFO) reduces the risk of recurrent cryptogenic stroke specifically in younger patients. The three randomized controlled trials that led to the widespread adoption of PFO closure excluded patients over the age of 60 years. Older patients frequently have other cardiac and vascular conditions that are common risk factors for stroke, whereas paradoxical embolism through a PFO is relatively rare. Younger patients theoretically benefit the most from closure due to longer lifetime exposure risk and absence of other traditional risk factors. PFO in older patients with cryptogenic strokes is often encountered in clinical practice, making up an increasing number of cardiology referrals, yet cardiologists lack guidelines and evaluation tools for these patients. This review explores the history of PFO closure – emphasizing data in older adults – and discusses the evaluation and treatment of older people with cryptogenic stroke and PFO while further trials in this important population are awaited.

Keywords

Patent foramen ovale, closure, cryptogenic stroke, elderly, risk assessment.

Disclosure: The authors have no conflicts of interest to declare.

Received: December 2, 2020 Accepted: April 20, 2021 Citation: US Cardiology Review 2021;15:e20. DOI: https://doi.org/10.15420/usc.2020.40 Correspondence: Stacey Clegg, Division of Cardiology, 1501 San Pedro Dr SE, Albuquerque, NM 87107. E: stacey.clegg@va.gov Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Cryptogenic stroke is defined as a stroke without definitive etiology, not attributed to cerebral atherosclerotic disease, cardiac arrhythmia or structural cardiac abnormalities. Patent foramen ovale (PFO) has been shown to be a route by which paradoxical embolus can cause strokes.

While PFO is found in approximately 25% of the general population, PFOs are significantly more common among patients with cryptogenic stroke, with a prevalence of up to 40%.1,2 Historically, closure of PFO to reduce the risk of stroke due to paradoxical embolism has been controversial with conflicting data and conflicting expert opinion.

However, in the last 3–4 years, several large randomized trials have solidified PFO closure as an option for young patients with cryptogenic stroke and a PFO.3–5 The RESPECT-LT trial, which extended follow-up to a median of 5.9 years, linked PFO closure to a significant 45% reduction in risk for stroke compared with medical therapy alone. This pivotal trial led to the Food and Drug Administration (FDA) approval of the Amplatzer PFO Occluder (Abbott) device in the US. The mean age in RESPECT-LT was 46 years, with patients >60 years excluded from enrollment.3 Similarly, the mean age in the CLOSE and REDUCE trials was 43 and 45 years, respectively.4–6

lifetime risk of recurrent stroke. This fact, in combination with the data from the three main randomized controlled trials – RESPECT-LT, CLOSE and REDUCE and the several meta-analyses that followed – has shifted societal guidelines towards recommending PFO closure in younger patients with cryptogenic stroke.7–12 This raises questions. What is the definition of young? Is there an age cut off beyond which PFO closure should not be offered? Is there additional evaluation that should be considered in older patients before considering closure? As the population ages and PFOs are frequently discovered during cardiac evaluations, it is not surprising that older patients with more comorbidities are being referred to cardiologists for evaluation and consideration of PFO closure.

This review will explore the history of PFO closure, emphasizing data in older adults. We propose a practical algorithm for evaluation and treatment of older adults with cryptogenic stroke and PFO while we await additional trials in this important population.

History of Patent Foramen Ovale Closure

The foramen ovale is a cardiac shunt present in the embryologic phase to bypass the lungs. This passageway normally closes at birth, once the lungs are functional and the left atrial pressure surpasses the right atrial pressure.13 However, this connection between the atria persists in approximately one in four adults.14 In general, most patients with PFO remain asymptomatic throughout their lifetime. However, it has been demonstrated that PFO is associated with paradoxical embolism and can lead to cryptogenic stroke and arterial emboli when a right to left shunt is present either transiently or permanently.1 PFO closure to protect against paradoxical emboli was first proposed in 1992.15 Multiple devices have been designed for the percutaneous closure of PFOs. Nevertheless, until

Lack of data in older patients has hindered the development of clinical guidelines for PFO closure. In general, older patients are at higher risk for stroke based on vascular risk factors alone, and the presence of a PFO is often an incidental finding. Conversely, older patients may also have additional risk factors that predispose to paradoxical embolism, such as acquired hypercoagulable states and immobility leading to venous thromboembolism. Younger patients with traditionally fewer vascular risk factors have a higher probability of a true cryptogenic stroke, and a longer

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PFO Closure in Older Adults Table 1: Clinical Comparison of Patients with Cryptogenic Stroke or Transient Ischemic Attack and Difficulty in Using the RoPE Score Alone in Older Patients Clinical Presentation

Risk Factors

RoPE Score

Chance That Stroke is Due to PFO (%)

2-year Risk of recurrence of TIA or Stroke (%)

38-year-old patient with TIA

None

8

84

6

52-year-old patient with TIA

None

6

62

8

66-year-old patient with TIA

None

5

34

7

52-year-old patient with TIA

Hypertension and diabetes

3

0

20

66-year-old patient with TIA

Hypertension and diabetes

2

0

20

The chance that the PFO is causally related to stroke drops significantly as the RoPE score decreases. The 38-, 52-, and 66-year-old patients have no clinical risk factors, but the chance that the PFO is the culprit for stroke drops from 84% to 34%. Paradoxically, the risk of recurrent stroke is higher in the older patients. The RoPE score is useful for predicting the biologic mechanism of stroke but must be used in conjunction with other data to determine whether or not to close the PFO. RoPE = Risk of Paradoxical Embolism; TIA = transient ischemic attack.

Table 2: Major Trials of Patent Foramen Ovale Closure Versus Medical Therapy Trial Names

Arms

n

Age (Years), Mean ± SD

Mean Follow-up (Years)

Conclusions (Closure Superior to Medical Therapy)

CLOSURE I 201237

Closure Medical therapy

447 462

46.3 ± 9.6 45.7 ± 9.1

2

No

PC 201338

Closure Medical therapy

204 210

44.3 ± 10.2 44.6 ± 10.1

4.1

No

RESPECT 201339

Closure Medical therapy

499 481

45.7 ± 9.7 46.2 ± 10

2.6

No

RESPECT (long-term follow-up) 20173

Closure Medical therapy

499 481

45.7 ± 9.7 46.2 ± 10

5.9

Yes

CLOSE 20174

Closure Medical therapy

238 235

42.9 ± 10.1 43.8 ± 10.5

5.3

Yes

REDUCE 20175

Closure Medical therapy

441 223

45.4 ± 9.3 44.8 ± 9.6

3.2

Yes

DEFENSE-PFO 201818

Closure Medical therapy

60 60

49 ± 15 54 ± 12

2.8

Yes

recently it was unclear whether PFO closure offers any benefits compared to medical therapy.

Before 2016, randomized controlled trials produced contradictory data and lacked long-term follow-up. However, the results of three important randomized controlled trials published in 2017 changed the direction of PFO management. RESPECT-LT, CLOSE and REDUCE included follow-up of 3.2–5.9 years and all three trials showed significant reduction in risk of recurrent stroke in the closure groups when compared with medical therapy (Table 2).3–6 The RESPECT-LT trial led to the FDA approval of the Amplatzer PFO Occluder device in the US for patients between the ages of 18–60 years with a PFO and cryptogenic stroke. Subsequently the FDA has approved closure with the Gore Cardioform Septal Occluder (Gore). In our experience, since 2016 the number of referrals for PFO closure has dramatically increased, including patients over 60 years of age.

In 2013, the RoPE study proposed a scoring method to stratify the likelihood of the index stroke being PFO-related as opposed to the PFO being a bystander finding.16 The RoPE score uses just six clinical variables (hypertension, diabetes, smoking status, prior history of cerebral ischemia, imaging evidence of cortical infarct, and age) to predict the likelihood that the stroke is due to PFO as well as risk of recurrent stroke/transient ischaemic attack (TIA). Younger patients receive more points in the RoPE score, with additional points given for the clinical variables. A high RoPE score suggests the PFO is more likely to be the cause of stroke. While this is helpful in categorizing strokes as likely cryptogenic versus PFO-related, caution is warranted when using the score. The RoPE score does not provide a cut-off value for recommending PFO closure, nor does it provide guidance on whether to treat patients with PFO closure or medical therapy. It also does not include some nuanced variables that might sway decision-making on an individual basis such as anatomical considerations (long tunnel, large shunt, hypermobile septum) or specific AF risk factors (heart failure, left atrial enlargement). While it is a helpful tool it cannot be used by itself to decide treatment. Table 1 outlines several clinical scenarios and associated RoPE scores to illustrate the complexity of the RoPE score in older patients.

Patent Foramen Ovale and Cryptogenic Stroke in Patients Aged >60 Years

The prevalence of PFO is almost three times higher in elderly patients with cryptogenic strokes compared with patients of the same age with a known cause of stroke, suggesting that elderly patients may derive benefit from PFO closure.17 Although the RESPECT-LT, CLOSE and REDUCE trials established the superiority of PFO closure versus medical therapy for preventing recurrent ischemic stroke, none of them included patients older than 60 years. While a randomized controlled trial comparing patients aged >60 years with PFO closure versus medical therapy has not

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PFO Closure in Older Adults been performed, a few recent small studies suggest that PFO closure in the elderly is safe and may decrease the risk of recurrent stroke. The DEFENSE-PFO trial included patients older than 55 years and demonstrated positive results for PFO closure compared with medical therapy alone, although the mean age was only 51.8 years and total enrollment only 120 patients with 2 years follow-up. The DEFENSE-PFO results support PFO closure over medical therapy in middle-aged patients with high-risk anatomic features including PFO size, atrial septal hypermobility, and atrial septal aneurysm.18

using the Valsalva maneuver to promote right to left shunting.25 Transthoracic echocardiography (TTE) should be used as the first imaging modality at any age to rule out intra-cardiac shunting, including possible cardiac abnormalities that could be associated with an increased risk for paradoxical emboli (e.g. atrial septal aneurysm). In addition, a TTE provides information to rule out structural heart diseases such as left ventricular (LV) dysfunction or valvular heart disease that might predispose to left sided thrombus or an increased risk of AF. LV dysfunction – even in the absence of LV thrombus – in a patient aged >55 years, strongly suggests a non-PFO mechanism of stroke.26,27

It is unclear to what extent elderly patients derive benefit from PFO closure.

Small retrospective studies have not provided definitive answers and – similar to DEFENSE-PFO – they have limited follow-up duration and number of enrollees aged >55, with even fewer enrollees aged >65. For example, one single-center retrospective cohort study identified 14 elderly patients (mean age 75.2 years) with a high-risk PFO and prior cerebrovascular event who underwent PFO closure. After following up for 2.6 ± 1.8 years, none of them experienced recurrent cerebrovascular events and the complications were not higher than expected.19 While this was a positive result in this very advanced age group, the small sample size and short follow-up duration are limitations. Another contemporary series with a longer mean follow-up period (4.5 years) included 458 patients who underwent PFO closure for cryptogenic cerebral ischemia.20 The 151 patients who were older than 55 years had a higher risk of recurrent ischemia, with age being the only independent predictor. Most events were more than 3 years out from the procedure and therefore not associated with peri-procedural complications.

Neither group had significant residual shunting that would account for recurrent events being higher due to PFO-related mechanisms, and complexity of the PFO anatomy was not different between the two groups.

The authors concluded that recurrent events were most likely associated with underlying conditions in the older population as might be predicted from the RoPE score.

Transesophageal echocardiography (TEE) has a higher sensitivity for and provides better visualization of the PFO, especially defining the direction of the flow through the shunt and distinguishing it from pulmonary arteriovenous shunting. Therefore, if the TTE is negative, we recommend performing a TEE if there is high suspicion of a PFO.28,29 Transcranial Doppler can detect right to left shunt by identifying bubbles from agitated contrast saline in arteries that supply perfusion to the brain. However, the limitation of this modality is that it does not provide anatomic characteristics or location of the shunt.30 Although less sensitive than TEE, other potential modalities that can detect a PFO are cardiovascular MRI and multidetector CT. TEE can also visualize the aorta and provide information on aortic atheroma. While this finding may confirm a diagnosis of vascular disease, it should not by itself preclude closure of a PFO and should be treated similarly to stable coronary artery or carotid artery disease.

Initial Neurologic Evaluation

Patients referred with cryptogenic stroke should have already had routine brain imaging with MRI as well as a cerebrovascular evaluation with magnetic resonance angiography (MRA) or CT angiography (CTA) or carotid duplex. Cortical defects or multiple areas of infarct point to an embolic source of stroke. Lacunar strokes may be caused by small emboli but in general are thought to be non-embolic and not an indication for PFO closure (Figure 1).31

Proponents of PFO closure point out that the procedure is safe and low risk, but without randomized clinical trial data in older patients we can only weigh up the clinical variables, vascular risk factors, lifestyle and life expectancy and make an appropriate judgement for each individual patient.

Carotid duplex and MRA/CTA should also be first-line studies, as carotid artery dissection or atherosclerotic lesions are a common cause of TIA and embolic stroke. Carotid disease with evidence of ≥70% stenosis and an ipsilateral associated cortical imaging defect should prompt further evaluation by a vascular surgeon and neurologist rather than PFO closure.

Stable carotid disease ≥70% should not in itself exclude PFO closure, but increases the likelihood that a stroke is unrelated to the PFO.

Evaluation and Treatment Considerations

Early guidelines for the closure of PFO after stroke were written before 2017, prior to publication of REDUCE, CLOSE and DEFENSE-PFO trials that demonstrated positive results in favor of PFO closure.21,22 However, two newer guidelines have been released: a position paper from the European Heart Journal in 2018 and an advisory update from the American Academy of Neurology in 2020.23,24 There are some differences between these guidelines. Nevertheless, both concur that PFO closure should be considered in elderly patients with cryptogenic stroke and no evident alternative mechanism other than paradoxical embolization. Neither guideline provides a specific age cut off or a combination of risk factors that would preclude PFO closure or guide further workup. The following sections outline important considerations for the cardiologist when evaluating older patients with possible PFO-related stroke.

Monitoring for AF

Extended cardiac monitoring in patients at high risk for AF is recommended.

European guidelines suggest that patients aged 55–65 years (level of evidence [LOE] C) or >65 years (LOE B) with a high risk for AF should be monitored for 6 months with an implantable cardiac monitor.24 The 2019 Focused Update of the American College of Cardiology/American Heart Association/Heart Rhythm Society 2014 Guidelines for the Management of Patients with AF recommend extended cardiac monitoring for any patient older than 40 years with suspected AF.32 The American Academy of Neurology recommends at least 28 days of cardiac monitoring in patients who are being considered for PFO closure (LOE B).23

Initial Cardiac Evaluation

PFO with a right to left shunt can be detected by using ultrasound with color Doppler imaging in combination with agitated saline contrast and maneuvers like Valsalva that transiently increase right atrial pressure. The American Society of Echocardiography defines a positive bubble study as the appearance of microbubbles in the left atrium within three to six cardiac beats of opacification of the right atrium either at baseline or by

The type and length of AF monitoring remain controversial. The European position paper on the management of patients with PFO suggests that implantable cardiac monitoring (ICM) is useful in patients over 65 and can

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PFO Closure in Older Adults Figure 1: A Practical Approach to Patent Foramen Ovale and Cryptogenic Stroke in Patients >55 Years Old

evidence of left atrial enlargement using the P-wave terminal force in lead V1 can be a marker of left atrial abnormality and has been associated with cardiogenic stroke.33 This finding might point to an atrial pathology rather than paradoxical embolism as the cause of the stroke. ECG findings data should be taken in conjunction with the associated imaging, clinical history and RoPE score.

Patient with a cryptogenic TIA/CVA and age >55 years

Anatomical Considerations

Lacunar CVA Yes

Multiple studies have associated anatomical characteristics of PFOs with initial and recurrent paradoxical embolism and stroke. These include large PFO with an opening of >3 mm and large right to left shunt. An atrial septal aneurysm defined as atrial septal bowing ≥10 mm has been associated with a higher risk for cryptogenic strokes, although this finding was contradicted by the Patent Foramen Ovale in Cryptogenic Stroke Study, which demonstrated no association between the presence of PFO and atrial septal aneurysm.34 Large eustachian valves and/or Chiari networks may contribute to paradoxical embolism by diverting blood from the inferior vena cava to the interatrial septum.35 While the role of highrisk anatomic features in decision making is not clear, we suggest that these findings be used in tandem with other patient-specific risk factors and features to help determine the need for PFO closure.

No

Low probability for PFO-related CVA

Known AF or prothrombotic state?

Yes

No

Low risk for paradoxical embolism

TTE/TCD and/or TEE Yes Evidence of PFO Yes

No

Structural heart disease (LV dysfunction, severe valvular disease) No

Multidisciplinary Evaluation

No further workup

All patients who are considered for PFO closure should be evaluated by a multi-disciplinary team, including a neurologist and a cardiologist, in particular the older patient with evidence of vascular disease. The input of a neuroimaging expert should be considered given that it is important to determine if ischemic strokes are more likely embolic or due to intrinsic vascular disease and to help interpret unusual findings in the cerebral vasculature. PFO-related strokes are often associated with different vascular territories. For example, patients with a PFO and a history of cryptogenic stroke more often have posterior circulation involvement, whereas patients with other comorbidities such as hypertension and left atrial cardiomyopathy had involvement of multiple vascular territories.

Patients with carotid plaque and dyslipidemia more often had anterior vascular territory strokes.36

Yes

Cardiac monitor ≥6 months to detect AF

Yes

No High risk features?

- Large size (>3 mm) - Large right to left shunt - Prominent Eustachian valve or Chiari network - Hypermobility of the septum during Valsalva - Concurrent atrial septal aneurysm Yes

Consider PFO closure

No

Risk factors for venous thromboembolism such as cancer or hypercoagulable disorders need to be considered and in cases of complex hypercoagulable disorders a hematologist should be part of the multidisciplinary team. Primary care physicians can provide input regarding patient specific factors (including frailty and life expectancy) that shape the risk-to-benefit ratio.

Consider medical therapy

CVA = cerebrovascular accident; LV = left ventricular; PFO = patent foramen ovale; TCD = transcranial Doppler; TEE = transesophageal echocardiography; TIA = transient ischemic attack; TTE = transthoracic echocardiography.

Conclusion

be considered for those under 55 and at high risk for AF, where high risk features include uncontrolled hypertension, structural heart disease such as LV hypertrophy or left atrial enlargement, uncontrolled diabetes or congestive heart failure.24 Considering all of these documents, as well as the epidemiological burden of AF in people older than 55 years versus those aged 40–55, we propose an algorithm that includes the use of extended intracardiac monitoring for at least 6 months to rule out AF prior to the PFO closure in patients over the age of 55 years (Figure 1). After 6 months, these patients should have ICM continued for the full battery life of the monitor, given the possibility of a late recurrent paroxysmal AF. Importantly, the presence of short bursts of AF might not exclude the need for PFO closure, especially if the PFO has anatomical high-risk features.

In addition to the more complex intracardiac monitoring, a routine 12-lead ECG should always be performed as part of the initial evaluation. ECG

In an age of patient-centered care and with the available data, we should not exclude patients over 55 – or even over 65 years – from PFO closure in the setting of cryptogenic stroke. While a low RoPE score may suggest that the PFO is not the causal mechanism of stroke, a low RoPE score is not a contraindication to closure. PFO closure is a relatively low-risk procedure, and patient selection and shared decision making are critical.

Careful multi-specialty evaluation is important, including long-term cardiac monitoring specifically looking for occult AF. A large size and highrisk morphology of the PFO may also influence a decision to perform closure. Trial data in older patients is limited and additional trials are needed to assess the benefits of PFO closure as our population ages and stroke remains a major cause of morbidity and mortality for people over the age of 60 years.

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PFO Closure in Older Adults 1. Di Tullio M, Sacco RL, Gopal A, et al. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 1992;117:461–5. https://doi.org/10.7326/0003-4819-117-6-461; PMID: 1503349.

2. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988;318:1148–52. https://doi.org/10.1056/ NEJM198805053181802; PMID: 3362165.

3. Saver JL, Carroll JD, Thaler DE. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017;377:1022–32. https://doi. org/10.1056/NEJMoa1610057; PMID: 28902590.

4. Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017;377:1011–21. https://doi.org/10.1056/ NEJMoa1705915; PMID: 28902593.

5. Søndergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke.

N Engl J Med 2017;377:1033–42. https://doi.org/10.1056/ NEJMoa1707404; PMID: 28902580.

6. Wiktor DM, Carroll JD. The case for selective patent foramen ovale closure after cryptogenic stroke. Circ Cardiovasc Interv 2018;11:e004152. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.004152; PMID: 29870380.

7. Ntaious G, Papavasileiou V, Sagris D, et al. Closure of patient foramen ovale versus medical therapy in patients with cryptogenic stroke or transient ischemic attack: updated systematic review and meta-analysis. Stroke 2018;49:412–8. https://doi.org/10.1161/ STROKEAHA.117.020030; PMID: 29335335.

8. Stortecky S, Costa BR, Mattle HP, et al. Percutaneous closure of patent foramen ovale in patients with cryptogenic embolism: a network meta-analysis. Eur Heart J 2015;36:120–8. https://doi.org/10.1093/eurheartj/ehu292; PMID: 25112661.

9. Nasir UB, Qureshi WT, Jogu H, et al. Updated meta-analysis of closure of patent foramen ovale versus medical therapy after cryptogenic stroke. Cardiovasc Revasc Med 2019;20:187–93. https://doi.org/10.1016/j.carrev.2018.06.001; PMID: 30905408.

10. Agarwal S, Bajaj NS, Kumbhani DJ, et al. Meta-analysis of transcatheter closure versus medical therapy for patent foramen ovale in prevention of recurrent neurological events after presumed paradoxical embolism. JACC Cardiovasc Interv 2012;5:777–89. https://doi.org/10.1016/j. jcin.2012.02.021; PMID: 22814784.

11. Messé SR, Gronseth GS, Kent DM, et al. Practice advisory update summary: Patent foramen ovale and secondary stroke prevention: Report of the Guideline Subcommittee of the American Academy of Neurology. Neurology 2020;94:876–85. https://doi.org/10.1212/ WNL.0000000000009443; PMID: 32350058.

12. Horlick E, Kavinsky CJ, Amin Z, et al. SCAI expert consensus statement on operator and institutional requirements for PFO closure for secondary prevention of paradoxical embolic stroke. Catheter Cardiovasc Interv 2019;93:859-74. https://doi.org/10.1002/ccd.28111; PMID: 30896894.

13. Sadler TW. Langman’s Essential Medical Embryology.

Philadelphia, PA: Lippincott Williams and Wilkins, 2004.

14. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc

1984;59:17–20. https://doi.org/10.1016/S00256196(12)60336-X; PMID: 6694427.

15. Bridges ND, Hellenbrand W, Latson L, et al. Transcatheter closure of patent foramen ovale after presumed paradoxical embolism. Circulation 1992;86:1902–8. https://doi. org/10.1161/01.CIR.86.6.1902; PMID: 1451261.

16. Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013;81:619–25. https://doi. org/10.1212/WNL.0b013e3182a08d59; PMID: 23864310.

17. Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007;357:2262–8. https://doi.org/10.1056/NEJMoa071422; PMID: 18046029.

18. Lee PH, Song JK, Kim JS, et al. Cryptogenic stroke and high-risk patent foramen ovale: The DEFENSE-PFO trial. J Am Coll Cardiol 2018;71:2335–42. https://doi.org/10.1016/j. jacc.2018.02.046; PMID: 29544871.

19. Takafuji H, Hosokawa S, Ogura R, Hasa Y. Percutaneous transcatheter closure of high-risk patent foramen ovale in the elderly. Heart Vessels 2019;34:1657–62. https://doi. org/10.1007/s00380-019-01379-0; PMID: 30868214.

20. Scacciatella P, Meynet I, Presbitero P, et al. Recurrent cerebral ischemia after patent foramen ovale percutaneous closure in older patients: a two-center registry study: PFO Closure in Older Patients. Catheter Cardiovasc Interv 2016;87:508–14. https://doi.org/10.1002/ccd.26053; PMID: 26106024.

21. Lansberg MG, O’Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl 2):e601S–36. https://doi.org/10.1378/chest.141.4.1129b; PMID: 22315273.

22. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:2160–236. https://doi.org/10.1161/ STR.0000000000000024; PMID: 24788967.

23. Messé SR, Gronseth GS, Kent DM, et al. Practice advisory update summary: patent foramen ovale and secondary stroke prevention. Report of the Guideline Subcommittee of the American Academy of Neurology. Neurology 2020;94:876–85. https://doi.org/10.1212/ WNL.0000000000009443; PMID: 32350058.

24. Pristipino C, Sievert H, D’Ascenzo F, et al. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. Eur Heart J 2019;40:3182–95. https://doi. org/10.1093/eurheartj/ehy649; PMID: 30358849.

25. Silvestry FE, Cohen MS, Armsby LB, et al. Guidelines for the echocardiographic assessment of atrial septal defect and patent foramen ovale: from the American Society of Echocardiography and Society for Cardiac Angiography and Interventions. J Am Soc Echocardiogr 2015;28:910–58. https:// doi.org/10.1016/j.echo.2015.05.015; PMID: 26239900.

26. Woods TD, Patel A. A critical review of patent foramen ovale detection using saline contrast echocardiography: when bubbles lie. J Am Soc Echocardiogr 2006;19:215–22. https:// doi.org/10.1016/j.echo.2005.09.023; PMID: 16455428.

27. Gazzaniga P, Buscarini E, Leandro G, et al. Contrast

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echocardiography for pulmonary arteriovenous malformations screening: does any bubble matter? Eur J Echocardiogr 2009;10:513–8. https://doi.org/10.1093/ ejechocard/jen317; PMID: 19091794.

28. Schneider B, Zienkiewicz T, Jansen V, et al. Diagnosis of patent foramen ovale by transesophageal echocardiography and correlation with autopsy findings. Am J Cardiol 1996;77:1202–9. https://doi.org/10.1016/S00029149(96)00163-4; PMID: 8651096.

29. Pearson AC, Labovitz AJ, Tatineni S, Gomez, CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Coll Cardiol 1991;17:66–72. https:// doi.org/10.1016/0735-1097(91)90705-E; PMID: 1987242.

30. Droste DW, Lakemeier S, Wichter T, et al. Optimizing the technique of contrast transcranial Doppler ultrasound in the detection of right-to-left shunts. Stroke 2002;33:2211–6. https://doi.org/10.1161/01.STR.0000027884.03365.AC; PMID: 12215589.

31. Ay H, Oliveira-Filho J, Buonanno FS, et al. Diffusionweighted imaging identifies a subset of lacunar infarction associated with embolic source. Stroke 1999;30:2644–50. https://doi.org/10.1161/01.STR.30.12.2644; PMID: 10582991.

32. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2019;16:e66–93. https://doi.org/10.1016/j.hrthm.2019.01.024; PMID: 30703530.

33. Lattanzi S, Cagnetti C, Pulcini A, et al. The P-wave terminal force in embolic strokes of undetermined source. J Neurol Sci 2017;375:175–8. https://doi.org/10.1016/j.jns.2017.01.063; PMID: 28320124.

34. Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study.

Circulation 2002;105:2625–31. https://doi.org/10.1161/01. cir.0000017498.88393.44; PMID: 12045168.

35. Schuchlenz HW, Saurer G, Weihs W, et al. Persisting eustachian valve in adults: relation to patent foramen ovale and cerebrovascular events. J Am Soc Echocardiogr 2004;17:231–3. https://doi.org/10.1016/j.echo.2003.12.003; PMID: 14981420.

36. Lattanzi S, Rinaldi C, Pulcini A, et al. Clinical phenotypes of embolic strokes of undetermined source. Neurol Sci 2021;42:297–300. https://doi.org/10.1007/s10072-02004700-2; PMID: 32914246.

37. Furlon A, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale.

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38. Meier B, Kalesan, B, Mattle H, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013;368:1083–91. https://doi.org/10.1056/NEJMoa1211716; PMID: 23514285.

39. Carroll J, Saver J, Thaler D, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke.

N Engl J Med 2013;368:1092–100. https://doi.org/10.1056/ NEJMoa1301440; PMID: 23514286.

Cardiogenic Shock

Current Landscape of Temporary Percutaneous Mechanical Circulatory Support Technology Rani Upadhyay, MD ,1 Hussayn Alrayes, MD ,2 Scott Arno, MD ,2 Milan Kaushik, MD

3

and Mir B Basir, DO

2

1. Section of Interventional Cardiology, Stanford Health Care, Oakland, CA; 2. Division of Cardiology, Henry Ford Hospital, Detroit, MI; 3. Wayne State University, Detroit, MI

Abstract

Mechanical circulatory support devices provide hemodynamic support to patients who present with cardiogenic shock. These devices work using different mechanisms to provide univentricular or biventricular support. There is a growing body of evidence supporting use of these devices as a goal for cardiac recovery or as a bridge to definitive therapy, but definitive, well-powered studies are still needed. Mechanical circulatory support devices are increasingly used using shock team and protocols, which can help clinicians in decision making, balancing operator and institutional experience and expertise. The aim of this article is to review commercially available mechanical circulatory support devices, their profiles and mechanisms of action, and the evidence available regarding their use.

Keywords

Cardiogenic shock, MI, heart failure, mechanical circulatory support, devices Disclosure: MBB is a consultant for Abbott Vascular, Abiomed, Cardiovascular Systems, Chiesi, Procyrion, and Zoll. All other authors have no conflicts of interest to declare.

Received: April 5, 2021 Accepted: July 6, 2021 Citation: US Cardiology Review 2021;15:e21. DOI: https://doi.org/10.15420/usc.2021.15 Correspondence: Rani Upadhyay, MD, 365 Hawthorne Avenue, Suite 201, Oakland, CA 94609. E: RUpadhyay@stanfordhealthcare.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Several technologies are available to provide mechanical circulatory support (MCS) for patients in cardiogenic shock (Table 1). Device selection should be ideally customized to patients based upon the etiology of shock, the stage of shock, hemodynamic needs and the overall goal of a patient’s care (Figures 1 and 2). Furthermore, device selection must include consideration of the clinician’s and institution’s experience and expertise using specific MCS devices (Table 2).

Intra-aortic Balloon Pumps

Intra-aortic balloon pumps (IABPs) have been available since the 1960s and use counter-pulsation to provide hemodynamic support. They can be inserted from the femoral, brachial or axillary artery and are placed in the descending aorta. The balloon is inflated during diastole and rapidly deflated during systole. IABPs therefore require native cardiac contractility to function. IABPs synchronize with the heart using either a pressure or an ECG trigger for timing. There are several different IABP sizes – ranging from 40 to 60 cm3 – and they are inserted using a 7–8 Fr sheath. The device is usually set to one inflation per cardiac cycle (1:1). However, the level of support can be weaned down by changing the frequency of inflation (1:2 or 1:3). The main hemodynamic effects include an increase in coronary perfusion and decrease in afterload, which result in decreased myocardial oxygen demand and left ventricular (LV) workload.

Impella Devices

Impella (Abiomed) LV assist devices (LVAD) are continuous, axial flow devices that aspirate blood from the left ventricle and expel blood into the ascending aorta. An Impella can be inserted using a femoral, axillary or

transcaval access. Currently there are four LV support systems available.

The Impella 2.5 (provides ~2.5 l/min of flow) and the Impella CP (provides ~3.5 l/min of flow), are typically inserted percutaneously using a 13 Fr and 14 Fr sheath, respectively. The Impella 5.0 (provides ~5.0 l/min of flow) is typically inserted using a surgical cut down, though it can be placed percutaneously using transcaval access and requires a 22 Fr sheath. The Impella 5.5 (provides ~5.5 l/min of flow) is a shorter, more rigid device when compared to the Impella 5.0, which allows easier maneuverability in placing the device using an axillary cut down. The main hemodynamic effects of left-sided Impella devices are to increase cardiac output and cardiac power. These devices unload the left ventricle by decreasing LV end-diastolic pressure and LV wall stress. In combination, Impella devices decrease myocardial oxygen demand from LV failure.

The Impella RP is a right-sided MCS device that can be used in the setting of cardiogenic shock secondary to right ventricular (RV) failure or in conjunction to a left-sided device in patients with biventricular shock. An Impella RP must be placed from the femoral vein and requires placement using a 22 Fr sheath. An Impella RP aspirates blood from the inferior vena cava to the pulmonary artery and delivers a flow rate up to ~5.0 l/min.

TandemHeart

TandemHeart (LivaNova) is a percutaneous centrifugal LVAD that pumps blood from the left atrium to the descending aorta. The device provides flows of ~3–5 l/min based on the size of the outflow cannula. There are four main components when using a Tandem Heart device: a 21 Fr transseptal inflow cannula that is placed in the left atrium, a 15–19 Fr

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Percutaneous Mechanical Circulatory Support Table 1: Comparison of Temporary Mechanical Circulatory Support Systems Intra-aortic Balloon Pump

Impella

TandemHeart

VA-ECMO

Cardiac flow

0.3–0.5 l/min

2–5.5 l/min

2.5–5 l/min

3–7 l/min

Mechanism

Pneumatic

Axial

Centrifugal

Centrifugal

Blood flow

NA

LV → AO

LA → femoral

RA → femoral

Sheath size

7–8 Fr

13 Fr (2.5) 14 Fr (CP) 22 Fr (5.0) 18 Fr (5.5)

15–19 Fr (arterial) 21 Fr (venous)

15–19 Fr (arterial) 18–29 Fr (venous)

Need for cardiac synchrony

Yes

No

No

No

LV afterload

↓

↓

↑

↑↑

MAP

↑

↑↑

↑↑

↑↑

Cardiac power

↑

↑↑

↑↑

↑↑

LVEDP

↓

↓↓

↓↓

†

PCWP

↓

↓↓

↓↓

†

LV preload

–

↓

↓↓

↓↓

Coronary perfusion

↑

↑

↑

–

Myocardial oxygen demand

↓

↓

↓

†

Venous access

None

None

Yes

Yes

Systemic anticoagulation

Recommended

Required

Required

Required

Indications

Acute decompensated CHF, high risk PCI, AMI with <TIMI 3 flow post-PCI, post-cardiotomy shock

Acute decompensated CHF, cardiogenic shock (particularly in AMI), refractory malignant arrhythmias, high-risk PCI

Acute decompensated CHF, cardiogenic shock, refractory malignant arrhythmias, high-risk PCI

Acute decompensated CHF, cardiogenic shock, massive PE, cardiac arrest, refractory malignant arrhythmias

Support provided

Minimal hemodynamic support

Partial LV support: 2.5 and CP Complete LV support: 5.0, 5.5

Partial to complete LV support based upon the size of the outflow (arterial) cannula

Complete BiV support

Considerations

Can be used without anticoagulation, mobile, not labor intensive for nursing

Active LV unloading; surgical axillary placement allows for mobility and subacute recovery

Requires septostomy, indirect LV unloading by decompressing the left atrium

Bedside insertion is possible, may require strategies to unload the LV. Ideal for active cardiac arrest by providing BiV cardio/pulmonary support, labor intensive (nursing/ perfusionist)

Management

CXR for position (tip 1–4 cm below AO notch), wean by ↓ ratio (then return to 1:1, stop AC, pull)

CXR/echo position, P1 (lowest) to P9 (highest) support, urine color (hemolysis), suction events (↓ preload, RV failure, position), ventricular arrhythmias (device migration)

Ensure daily optimal device placement due to risk of migration from LA to RA, avoid patient maneuvering

Typically stable position, monitor for north/south syndrome, aortic valve closure

Complications

Limb ischemia, vascular injury, thromboembolism, bleeding, stroke, balloon leak/rupture

Bleeding, limb ischemia, thromboembolism, vascular injury, stroke

Bleeding, limb ischemia, thromboembolism, vascular injury, stroke, residual atrial septal defect

Bleeding, limb ischemia, thromboembolism, vascular injury, stroke

↓ = decreased; ↑ = increased; ↑↑ = markedly increased; ↓↓ = markedly decreased; † = neutral. AC = anticoagulation; AMI = acute MI; AO = aorta; BiV = biventricular; CHF = congestive heart failure; CXR = chest X-ray; LA = left atrium; LV = left ventricular; LVEDP = LV end diastolic pressure; MAP = mean arterial pressure; NA = not applicable; PCI = percutaneous coronary intervention; PCWP = pulmonary capillary wedge pressure; PE = pulmonary embolism; RA = right atrium; RV = right ventricle; TIMI = thrombolysis in MI; VA-ECMO = veno-arterial extracorporeal membrane oxygenation.

arterial outflow cannula, a centrifugal pump, and the control console. The cannulas are typically placed via the femoral artery and vein and require operator expertise in transseptal catheterization. The outflow cannula can be placed in the axillary artery if needed. The main hemodynamic effects of a TandemHeart device are increasing cardiac output and cardiac power. The device indirectly unloads the left ventricle by bypassing blood directly from the left atrium and therefore results in decreasing LV end diastolic pressure. Similar to the Impella, TandemHeart decreases myocardial oxygen consumption. Unlike veno-arterial extracorporeal

membrane oxygenation (VA-ECMO), a TandemHeart does not require an oxygenator, as oxygenated blood is directly aspirated from the left atrium and delivered to the femoral artery via the outflow cannula.

The Protek Duo (TandemLife) is a right-sided MCS that also be used in the setting of cardiogenic shock secondary to RV failure or in conjunction to a left-sided device in patients with biventricular shock. A Protek Duo must be placed from the internal jugular vein and requires placement of a 29 Fr or 31 Fr cannula. A Protek Duo aspirates blood from the right atrium and

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Percutaneous Mechanical Circulatory Support

Veno-arterial Extracorporeal Membrane Oxygenation

VA-ECMO provides biventricular support and oxygenation for patients in cardiogenic shock. VA-ECMO systems have five components comprising a centrifugal flow pump, membrane oxygenator, venous inflow cannula, arterial outflow cannula, and a control console. Blood is taken from the venous system typically at the level of the right atrium using a 25–29 Fr cannula placed in the femoral or internal jugular vein, oxygenated, and delivered to the systemic circulation using a 15–19 Fr outflow cannula placed typically in the femoral or axillary artery. In order to prevent limb ischemia, reperfusion sheaths can be placed in the femoral or superficial femoral arteries to improve distal limb perfusion (or in the radial, ulnar, or brachial arteries when using axillary access). VA-ECMO cannulas can also be placed using central cannulations by surgical teams to avoid peripheral complications such as limb ischemia. VA-ECMO is able to provide 4–7 l/ min of flow based upon the size of the outflow cannula. Hemodynamically, VA-ECMO can increase LV afterload and end-diastolic pressure, particularly in patients with severely reduced LV ejection fractions. To overcome these physiologic concerns VA-ECMO can be combined with devices such an IABP or Impella which can unload the left ventricle. Other strategies to unload the left ventricle include septostomy or outflow cannulation placement in the left atrium (LAVA-ECMO). It is important to mention that VA-ECMO is the only device that provides biventricular support using a single device.

Figure 1: Treatment Strategy and Suggested Algorithm Depending on CS Stages Decompensated HF/cardiomyopathy ECMO + LV vent Impella 5.0/5.5 TandemHeart

Acute cardiogenic shock/AMI

EXTREMIS

ECMO + LV vent Impella 5.0/5.5 TandemHeart

ECMO + LV vent Impella 5.0/5.5 TandemHeart

Deteriorating

ECMO + LV vent Impella 5.0/5.5 TandemHeart

Inotropes IABP Impella CP TandemHeart

Classic

Impella CP Tandem Heart

OMT

Beginning

IABP

OMT

At risk

OMT

Early stages of CS outline a role for OMT, while progressive and advanced stages of CS deserve consideration of escalating MCS. AMI = acute MI; CS = cardiogenic shock; ECMO = extracorporeal membrane oxygenation; HF = heart failure; IABP = intra-aortic balloon pump; LV vent = left ventricular venting; MCS = mechanical circulatory support; OMT = optimal medical therapy.

Figure 2: Distinct Hemodynamic Effects of Each MCS Device Portrayed by Pressure–Volume Loops CS CS + IABP CS + TandemHeart CS + Impella CS + VA-ECMO LV pressure

delivers blood to the pulmonary artery using a dual lumen cannula. The Protek Duo delivers flows up to ~5.0 l/min. Unlike an Impella RP, a Protek Duo allows for the addition of an oxygenator to the circuit and therefore can function as a veno-venous extracorporeal membrane oxygenator (VV-ECMO).

Goals of Mechanical Circulatory Support in Acute MI and Cardiogenic Shock

Cardiogenic shock occurs in 5–7% of patients hospitalized with STelevation MI but carries an in-hospital mortality rate of ~50%.1,2 Inotropes are frequently used to initially support hemodynamic collapse. The number of inotropes used, along with time on inotropic support, is correlated with increased mortality.1,2 Although inotropes aim to increase cardiac output, they also carry a risk of increased myocardial oxygen consumption and arrhythmia.3 The use of MCS to support cardiovascular collapse has therefore been increasingly used. MCS circumvents the undesirable effects of inotropes by unloading the ventricle, reducing myocardial oxygen consumption and wall tension, and increasing coronary perfusion. Use of MCS in acute MI cardiogenic shock (AMICS) may help to maintain cardiac output and end-organ perfusion, while simultaneously reducing infarct size and salvaging left ventricle function as well.4 However, these physiological benefits must be weighed against the risk of device-related complications, such as stroke, vascular access complication, bleeding, and limb ischemia. The following sections review the latest data on the use of these devices in AMICS.

Intra-aortic Balloon Pumps in Acute MI Cardiogenic Shock

Use of IABP has gradually declined after publication of the IABP-SHOCK II trial.5 Nevertheless, IABPs remain the most commonly used MCS for AMICS. The IABP-SHOCK II trial compared outcomes between use of IABP and medical therapy in those presenting with AMICS with plans for early revascularization. The study was powered to detect differences in mortality and enrolled >600 patients. All-cause mortality was similar between those treated with IABP and those in the control group at 1-month

LV volume Selection of MCS should be tailored to the patient specific clinical scenario. CS = cardiogenic shock; IABP = intra-aortic balloon pump; LV = left ventricular; MCS = mechanical circulatory support; VA-ECMO = veno-arterial extracorporeal membrane oxygenation.

and 12-month follow-up.5 The trial led the European Society of Cardiology to downgrade its recommendation for the routine use of IABP for the management of AMICS to a class III indication, while the US guideline downgraded its recommendation to a class II indication.6 This, combined with the increased availability of other forms of MCS, has led to reduced use of IABP in AMICS.7 Use of IABP may still be considered for select patients with AMICS as a bridge to a more definitive therapy. Such examples may include patients being transferred to a shock center with more robust MCS options, in patients awaiting surgical intervention, in patients who received inadequate revascularization with <3 thrombolysis in MI flow, and in patients with significant peripheral arterial disease or inadequate vessel size for more robust MCS. Given the lack of benefit associated with the routine use of IABP in AMICS, alternative MCS devices such as Impella, TandemHeart and VA-ECMO have become increasingly used. Nevertheless, despite this increasing use, there are no definitive studies demonstrating clear benefit or harm when using these devices. However, well-powered trials relating to the use of Impella and ECMO in AMICS are needed.

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Percutaneous Mechanical Circulatory Support Table 2: Patient-tailored Considerations for Mechanical Circulatory Support Device Selection Patient Needs

Technological Capabilities

Hemodynamic deficit

Complication risk

Univentricular/biventricular failure

Operator expertise

Therapeutic goal

Institutional experience

Systematic decision-making is imperative to determine the optimal mechanical circulatory support device for treatment of cardiogenic shock. Variables include degree of hemodynamic deficit, etiology of cardiomyopathy, and goals of mechanical circulatory support placement. Limitations include operator expertise, device availability, anatomic considerations, and burden of potential complications.

Impella in Acute MI Cardiogenic Shock

There is increasing use of Impella in AMICS in an effort to improve the physiological collapse in such patients. The Impella-EUROSHOCK registry was one of the first studies evaluating outcomes with the use of the first generation Impella 2.5 device in AMICS. The investigators evaluated outcomes in 120 patients and found that use of Impella was associated with reduced lactate levels suggesting improved systemic perfusion, but overall mortality in the study was high at 64%.8 This was followed by the results of the USpella registry, which evaluated 154 patients with AMICS. The investigators found that patients treated with Impella had better survival if they were treated with Impella pre-percutaneous coronary intervention (PCI; 65.1%) when compared to post-PCI (40.7%).9 Loehn et al. similarly demonstrated improved survival with the use of Impella before PCI (50% pre-PCI Impella versus 23.1% post-PCI Impella).10 Small, underpowered studies comparing the outcomes between Impella and IABP have not yielded definitive conclusions. The ISAR-SHOCK trial included 26 patients and demonstrated physiologic improvements with use of an Impella 2.5 compared with an IABP, with no difference in 30-day mortality.11 The IMPRESS trial recruited a very sick cohort of patients, many of whom had cardiac arrest, and is the largest randomized controlled trial comparing outcomes of Impella to IABP in AMICS.12 The study randomized 48 patients and demonstrated no differences in mortality at 1-month or 6-month follow-up.

Given the difficulties of performing randomized control trials in cardiogenic shock, matched cohort studies have also been performed.13 Schrage et al. matched patients from the IABP-SHOCK II trial to patients supported with an Impella device using a large European registry.14 The investigators demonstrated no significant difference in 30-day all-cause mortality (48.5% versus 46.4%; p=0.64), but did demonstrate higher rates of severe bleeding and vascular complications in the Impella arm. The main limitation of this study was that the degree of cardiogenic shock was not taken into account when matching patients. Helgestad et al. were able to control for the degree of shock in their matched analysis that included controlling for age, LV ejection fraction, lactate levels, kidney function, and the presence of cardiac arrest. The investigators demonstrated lower 30-day mortality in patients receiving Impella when compared to a matched control group that underwent IABP placement (40% versus 77.5%; p log rank <0.001).15 Perhaps the strongest evidence for the use of Impella in AMICS comes from the cardiogenic shock initiative.16,17 The investigators used a combination of best practices in shock management along with the use of Impella to create a standard shock protocol that was implemented in 73 hospitals across the US. Overall, the study included >400 patients with similar characteristics to patients previously enrolled in randomized

control trials (i.e. the inclusion and exclusion criteria mimicked those of prior studies). The investigators found that survival to hospital discharge and at 30-days was >70%. The high survival rate was reproducible in both community and academic centers and will be the basis of a well-powered, randomized control trial.

TandemHeart Therapy for Acute MI Cardiogenic Shock

While there are several small trials evaluating the use of TandemHeart in cardiogenic shock, only a few of these studies included patients with AMICS. Thiele et al. conducted a randomized controlled study, enrolling 41 patients with AMICS. They randomized patients to receive either TandemHeart or IABP. Despite markers of hemodynamic improvement favoring TandemHeart, mortality at 30 days was similar between those treated with TandemHeart or IABP (45% and 43%, respectively).18 Burkhoff et al. similarly randomized patients to TandemHeart or IABP in patients with refractory cardiogenic shock (of the 42 patients included, 26 had AMICS). They similarly demonstrated improvements in hemodynamics including cardiac index and pulmonary capillary wedge pressure in the TandemHeart cohort, but there was no difference in mortality between the two groups.19 Finally, Negi et al. randomized 35 patients with AMICS to TandemHeart or VA-ECMO. Survival was similar in both groups (58% versus 56% at 30 days), with no difference in limb ischemia requiring surgery, need for renal replacement therapy, stroke, or recurrent MI.20 Observational studies using TandemHeart in AMICS consistently demonstrate improved hemodynamics. Kar et al. evaluated 80 patients and found that TandemHeart led to a rapid improvement several hemodynamic measures, including cardiac index, systolic blood pressure, urine output, and lactic acid levels.21 The mortality rates were 40.2% and 45.3% at 30 days and 6 months for AMICS patients. Smith et al. analyzed 55 patients, 16 (29%) of whom had AMICS, and found that survival was greatly influenced by the indication for use of TandemHeart with a survival of 23.8% when used as a bridge to recovery and 51% when used as a bridge to LVAD or surgery (p=0.04).22 They also found that patients who did not receive definitive therapy had very poor outcomes (13.8% survival to hospital discharge). Continued observational data are being collected in the THEME registry, an ongoing multicenter study (NCT02326402).

Veno-arterial Extracorporeal Membrane Oxygenation Therapy for Acute MI Cardiogenic Shock

There has been significant enthusiasm for use of ECMO in AMICS after the publication of the IABP-SHOCK study and increasing use of mobile ECMO circuits. However, similar to other MCS options, there are limited randomized studies evaluating the outcomes of ECMO in AMICS. Garan et al. conducted a prospective study in 2019 comparing the outcomes of 51 patients treated with VA-ECMO or Impella following AMICS.23 Patients with VA-ECMO required an increased number of vasopressors and were more likely to have an IABP in place when compared to patients treated Impella. Survival to discharge between the cohorts was similar (50% for VA-ECMO versus 63.6% for Impella). However, the study was limited in that sicker patients were more likely to receive VA-ECMO and 47.1% of patients were supported with both devices simultaneously, though data were analyzed according to which device was initially used.23 Vallabhajosyula et al. performed a large analysis using the National Inpatient Sample (NIS) database and evaluated ~9 million acute MI admissions from 2000–2014, of whom 4.6% were noted to have cardiogenic shock. ECMO was used in a total of 2,962 (<0.01%) patients and same-day PCI was performed in only 23% of the group. In-hospital

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Percutaneous Mechanical Circulatory Support mortality occurred in 59.2% of admissions treated with ECMO. However, the in-hospital mortality in those receiving ECMO for AMICS significantly reduced over time, from 100% in 2000 to 45.1% in 2014. A major limitation of the study was the difficulty distinguishing between the use of VVECMO as opposed to VA-ECMO using ICD-9 codes.24 Lemor et al. similarly used the NIS database to evaluate 6,290 admissions for AMICS who underwent PCI and were treated with ECMO or Impella. There was a strong preference for use of Impella (91%) over ECMO (9%) for hemodynamic support and a significantly higher overall in-hospital mortality for the ECMO cohort (45.5% versus 41.4%). After propensity matching, ECMO was associated with a significantly higher mortality compared with Impella (43.3% versus 26.7%). However, matching was limited as the ECMO cohort had high rates of in-hospital cardiac arrest (30% versus 16.7%), and therefore may have reflected a more critically ill population when compared to the Impella cohort.25 Sheu et al. evaluated 115 patients with AMICS from 1993–2002 without ECMO support and compared them with 219 patients with AMICS from 2002–2009 with ECMO support.26 The 30-day mortality for patients with ECMO was lower than the non-ECMO cohort (30.1% versus 41.7%; p=0.034).

A subgroup analysis of patients in profound cardiogenic shock found a significant difference in mortality between groups (39.1% in ECMO versus 72% in non-ECMO; p=0.008). However, in patients without profound shock there was no significant difference in 30-day mortality between the groups (26.1% versus 21.9%; p=0.39). Esper et al. studied 18 patients who underwent VA-ECMO in the catheterization laboratory for AMICS and found an in-hospital survival rate of 67% and 6-month survival of 55%.27 More than one-third of patients had an IABP placed and were on vasopressors or inotropes. Similarly, Negi et al. studied 15 patients with AMICS (one-third presenting with cardiac arrest) and showed a 47% survival rate.28 More than 90% of patients were on one to two inotropes at the time of ECMO, 60% had an IABP, and the vascular complication rate was >50%.

Currently, there are two randomized controlled trials underway comparing the efficacy of ECMO therapy to standard treatment in AMICS (NCT03637205 and NCT03813134).

Mechanical Circulatory Support in Acute Decompensated Heart Failure and Cardiogenic Shock

The physiology of acute on chronic heart failure and cardiogenic shock (HF-CS) is distinct from AMICS and other acute pathologies. HF-CS is typically secondary to an acute decompensation in the setting of a longstanding cardiomyopathy. Decompensation can occur because of worsening valvular disease, new or refractory arrhythmias, medical or dietary non-adherence, or worsening of the patient’s underlying cardiomyopathy.

Irrespective, patients with long-standing cardiomyopathies have undergone significant myocardial remodeling and compensatory physiological changes and can therefore tolerate lower cardiac outputs when compared to patients presenting with acute cardiogenic shock pathologies. Patients with HF-CS therefore have different needs regarding MCS. For example, a patient with chronic heart failure is much more likely to respond to an IABP, whereas a similar patient presenting with acute cardiogenic shock may require a more robust form of MCS. The study of temporary MCS in decompensated heart failure has been even more challenging than AMICS due of the diversity of etiologies of shock and the etiology of decompensation. The current use of specific devices is thus often dependent on the operator and institutions experience and expertise rather than clinical trials.

The most commonly used device for refractory acute decompensated HFCS is an IABP. Despite several trials failing to demonstrate survival benefit in AMICS, there are data to suggest the effectiveness of IABP in HF-CS.29–31 Several retrospective studies have demonstrated use of an IABP resulting in acute stabilization and improvement in hemodynamic parameters in this subset.31–33 Malick et al. compared 73 patients with AMI-CS and 132 patients with HF-CS treated with IABP. The investigators found patients with HF-CS had cardiac output augmentation that was almost fivefold higher when compared to patients AMI-CS. The mean cardiac output augmentation was slightly >0.5 l/min in the HF-CS cohort, which may be enough improvement to stabilize such patients as they have a low cardiac output at baseline.34 Though not definitive, the study demonstrates well how the response to IABP is very dependent on the etiology of CS. There are plans for a well-powered trial evaluating the use of IABP in HF-CS.35 An Impella device is able to provide more cardiac output compared to IABP and has been increasingly used in HF-CS patients who decompensate despite optimal medical therapy.36–38 An Impella has the advantage of being able to fully unload the left ventricle and provide nearly complete ventricular support to most patients when using the larger 5.0 or 5.5 models.39,40 However, there are no trials to definitively prove mortality benefit.

Patients with refractory cardiogenic shock with concomitant respiratory failure may require full cardiopulmonary support with VA-ECMO and evidence for its utility in the treatment of cardiogenic shock is also increasing.41,42 A recent multicenter, retrospective cohort study of patients with mixed septic and cardiogenic shock demonstrated improvements in 90-day survival with VA-ECMO when compared to controls treated with conventional medical treatments alone; this was despite the fact that the treatment arm had greater degrees of organ and myocardial dysfunction compared with controls.43 Registry data from the Extracorporeal Life Support Organization in 2018 demonstrated a survival to discharge benefit for patients in refractory cardiogenic shock supported with ECMO.44 The magnitude of success for which depended on the etiology of the shock, with myocarditis patients faring the best and post-surgical patients doing the worst.45 This is an example of how the etiology of cardiogenic shock plays a key role in device selection and hemodynamic improvement with MCS. The optimal candidate for ECMO in cardiogenic shock remains an active area of investigation and there are multiple scoring systems being used to predict the outcome of ECMO in an individual patient with cardiac failure.45

Mechanical Circulatory Support for Right Ventricular Failure

Predominant RV failure constitutes up to 5% of patients presenting with AMICS, while concomitant RV failure in the setting of predominant LV failure is more common at 40%.46,47 RV failure can be identified by imaging as well as by hemodynamic parameters such as a central venous pressure (CVP) >12 mmHg, a CVP/pulmonary capillary wedge pressure ratio >0.63, a pulmonary artery pulsatility index <1.5, and a RV stroke work index <300 mmHg*ml/m2.

In AMICS, RV failure can be caused by right coronary artery occlusion. RV ischemia leads to decreased systolic function and decreasing transpulmonary flow into the LV. Decreasing preload results in decreasing cardiac output and hemodynamic compromise. RV failure should therefore first be treated with fluids, then consideration of inotropes. In patients with LV failure, increased LV pressures and pulmonary venous pressures leads to increased RV afterload and decreased RV function. The bulk of

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Percutaneous Mechanical Circulatory Support studies evaluating the use of RV MCS devices have therefore occurred in patients with RV failure in the setting of LV failure, such as in patients postLVAD or those with chronic heart failure.

Gramega et al. conducted a small retrospective study that demonstrated improvements in systolic blood pressure, CVP and lactate with the use of an Impella RP in AMICS with RV failure.48 Cheung et al. studied 18 patients, 39% of whom had AMI, and found that the Impella RP led to improvements in hemodynamic measures and reported a 30-day survival rate of 72% and a 1-year survival rate of 50%.49 Anderson et al. conducted a prospective study in 2018 including 60 patients. Patients were divided into two cohorts based on the etiology of their RV failure. One cohort was post-LVAD implantation and the other post-surgery or AMICS. Similar to other studies hemodynamics improved, including cardiac index and CVP along with decreasing use of inotropes.50 Kapur et al. performed a retrospective study evaluating 46 patients with predominant RV failure of various etiologies and sought to evaluate the hemodynamic effects and clinical outcomes of using either a percutaneously or surgically cannulated TandemHeart-RV support device. Hemodynamic parameters including mean arterial pressure, cardiac index and CVP significantly improved the use of RV-MCS.51 VA-ECMO is a powerful RV-MCS as it can bypass the 1. Basir MB, Schreiber TL, Grines CL, et al. Effect of early initiation of mechanical circulatory support on survival in cardiogenic shock. Am J Cardiol 2017;119:845–51. https://doi. org/10.1016/j.amjcard.2016.11.037; PMID: 28040188.

2. Shahin J, DeVarennes B, Tse CW, et al. The relationship between inotrope exposure, six-hour postoperative physiological variables, hospital mortality and renal dysfunction in patients undergoing cardiac surgery. Crit Care 2011;15:R162. https://doi.org/10.1186/cc10302; PMID: 21736726.

3. Tariq S, Aronow WS. Use of inotropic agents in treatment of systolic heart failure. Int J Mol Sci 2015;16:29060–8. https:// doi.org/10.3390/ijms161226147; PMID: 26690127.

4. Saku K, Kakino T, Arimura T, et al. Left ventricular mechanical unloading by total support of impella in myocardial infarction reduces infarct size, preserves left ventricular function, and prevents subsequent heart failure in dogs. Circ Heart Fail 2018;11:e004397. https://doi. org/10.1161/CIRCHEARTFAILURE.117.004397; PMID: 29739745.

5. Thiele H, Zeymer U, Neumann FJ, et al. Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial. Lancet 2013;382:1638–45. https://doi.org/10.1016/S0140-6736(13)61783-3; PMID: 24011548.

6. Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2018;39:119–77. https://doi.org/10.1093/eurheartj/ehx393; PMID: 28886621.

7. Patel H, Shivaraju A, Fonarow GC et al. Temporal trends in the use of intraaortic balloon pump associated with percutaneous coronary intervention in the United States, 1998-2008. Am Heart J 2014;168:363–73. https://doi. org/10.1016/j.ahj.2014.02.015; PMID: 25173549.

8. Lauten A, Engström AE, Jung C, et al. Percutaneous leftventricular support with the Impella-2.5-assist device in acute cardiogenic shock: results of the ImpellaEUROSHOCK-registry. Circ Heart Fail 2013;6:23–30. https:// doi.org/10.1161/CIRCHEARTFAILURE.112.967224; PMID: 23212552.

9. O’Neill WW, Schreiber T, Wohns DH, et al. The current use of Impella 2.5 in acute myocardial infarction complicated by cardiogenic shock: results from the USpella Registry. J Interv Cardiol 2014;27:1–11. https://doi.org/10.1111/joic.12080; PMID: 24329756.

10. Loehn T, O’Neill WW, Lange B, et al. Long term survival after early unloading with Impella CP® in acute myocardial infarction complicated by cardiogenic shock. Eur Heart J Acute Cardiovasc Care 2020;9:149–57. https://doi. org/10.1177/2048872618815063; PMID: 30456984.

11. Seyfarth M, Sibbing D, Bauer I, et al. A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction. J Am Coll Cardiol 2008;52:1584–8.

venous system entirely. Particularly in the setting of concomitant leftsided failure, ECMO may be the preferred MCS modality as it provides biventricular support. Unfortunately, data on its use specifically for RV failure are limited.

Conclusion

MCS devices are increasingly used for the treatment of cardiogenic shock.

Clinicians use these devices to improve hemodynamics in an effort to support coronary and systemic perfusion. These devices work through various mechanisms, resulting in different physiological responses. There is an increasing effort to enroll and study patients requiring MCS into studies to help refine patient and device selection. Current practice using shock protocols and multidisciplinary teams takes into account operator and institutional experience and expertise to allow for a safe delivery and use of such devices. When choosing an MCS device for a patient, clinicians must take into account the etiology of shock (acute versus acute on chronic pathologies), the stage of shock (including the extent of endorgan failure) and the patient’s age and beliefs along with the goals of care. With continued technological advancements these devices will continue to become smaller and more powerful, thus clinicians should be familiar with the risk and benefits of such devices.

https://doi.org/10.1016/j.jacc.2008.05.065; PMID: 19007597.

12. Ouweneel DM, Eriksen E, Sjauw KD, et al. Percutaneous mechanical circulatory support versus intra-aortic balloon pump in cardiogenic shock after acute myocardial infarction.

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13. Basir MB, Pinto DS, Ziaeian B, et al. Mechanical circulatory support in acute myocardial infarction and cardiogenic shock: challenges and importance of randomized control trials. Catheter Cardiovasc Interv 2021. https://doi.org/10.1002/ ccd.29593; PMID: 33682260; epub ahead of press.

14. Schrage B, Ibrahim K, Loehn T, et al. Impella support for acute myocardial infarction complicated by cardiogenic shock. Circulation 2019;139:1249–58. https://doi.org/10.1161/ CIRCULATIONAHA.118.036614; PMID: 30586755.

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Contemporary trends in use of mechanical circulatory support in patients with acute MI and cardiogenic shock.

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16. Basir MB, Schreiber T, Dixon S, et al. Feasibility of early mechanical circulatory support in acute myocardial infarction complicated by cardiogenic shock: the Detroit Cardiogenic Shock Initiative. Catheter Cardiovasc Interv 2018;91:454–61. https://doi.org/10.1002/ccd.27427; PMID: 29266676.

17. Basir MB, Kapur NK, Patel K, et al. Improved outcomes associated with the use of shock protocols: updates from the National Cardiogenic Shock Initiative. Catheter Cardiovasc Interv 2019;93:1173–83. https://doi.org/10.1002/ccd.28307; PMID: 31025538.

18. Thiele H, Sick P, Boudriot E, et al. Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 2005;26:1276–83. https://doi.org/10.1093/ eurheartj/ehi161; PMID: 15734771.

19. Burkhoff D, Cohen H, Brunckhorst C, et al. A randomized multicenter clinical study to evaluate the safety and efficacy of the TandemHeart percutaneous ventricular assist device versus conventional therapy with intraaortic balloon pumping for treatment of cardiogenic shock. Am Heart J 2006;152:469.e1–8. https://doi.org/10.1016/j. ahj.2006.05.031; PMID: 16923414.

20. Negi SI, Malahfji M, Sokolovic M et al. TCT-199. A comparative analysis of use of extracorporeal membrane oxygenation and peripheral ventricular assist device tandemheart in acute myocardial infarction. J Am Coll Cardiol 2015;66(15 Suppl):B75–6. https://doi.org/10.1016/j. jacc.2015.08.213.

21. Kar B, Gregoric ID, Basra SS, et al. The percutaneous ventricular assist device in severe refractory cardiogenic shock. J Am Coll Cardiol 2011;57:688–96. https://doi. org/10.1016/j.jacc.2010.08.613; PMID: 20950980.

22. Smith L, Peters A, Mazimba S, et al. Outcomes of patients with cardiogenic shock treated with TandemHeart®

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percutaneous ventricular assist device: Importance of support indication and definitive therapies as determinants of prognosis. Catheter Cardiovasc Interv 2018;92:1173–81. https://doi.org/10.1002/ccd.27650; PMID: 29745477.

23. Garan AR, Takeda K, Salna M, et al. Prospective comparison of a percutaneous ventricular assist device and venoarterial extracorporeal membrane oxygenation for patients with cardiogenic shock following acute myocardial infarction.

J Am Heart Assoc 2019;8:e012171. https://doi.org/10.1161/ JAHA.119.012171; PMID: 31041870.

24. Vallabhajosyula S, Bell MR, Sandhu GS, et al. Complications in patients with acute myocardial infarction supported with extracorporeal membrane oxygenation. J Clin Med 2020;9:839. https://doi.org/10.3390/jcm9030839; PMID: 32204507.

25. Lemor A, Hosseini Dehkordi SH, et al. Impella versus extracorporeal membrane oxygenation for acute myocardial infarction cardiogenic shock. Cardiovasc Revasc Med 2020;21:1465–71. https://doi.org/10.1016/j. carrev.2020.05.042; PMID: 32605901.

26. Sheu JJ, Tsai TH, Lee FY, et al. Early extracorporeal membrane oxygenator-assisted primary percutaneous coronary intervention improved 30-day clinical outcomes in patients with ST-segment elevation myocardial infarction complicated with profound cardiogenic shock. Crit Care Med 2010;38:1810–7. https://doi.org/10.1097.

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27. Esper SA, Bermudez C, Dueweke EJ, et al. Extracorporeal membrane oxygenation support in acute coronary syndromes complicated by cardiogenic shock. Catheter Cardiovasc Interv 2015;86 Suppl 1:S45–50. https://doi. org/10.1002/ccd.25871 PMID: 25639707.

28. Negi SI, Sokolovic M, Koifman E, et al. Contemporary use of veno-arterial extracorporeal membrane oxygenation for refractory cardiogenic shock in acute coronary syndrome.

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29. Mizuno M, Sato N, Kajimoto K, et al. Intra-aortic balloon counterpulsation for acute decompensated heart failure. Int J Cardiol 2014;176:1444–6. https://doi.org/10.1016/j. ijcard.2014.08.154; PMID: 25223815.

30. Malick W, Fried JA, Masoumi A, et al. Comparison of the hemodynamic response to intra-aortic balloon counterpulsation in patients with cardiogenic shock resulting from acute myocardial infarction versus acute decompensated heart failure. Am J Cardiol 2019;124:1947– 53. https://doi.org/10.1016/j.amjcard.2019.09.016; PMID: 31648782.

31. Fried JA, Nair A, Takeda K, et al. Clinical and hemodynamic effects of intra-aortic balloon pump therapy in chronic heart failure patients with cardiogenic shock. J Heart Lung Transplant 2018;37:1313–21. https://doi.org/10.1016/j. healun.2018.03.011; PMID: 29678608.

32. Sintek MA, Gdowski M, Lindman BR, et al. Intra-aortic balloon counterpulsation in patients with chronic heart failure and cardiogenic shock: clinical response and predictors of stabilization. J Card Fail 2015;21:868–76.

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33. Hsu S, Kambhampati S, Sciortino CM, et al. Predictors of intra-aortic balloon pump hemodynamic failure in non-acute myocardial infarction cardiogenic shock. Am Heart J 2018;199:181–91. https://doi.org/10.1016/j.ahj.2017.11.016; PMID: 29754660.

34. Malick W, Fried JA, Masoumi A, et al. Comparison of the hemodynamic response to intra-aortic balloon counterpulsation in patients with cardiogenic shock resulting from acute myocardial infarction versus acute decompensated heart failure. Am J Cardiol 2019;124:1947– 53. https://doi.org/10.1016/j.amjcard.2019.09.016; PMID: 31648782.

35. Morici N, Marini C, Sacco A, et al. Early intra-aortic balloon pump in acute decompensated heart failure complicated by cardiogenic shock: rationale and design of the randomized Altshock-2 trial. Am Heart J 2021;233:39–47. https://doi. org/10.1016.j.ahj.2020.11.017; PMID: 33338464.

36. Nersesian G, Hennig F, Müller M, et al. Temporary mechanical circulatory support for refractory heart failure: the German Heart Center Berlin experience. Ann Cardiothorac Surg 201 ;8:76–83. https://doi.org/10.21037/acs.2018.12.01; PMID: 30854315.

37. Elkayam U, Schäfer A, Chieffo A, et al. Use of Impella heart pump for management of women with peripartum cardiogenic shock. Clin Cardiol 2019;42:974–81. https://doi. org/10.1002/clc.23249; PMID: 31436333.

38. Annamalai SK, Esposito ML, Jorde L, et al. Impella Microaxial flow catheter is safe and effective for treatment of myocarditis complicated by cardiogenic shock: an analysis from the global cVAD registry. J Card Fail

2018;24:706–10. https://doi.org/10.1016/j. cardfail.2018.09.007; PMID: 30244180.

39. Watanabe S, Fish K, Kovacic JC, et al. Left ventricular unloading using an Impella CP improves coronary flow and infarct zone perfusion in ischemic heart failure. J Am Heart Assoc 2018;7:e006462. https://doi.org/10.1161/ JAHA.117.006462: PMID: 29514806.

40. Monteagudo Vela M, Simon A, et al. Clinical indications of IMPELLA short-term mechanical circulatory support in a tertiary centre. Cardiovasc Revasc Med 2020;21:629–37. https://doi.org/10.1016/j.carrev.2019.12.010; PMID: 31859100.

41. van Diepen S, Katz JN, Albert NM, et al. Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association. Circulation 2017;136:e232–68. https://doi.org/10.1161/ CIR.0000000000000525; PMID: 28923988.

42. Paden ML, Conrad SA, Rycus PT, et al. Extracorporeal life support organization registry report 2012. ASAIO J 2013;59:202–10. https://doi.org/10.1097/ MAT.0b013e3182904a52; PMID: 23644605.

43. Bréchot N, Hajage D, Kimmoun A, et al. Venoarterial extracorporeal membrane oxygenation to rescue sepsisinduced cardiogenic shock: a retrospective, multicentre, international cohort study. Lancet 2020;396:545–52. https:// doi.org/10.1016/S0140-6736(20)30733-9; PMID: 32828186.

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Interventional Cardiology

Rediscovered and Unforgotten: Transcatheter Interventions for the Treatment of Severe Tricuspid Valve Regurgitation Kusha Rahgozar, MD, ,1 Sharon Bruoha, MD, ,1 Edwin Ho, MD, ,1 Ythan Goldberg, MD,1 Mei Chau, MD,2 and Azeem Latib, MD, 1 1. Department of Cardiology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY; 2. Department of Cardiothoracic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY

Abstract

Tricuspid valve regurgitation is both globally prevalent and undertreated. Historically, surgical intervention for isolated tricuspid regurgitation (TR) was avoided despite the prevalence of TR, largely due to poor surgical outcomes and an incomplete understanding of how it independently affects mortality. Over the past two decades, TR has been shown by several studies to be an independent predictor of worse functional status and poor survival on long-term follow-up. During this same time period, transcatheter interventions for the treatment of valvular heart disease have evolved dramatically. While the transcatheter repair and replacement of the tricuspid valve in patients with severe TR remains in the early stages of investigation relative to the mitral or aortic valve, the field is rapidly expanding. Here, the authors review the field of transcatheter tricuspid valve interventions for severe TR, focusing on the orthotropic devices and valves currently available worldwide.

Keywords

Tricuspid regurgitation, transcatheter tricuspid valve repair, edge-to-edge repair, annulus-reshaping Disclosures: AL is a consultant for Medtronic, Abbott, and Edwards Lifesciences. All other authors have no conflicts of interest to declare.

Received: February 23, 2021 Accepted: August 3, 2021 Citation: US Cardiology Review 2021;15:e22. DOI: https://doi.org/10.15420/usc.2021.06 Correspondence: Azeem Latib, Department of Cardiology, Montefiore Medical Center, 1825 Eastchester Rd, Bronx, New York 10461, NY. E: alatib@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

As the global population ages and grows, the burden of heart disease follows suit. In particular, tricuspid regurgitation (TR) has become a prevalent cardiac pathology, affecting more than 1.6 million people across the US and millions more across the globe.1,2 Long thought of as the ‘forgotten valve’, our understanding of tricuspid valve (TV) disease and its negative impact on survival and functional status has rapidly evolved in recent years. Numerous studies over the past decade have highlighted the increased mortality and decreased functional status that patients with severe TR experience, independent of all other comorbidities and cardiac pathologies.3,4 With an annual incidence of 200,000 patients per year coupled with a rapidly aging, more vulnerable patient population, the management of TR has rapidly evolved to meet the challenges at hand.

Here, we review the current state of available orthotropic transcatheter tricuspid interventions spanning from valve repair to valve replacement for the treatment of severe TR (Figure 1).

Pathophysiology

TR can be primary or secondary (functional) in etiology (Table 1). Primary TR is caused by damage to the valve leaflets and can either be congenital or acquired, such as from rheumatic heart disease, infectious endocarditis, radiation therapy, and iatrogenic in the setting of pacemaker leads or endomyocardial biopsy. Secondary (functional) TR is the most prevalent type of TR and refers to regurgitation in the setting of healthy leaflets but distorted annular geometry. Secondary TR is most often the byproduct of left-sided heart failure and left-sided valve disease with associated

pulmonary hypertension. These processes lead to volume and pressure overload in the right ventricle that then undergoes remodeling with extensive right ventricular geometric deformation, chamber enlargement and annular dilatation yielding malcoaptation of the valve leaflets.5 Once significant TR is present, the abnormal volume load on the right ventricle will ultimately lead to additional anatomical deformation and regurgitant volume escalation and ‘secondary TR begets TR’.6 The degree of coaptation defect is important to consider as substantial coaptation defects can exclude potential application of certain transcatheter repair devices.

Isolated TR is a subtype of secondary TR, which occurs when there is tricuspid annular dilatation without right ventricular remodeling or dilatation. Isolated TR is most often seen in elderly patients with AF and right atrial dilatation.7 The development of RV failure associated with severe TR is a critical milestone in the disease’s natural history as this is frequently irreversible despite invasive therapy.8 Consequently, severe RV dysfunction represents an important exclusion criterion in trials evaluating percutaneous devices for severe TR. Timely intervention is key to preventing the occurrence of RV failure. Late in the course of the disease, right ventricular dilatation and associated interventricular septum displacement result in left ventricular impingement and development of left heart failure.9 The current generation of transcatheter TV repair and replacement devices have mainly been used in patients with severe functional TR. For severe primary TR, surgical intervention remains the primary intervention and Class I recommendation in patients without

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Transcatheter Therapies for Tricuspid Valve Repair and Replacement Figure 1: Available Orthotropic Transcatheter Tricuspid Valve Repair and Replacement Devices Edge-to-edge repair devices

Annulus-reshaping devices

TriClip (Abbott)

Transcatheter valve replacement

Cardioband (Edwards Lifesciences)

PASCAL (Edwards Lifesciences)

Intrepid (Medtronic) Evoque (Edwards Lifesciences) LuX-Valve (Jenscare Biotechnology) NaviGate (NaviGate Cardiac Structures)

Table 1. Etiologies of Tricuspid Valve Regurgitation Etiologies of Primary Tricuspid Regurgitation Congenital: • Tricuspid valve dysplasia • Ebstein’s anomaly • Double-orifice tricuspid valve • Connective tissue disorder Rheumatic heart disease Infectious endocarditis Radiation therapy

Guidelines for the Treatment of Tricuspid Valve Disease

Surgery remains the Class I recommendation for TV repair in patients with primary TR and tricuspid stenosis. For primary isolated severe TR, the European Society of Cardiology 2017 guidelines give a Class I recommendation for TV repair for symptomatic patients without severe RV dysfunction. The recommendations for severe functional TR are not as well defined due to the relative novelty of many of the transcatheter procedures and devices used in this population. According to the 2017 ESC guidelines on management of valvular heart disease, the only Class I indication for secondary TR repair is during a concomitant left heart surgery.13 As the role of transcatheter TV interventions for secondary TR continues to grow and more outcomes data following these procedures is generated, it is possible that future guidelines will evolve to reflect the shifting landscape of the field as has happened with aortic valve interventions.

Transcatheter Repair and Replacement Strategies

Ischemia

Both transcatheter valve replacement and valve repair have emerged as feasible and effective interventions for severe functional TR (Table 2).

Transcatheter valve repair can broadly be grouped into two categories: leaflet-directed therapies and annulus-reshaping therapies.14 Currently leaflet-directed therapies constitute the majority of the outcomes data available, but small case series with both short and intermediate-term outcomes with annular-reshaping devices have also been published.

Papillary muscle dysfunction: • Papillary muscle rupture Iatrogenic Pacemaker leads Complication of endomyocardial biopsy Tricuspid valve prosthesis degeneration

Etiologies of Secondary Tricuspid Regurgitation

TV replacement is a rapidly growing area of interest with several potential advantages compared to valve repair. Valve replacement allows for complete elimination of TR, while repair often yields significant reduction but not complete elimination of regurgitant blood flow. Valve replacement can also be performed largely independent of tricuspid annulus morphology, while repair techniques are limited by the degree of annular dilation and the complexity of the underlying subvalvular apparatus.

Left-sided heart failure Left-sided valvular disease Primary pulmonary hypertension AF Hypothyroidism

evidence of right heart dysfunction and in patients undergoing concomitant left-sided valve surgery.

Historical Context

understanding of how severe TR affects patient survival started to change after a retrospective review by Nath et al. of more than 5,000 patients from Veterans Affairs Medical Centers. The authors showed that mortality was associated with the severity of TR and that moderate or greater TR was independently associated with increased mortality regardless of left ventricular ejection fraction or pulmonary artery pressure.4 Subsequently, over the past decade, a growing body of evidence has shown that the prevalence of severe TR in hospitalized patients is increasing, and also that severe TR is an independent predictor of poor survival.3,4,12 As transcatheter structural heart interventions for left-sided valve disorders have grown in availability, safety, and feasibility, the application of these interventions to correct severe TR has become of interest. The possibility of performing TV repair without sternotomy or cardiopulmonary bypass has ushered in a new era for TV interventions.

Despite the presence of surgical techniques such as bicuspidization and DeVega annuloplasty, isolated surgical correction for functional TR has historically been avoided. Instead, the established historical consensus has been that functional TR will correct if left-sided valve disease is repaired.10 Early surgical data demonstrating that patients undergoing sternotomy for isolated TV repair had significant in-hospital mortality further reinforced the paradigm to avoid isolated TR intervention.11 The

Registry data pooling outcomes after valve repair and valve replacement have demonstrated high rates of procedural success, significant improvement in TR severity, and significant improvement in clinical symptoms at short- and mid-term follow-up.15 A closer look into the currently available transcatheter repair and replacement modalities for severe TR follows.

Leaflet-directed Therapies

Leaflet-directed therapies target the TV leaflets to reduce the effective regurgitant orifice area (EROA). They are the most widely used modality for transcatheter TV repair. Currently, three devices have outcomes data

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Transcatheter Therapies for Tricuspid Valve Repair and Replacement Table 2. Devices Currently Available and Under Investigation Leaflet-directed Repair

Mechanism

Potential Advantages

Potential Disadvantages

MitraClip/TriClip (Abbott)

Edge-to-edge repair replicating Alfieri stitch

Has the greatest operator experience and familiarity Has the most outcomes data available

May be of limited efficacy in cases of extreme annular dilatation May not completely eliminate TR Very dependent on high-quality TEE imaging of the TV

PASCAL (Edwards Lifesciences)

Edge-to-edge repair with concomitant central spacer

Independently moving paddles allow for more accurate and independent leaflet grasping Central spacer aids in EROA reduction

May be of limited efficacy in cases of extreme annular dilatation May not completely eliminate TR Less operator experience and outcomes data compared to MitraClip/TriClip Very dependent on high-quality TEE imaging of the TV

Dacron ring anchored into tricuspid annulus and cinched thus reducing septolateral annular diameter

Ample early outcomes data showing feasibility and durability of outcomes Leaflet-independent, thus allowing for potential future edge-to-edge repair if needed

Limited use in setting of extreme annular dilatation Procedural characteristics more complex than edge-to-edge repair

Annulus-reshaping Repair Cardioband (Edwards Lifesciences)

Transcatheter Valve Replacement Intrepid (Medtronic)

Self-expanding circular bovine pericardial trileaflet valve housed in nitinol frame Transfemoral delivery system

Recapturable and retrievable Not limited by degree of annular dilatation Potential for complete elimination of TR

May be limited by degree of baseline right heart dysfunction Only two sizes currently available and cannot treat large anatomies Large-bore delivery system

Evoque (Edwards Lifesciences)

Self-expanding valve that conforms to tricuspid annulus geometry via 29 Fr transfemoral delivery system

Not limited by degree of annular dilatation Potential for complete elimination of TR

May be limited by degree of baseline right heart dysfunction Only three sizes currently available and cannot treat very large anatomies

LuX-Valve (Jenscare Biotechnology)

Self-expanding bovine pericardial valve in nitinol frame Unique septal anchoring mechanism keeps valve in place as opposed to outwards radial force against annulus Transatrial delivery via mini-thoracotomy

Adaptive skirt conforms to anatomy of tricuspid annulus, allowing for optimal seal formation and minimization of paravalvular leak Not limited by degree of annular dilatation Potential for complete elimination of TR

Currently only delivery via transapical approach/mini-thoracotomy May be limited by degree of baseline right heart dysfunction

Navi-GATE (NaviGate Cardiac Structures)

Self-expanding nitinol framed valve composed of 3 xenogenic pericardial leaflets Transatrial delivery required for optimal valve positioning

Most outcomes data available compared to other transcatheter tricuspid valves Not limited by degree of annular dilatation Potential for complete elimination of TR

Requires transatrial approach for optimal positioning May be limited by degree of baseline right heart dysfunction

EROA = effective regurgitant orifice area; TEE = transesophageal echocardiogram; TR = tricuspid regurgitation; TV = tricuspid valve.

available following repair: MitraClip/TriClip (Abbott), PASCAL (Edwards Lifesciences), and FORMA Spacer (Edwards Lifesciences). The FORMA Spacer device is no longer available and will not be reviewed here.

MitraClip/TriClip

The MitraClip/TriClip system works by conceptually replicating the Alfieri stitch and was initially used for transcatheter mitral valve repair. This clipbased edge-to-edge repair technique has recently been adapted for the TV with promising early results. The EROA is reduced by attaching at least one clip to the TV leaflets. Multiple clips can be used depending on the size of the coaptation defect and the location of the regurgitant jet. The procedure is conducted via fluoroscopic and transesophageal echocardiographic guidance. As the most widely used transcatheter TR repair modality to date, operator familiarity with the procedure is a major advantage of MitraClip/TriClip.

The TRILUMINATE trial was an 85-patient prospective study looking at outcomes following TV repair with the TriClip system. At 30-day follow-up, the TR severity of 87% of patients in the study had reduced by at least one

grade. Additionally, the majority of patients in the study had significant improvements in their New York Heart Association (NYHA) class and 6-minute walk distance on short-term follow-up.16 Given the promising results of the study, recruitment for the TRILUMINATE Pivotal IDE trial (NCT03904147) is now in progress. The IDE trial will recruit about 700 patients with severe TR and randomize them to medical therapy or TriClip repair. Long-term follow-up will be assessed at 5 years.

PASCAL

Another intervention originally designed for transcatheter mitral valve repair and subsequently adapted to the TV, the PASCAL repair system has shown significant promise as a leaflet-directed repair modality for TR. The PASCAL system replicates the Alfieri stitch and clipping together valve leaflets to reduce the EROA similar to the MitraClip/TriClip.

There are several distinct factors for the PASCAL system that serve as potential advantages compared with MitraClip/TriClip. First is the presence of a central spacer that sits within the regurgitant orifice, helping to reduce the EROA. Second is the ability for operators to move the device’s

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Transcatheter Therapies for Tricuspid Valve Repair and Replacement graspers independently and simultaneously, thus yielding greater flexibility and accuracy during the leaflet grasping process. A trial of 28 patients undergoing repair with the PASCAL system was recently published with promising results. The majority (86%) had successful device implantation with a post-procedure TR grade of moderate or less.

At 30-day follow-up, 85% of patients had a TR grade of moderate or less, and 88% of patients had NYHA class I or II.17

Annular-reshaping Therapies

Annular-reshaping devices treat TR by directly reshaping the tricuspid annulus without altering the valve leaflets. A major advantage of annular-reshaping therapies is that they are ‘leaflet independent’, thus allowing operators to perform additional edge-to-edge repair if needed in the future. Annular-reshaping devices have been shown to be efficacious in decreasing TR and improving functional status in the majority of patients with severe TR; however, the utility of these devices in the setting of extreme annular dilation is limited. The three annularreshaping devices that have been implanted in humans are Cardioband (Edwards Lifesciences), TriCinch (4Tech), and Trialign (Mitralign).

However, both the Trialign and TriCinch are no longer available and will not be reviewed.

Cardioband

As with the majority of current transcatheter tricuspid repair devices, the Cardioband repair system was originally developed for transcatheter mitral valve repair. The device consists of an adjustable Dacron ring that is anchored into the tricuspid annulus without sutures. Following implantation, the ring’s diameter is reduced via a cinching mechanism, thus also reducing the septolateral annular diameter of the valve.

Procedurally, both fluoroscopy and transesophageal echocardiography are used to guide ring implantation and cinching in real time.

Initial data reporting short-term outcomes following repair with the Cardioband system demonstrated high rates of procedural success and improvement in TR. In a prospective multicenter study of 22 patients with severe TR at baseline, repair with the Cardioband system yielded a 96% technical success rate and no mortality at 30-day follow-up. In this cohort, patients had 38% reduction in their EROA at 30 days. Additionally, the number of NYHA class I or II patients increased from 27% at baseline to 71% at 30-days post-procedure.18 Recently, results for the prospective Tri-Repair study (NCT02981953) were published further highlighting the technical feasibility and long-term durability of TV repair with the Cardioband system. In the Tri-Repair study, 30 patients with at least moderate TR and unacceptable high surgical risk underwent TR repair with Cardioband. Technical success was achieved in 100% of cases. At two-year follow-up, 82% of patients were NYHA class I or II compared to 17% at baseline, and 72% had a TR grade of moderate or less. Significant improvements in both the 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire (KCCQ) score were also seen at follow-up. 19

Transcatheter Tricuspid Valve Replacement

Transcatheter TV replacement is a rapidly growing area of interest for the transcatheter treatment of severe TR. There are several differentiating factors – and potential advantages – that distinguish complete TV replacement from repair in the setting of severe functional TR. First, valve replacement yields complete elimination of TR whereas TV repair most often yields significant reduction but not complete elimination of TR. Second, valve replacement can be performed largely independently of TV

anatomic limitations such as extreme annular dilation or complex subvalvular anatomy. In contrast, the currently available transcatheter TV repair devices are often limited in their therapeutic efficacy by preprocedural TV characteristics such as extreme annular dilation. Last, by implanting a valve in the tricuspid annulus, transcatheter valve replacement opens the possibility for future valve-in-valve interventions if needed following initial valve replacement. There are four valves currently being investigated for use in the tricuspid position: Intrepid (Medtronic), Evoque (Edwards Lifesciences), LuX-Valve (Ningbo Jenscare Biotechnology), and NaviGate (NaviGate Cardiac Structures). A brief review of each will be presented here.

Intrepid Valve

The Intrepid valve was originally developed for transcatheter mitral valve replacement, and has recently been implemented in the tricuspid position as well. The valve is a self-expanding, circular, bovine pericardial trileaflet valve housed within a nitinol frame. A dedicated delivery system and the ability to recapture and retrieve the valve makes Intrepid different from other transcatheter options currently under investigation. Data from a recent first-in-man case series of three patients undergoing valve replacement with the Intrepid valve highlighted a 100% rate of successful valve deployment and implantation without complications.20 An early feasibility trial (NCT04433065) is currently ongoing in the US.

Evoque Valve

Available for compassionate use, with eligibility determined on a case-tocase basis per local heart team discussion, the Evoque valve is another transcatheter valve currently under investigation and recruiting for an early feasibility study in the US (NCT04221490). The valve has a unique frame that conforms to the shape of the tricuspid annulus, yielding the most optimal retention forces for each patient’s respective anatomy. To date, outcomes from 25 compassionate use cases with the 29 Fr transfemoral Evoque system have been reported. All patients had severe TR and right heart failure at baseline. Technical success was achieved in 92% of cases, and 30-day rates of mortality, stroke, device embolization, and MI were 0%. The proportion of patients with TR grade 0 increased from 0% pre-operatively to 88% after valve replacement. The number of patients with NYHA class III or IV symptoms was 24% after valve replacement, down from 96% at baseline.21 These promising results highlight the potential of transcatheter TV replacement. Future studies will continue to build on this existing literature while also evaluating longterm outcomes and valve performance.

LuX-Valve

The LuX-Valve is another nitinol-framed self-expanding bovine pericardial valve that has been used for transcatheter TV replacement. Currently, the device requires transapical deployment via a mini-thoracotomy. Unlike other valves that rely on outwards radial force against the annulus, the LuX-Valve uses a septal anchoring mechanism to remain in position. The LuX-Valve is unique in that it has an adaptive skirt which conforms to each patient’s annular anatomy, reducing the potential for paravalvular leak.

Outcomes from an early experience series of 35 compassionate-use cases were presented at the 2019 Transcatheter Cardiovascular Therapeutics Conference (TCT; San Francisco, CA). All patients had severe TR at baseline and all were either NYHA class III or IV. Transcatheter TV replacement with the LuX-Valve was successful in 100% of cases with no reported conversions to open surgery. At 30-day follow-up, mortality was 5.7%. There were no reported cases of pulmonary embolism, third-degree atrioventricular block, or right-coronary artery injury on follow-up.

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Transcatheter Therapies for Tricuspid Valve Repair and Replacement Significant improvements in NYHA class and 6-minute walk distance were seen after valve replacement at 30 days.22

NaviGate

The NaviGate valve is a self-expanding nitinol framed valve composed of three xenogenic pericardial leaflets. The valve is currently available in five sizes (36 mm, 40 mm, 44 mm, 48 mm, 52 mm), and requires a transapical approach for optimal positioning. Following a first-in-man case in 2016, there have been 32 compassionate-use cases of transcatheter TV replacement with the NaviGate valve worldwide. Data presented from these cases at TCT 2018 (San Diego, CA) showed that 100% of patients had either severe or torrential TR at baseline. In 100% of cases, TR was reduced to moderate or less and 96% of cases had mild TR after valve replacement. Additionally, 91% of patients were NYHA class I or II following valve replacement. The 30-day mortality rate was 12.5%. Poor baseline RV function was a reliable predictor of worse outcomes in the compassionateuse cohort.23,24 Further studies are needed to identify additional predictors of poor outcomes. The degree of RV dysfunction that should be considered limiting is also currently unknown.

Patient Selection and Current Limitations

Given the vast heterogeneity in device availability and operator experience for transcatheter TV interventions, the creation of uniformly applicable patient selection recommendations may not yet be realistic or accurate.

There are, however, several considerations and uniformly applicable principles that we will highlight here. All patients with severe functional TR should be medically optimized to the fullest extent possible prior to consideration for transcatheter TV intervention. Volume management with diuretic therapy, pharmacological neurohormonal blockage, and rate control (as well as rhythm control in selected patients) should all be titrated to the maximum extent tolerated.

Left-sided valvular disease that requires intervention should be treated prior to TV intervention. The overall health and functional status of the patient should be carefully assessed and taken into consideration.

Patients with a limited life-expectancy <1 year or with extreme fragility should continue with medical therapy only without invasive TV repair/ replacement given the limited data on clinical benefit following transcatheter TV intervention in this population.

To evaluate patients for transcatheter TV intervention, a complete multidisciplinary heart valve team assessment should take place. Device availability and institutional experience should be factored into the decision of which modality of TV intervention to perform. Pre-procedural imaging with transthoracic echocardiography and transesophageal echocardiography should be performed in order to gain complete understanding of right ventricular anatomy and function, and of TV anatomy including the leaflets, annulus and subvalvular apparatus. Based on the device under consideration and on institutional preference, multidetector CT, cardiac MRI, and coronary angiography may also be obtained during the procedural planning phase for more detailed assessment of right ventricular structure and function and of coronary anatomy with particular attention paid to the right coronary artery.

When deciding which specific transcatheter device to select for TV intervention, head-to-head comparison and prescriptive recommendations are not yet possible given the nascency of the field and the significant regional variability present in device availability and operator experience. Generally speaking, TV replacement may be a better option in patients with TV anatomy considered suboptimal for

transcatheter TV repair, such as patients with significant leaflet tethering, extreme annular dilation, and coaptation defects >10 mm. TV replacement also carries the advantage of completely eliminating TR whereas TV repair most often only reduces TR severity. The long-term benefit of complete TR elimination over TR reduction remains yet to be fully elucidated. Transcatheter TV repair may prove more beneficial when TV replacement is unable to be performed due to poor RV function, the major limiting factor for TV replacement. Deciding between the various transcatheter TV repair modalities currently available comes down to device availability and operator/institutional experience. Both annular-reshaping and leaflet-direct TV repair devices have been shown to durably reduce TR severity after repair and decrease the burden of symptoms for patients.

Unanswered Questions and Future Directions

The understanding of severe TR and its impact on patient morbidity and mortality has evolved dramatically over the past decade and the technologies and procedural capabilities available to treat severe TR have dramatically grown. As this evolution continues, the phenotype of the prototypical severe TR patient undergoing transcatheter TV intervention will likely evolve as well. Earlier detection of severe TR and earlier heart team referral prior to the onset of RV dysfunction or significant annular dilation will expand the number of potential treatment modalities operators can choose from. Heart teams will need to discover what the optimal timing for TV intervention in patients with severe TR is. Waiting too long may lead to irreversible anatomical remodeling and decreased RV function which will limit the possible treatment options. Intervening too early may lead to unnecessary risk and unclear added benefit.

The durability of both transcatheter TV repair devices and transcatheter TV valves over the long term is another unanswered question. It is possible that devices implanted within the right heart will remain mechanically intact longer than left-sided devices due to the lower pressures they are subjected to, however this hypothesis is yet to be affirmed by outcomes data due to the young state of the field. Moving forward, as transcatheter TV replacement systems evolve and experience with these systems grows, it is possible that valve replacement may become the preferred modality of intervention for severe TR due to the ability to completely eliminate it. However, whether complete TR elimination in patients with severe TR yields added benefit to postprocedural functional status and decreased mortality over TR grade reduction but not TR elimination remains unknown.

Conclusion

Valve repair and replacement play integral roles in the treatment of TR. As the number of procedures, devices, and valves under investigation continues to grow, our understanding of which interventions to use, when to use them, and for which patients will become more refined. Large patient registries such as TriValve have already been created as a collaborative means of assessing patient outcomes following TR repair.

The collection and analysis of such data is essential to address the multitude of unanswered questions remaining in the field. These questions include the identification of optimal timing for valve intervention, better understanding of the influence of various anatomical considerations on device selection, and the development of a patient selection paradigm for TV repair or replacement that yields the best outcomes in each category.

The forgotten valve no more, our understanding and therapeutic approach to TV disease is expanding and maturing now faster than ever. While TR remains a prevalent and globally undertreated valvular disorder, the future of TR interventions is optimistically bright.

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Cardiogenic Shock

Extracorporeal Life Support for Cardiac Arrest and Cardiogenic Shock Andrea Elliott, MD, ,1 Garima Dahyia, MD, ,1 Rajat Kalra, MBChB, MS, ,1 Tamas Alexy, MD, ,1 Jason Bartos, MD PhD, ,1 Marinos Kosmopoulos ,2 and Demetri Yannopoulos, MD1 1. Department of Medicine, Division of Cardiology, University of Minnesota, Minneapolis, MN; 2. Department of Medicine, Division of Cardiology, Center for Resuscitation Medicine, University of Minnesota, Minneapolis, MN

Abstract

The rising incidence and recognition of cardiogenic shock has led to an increase in the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). As clinical experience with this therapy has increased, there has also been a rapid growth in the body of observational and randomized data describing the clinical and logistical considerations required to institute a VA-ECMO program with successful clinical outcomes. The aim of this review is to summarize this contemporary data in the context of four key themes that pertain to VA-ECMO programs: the principles of patient selection; basic hemodynamic and technical principles underlying VA-ECMO; contraindications to VA-ECMO therapy; and common complications and intensive care considerations that are encountered in the setting of VA-ECMO therapy.

Keywords

Veno-arterial extracorporeal membrane oxygenation, mechanical circulatory support, extracorporeal cardiopulmonary resuscitation, hemodynamic support, cardiac arrest, cardiogenic shock, left ventricular unloading Disclosure: The authors have no conflicts of interest to declare.

Received: March 23, 2021 Accepted: July 23, 2021 Citation: US Cardiology Review 2021;15:e23. DOI: https://doi.org/10.15420/usc.2021.13 Correspondence: Andrea Elliott, University of Minnesota, Department of Medicine, Division of Cardiology, 420 Delaware St SE, MMC 508, Minneapolis, MN 55455.

E: elliotta@umn.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Shock is the physiologic state of reduced tissue perfusion resulting in anaerobic metabolism, cellular injury, and ultimately death. Tissue perfusion is maintained by adequate cardiac output (CO) and sufficient systemic vascular resistance. Cardiogenic shock (CS) is a decrease in CO leading to a state of systemic hypoperfusion and accounts for 100,000 hospitalizations annually in the US, with a reported in-hospital mortality of 27.1–41%.1–3 Historically, landmark trials have used various definitions of CS. However, it is generally accepted that refractory cardiogenic shock (rCS) is defined as systolic blood pressure ≤90 mmHg for longer than 30 minutes or when vasopressors are required to achieve a systolic blood pressure ≥90 mmHg, severely reduced cardiac index (≤1.8 l/min/m2 or ≤2.2 l/min/m2), elevated biventricular filling pressures (central venous pressure ≥10mmHg; pulmonary capillary wedge pressure ≥15 mmHg) and evidence of endorgan dysfunction related to hypoperfusion such as an arterial lactic acid >2.0 mmol/l and/or a low mixed venous oxygen saturation despite maximal pharmacological interventions such as inotropes and the above-mentioned vasopressors.4–10 Recently, the Society for Cardiac Angiography and Interventions (SCAI) published an expert consensus statement to emphasize that CS is a continuum rather than being simply present or absent in an effort to facilitate early recognition of progressive shock.11 Cardiac arrest (CA) shares a similar, albeit more imminent, final common pathway with rCS. During CA, all CO ceases, leading to low end-organ perfusion even with optimal cardiopulmonary resuscitation (CPR), and ultimately death if the return of spontaneous circulation is not achieved.

Out-of-hospital cardiac arrest (OHCA) affects approximately 378,000 patients/year in the US with a survival rate of 10.6%; and 8.5% of the total survive with good neurologic status.12 In-hospital cardiac arrest has a slightly better mortality outcome (26.7% of whom 80.3% have good neurologic status) but, overall, prognosis is still quite grim.12 The high mortality associated with both rCS and CA coupled with the failure of advances in care to improve outcomes in the past decade have made veno-arterial extracorporeal membrane oxygenation (VA ECMO) an attractive rescue strategy to provide immediate perfusion and pulmonary support while investigating and correcting the underlying pathology.1–3,12–17 Consequently, the use of VA ECMO in the management of rCS and refractory CA has increased.1–3,17–19 While many patients with CS or CA will benefit from VA ECMO, the overall outcomes for patients placed on VA ECMO remain less than ideal. To this end, it is incumbent upon the cardiology, critical care and cardiothoracic surgery communities to identify patients who may benefit in the form of neurologically intact survival, improve delivery of VA ECMO and increase the understanding of the best practices for managing VA ECMO in an effort to minimize complications and optimize recovery in a timely and cost-effective manner.

In this review, we focus on patient selection, principles of VA ECMO, contraindications, complications, and management including care after a cardiac arrest.

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VA ECMO in Cardiogenic Shock and Cardiac Arrest Table 1: Indications and Contraindications for VA ECMO Indications

Contraindications

Cardiogenic shock: • Acute MI • Fulminant myocarditis • Acute on chronic decompensated left, right or biventricular dysfunction • Peripartum cardiomyopathy • Stress cardiomyopathy • Sepsis-induced cardiomyopathy • Post-cardiotomy shock • Primary graft failure after cardiac transplant • Bridge to cardiac transplant • Myocardial contusion • Massive pulmonary embolism Refractory ventricular arrhythmias Severe hypothermia Refractory cardiac arrest; ECPR Medication overdose Amniotic fluid embolism

Absolute: • Life expectancy <1 year or severe systemic illness • DNR/DNI advanced directives • Inability to cannulate due to peripheral vascular disease Relative: • Aortic dissection • Moderate to severe aortic insufficiency • Active, uncontrollable bleeding Specific to ECPR:51,58,78–80 • Unwitnessed cardiac arrest/lack of bystander CPR • CPR >1 hour • Non-shockable presenting rhythm • Severe metabolic perturbations, e.g., lactate (>15–18 mmol/l); PaO2 <50 mmHg • Advanced age (>70–75 years)* • End tidal CO2 <10 mmHg

*Advanced age as a contraindication has a variable threshold dependent on comorbities and frailty. CPR = cardiopulmonary resuscitation DNR/DNI = do not resuscitate/do not intubate; ECPR = extracorporeal cardiopulmonary resuscitation.

Patient Selection for VA ECMO in Cardiogenic Shock and Cardiac Arrest Cardiogenic Shock

selection process for VA ECMO cannulation in rCS patients.27,28 These scores use variables that have been associated with higher mortality in patients placed on VA ECMO, including advanced age (increased risk with increased age), female sex, higher weight, impaired renal and/or liver function, previous cardiac arrest, central nervous system dysfunction, duration of intubation, peak inspiratory pressure, as well as markers of severity of cardiac dysfunction, such as lower pulse pressure prior to ECMO (<20 mmHg), elevated lactate (increasing risk with increasing levels above 2 mmol/l), reduced prothrombin activity (<50%) and elevated diastolic blood pressure prior to initiation of ECMO (>40 mmHg).27–30

Providers have various considerations when deciding if MCS is appropriate. Although a complete understanding of a particular patient’s prognosis is lacking, timely decisions regarding escalation to MSC are critical before irreversible damage from poor perfusion to end organs leads to catastrophic, irrecoverable injury; ideally, it should be initiated within 60 minutes of recognition of rCS.21 In these circumstances, MCS may be viewed as a bridge to recovery, to a decision or to a more definitive therapy such as permanent left ventricular assist device (LVAD) or heart transplant if the patient is a candidate.

Cardiac Arrest

The etiologies of CS are broad; some are listed in Table 1. Recognizing the etiology and establishing the SCAI stage of CS rapidly is critical because ongoing use of high-dose pharmacologic agents such as inotropes and vasopressors may prove inadequate or cause unintended side effects including arrhythmias and increased myocardial oxygen consumption.20 These may hinder myocardial recovery or even become life threatening if mechanical circulatory support (MCS) devices are not offered.

Further complicating the decision to offer mechanical support in the form of VA ECMO is the lack of randomized controlled trials supporting improved mortality; however, three randomized controlled trials (RCTs) – EURO-SHOCK , ANCHOR (NCT04184635) and ECLS-SHOCK (NCT03637205) – are expected to provide clarity regarding mortality benefits associated with MCS in the population of patients experiencing CS at or around the time of an acute coronary syndrome event.22 Once the need for MCS has been identified, consideration should be given to the etiology of CS as there is significant heterogeneity in survival across groups.23,24 For example, patients with fulminant myocarditis and primary graft failure after heart transplantation have a better prognosis likely owing to the higher chances of myocardial recovery.23–26 The Survival After Veno-arterial-ECMO (SAVE) score and the Prediction of Cardiogenic Shock Outcome for acute MI Patients Salvaged by VA ECMO (ENCOURAGE) score have been developed based on pre-ECMO risk factors associated with poor outcomes in an effort to help facilitate the

CA is divided into shockable, ventricular tachycardia (VT) and ventricular fibrillation (VF), and non-shockable, pulseless electrical activity (PEA) and asystole rhythms.

PEA is cardiac electrical activity that does not result in meaningful CO and is often caused by obstruction of blood flow leading to poor cardiac filling (massive pulmonary embolism, cardiac tamponade or tension pneumothorax) or profound loss of systemic vascular resistance (SVR) owing to metabolic perturbations. Low SVR ultimately leads to a precipitous fall in preload, resulting in low or no CO. Patients with VT/VF have a significantly lower mortality than those presenting in PEA arrest, in part, because of the reversible nature of the underlying pathophysiology where VT/VF is frequently seen in the setting of acute MI.31 Within minutes of myocardial ischemia, there are changes in membrane potential, calcium transport, and intracellular concentrations of potassium, which lead to a heterogeneous refractory period and an environment ripe for micro reentry circuits. In scarred myocardium or dilated cardiomyopathy, macro re-entry circuits exist that lead to VT/VF. Without intervention, VT/VF will inevitably progress to asystole, so it can be inferred that if a presenting rhythm is VT/VF rather than asystole, there is a higher likelihood the patient has had a shorter duration CA, which is associated with a better prognosis owing, in part, to a shorter duration of hypoperfusion.

VT/VF occurs in 15–30% of all OHCA patients in the US with some emergency medical services reporting higher and some lower numbers.1

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VA ECMO in Cardiogenic Shock and Cardiac Arrest However, 60–80% of all CA survivors with neurologically favorable function come from this group.13 Despite the more favorable prognosis, only 35–50% of treated VT/VF patients overall survive to discharge.31 Presumably, some portion of this group develops refractory VT/VF (rVT/VF) and patients are declared dead before admission. rVT/VF is typically defined as VT/VF that persists despite at least three defibrillation attempts during standard resuscitative efforts. Taken together, this suggests VT/VF patients have the highest potential for recovery, presenting a group in which further attempts at immediate and advanced cardiorespiratory support may be of significant benefit. Of patients with rVT/VF, 70–85% have underlying acute or chronic coronary artery disease.12,13,32–42 This supports the notion there is a potential for curative interventions if endorgan damage owing to the CA can be limited by extracorporeal cardiopulmonary resuscitation (ECPR).33,34,41 ECPR survival has historically been low, in a range of 8–38%.18,43–48 The 2020 Extracorporeal Life Support Organization (ELSO) registry reported 29% survival to discharge among ECPR patients while the total population of VA ECMO patients survival to discharge rate was 45%.17 These comparatively dismal statistics in the setting of a potentially reversible etiology has stimulated continued interest in improving the use of ECPR as a rescue therapy.

The International Liaison Committee on Resuscitation advanced life support task force commissioned a systematic review in 2018 that concluded ECPR could be considered for select patients when conventional CPR was failing (weak recommendation, low certainty of evidence).49 Similarly, the 2020 American Heart Association resuscitation guidelines offer a 2b recommendation for ECPR, citing 15 observational studies, most of which reported improved neurologically intact survival, but there were no RCTs to support the use of ECPR.50,51 Confounding these data were highly variable inclusion criteria, ECMO settings, study design, and possible selection bias.51 However, the ARREST trial, a highly anticipated prospective RCT demonstrated improvement in neurologically favorable outcome with ECPR (42.9%) compared with standard advanced cardiac life support (6%) in 30 patients. While this was a single-center, open-label trial, the promising results warrant further investigation.52 At this time, there are no clear, society-endorsed guidelines regarding when and in whom VA ECMO should be used. Given this, it is widely accepted that institutional experience will impact outcomes for this highly technical procedure that is time sensitive and requires specialized management.53 The best and most consistent outcomes in ECPR patients seem to be paired with a highly structured, community-wide approach focused on early, effective CPR followed by short-duration to VA-ECMO insertion and minimization of VA ECMO-induced complications that ultimately affect survival.54 These efforts include: programs to increase bystander CPR facilitated by 911 dispatchers; early patient identification by highly trained paramedic teams; the use of mechanical CPR devices during transport to ensure high-quality uninterrupted CPR; clear algorithms for paramedics regarding transport of patients to facilities capable of initiating VA ECMO; a specialized team available for emergent (team available within 30 minutes/on arrival to hospital, 24/7) ultrasoundguided, fluoroscopically confirmed cannulation; and, finally, a centralized intensive care unit (ICU) for post-cannulation care with technically trained nursing staff and critical care cardiologists.32,33,55,56 In an effort to further reduce the duration of low-flow state associated with CPR, some groups have trialed cannulation in a variety of settings including the emergency room and in the field. 56–58

In this emerging field, for now, it is common to rely on expert opinion and institutional experience in the decision to implement ECMO as a rescue strategy for either CA or CS. While both SAVE and ENCOURAGE scores exclude ECPR patients and the SAVE score specifically does not correlate with mortality in the ECPR population, there is some evidence that similar risk factors, among others, may influence mortality.59 In ECPR, younger age, witnessed arrests, rhythm other than asystole and recovery of mean arterial pressure are predictive of good outcomes.47,60 The ECPR score makes an effort at using these risk factors in a risk prediction model for surviving to discharge in CA patients placed on ECPR.61 In general, patient selection for VA ECMO in rCS continues to evolve but generally revolves around myocardial recovery potential or an exit strategy to some longer-term support options and selection for younger patients with few comorbid conditions. Patient selection in CA remains more opaque and decision making is more complex because interventions are needed immediately. Specific algorithms used by mature ECPR programs, similar to those presented in the ARREST trial, will begin to shape our understanding as to which patients may benefit from this rescue strategy.52

Basic Principles and VA ECMO Circuit Set-Up

VA ECMO provides full cardiopulmonary support to patients in CA or CS with or without concomitant respiratory failure. The VA ECMO circuit consists of an inflow cannula that pulls deoxygenated blood from the venous system via a centrifugal pump. Blood is passed through a hollowfiber membrane oxygenator or blood-gas exchange unit for removal of carbon dioxide and oxygenation then it is returned, via an arterial (outflow) cannula to the systemic circulation.62 The inner surface of the circuit tubing is typically coated with heparin to minimize complement activation, platelet adhesion and inflammation.63 Notably, this tubing is safe in patients with heparin-induced thrombocytopenia due to covalent binding of the heparin to the artificial surfaces.64 VA ECMO can be implemented in two forms, with the nomenclature reflecting cannulation site. Central VA ECMO can be placed by midline sternotomy or thoracotomy with cannulation of the superior vena cava, inferior vena cava, or, most commonly, the right atrium for venous access, and the aorta, subclavian/innominate or pulmonary artery for arterial return. Peripheral VA ECMO uses large-bore cannulas placed percutaneously or via Dacron grafts placed by surgical cutdown in one of several configurations. Venous access is gained through the femoral vein most commonly during CA due to the ease of cannula insertion, but, alternatively, the right internal jugular vein can be utilized.

Arterial access is most often gained in the femoral artery, although severe peripheral vascular disease can limit this option and the subclavian artery can also be accessed. It is notable that hyperperfusion of the upper extremity in the latter scenario can lead to complications such as compartment syndrome, but it does have the added benefit of potential for ambulation if paired with right internal jugular venous access.65 In femoral cannulation, the distal tip for the arterial cannula typically lies in the descending aorta or common iliac artery and the distal tip of the venous cannula lies somewhere between the superior vena cava, right atrium and inferior vena cava depending on the approach and patient size.53,66 The venous cannulas are typically multistaged, which means there are multiple perforations at various points to allow flow along the cannula. Arterial cannulas are 15 cm or 23 cm long and range in size from 15 Fr to 21 Fr, while venous return cannula are 55 cm long and range in

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VA ECMO in Cardiogenic Shock and Cardiac Arrest Table 2: Complications Associated with ECMO Use Vascular Complications

ECMO Circuit-related Issues

Vessel dissection88–90

Machine, pump thrombosis110

Vessel perforation

Hemolysis84,109

Pseudoaneurysm88–90

Harlequin, north/south or dual circulation syndrome89,119–123

88–90

Limb ischemia (poor flow or embolic events)90–92

Bleeding

Thrombosis

Access site bleeding92

Intracardiac thrombus97

Retroperitoneal hematoma

Thrombo-embolic stroke84,92,96

Intra-abdominal bleeding

Other relative contraindications include advanced age (typically >70–75 years), bleeding diathesis and prior aortic or mitral valve prosthesis due to decreased flow increasing risk for valve thrombus.75–77 The specific contraindications of ECPR are not well defined and exclusion criteria vary across studies. Table 1 outlines the commonly used exclusion criteria.52,56,58,78–80

Vascular thrombosis92

Stroke, cerebral hemorrhage

92,95,96

Pump/oxygenator thrombosis

Complications

Gastrointestinal bleeding92 Hemopericardium/hemothorax Soft tissue hematoma

Infectious Complications

End-organ Hypoperfusion

Bacteremia

Ischemic hepatitis111

Cellulitis

Acute kidney injury, acute tubular necrosis90,111–113

Ventilator-associated pneumonia95

Seizures, hypoxic brain injury95,96

118

Some relative contraindications require a multidisciplinary team discussion before proceeding. For example, some patients in whom there is no clear exit strategy in the case of failure of myocardial recovery may benefit from evaluation and consideration for a trial of cannulation as a bridge to recovery. The presence of an aortic dissection is another relative contraindication due to risks of additional fenestrations and false lumen cannulation.71–74

size from 21 Fr to 29 Fr, with the venous cannula diameter typically the flow-limiting component in the circuit.53 The amount of circulatory support provided by VA ECMO is determined by the flow rate through the circuit, which is set by adjusting the revolutions per minute on the pump. The initial goal is typically 50–70 ml/kg/min (about 3–6 l/min) and a mean arterial pressure of >60 mmHg.53 The extent of ventilation or carbon dioxide removal and oxygenation is adjusted by modifying the sweep or countercurrent gas flow and the fraction of inspired oxygen (FiO2) through the oxygenator, respectively.53,62 Due to efficiency of the oxygenator, full respiratory support can typically be provided to allow for full pulmonary rest, minimizing barotrauma so long as an adequate portion of the total CO is passing through the circuit.67 Likewise, the efficiency of the oxygenator increases the risk of hyperoxia, which is associated with worse outcomes particularly in post CA patients.68–70 Finally, most circuits contain a heater/cooling system to return blood at a set temperature. This is particularly useful with targeted temperature management in post-CA patients.

Contraindications

Absolute contraindications for VA ECMO are largely based on expert opinion and somewhat fluid (Table 2). They typically include a life expectancy of less than 1 year even with successful cardiac recovery, disseminated malignancy, previous end-stage organ failure, severe irreversible brain injury, and/or patient goals that limit aggressive measures.

Severe peripheral arterial disease can be an absolute contraindication for peripheral cannulation if access is not obtainable. Moderate to severe aortic regurgitation is at least a relative contraindication owing to the retrograde flow of VA ECMO causing severe left ventricular dilatation and subsequent pulmonary edema.

The literature surrounding complications associated with VA ECMO are highly heterogeneous with no standardized definitions. Most data are from observational studies or case reports and lack granularity. A broad range of complications are reported (Table 2), some associated with high morbidity and mortality, that must be prevented if possible, recognized early, and treated promptly when necessary.

Vascular Injuries and Leg Ischemia in Peripheral VA ECMO

Vascular complications are reported at rates of 20–30% and often potentiated due to systemic anticoagulation (AC) for the ECMO circuit (Table 2).18,19,81,82 Distal limb ischemia with peripheral cannulation is relatively common, with a reported prevalence of 17–40%.18,19,25 The risk is higher if the target vessel's diameter is not at least 1–2 mm larger than the cannula diameter.62 Additionally, leg ischemia has been associated with female sex, younger patients (30–40 years vs 50–60 years) because of to smaller vessel size and fewer collateral vessels, severe peripheral arterial disease and a cannula size over 20 Fr. 83,84 This issue has largely been addressed by the routine insertion of a distal perfusion catheter (DPC). Typically, a 5–8 Fr cannula is inserted into the superficial femoral artery or posterior tibial artery, which redirects a small portion of the arterial return flow from the ECMO circuit to the distal circulation of the cannulated limb.

Lamb et al. described leg ischemia in 33% of patients who did not receive DPC and in none of those with a catheter; the absence of leg ischemia was associated with increased survival.83 Limb perfusion should be monitored using physical examination or near-infrared spectroscopy (NIRS) placed on the bilateral calves in addition to routine Doppler evaluation of the distal extremity regardless of the presence of a DPC. Highly trained and experienced teams have lower complication rates, and percutaneous access VA ECMO initiation has lower rates of complications than surgical or hybrid approaches.52,85

Bleeding and Thrombosis

There is a delicate balance between bleeding and thrombosis risk in patients on VA ECMO, with both often occurring simultaneously.

Bleeding complications occur in 18–56% of patients.23,24,28,30,44,45,86 However, the VA ECMO circuit is itself considered prothrombotic due to blood exposure to synthetic surfaces, endothelial injury during vascular access, shear stress and platelet activation, and consumptive coagulopathies leading to hemostatic imbalances.87,88 Bleeding complications vary in severity (Table 2). Perhaps the most consequential

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VA ECMO in Cardiogenic Shock and Cardiac Arrest – intracranial hemorrhage – occurs in 2–3% of patients, and has a mortality rate of near 90%.53,86,89 Similarly, a hypercoagulable state can lead to thromboembolic events, including stroke (4–7%), limb ischemia and intracardiac thrombus, or aortic root thrombus, particularly if antegrade CO is low.77,86,89,90 Rarely, machine failure can cause thrombosis/embolization of the oxygenator or the pump. For these reasons, it is standard to use systemic anticoagulation (AC) while patients are supported with VA ECMO.77 Although debated, the use of hollow-fiber polymethylpentene oxygenators, heparin-coated tubing, and newer centrifugal pumps with limited heat generation and thrombogenicity are thought to have reduced the overall hypercoagulability of the circuit.91–94 Given these complexities, guidelines for optimal AC rely on expert opinion and there is considerable variation between institutional practices. These range from no AC to holding AC for up to 3 days in the setting of bleeding while flow remains over 3 l/min, to use of direct thrombin inhibitors such as argatroban or bivalirudin as the anticoagulant of choice, especially in the setting of heparin-induced thrombocytopenia.95–99 The ELSO 2014 AC guideline recommends that patients on VA ECMO should be targeted to an activated coagulation time (ACT) of 180–220 seconds with the use of unfractionated heparin.100 Given concerns over the poor association between ACT value and bleeding events, many institutions have moved to an anti-Xa assay strategy with a goal ACT of between 0.3 and 0.7 seconds despite little evidence in VA ECMO patients.

Some institutions use partial thromboplastin time (aPTT) and anti-thrombin III assays to further refine their AC strategy with heparin.101,102 Daily evaluation for clot formation with visual inspection of the oxygenator as it is the most common site for thrombus formation should be carried out and measures of hemolysis such as lactate dehydrogenase, plasmafree hemoglobin, and bilirubin should be monitored.77,102,103 Excessive hemolysis can be seen after large transfusions and with hematoma absorption of hematoma but also related to excessive ECMO flow/pump speed, a too-small cannula, high negative venous pressures (usually associated with circuit ‘chatter’ or swinging of the circuit tubing that occurs when maximum blood flow rate has been exceeded due to venous collapse), pump thrombosis, or a clot in the oxygenator, which would suggest a patient may benefit from modification or exchange in the circuit.

Liver and Kidney Injury

Injury to the liver (hyperbilirubinemia; 12%) and kidney (12–56%, with need for hemodialysis in ~12–15%) are common in patients on VA ECMO.83,104–108 However, it is difficult to differentiate between injury related to the inciting CS, CA or other therapies such as drug toxicity, or hypotension from injury related directly to ECMO. Masha et al. showed that, in 223 patients on VA ECMO, an increase in total bilirubin significantly correlated, in a linear fashion with mortality. In addition, no patient with a bilirubin level greater than 30 mg/dl survived, and a bilirubin level of approximately 11 mg/dl was the threshold for 90% mortality in univariate analysis, which suggests that bilirubin is an important marker of prognosis in patients on VA ECMO support and may be a sign of intolerance of the circuit.109 Alkaline phosphatase has also been reported as a predictive marker for mortality in VA ECMO.110

Infections

As with any indwelling catheter in place for a prolonged period of time, VA ECMO can be associated with cellulitis, bacteremia, and sepsis; this affects 3–18% of patients and is associated with mortality as high as 64%.81,111 In addition to line/circuit-associated infections, patients in this population are also at risk of pneumonia as with all those in ICU who require mechanical ventilation.

Harlequin, North/South, or Dual Circulation Syndrome

Harlequin syndrome is a well-described phenomenon unique to the femoral VA ECMO set-up. Cardiac contractility recovers in this scenario while alveolar gas exchange remains inadequate due to either insufficient ventilator settings or ongoing severe lung injury. Native CO increases and therefore poorly oxygenated, carbon dioxide-rich blood leaves the left ventricle (LV). Consequently, a mixing cloud develops in the proximal ascending aorta and moves distally as the native CO increases, pushing the reach of oxygenated blood provided by the ECMO circuit further distal in the aorta.

Signs of this are decreased oxygen delivery to the first branches of the ascending aorta, including the coronary arteries and the innominate artery leading to decreased oxygen delivery to the cerebral and right subclavian vessels. Accordingly, right-hand saturation and arterial blood gas monitoring and/or new or increasing discrepancy in upper extremity NIRS monitoring are critical for early identification.82,112–116 If unrecognized, this syndrome can lead to prolonged hypoxia of myocardial tissue and anoxic brain injury.

Ways to combat this phenomenon include modifying ventilator settings, increasing ECMO flow, and decreasing inotropic support, and, if these measures fail, conversion to veno-arterial-veno (VAV) configuration can be considered.111, 117–119 In the VAV setup, a portion of the oxygenated blood returning from the circuit is diverted to a second outflow cannula (flow controlled with a roller clamp) placed in a central vein with outflow at or near the right atrium. It provides pre-oxygenated blood that circulates through the pulmonary vasculature and, ultimately, is ejected from the left ventricle. Therefore, oxygen-rich blood flow to the proximal aortic branches will be restored.

Other Management Issues Left Ventricular Unloading

The physiologic changes noted in CS in the setting of left heart failure are primarily due to a decline in LV contractility. This leads to reduced stroke volume (SV), high LV end diastolic pressure (LVEDP), high pulmonary capillary wedge pressure and a neurohormonal-reflex mediated increase in systemic vascular resistance.120–122 By diverting venous blood flow into an external circuit, VA ECMO decreases systemic venous congestion and right ventricular preload.120,123,124 However, the hemodynamic effect on the LV remains debated.

Observational clinical and translational studies using computer modeling suggest higher LV stroke work and LVEDP after VA ECMO is started owing to an increase in LV afterload caused by retrograde return of blood into the arterial circulation.125–127 It has been hypothesized that increased afterload increases LVEDP and decreases SV and CO. Consequently, this increases stroke work, resulting in a decrease in coronary perfusion pressure and, in so doing, worsening myocardial ischemia and/or adversely affecting myocardial recovery.128–131 Simultaneously, increased afterload may reduce the opening of the aortic valve with each cardiac

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VA ECMO in Cardiogenic Shock and Cardiac Arrest Figure 1: Evaluation for Weaning Readiness • Have 48 hours passed?

• Underlying etiology for VA ECMO adequately resolved?

• Approaching euvolemia?

Hemodynamics • Pulsatility >30 mmHg • Low levels of inotropes/vasopressors • MAP >60–65 mmHg

Yes to all

Assess hemodynamics, end-organ function and echocardiographic biventricular function

End-organ function • Recovering/stable liver and renal function • Improving/stable metabolic derangements • Stable ventilator support (PaO2/FiO2 ~200 mmHg)

Echocardiography • LVEF ≥20–25% • Signs of RV recovery

Attempt weaning trial with invasive hemodynamic and echocardiographic assessment (Figure 2)

Basic parameters reported in the literature evaluated before weaning from VA ECMO to assess for readiness and success of a protocolized wean.157–162 VA ECMO = veno-arterial extracorporeal membrane oxygenation; PaO2 = partial pressure of oxygen; FiO2 = fraction of inspired oxygen; LVEF = left ventricular ejection fraction; MAP = mean arterial pressure; RV = right ventricle.

cycle because the LV is unable to generate pressures higher than the aortic pressure, leading to stasis of blood in the LV and thrombi formation.132,133 Conversely, recent clinical experience, including evidence from the ARREST trial and others, suggests VA ECMO support alone provides a favorable environment for myocardial recovery.52,134 Given the concerns that VA ECMO may impair myocardial recovery, there has been increased use of various LV unloading strategies. These include the infusion of inotropes or vasodilators for afterload reduction, the use of percutaneous mechanical assist devices such as an intra-aortic balloon pump (IABP) or Impella, transseptal left atrial cannulation devices, and surgical LV venting.120,127,135–143 Strategy selection often depends on patient comorbidities, complications, resource availability, and institutional preference.144 The efficacy of the most broadly used strategies, the IABP or Impella in combination with ECMO, remains largely understudied on a prospective basis.145 Meta-analyses evaluating concomitant IABP use with VA ECMO versus VA ECMO alone have not identified substantial improvement in mortality among patients with CS or CA.146–148 However, in subset analyses of patients with CS secondary to acute MI, the addition of IABP to VAECMO was associated with lower mortality.

The addition of an Impella to VA ECMO for LV unloading has been predominantly evaluated in animal, observational, and retrospective studies to date.149–150 Schrage et al. recently assessed the impact of VA-ECMO plus Impella versus VA-ECMO alone in CS in a 1:1 propensity-score-matched cohort.127 The VA ECMO plus Impella group was associated with a lower 30day mortality but had a higher rate of complications including severe bleeding, access site-related ischemia and renal replacement therapy.

A meta-analysis of 17 observational trials including patients with CS found survival benefit with an LV unloading device (IABP, Impella or transseptal LA cannula) compared to ECMO alone and found no significant difference in bleeding, organ failure, stroke, and limb ischemia.148 To date, observational clinical data favor the use of mechanical LV unloading devices in addition to ECMO with appropriate patient selection; however, clinical investigation, hemodynamic data, and physiologic changes related to each method are urgently needed to optimize future care and costs associated with VA ECMO.

Weaning and Decannulation

VA ECMO-weaning protocols, if available, vary highly between institutions, reflecting the limited literature on the topic. Only a few articles include data from large cohorts and none have a prospective approach to compare methods.151 The minimum requirement for readiness for weaning are subject to debate. In general, a weaning trial can be pursued after some degree of myocardial recovery is seen, usually after 48 hours of cannulation,improvement in liver function, and only minimal hemodynamic/ respiratory support is required.53,152–156 However, what defines minimal support is debated.

Pulse pressure waves are typically small or flat when non-functioning or minimally functioning myocardium is paired with relatively higher VA ECMO flows. Predictably, pulse pressure waves increase upon myocardial recovery. While no exact pulse pressure threshold has been established, higher pulse pressure is considered a clinical marker for readiness for a weaning trial and has been associated with weaning success.152,157,158 In addition to identifying predictors of success, a multidisciplinary discussion between the cardiology team, heart failure specialists,

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VA ECMO in Cardiogenic Shock and Cardiac Arrest Figure 2: Summary of Weaning Strategies Rapid weaning protocol •

Slow weaning protocol

Decrease flow to 2/3 flow for 10–15 min, then decrease flow to 1/3 for 10–15 min, then to a minimum of 1–1.5 l/min for at least 15 min

•

Decrease flow to 50% for 10 mins, then decrease flow to 25% for 5 mins; if tolerated, maintain 75% flow for 24 hours followed by 50% flow for another 24 hours

or •

or

Decrease flow by 0.5–1 l/min at set intervals (min)

•

lnvasive hemodynamics and laboratory values • MAP ≥60–65 mmHg • Cl >2.2–2.4 l/min/m2 and SvO2 >60 • No substantial vasopressor or inotrope use • CVP <15–18 mmHg and PCWP <18 mmHg • Stability of renal function, liver function and lactate

Decrease flow in increments of 0.5 l/min every 3–6 hours to a minimum of 2–1.5 l/min and maintain flow for 12–24 hours

Echocardiography • LVEF 20–25% with no evidence of distension, stasis or ‘smoke’ • 3D RVEF >24.6% and no evidence of distension • Aortic VTI ≥10 cm • Lateral mitral annulus peak systolic velocity ≥6cm/s

Failed weaning trial: consider optimizing hemodynamics and reattempting wean in 48 hours or durable mechanical support

Successful weaning trial: consider decannulation

Examples of faster (over minutes to a few hours) and slower (over days) weaning protocols as well as hemodynamic, laboratory and echocardiographic values evaluated during these in published protocols.157–162 MAP = mean arterial pressure; CI = cardiac index; SvO2 = mixed venous oxygen saturation; CVP = central venous pressure; PCWP = pulmonary capillary wedge pressure; LVEF = left ventricular ejection fraction; 3D RVEF, 3D right ventricular ejection fraction; VTI = velocity-time integration.

intensivists, and cardiothoracic surgeons, as well as the patient and/or their family should be considered in case of weaning or decannulation failure. Weaning algorithms that predict successful decannulation include various combinations of echocardiographic, invasive hemodynamic, and biomarker data, collected as the VA ECMO flow is slowly decreased to 1–1.5 l/min (Figures 1 and 2).77,159 Importantly, it is generally accepted that the risk for thrombus formation increases at ECMO flows below 2 l/min, and adequate AC is strongly encouraged when proceeding with the turn-down study.53 LV echocardiographic data that predicts successful weaning include higher aortic velocity-time integrals (>10 cm), LV ejection fraction (20–25%), and lateral mitral annulus peak systolic velocity (>6 cm/s) while mitral E/tissue Doppler Ea’ suggesting higher filling volumes predict worse outcomes.152 Evaluation of right ventricular parameters predictive of weaning success are less robust. A small cohort study showed that a 3D right ventricle ejection fraction of >24.6% was associated with higher weaning success and lower 30-day mortality.160 Although it is not approved in the US, a handful of studies have looked at pretreatment with levosimendan and found it may increase the chances of weaning success.161,162

ICU Considerations

Details of ICU post-arrest management are beyond the scope of this review, but the complexities of care in this setting, including nuances of targeted temperature management, post-arrest hemodynamic goals, neuroprotective strategies such as permissive hypercapnia, and

oxygenation strategies, among others, underline the importance of having a multidisciplinary team caring for VA ECMO patients.163–191 Specialists including heart failure, critical care, cardiothoracic surgery and/or vascular surgery, nephrology, palliative care and neurology physicians along with perfusionists, respiratory therapists, pharmacists, nutritionists, and specially trained nurses for a framework to care for some of the most medically complex patients in the hospital.75,192–194 While some patients will recover cardiac function allowing liberation from ECMO, others will not. It is prudent for the team caring for a patient to prioritize early identification and planning for patients who need long-term mechanical support or transplant evaluation. Commonly, the assessment for appropriateness for advanced options takes time and, if delayed, complications related to VA ECMO can become barriers to eligibility.

Conclusion

In summary, VA ECMO offers an appealing salvage therapy to patients who likely would not otherwise have any chance of survival. Our understanding of how to more effectively deliver VA ECMO combined with advances in technology have manifested as increased use of ECMO and have been bolstered by early signs in the literature that we may be able to improve outcomes. Nonetheless, knowledge gaps persist, mortality remains suboptimal, and widespread reproducibility is difficult. Expert opinion and institutional preferences largely dominate care. More rigorous prospective RCTs similar to the ARREST trial are desperately needed to standardize care in the form of guidelines to maximize survival for patients.

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187. Elmer J, Scutella M, Pullalarevu R, et al. The association between hyperoxia and patient outcomes after cardiac arrest: analysis of a high-resolution database. Intensive Care Med 2015;41:49–57. https://doi.org/10.1007/s00134-014-35556; PMID: 25472570.

188. Ihle JF, Bernard S, Bailey MJ, et al. Hyperoxia in the intensive care unit and outcome after out-of-hospital ventricular fibrillation cardiac arrest. Crit Care Resusc 2013;15:186–90. PMID: 23944204.

189. Bellomo R, Bailey M, Eastwood GM, et al. Arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest. Crit Care 2011;15:R90. https://doi.org/10.1186/cc10090; PMID: 21385416.

190. Nelskylä A, Parr MJ, Skrifvars MB. Prevalence and factors correlating with hyperoxia exposure following cardiac arrest – an observational single centre study. Scand J Trauma Resusc Emerg Med 2013;21:35. https://doi.org/10.1186/17577241-21-35; PMID: 23639102.

191. Rachmale S, Li G, Wilson G, et al. Practice of excessive FIO2 and effect on pulmonary outcomes in mechanically ventilated patients with acute lung injury. Respir Care 2012;57:1887–93. https://doi.org/10.4187/respcare.01696; PMID: 22613692.

192. Mongero LB, Beck JR, Charette KA. Managing the extracorporeal membrane oxygenation (ECMO) circuit integrity and safety utilizing the perfusionist as the ‘ECMO specialist’. Perfusion 2013;28:552–4. https://doi. org/10.1177/0267659113497230; PMID: 23873487.

193. Hackmann AE, Wiggins LM, Grimes GP, et al. The utility of nurse-managed extracorporeal life support in an adult cardiac intensive care unit. Ann Thorac Surg 2017;104:510–4. https://doi.org/10.1016/j.athoracsur.2016.11.005; PMID: 28193535.

194. Doll JA, Ohman EM, Patel MR, et al. A team-based approach to patients in cardiogenic shock. Catheter Cardiovasc Interv 2016;88:424–33. https://doi.org/10.1002/ccd.26297; PMID: 26526563.

Editorial

The Contemporary Cardiogenic Shock ‘Playbook’ Alexander G Truesdell, MD Virginia Heart/Inova Heart and Vascular Institute, Falls Church, VA

Keywords: Cardiogenic shock, cardiovascular hemodynamics, mechanical circulatory support, cardiac intensive care, multidisciplinary teams, heart transplantation Disclosure: AGT is a consultant and member of the speakers bureau for Abiomed, and is Guest Editor of the cardiogenic shock special collection for US Cardiology Review.

Received: September 9, 2021 Accepted: October 12, 2021 Citation: US Cardiology Review 2021;15:e24. DOI: https://doi.org/10.15420/usc.2020.28 Correspondence: Alexander G Truesdell, Virginia Heart/Inova Heart and Vascular Institute, 2901 Telestar Court, Falls Church, VA 22042. E: agtruesdell@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

“ You can’t really know where you are going until you know where you have been.”

– Maya Angelou1 Cardiogenic shock (CS) is a state of end-organ hypoperfusion and dysfunction, often complicated by a systemic inflammatory response, due to insufficient cardiac output despite adequate preload, secondary to left ventricular, right ventricular, or biventricular dysfunction. CS typically occurs in the setting of acute MI or acute decompensated heart failure, with or without cardiac arrest, and accounts for nearly 15% of all cardiac intensive care unit admissions.2 Inpatient mortality rates, once as high as 90%, remain elevated near 50% despite several decades of advances in pharmacological and device-based therapies, highlighting multiple unmet needs and unachieved goals in the diagnosis and management of this deadly condition.3 Complex, multidimensional, and resource-intensive problems, such as CS, typically require an organized approach to diagnosis, treatment, monitoring, and recovery. Due to the highly time-sensitive morbidity and mortality of CS, diagnosis and therapies must also be expeditious. A CS ‘playbook’ (Figure 1) may, therefore, aid individuals and teams to: visualize targets, identify capabilities and gaps, articulate critical elements for success, and distill strategies down to actionable component tasks with clearly defined individual and group roles and responsibilities to achieve desired end goals.4 “ Shock is the manifestation of the rude unhinging of the machinery of life.”

– Samuel V Gross5 The complexities of the shock syndrome, delays in illness recognition, inconsistencies in phenotype and severity definitions, barriers to access to potentially disease-modifying interventions, and undesired heterogeneities of care both within and between medical facilities all likely contribute to the persistent lethality of CS.6 The presence of multiple converging paths to death with both shock-related and shock-independent factors – to include age, cardiac arrest, organ failure, anoxic brain injury, and bleeding – also further complicate efforts to reduce disease morbidity and mortality.

In this special collection of US Cardiology Review, published contemporaneously with the multidisciplinary international SCAI Shock

2021 Virtual conference (https://scai.org/shock), a collection of worldwide multispecialty experts address the optimal contemporary ‘playbook’ for CS prevention, diagnosis, management, and research to include: advocacy and legislative initiatives, drug and device development, diagnostic frameworks and modalities, therapeutic technologies, multidisciplinary systems of care, cardiac intensive care unit management strategies, rescue and replacement innovations, ongoing clinical research efforts, and future outlook for the field. “ Without good data, we’re flying blind. If you can’t see it, you can’t solve it.”

– Kofi Annan7 Therapeutic decision-making, and appropriate drug and device selection are influenced by pre-shock cardiovascular state, extracardiac comorbidities, shock etiology and phenotype, severity of illness, and the presence or absence of concomitant respiratory failure and/or cardiac arrest. There remains much uncertainty regarding the appropriate definitions, identification, and optimal management of different etiologies, phenotypes, and stages of CS – to include appropriate targets of metabolic tissue perfusion and pump function, and preferred modalities, combinations, and sequence of pharmacological and device-based therapies.8 Shock states often encompass intersecting acute MI, acute decompensated heart failure, post-cardiotomy, pulmonary embolism, cardiac arrest, and valvular heart disease-related entities with etiologyspecific risk-related classifications and invasive hemodynamic profiles.

Understanding the relationships between disease acuity and severity, hemodynamic phenotypes, age, extracardiac organ involvement, and underlying comorbidities and pre-existing chronic illness, while challenging, is key to successful management.

As shock is a rapidly evolving condition, full-spectrum management requires vigilance and an “unblinking eye” approach to monitoring and therapy across an often prolonged and highly dynamic clinical course.

Optimal tailored care necessitates constant hemodynamic situational awareness guided by serial measured and derived hemodynamic parameters to frequently profile and repeatedly re-profile shock states to track clinical trajectories, and guide appropriate weaning and escalation

© RADCLIFFE CARDIOLOGY 2021 Access at: www.USCjournal.com

Cardiogenic Shock Figure 1: Key Components of Optimal Contemporary Multidisciplinary Cardiogenic Shock Diagnosis, Management, and Research Initiatives

Advocacy and legislation initiatives Clinical research trials

Chronic heart failure management

Drug and device development

Cardiovascular disease prevention

Early recognition of shock states

Shock protocols and shock teams

Cardiogenic shock ‘playbook’

LVAD and transplant innovation

Spoke-and-hub systems of care

Intensive care unit management

Standardized terms and definitions

Temporary mechanical circulatory support technology

Hemodynamic assessment and profiling

LVAD = left ventricular assist device.

of therapies.9 Optimal management additionally requires detailed and systematic assessments of non-cardiac organ systems, balancing the risks and benefits of individual medical investigations and interventions, while simultaneously surveilling, preventing, and managing the many complications associated with critical illness.10 “ Coming together is the beginning. Keeping together is progress.

Working together is success.”

– Henry Ford Patients in CS often deteriorate rapidly, and as shock persists, end-organ hypoperfusion, ischemia, and acidosis worsen, often irreversibly.

Successful diagnostic and therapeutic decision-making must, therefore, be both timely and rapidly effective. Use of newer advanced therapies and various forms of mechanical circulatory support often require the coordinated efforts of multiple medical specialists – to include interventional cardiologists, cardiothoracic surgeons, advanced heart failure specialists, and cardiac intensivists.

Multidisciplinary team-based, protocol-driven CS care has demonstrated promising potential to improve clinical outcomes beyond the historical 50% glass ceiling of the past three decades.11 Despite recent consensus efforts to standardize definitions, the complex hemodynamics and variable clinical phenotypes of the CS syndrome mean that the diagnosis and management of CS remains challenging, and often requires expertise across a range of medical specialties.12 Modern multidisciplinary CS teams are designed to enhance the individual strengths of component team members, streamline care delivery, and reduce care variability and disparities to optimize outcomes for these medically complex and resource-intensive patients. The Venn diagram of optimal management thus lies at the crossroads of multiple collaborating cardiovascular and non-cardiovascular specialists working together as a “team of teams.”

At the regional level and beyond, it is critical that big and small community hospitals, academic medical centers, and health systems partner for early identification and stabilization of CS patients with expedited follow-on consultation and/or transfer for definitive management. Intra- and interinstitutional case and process reviews are critical to identify

successes, failures, opportunities for improvement, and specific tasks and timelines to become continuously learning and improving organizations. “ Look to the future because that’s where you’ll spend the rest of your life.”

– George Burns Five key treatment objectives have been increasingly promoted in the acute management of CS: circulatory support, ventricular support, myocardial perfusion, decongestion, and prevention and management of extracardiac critical illness. Although the optimal recipe for successful management of acute MI and acute decompensated heart failure CS remains to be discovered, thus far the “playbook” appears to be: appropriate patient selection and triage, hemodynamically guided diagnosis and treatment, dynamic management algorithms and protocols, combined pharmacological and device therapies, and collaborative multidisciplinary team-based cardiac intensive care unit care.13 Beyond initial stabilization and management strategies, we must continue to pursue ongoing innovations in chronic heart failure pharmacological therapies, as well as temporary and durable ventricular assistance and heart transplantation to maximize heart recovery, reduce symptoms, prevent sudden cardiac death, and provide feasible options for nonrecoverable patients.14,15 There is also a parallel need for legislative efforts to develop structured local and regional shock care networks with a tiered model for care delivery for this sickest population of cardiac patients.16 While clinical trials that evaluate drugs, devices, and best practices for CS have been challenging to conduct and slow to enroll, they remain critically important to scientific progress. Barriers to generating high-quality evidence include: non-standardized definitions of CS, heterogeneity of study inclusion criteria, the rapid lethality of CS and associated time-sensitivity of diagnostic and therapeutic interventions, multiplicity of pathways to death, overlapping interactions of technologies and systems of care, and difficulties in achieving informed consent in emergency conditions and situations. Looking forward, we must continue to work collectively to overcome these barriers to generating high-quality evidence.3,17 Although the journey may be long, the destination is vitally important to us all.

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Cardiogenic Shock 1. America’s Renaissance Woman. Academy of Achievement.

January 22, 1997. https://achievement.org/achiever/mayaangelou/#interview (accessed November 12, 2021) 2. Berg DD, Bohula EA, van Diepen S, et al. Epidemiology of shock in contemporary cardiac intensive care units. Circ Cardiovasc Qual Outcomes 2019;12:e005618. https://doi. org/10.1161/CIRCOUTCOMES.119.005618; PMID: 30879324.

3. Samsky M, Krucoff M, Althouse AD, et al. Clinical and regulatory landscape for cardiogenic shock: a report from the Cardiac Safety Research Consortium ThinkTank on cardiogenic shock. Am Heart J 2020;219:1–8. https://doi. org/10.1016/j.ahj.2019.10.006; PMID: 31707323.

4. Truesdell AG, Tehrani D, Singh R, et al. ‘Combat’ approach to cardiogenic shock. Interv Cardiol 2018;13:81–6. https://doi. org/10.15420/icr.2017:35:3; PMID: 29928313.

5. Gross SG. A System of Surgery: Pathological, Diagnostic, Therapeutic, and Operative. Philadelphia: Lea & Febiger, 1872.

6. Vallabhajosyula S, Dunlay SM, Barsness GW, et al. Hospitallevel disparities in the outcomes of acute myocardial infarction with cardiogenic shock. Am J Cardiol 2019;124:491– 8. https://doi.org/10.1016/j.amjcard.2019.05.038; PMID: 31221462.

7. Annan K. Data can help to end malnutrition across Africa.

Nature 2018;555:7. https://doi.org/10.1038/d41586-01802386-3; PMID: 29493625.

8. van Diepen S, Katz JN, Albert NM, et al. Contemporary management of cardiogenic shock: a scientific statement

9.

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from the American Heart Association. Circulation 2017;136:e232–68. https://doi.org/10.1161/ CIR.0000000000000525; PMID: 28923988.

Thayer KL, Zweck E, Ayouty M, et al. Invasive hemodynamic assessment and classification of in-hospital mortality risk among patients with cardiogenic shock. Circ Heart Fail 2020:13:e007099. https://doi.org/10.1161/ CIRCHEARTFAILURE.120.007099; PMID: 32900234.

Fordyce CB, Katz JN, Alviar CL, et al. Prevention of complications in the cardiac intensive care unit: a scientific statement from the American Heart Association. Circulation 2020;142:e379–406. https://doi.org/10.1161/ CIR.0000000000000909; PMID: 33115261.

Moghaddam N, van Deipen S, So D, et al. Cardiogenic shock teams and centres: a contemporary review of multidisciplinary care for cardiogenic shock. ESC Heart Fail 2021;8:988–98. https://doi.org/10.1002/ehf2.13180; PMID: 33452763.

Baran DA, Grines CL, Bailey S, et al. SCAI clinical expert consensus statement on the classification of cardiogenic shock. This document was endorsed by the American College of Cardiology (ACC), the American Heart Association (AHA), the Society of Critical Care Medicine (SCCM), and the Society of Thoracic Surgeons (STS) in April 2019. Catheter Cardiovasc Interv 2019;94:29–37. https://doi.org/10.1002/ ccd.28329; PMID: 31104355.

Tehrani BN, Truesdell AG, Psotka MA, et al. A standardized

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and comprehensive approach to the management of cardiogenic shock. JACC Heart Fail 2020;8:879–91. https:// doi.org/10.1016/j.jchf.2020.09.005; PMID: 33121700.

Writing Committee; Maddox TM, Jannuzi Jr JL, et al. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;77:772–810. https://doi.org/10.1016/j.jacc.2020.11.022; PMID: 33446410.

Miller L, Birks E, Guglin M, et al. Use of ventricular assist devices and heart transplantation for advanced heart failure. Circ Res 2019;124:1658–78. https://doi.org/10.1161/ CIRCRESAHA.119.313574; PMID: 31120817.

Tchantchaleishvili V, Hallinan W, Massey HT. Call for organized statewide networks for management of acute myocardial infarction-related cardiogenic shock. JAMA Surg 2015;150:1025–6. https://doi.org/10.1001/ jamasurg.2015.2412; PMID: 26375168.

Arrigo M, Price S, Baran DA, et al. Optimising clinical trials in acute myocardial infarction complicated by cardiogenic shock: a statement from the 2020 Critical Care Clinical Trialists Workshop. Lancet Respir Med 2021;9:1192–1201. https://doi.org/10.1016/S2213-2600(21)00172-7; PMID: 34245691.

Lifetime Management of Aortic Valve Disease

Shockwave and Non-transfemoral Transcatheter Aortic Valve Replacement Eden C Payabyab, MD ,1 Lindsay S Elbaum, MD ,2 Navneet Sharma, MD,2 Isaac George, MD,3 and Stephanie L Mick, MD1 1. Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York City, NY; 2. Division of Cardiology, Department of Medicine, Weill Cornell Medical College, NewYork-Presbyterian Hospital, New York City, NY; 3. NewYork-Presbyterian Hospital, Columbia University Medical Center, New York City, NY

Abstract

Transcatheter aortic valve replacement (TAVR) has become a widely adopted treatment modality for severe aortic stenosis. Transfemoral access is the approach of choice; however, approximately 25% of patients undergoing TAVR also have concomitant peripheral arterial disease.

The recent advent of intravascular lithotripsy has enabled preservation of transfemoral access in some patients; although, a proportion still require alternative, non-femoral access. Alternative access sites can be broadly categorized into transthoracic and peripheral, facilitated by surgical or percutaneous techniques. In this review, the technical details and clinical outcomes of various TAVR accesses are discussed. Initially, transthoracic approaches were most common, but recently, the trend has been toward alternative peripheral access due to superior outcomes.

Although there are no randomized data to support all the alternative access sites, the experiences reported provide available options for a large portion of patients to be candidates for TAVR. The intervention site should be selected by a multidisciplinary heart team based on patient anatomical factors and institutional expertise.

Keywords

Transcatheter aortic valve replacement, alternative access, Shockwave, transcarotid, transaxillary, transcaval, transthoracic Disclosure: The authors have no conflicts of interest to declare.

Received: 12 May 2021 Accepted: 22 September 2021 Citation: US Cardiology Review 2021;15:e25. DOI: https://doi.org/10.15420/usc.2021.16 Correspondence: Stephanie L Mick, Department of Cardiothoracic Surgery, 525 East 68th St, Suite M404, New York City, NY 10065. E: slmick@med.cornell.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve replacement (TAVR) has become a widely adopted treatment modality for the treatment of severe aortic stenosis.

Successful implementation of TAVR requires vascular access that is suitable to accommodate the delivery systems. Advances in sheath and delivery system designs have led to smaller profile devices and expandable sheaths that can be successfully delivered via the transfemoral (TF) approach. The transfemoral TAVR approach, as compared with surgical aortic valve replacement (SAVR), has become the approach of choice for patients due to its ease of use, ability for early mobility, allowance of awake procedures and fast track protocols, and avoidance of surgical incisions. Its superiority as a first-line approach has been confirmed in numerous registries, and also in the PARTNER high- and intermediate-risk studies, in which significantly improved clinical outcomes, such as death and stroke, were demonstrated for the TF approach over transaortic or transapical access.1–4 However, it is estimated that one-quarter of the patients undergoing TAVR also have concomitant peripheral arterial disease.5 Despite technological advances, a recent analysis of the Transcatheter Valve Therapy registry showed that 7.6 % of TAVR required non-transfemoral, alternative access.6 Alternative access sites can be broadly categorized into transthoracic and peripheral approaches, facilitated by either surgical or percutaneous techniques. Transthoracic approaches include transapical, transaortic, and subclavian access. Peripheral options include transaxillary, transcarotid, and transcaval access (Figure 1). Current American and European guidelines both recommend TF approach as the access of

choice, but do not provide guidance in choosing between various alternative access choices.1,7 In this review, we discuss the technical details and clinical outcomes of various TAVR access approaches for patients with unfavorable transfemoral anatomy.

Shockwave

In patients with calcified iliofemoral vessels with luminal diameters of marginal, but not prohibitive, size, intravascular lithotripsy (Shockwave IVL; Shockwave Medical) is a technique that utilizes electro-hydraulically generated high-speed sonic waves that provide mechanical energy to selectively disrupt vascular calcium. Disruption of intimal and medial calcium in peripheral vessels results in increased compliance without vessel recoil and allows for large bore sheath delivery. IVL balloon catheters are compatible with 6 or 7 Fr sheaths, delivered over 0.014-inch coronary wires, and range from 5.0 mm to 7.0 mm in diameter. This technology has gained Food and Drug Administration approval for use in calcified peripheral arteries in June 2017.8 There are several advantages to IVL. First, IVL distributes sonic pressure waves equally across the lumen diameter and is not subject to guidewire bias. Second, since the IVL balloon is utilized at low pressures, there is a lower risk of vascular injury compared with balloon angioplasty, including dissections and perforations. In fact, the Disrupt PAD III study showed a significantly lower rate of flow-limiting dissections, 1.4% versus 6.8% in IVL compared with balloon angioplasty, and no perforations in the IVL group.9 Finally, IVL theoretically could be expected to reduce the risk of distal

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Shockwave and Non-transfemoral TAVR Figure 1: Alternative Access Transcatheter Aortic Valve Replacement Sites

Transcarotid Transaxillary*

Transaortic

Innominate

Transapical

Transcaval Transfemoral

Peripheral surgical access Thoracic surgical access Peripheral non-surgical access

*Transaxillary access has been described as surgical and peripheral in the literature.

atheromatous embolization, but this has not yet been demonstrated by data.

Therefore, IVL is an important treatment option in concomitant aortic stenosis and peripheral arterial disease to maintain the TF approach.

Given these advantages of using IVL, its indicated use has been expanded to treat calcified and stenotic vascular anatomy. Disadvantages to its use include its very high cost, which is not reimbursable, and challenging bailout situations if major aortoiliac injuries occur. Iliac artery calcification is the primary reason for abandoning the TF approach to TAVR.10,11 Small (n=42) multicenter registry data have shown promising results with successful TAVR in all patients with treated vessels. It is worthwhile to note that in this group of patients, 80% received 14 Fr sheaths, likely chosen because of the smaller diameter and deliverability in calcified and tortuous anatomies.11 Further data are ongoing and will help provide guidance for the use of IVL in TAVR.

Transthoracic Approaches

During workup for TAVR, assessment of iliofemoral anatomy may show inadequate lumen diameter, excessive tortuosity, and calcification.

Luminal diameter must be large enough to accommodate delivery sheath size. Femoral artery calcification has been identified to be predictive of vascular complications in TF TAVR.12 In cases of inadequate luminal diameter and high-risk peripheral anatomy, a transthoracic approach can be considered.

Transapical

The transapical TAVR (TA-TAVR) was the first alternative transthoracic access described. TA-TAVR requires general anesthesia and is most often performed in a surgical hybrid suite. A thorough workup of pulmonary and ventricular function should be undertaken in patients considered for TATAVR. The left ventricular apex is approached using an anterolateral minithoracotomy in the fifth or sixth intercostal space. Two apical purse-string sutures are placed, allowing for the apex to be punctured, followed by wire, sheath, and device delivery insertion.13,14 Patients who have undergone TA-TAVR have typically been the most comorbid patients; for instance, with the highest EuroScore and Society of Thoracic Surgeons (STS) scores. The TA approach was an integral part of

the original PARTNER trial, which included 1,100 patients who underwent TA-TAVR. In PARTNER A, TA-TAVR was associated with higher early mortality and stroke compared with TF-TAVR.15 These results were reassessed by Blackstone et al. using a propensity analysis in an effort to determine whether these results were attributable to the procedural risk of TA-TAVR or to patient selection factors.16 In this analysis, more adverse periprocedural events and a longer recovery time were demonstrated for TA-TAVR, but with equivalent incidence of stroke and lower incidence of significant aortic regurgitation in the TA-TAVR group. Based on these results, the TF approach was recommended as the first access strategy if anatomically feasible.

At the conclusion of the randomized PARTNER trial, the group continued to enroll patients into a non-randomized continued access cohort. The randomized cohort included 104 transapical and 92 surgical aortic valve replacements in the TA group. A total of 975 patients were enrolled in the non-randomized continued access group. The study analyzed the outcomes in the non-randomized TA-TAVR group and compared them with the outcomes of the SAVR randomized group. The groups had no difference in STS-predicted risk of mortality, but the non-randomized TA cohort was older and had a higher incidence of prior cardiovascular interventions. The study showed equivalent 30-day, in-hospital, and 1-year mortality. There was a lower incidence of 30-day or in-house stroke mortality and overall neurological events among the non-randomized TA group compared with patients randomized to SAVR. The favorable outcomes of the TA group may be attributable to patient selection factors in this non-randomized study.16 The evaluation of SAVR versus TA-TAVR in intermediate-risk patients was reported in a subgroup analysis of the PARTNER II trial. The analysis showed no significant difference in death from any cause or stroke between the SAVR and TA-TAVR groups, suggesting no specific advantage of TA-TAVR over SAVR in moderate-risk patients.3 Furukawa et al. compared minimally invasive aortic valve replacement versus transapical TAVR versus transfemoral TAVR in intermediate-risk patients.17 Occurrence of stroke, perioperative MI, and mortality were similar among the three groups. Each group had varying periprocedural complications. Although there was no statistical difference in survival, there was a trend toward worse survival in the TA-TAVR group compared with both the TF-TAVR and SAVR group. The study highlights the importance of carefully evaluating patient characteristics to determine the most appropriate approach for aortic valve replacement.

Transaortic

Transaortic (TAo) is an alternative transthoracic approach available to patients with anatomy unsuitable for transapical, such as chest wall deformity, poor pulmonary function, or decreased left ventricular function.

The approach avoids a thoracotomy, decreasing the incidence of pain, and minimizes the effect on respiratory status, which may contribute to the decreased length of hospital stay in this approach compared with TA.18 Avoiding a left ventricular incision decreases the risk of myocardial injury and left apical bleeding.19 Because of these advantages, the TAo approach quickly supplanted the TA approach among TAVR operators. The use of a transaortic approach is limited in patients with heavily or circumferentially calcified ascending aortas.

Access to the ascending aorta is obtained using an upper hemisternotomy or right mini-thoracotomy (in select cases). A pericardial incision is created to expose the ascending aorta. Two pledgetted sutures in a purse string or U-stitch configuration are placed at the selected location to allow for

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Shockwave and Non-transfemoral TAVR direct needle puncture of the aorta. A soft wire is introduced, the aortic valve is crossed, and a sheath is placed to allow for introduction of the delivery device and valve deployment.20 Dunne et al. performed a systematic review comparing the short-term outcomes of transapical and transaortic approaches for TAVR.21 The review included 60 articles with a study population of 9,961 patients, which included 342 transaortic patients and 9,619 transapical patients.

They reported similar baseline characteristics for the two groups. The 30day mortality in the transaortic group was 7.9%, which was slightly lower compared with 9.7% seen in the transapical group. Statistical significance was not met when evaluating the stroke rate, but a trend toward a lower rate was seen in the transaortic group. The occurrence of conversion to a surgical valve, paravalvular leak, pacemaker requirement, and major bleeding were equivalent in the two groups.

Long-term outcomes comparing the two transthoracic approaches were evaluated by Lardizabal et al.22 This single-institution retrospective evaluation compared the 1-year and longer outcomes of patients who underwent TAo and TA-TAVR. All-cause 30-day mortality was similar in both groups. The long-term, all-cause death at 1 year was higher in the TA-TAVR group, which may be attributable to the higher degree of comorbidity in the TA group, who had a higher median STS score.

Peripheral Access

In patients who are not candidates for standard TF TAVR, guidelines endorse a surgical option to be re-evaluated.23 However, with advancements in TAVR techniques and device profiles, non-femoral peripheral (n-FP) accesses (transcarotid and trans-subclavian/axillary) have arisen as safe and efficacious alternatives with similar outcomes to TF. The largest experience comparing femoral peripheral (FP) access and n-FP comes from Beurtheret et al. in their multicenter analysis of data from the FRANCE TAVI registry of n-FP procedures performed from 2013 to 2017.23 All 1,613 n-FP cases utilized a surgical approach. The n-FP cohort was a sicker population with higher mean logistic EuroSCORE, and higher rates of peripheral vascular disease and cardiopulmonary comorbidities than the TF counterpart. After propensity score-based matching of patients with FP and n-FP interventions, the groups had similar outcomes at 30 days, with no differences in post-procedural death, access site complications, or stroke. However, patients in the n-FP group experienced a twofold lower rate of major vascular complications and unplanned vascular repairs.

Transcarotid

In patients with challenging iliofemoral anatomy unsuitable for transfemoral TAVR, a transcarotid option can be explored. The patient’s anatomy is evaluated for TAVR workup using CT imaging and Doppler ultrasound. Carotid artery dimensions with a luminal diameter of ≥6 mm are sought, and significant stenosis ≥50% or plaque at high risk of embolization should be ruled out. Careful evaluation for other contraindications to the transcarotid approach should also be assessed, which include subclavian, vertebral, carotid stenoses or occlusion, or aortic arch variants. The patency of the circle of Willis, which is important to provide flow from the contralateral carotid during a transcarotid approach, should also be evaluated using imaging, including cerebral magnetic resonance angiography and transcranial Doppler ultrasound.24 An incision is made along the anterior sternocleidomastoid border above the clavicle to expose the common carotid artery at the level of the

omohyoid muscle. The carotid sheath is incised and mobilized, allowing for encircling vessel loops to be placed for distal and proximal control. A micropuncture kit is typically used to enter the artery and exchanged for a 5 Fr sheath. Once the aortic valve is crossed and the delivery wire is in place in the ventricle, the vessel loops are then tightened and the distal common carotid artery may be clamped to prevent distal embolization during delivery sheath placement and valve deployment (depending on surgeon preference). A transverse arteriotomy is typically created to allow for delivery sheath passage. After valve deployment and system removal, the artery is back bled and closed or repaired primarily.24–26 Carotid exposure can be performed under local anesthesia and conscious sedation or general anesthesia. Debry et al. compared outcomes between the two types of anesthesia. They found no difference in 30-day or 1-year mortality, or 1-month clinical efficacy or early safety.27 In their cohort, they found a higher rate of stroke and transient ischemic attacks in the general anesthesia group compared with the local anesthesia group. Ultimately, though, the choice of anesthesia at a given institution will be dependent upon the heart valve team’s experience and expertise.

One cited advantage of the transcarotid approach, as compared with, for instance, a subclavian approach, is the shorter distance to the aortic valve, which allows for favorable device control.28 Safety outcomes are similar to TF-TAVR. Watanabe et al. demonstrated non-inferiority of transcarotid to TF in their retrospective study examining 30-day outcomes of 726 patients.29 There were no significant differences in 30-day mortality (8.4% versus 5.0%) or stroke rate (1.2% versus 2.6%) in the transcarotid versus TF groups, and both had similar favorable outcomes with regard to echocardiographic parameters. There was a trend toward increased major vascular complications in the TF cohort. Fluoroscopy time and radiation exposure were significantly shorter in the transcarotid group.

Overtchouck et al. reported outcomes of 314 patients who underwent transcarotid TAVR who were ineligible for TF TAVR. All cases were performed under general anesthesia and predominantly utilized the left carotid artery. The stroke or transient ischemic attack rate was 1.4%, with a 30-day mortality of 3.2%, similar to rates of the TF approach in PARTNER II.3,24 The transcarotid approach has also been compared with transthoracic approaches. Chamandi et al. considered a multicenter consecutive cohort of patients who required alternative access TAVR. In this cohort, 101 patients underwent transcarotid approaches, while 228 underwent transthoracic approaches. There were similar rates of 30-day mortality, stroke, need for new pacemaker, and major vascular complications between groups, but the transcarotid TAVR group experienced less newonset AF, bleeding, and acute kidney injury, and had a shorter median length of stay. The results of this cohort suggest a clinical benefit of transcarotid compared with alternative transthoracic access options.30 Allen et al. compared short- and medium-term outcomes in a retrospective study of patients with similar risk profile and STS score undergoing transcarotid versus transapical and transaortic access for TAVR.26 They found a trend toward lower 30-day mortality in the transcarotid group, and significantly improved survival at 2 years in favor of transcarotid access. Additionally, the transcarotid group experienced shorter hospital length of stay, fewer transfusions, and more frequent discharges home than the central access cohorts. There was no difference in stroke rate at 30 days, 2.4% in the transcarotid, 3% in the transaortic, and 2.1% in the transapical group.

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Shockwave and Non-transfemoral TAVR Transaxillary/Subclavian

The axillary/subclavian artery is an additional peripheral vessel alternate to the femoral or carotid arteries. The use of the axillary artery for TAVR has traditionally been through a surgical cutdown followed by direct arterial puncture or via a Dacron graft conduit. The axillary artery is approached in the deltopectoral groove lateral to the pectoralis muscle, whereas the subclavian artery requires an infraclavicular incision medial to the pectoralis minor.31 In the direct arterial puncture approach, direct repair of the artery is typically undertaken. The axillary artery is a more fragile vessel than, for instance, the femoral artery; its decreased tensile strength and compressibility can be attributed to its diminutive media layer. This, along with its close anatomical relationship to the brachial plexus, has led many to prefer the surgical approach; however, percutaneous access is also possible and is growing in popularity.32,33 The percutaneous approach is performed using direct puncture in the deltopectoral groove using ultrasound and fluoroscopic guidance with contrast injected via the brachial artery, or by placing a wire from the femoral artery into the axillary artery for guidance with fluoroscopy.31 After valve deployment, the access site is closed using percutaneous closure devices.34 Achieving hemostasis can be challenging at times, as the clavicle prohibits direct pressure application to the artery. When considering the axillary artery for alternative access, vessel size, tortuosity, presence of a patent internal thoracic mammary conduit, angulation of the subclavian to the arch, and the aortic root angle must be evaluated.

The left axillary artery is more often used given the more direct course to the aortic annulus, allowing for a larger range of aortic root angles.32 Subclavian/axillary access has also been found to have equivalent outcomes to those of TF in the propensity matched analysis of patients from the CoreValve (Medtronic) US Pivotal Trial Program.35 General anesthesia was used in 99% of the trans-subclavian cohort, and 96% underwent a surgical cutdown; the remainder were performed percutaneously. There was no difference in procedural times, all-cause mortality, major vascular complications, stroke, or bleeding at 30 days and 1 year. Dahle et al. analyzed the frequency of transaxillary TAVR in the Transcatheter Valve Therapy registry report.36 The analysis showed that transaxillary TAVR is the most frequently used alternative access with high procedural success (97.4%) and low vascular complication risk (2.5%).

There was a 30-day stroke rate of 6.1%, which is higher than reported rates in the high and intermediate cohorts of the PARTNER trial; the reason for the high event rate is unclear from the data.

At many centers, the transaxillary approach has evolved to be the alternative access option of choice. Kindzelski et al. reported their group’s experience with alternative access from 2006 to 2019, which included 2,446 TAVR patients (342 transthoracic and 56 transaxillary). They found that patients who underwent a transaxillary approach required fewer blood transfusions, less prolonged ventilation, and shorter length of stay compared with transthoracic approaches. Survival and major morbidity were similar in the matched comparisons of the transfemoral and transaxillary approaches. No brachial plexus injuries occurred with transaxillary access.37

Comparison of Carotid and Subclavian Outcomes

A small, single-center, retrospective study found similar safety and efficacy outcomes comparing the transcarotid and trans-subclavian TAVR.38 All but one of the 71 patients evaluated underwent surgical cutdown under general anesthesia. The transcarotid approach had a shorter procedural time, and a trend toward less fluoroscopy time and

radiation exposure. In-hospital and 30=day post-procedural outcomes were similar between the groups. There were no differences in mortality, composite major bleeding and vascular complications, perioperative blood transfusion, or need for a postoperative permanent pacemaker at these time points. The 0% and 3% 30-day mortality in the transcarotid and trans-subclavian group, respectively, was substantially lower than in previous studies. The 30-day stroke risk was not statistically different between the groups.

The risk of stroke is of particular concern when accessing the carotid or subclavian/axillary artery. The 2016 study by Mylotte et al. evaluating 96 elderly patients in the French Transcarotid TAVR Registry had an overall 30-day transient ischemic attack/stroke risk of 6.3%.39 A variety of potential mechanisms of stroke during transcarotid TAVR have been proposed: embolization from arterial puncture, access site trauma leading to in situ thrombosis, inadequate contralateral perfusion, and embolization of debris from the calcified aortic valve. While seemingly counterintuitive, it has been suggested that the risk of embolization of debris may actually be reduced with the carotid artery sheath occluding the neck vessel during transcatheter heart valve deployment.

While data suggest equivalent patient outcomes between the two approaches, a few additional factors are worth mentioning. Some particularly favor the right transcarotid for its very direct path to the aortic valve, simplifying TAVR prosthesis deployment. Others favor the left common carotid artery, as its anatomical location minimizes any potential injury or embolization to the innominate artery that feeds the right carotid and vertebral distribution.38 Axillary/subclavian cutdown may be challenging in obese patients. However, other experts prefer trans-subclavian for its close proximity and relatively straight course to the annulus.35 Additionally, there is a theoretical decreased stroke risk with use of the left subclavian, as it only traverses the left vertebral artery territory.31 The selection is often dictated by the vessel with larger size and least tortuosity along with the level of expertise of the surgical team in arterial exposure and handling.

Suprasternal Direct Innominate Artery

A more recent method is the use of the innominate artery with a suprasternal approach, avoiding a sternotomy or thoracotomy for alternative access TAVR. Under general anesthesia, an incision is made at the suprasternal notch, the platysma is divided, and the strap muscles are mobilized, exposing the avascular plane over the trachea. Blunt dissection behind the sternum between the innominate artery and vein, with division of the right sternothyroid muscle, exposes the anterior surface of the innominate artery. Two Prolene purse-string sutures are placed to allow for access and placement of the sheaths and delivery system of the TAVR. Once the valve is deployed, the system is removed, and the purse strings are tied down to obtain hemostasis at the access site.40 The use of the suprasternal approach has been shown to be a safe alternative approach in patients who are not candidates for TF TAVR.41,42 Eudailey et al. retrospectively reviewed patients who underwent suprasternal TAVR. A total of 84 patients underwent suprasternal TAVR, all of whom had technical success with a 30-day survival of 98.8% and no transient ischemic attacks or strokes, with a low incidence of any major bleeding or return to the operating room for bleeding. They found the technique to be safe and reliably reproducible.43

Transcaval

Transcaval access is accomplished through the creation of an aortocaval tract, and makes use of the IVC and retroperitoneal pressure gradient,

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Shockwave and Non-transfemoral TAVR Table 1: Advantages and Disadvantages of Alternative Transcatheter Aortic Valve Replacement Access Methods Access

Use (%)

Advantages

Disadvantages

Transapical

<5%

Short distances to aortic annulus No limitation to sheath size

Requirement of minithoracotomy and left ventriculotomy Increased risk of bleeding, false aneurysm

Transaortic

<5%

Avoids thoracotomy Use in patients with chest wall deformities, poor pulmonary function, or decreased left ventricular function Decreased incidence of pain, effect on respiratory status

Requires hemisternotomy or anterior thoracotomy Limited use in patients with calcified aortas

Transcarotid

10%

Can be performed under sedation Shorter fluoroscopy time and less radiation Shorter hospitalization time and early ambulation Lower incidence of AF and acute kidney injury

Increased risk of stroke (requires evaluation of intact circle of Willis)

Transaxillary/subclavian

35%

Can be used as safe alternative vascular access in patients with calcified aortas Percutaneous option

Arterial characteristics, diminutive medial layer and decreased tensile strength Relative contraindications with ipsilateral patent internal mammary arterial grafts Required vessel size, tortuosity, and angulation of the subclavian artery to the aortic arch

Suprasternal innominate artery

<5%

Avoids sternotomy/thoracotomy Use in obese patients Decreased risk of TIA or strokes

Limited in use in select centers

Transcaval

<1%

Avoids sternotomy/thoracotomy Maintains advantages of transfemoral access

Access and closure require substantial operator experience High resource utilization

TIA = transient ischemic attack.

such that blood from the aorta shunts to the IVC through the tract. The key to planning for transcaval access is identifying a non-calcified aortic segment below the renal vessels and above the aorto-iliac bifurcation that can be stented with a covered graft if a bailout is required, but also close enough to the venous puncture site that can accommodate a 35–40 cm sheath.44,45 A guiding catheter is placed in the IVC with a heavy tip load wire (e.g.

Confianza pro 12 or Astato 20; Asahi) on a 0.014–0.035 inch wire converter piggyback catheter that will later facilitate exchange for a 0.035-inch Lunderquist wire. The back end of the venous wire is attached to an electrocautery via a hemostat. The 0.014 inch wire is advanced from the venous side to arterial side as 50-W cutting energy is applied for 1–2 s.

Once aortic position is confirmed, the 0.014 inch wire is snared and together advanced to the ascending aorta, and then exchanged for a Lunderquist via a 0.035 inch microcatheter.44,45 Following this, TAVR proceeds in the same stepwise fashion as TF TAVR. The closure of the transcaval site requires careful maneuvering of the closure device and the TAVR sheath to avoid aortic injury and premature or partial removal of the sheath, because this can result in retroperitoneal bleeding, as the aortic IVC channel is occluded. The choice of closure device depends on the length of the aortocaval tract, with AmplatzerTM muscular ventricle septal defect occluders used for tracts <7mm and Amplatzer duct occluders used for longer tracts. The diameter of the device is selected based upon the size of the sheath used.44 Mild aortocaval fistulas after closure device placement are common; any fistula with more than mild extravasation or hemodynamic compromise requires further investigation.

Early experience from transcaval TAVR studies has shown encouraging results.45 Device access and closure were successfully performed in 98 of 100 patients, with overall inpatient survival of 96% and 30-day survival of 92%. A total of 35% of patients required two or more units of blood

transfusion post-procedurally, and overall, 12% of patients were adjudicated as having life-threatening or major bleeding by the VARC-2 criteria. Vascular complications occurred in 13% of patients, and eight patients required covered stents. Further, post hoc multivariate analysis showed a significant increase in bleeding and vascular complications with lower center experience. Aortocaval fistulas were present in 64% of patients immediately after closure device deployment, which was reduced to 36% by 30 days on follow-up with CT and angiography. Four patients required covered stent placement due to ongoing extravasation, intolerable left to right shunt, or closure complications. One-year followup of the same cohort showed 71% survival. Additionally, 93% of fistulas were shown to be closed by CT, only one remained patent. There were no cases of occluder device fracture or migration.46 It is evident that transcaval access is more involved compared with shockwave-assisted TF access. Anatomically, transcaval access requires a calcium-free window in the aorta and absence of bilateral iliofemoral disease that are required for snare maneuvers or for bailouts. Moreover, safe transcaval access and closure requires operator experience and a substantial learning curve. Further, transcaval access also requires longer length of stay (2 days versus 4 days, p<0.001) and greater resource utilization. Despite the disadvantages, transcaval access seems to have similar procedural mortality, 30-day readmission rates, and 1-year survival compared with TF access.47 Therefore, avoiding surgical chest access via transcaval access may lead to similar procedural and intermediate-term benefits of TF access, and should thus be reserved when no other nonsurgical access is feasible.

Discussion

TAVR has become a common therapeutic option for patients with aortic valve stenosis. Femoral access is the standard, but alternative access is used in patients with unsuitable iliofemoral vessels. Shockwave has been employed in patients with calcified vessels that are found to be adequate in

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Shockwave and Non-transfemoral TAVR size, allowing for the use of TF-TAVR. Data from the Transcatheter Valve Registry showed that 7.6% of TAVRs are performed using alternative access.

Initially, transthoracic approaches (transapical and direct aortic access) were most common, but the trend has been away from those approaches and toward alternative peripheral access options.48 Registry data has demonstrated a significant difference in the evolution of the distribution of TAVR access sites between 2013 and 2018, with an 11% rise in FP TAVR, a 69% reduction in central access, and a stable frequency of n-FP TAVR.23 Currently in the US, transaxillary access appears to be the preferred alternative access strategy when TF is not feasible.37 In general, the trend away from transthoracic TAVR is supported by data demonstrating superior outcomes of peripheral approaches. For instance, using data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry, Kaneko et al. compared both short- and longer-term outcomes of 3,462 patients undergoing central access (TA and TAo) TAVR, and 3,725 trans-subclavian and transcarotid TAVR from 2015 to 2018.49 They found significantly lower allcause mortality in the peripheral access group at both 30 days and 1 year, as well as lower rates of blood transfusion, and reduced intensive care unit and hospital lengths of stay. Peripheral access patients suffered a higher rate of stroke at 30 days (5% versus 2.8% <0.001) and at 1 year (7.33% versus 5.54% <0.001).

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2. Nishimura RA, Otto CM, Bonow RO, et al. 3rd, Thompson A. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: A report of the American college of cardiology/American heart association task force on clinical practice guidelines. J Am Coll Cardiol 2017;70:252–89. https://doi.org/10.1016/j.jacc.2017.03.011; PMID: 28315732.

3. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. https://doi. org/10.1056/NEJMoa1514616; PMID: 27040324.

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5. Fanaroff AC, Manandhar P, Holmes DR, et al. Peripheral artery disease and transcatheter aortic valve replacement outcomes: a report from the Society of Thoracic Surgeons/ American College of Cardiology Transcatheter Therapy Registry. Circ Cardiovasc Interv 2017;10:e005456. https://doi. org/10.1161/CIRCINTERVENTIONS.117.005456; PMID: 29042398.

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7. Holmes DR Jr, Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/ STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol 2012;59:1200–54. https://doi.org/10.1016/j.jacc.2012.01.001; PMID: 22300974.

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9. Adams G, Shammas N, Mangalmurti S, et al. Intravascular lithotripsy for treatment of calcified lower extremity arterial stenosis: initial analysis of the Disrupt PAD III dtudy. J Endovasc Ther 2020;27:473–80. https://doi. org/10.1177/1526602820914598; PMID: 32242768.

10. Rehman A, Kodali A, Nazir R, et al. Shockwave lithotripsy for large bore access in highly calcified iliac arteries prior to transcatheter aortic valve replacement. J Am Coll Cardiol 2020;75(11 Suppl 1):2728. https://doi.org/10.1016/S07351097(20)33355-6.

11. Di Mario C, Goodwin M, Ristalli F et al. A prospective registry of intravascular lithotripsy-enabled vascular access for transfemoral transcatheter aortic valve replacement.

Across all of the available studies, those in the central access and peripheral cohorts have been a sicker patient population with more advanced comorbidities. Seemingly counterintuitive, despite the less healthy cohort, data from the high- and extreme-risk patients ineligible for TF-TAVR, who underwent transcarotid or trans-subclavian TAVR, have demonstrated equivalent and even improved 30-day and 1-year outcomes when compared with TF.23,29,35,49 There are advantages and disadvantages of the various approaches (Table 1). Although there are no randomized data to support all the alternative access sites, the experiences reported provide available options for a large portion of patients to be candidates for TAVR. The intervention site should be selected by a multidisciplinary heart team based on patient anatomical factors and institutional expertise. It is worthwhile to note that alternative access techniques are typically associated with much higher levels of radiation to the surgical operator than the transfemoral approach.

Finally, it bears specific mention that transthoracic approaches have not been demonstrated to be associated with a specific additional advantage of SAVR in intermediate- and low-risk patients. When a transthoracic alternative access option is considered, careful consideration must be given to the option of conventional aortic valve replacement.

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13. Wong DR, Ye J, Cheung A, Webb JG, et al. Technical considerations to avoid pitfalls during transapical aortic valve implantation. J Thorac Cardiovasc Surg 2010;140:196– 202. https://doi.org/10.1016/j.jtcvs.2009.07.081; PMID: 20122700.

14. Al-Attar N, Ghodbane W, Himbert D, et al. Unexpected complications of transapical aortic valve implantation. Ann Thorac Surg 2009;88:90–4. https://doi.org/10.1016/j. athoracsur.2009.03.070; PMID: 19559200.

15. Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 2012;366:1696–704. https://doi. org/10.1056/NEJMoa1202277; PMID: 22443478.

16. Dewey TM, Bowers B, Thourani VH, et al. Transapical aortic valve replacement for severe aortic stenosis: results from the nonrandomized continued access cohort of the PARTNER trial. Ann Thorac Surg 2013;96:2083–9. https://doi. org/10.1016/j.athoracsur.2013.05.093; PMID: 23968764.

17. Furukawa N, Kuss O, Emmel E, et al. Minimally invasive versus transapical versus transfemoral aortic valve implantation: A one-to-one-to-one propensity scorematched analysis. J Thorac Cardiovasc Surg 2018;156:1825– 34. https://doi.org/10.1016/j.jtcvs.2018.04.104; PMID: 29861110.

18. Etienne P-Y, Papadatos S, El Khoury E, et al. Transaortic transcatheter aortic valve implantation with the Edwards SAPIEN valve: feasibility, technical considerations, and clinical advantages. Ann Thorac Surg 2011;92:746–8. https:// doi.org/10.1016/j.athoracsur.2011.03.014; PMID: 21801942.

19. Clarke A, Wiemers P, Poon KKC, et al. Early experience of transaortic TAVI – the future of surgical TAVI? Heart Lung Circ 2013;22:265–9. https://doi.org/10.1016/j.hlc.2012.11.002; PMID: 23261328.

20. Bapat V, Thomas M, Hancock J, et al. First successful transcatheter aortic valve implantation through ascending aorta using Edwards SAPIEN THV system. Eur J Cardiothorac Surg 2010;38:811–3. https://doi.org/10.1016/j.ejcts.2010.03.044; PMID: 20692179.

21. Dunne B, Tan D, Chu D, et al. Transapical versus transaortic transcatheter aortic valve implantation: a systematic review.

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23. Beurtheret S, Karam N, Resseguier N, et al. Femoral versus nonfemoral peripheral access for transcatheter aortic valve replacement. J Am Coll Cardiol 2019;74:2728–39. https://doi. org/10.1016/j.jacc.2019.09.054; PMID: 31779788.

24. Overtchouk P, Folliguet T, Pinaud F, et al. Transcarotid approach for transcatheter aortic valve replacement with the Sapien 3 prosthesis: a multicenter French registry. JACC Cardiovasc Interv 2019;12:413–9. https://doi.org/10.1016/j. jcin.2018.11.014; PMID: 30772290.

25. Kirker EB, Hodson RW, Spinelli KJ, et al. The carotid artery as a preferred alternative access route for transcatheter aortic valve replacement. Ann Thorac Surg 2017;104:621–9. https://doi.org/10.1016/j.athoracsur.2016.12.030; PMID: 28274520.

26. Allen KB, Chhatriwalla AK, Cohen D, et al. Transcarotid versus transapical and transaortic access for transcatheter aortic valve replacement. Ann Thorac Surg 2019;108:715–22. https://doi.org/10.1016/j.athoracsur.2019.02.007; PMID: 30880139.

27. Debry N, Delhaye C, Azmoun A, et al. Transcarotid transcatheter aortic valve replacement: general or local anesthesia. JACC Cardiovasc Interv 2016;9:2113–20. https:// doi.org/10.1016/j.jcin.2016.08.013; PMID: 27765304.

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31. Edelman JJ, Meduri C, Yadav P, et al. Current evidence for alternative access transcatheter aortic valve replacement.

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35. Gleason TG, Schindler JT, Hagberg RC, et al. Subclavian/ axillary access for self-expanding transcatheter aortic valve replacement renders equivalent outcomes as transfemoral.

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37. Kindzelski B, Mick SL, Krishnaswamy A, et al. Evolution of alternative access transcatheter aortic valve replacement.

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PMID: 26356244.

45. Greenbaum AB, Babaliaros VC, Chen MY, et al. Transcaval access and closure for transcatheter aortic valve replacement: a prospective investigation. J Am Coll Cardiol 2017;69:51121. https://doi.org/10.1016/j.jacc.2016.10.024; PMID: 27989885.

46. Lederman RJ, Babaliaros VC, Rogers T, et al. The fate of transcaval access tracts: 12-month results of the prospective NHLBI transcaval transcatheter aortic valve replacement study. JACC Cardiovasc Interv 2019;12:448–56. https://doi. org/10.1016/j.jcin.2018.11.035; PMID: 30846083.

47. Paone G, Eng M, Kabbani LS, et al. Transcatheter aortic valve replacement: comparing transfemoral, transcarotid, and transcaval access. Ann Thorac Surg 2018;106:1105–12. https://doi.org/10.1016/j.athoracsur.2018.04.029; PMID: 29758214.

48. Carroll JD, Mack MJ, Vemulapalli S, et al. STS-ACC TVT registry of transcatheter aortic valve replacement. Ann Thorac Surg 2021;111:701–22. https://doi.org/10.1016/j. athoracsur.2020.09.002; PMID: 33213826.

49. Kaneko T, Yazdchi F, Hirji S, et al. Peripheral versus central access for alternative access transcatheter aortic valve replacement (TAVR): results from the TVT registry. J Am Coll Cardiol 2020;75(11 Suppl 1):1177. https://doi.org/10.1016/ S0735-1097(20)31804-0.

Lifetime Management of Aortic Valve Disease

Mixed-Valve Disease: Management of Patients with Aortic Stenosis and Mitral Regurgitation: Thresholds for Surgery Versus Percutaneous Therapies Jean-Bernard Masson, MD, FRCPC ,1,2 and Jessica Forcillo, MD, MPH, PhD, FRCSC

1,2

1. Division of Cardiology and Cardiac Surgery, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, Quebec, Canada; 2. Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada

Abstract

Significant mitral regurgitation (MR), frequently seen in the presence of severe aortic stenosis (AS), results in an association that negatively affects prognosis and imposes particular challenges for both the assessment of the severity of valvular lesions and decisions regarding treatment allocation. This article reviews the available literature with regards to the assessment of MR and AS in the presence of both; surgical management and results in patients with concomitant AS and MR; the effect of MR on outcomes in patients undergoing transcatheter aortic valve replacement; the effect of transcatheter aortic valve replacement on MR severity; and percutaneous treatment for MR after transcatheter aortic valve implantation. The authors aim to provide assistance in the decision-making process to treat patients with either a higher-risk double-valve procedure or a simpler, but perhaps incomplete, single-valve option.

Keywords

Transcatheter aortic valve replacement, surgical aortic valve replacement, intervention, risk assessment, aortic valve, valve surgery Disclosure: The authors have no conflicts of interest to declare.

Acknowledgment: The authors thank their Heart Team colleagues for their commentaries on this important topic.

Received: May 4, 2021 Accepted: September 29, 2021 Citation: US Cardiology Review 2021;15:e26. DOI: https://doi.org/10.15420/usc.2021.17 Correspondence: Jessica Forcillo, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, CHUM, 1051 Sanguinet, Montreal, Quebec H2X 3E4, Canada.

E: jessicaforcillo@hotmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Significant mitral regurgitation (MR), frequently seen in the presence of severe aortic stenosis (AS), results in an association that negatively affects prognosis and imposes particular challenges for both the assessment of the severity of valvular lesions and decisions regarding treatment allocation. Significant MR (Grade ≥2) is present in 25–30% of patients treated with transcatheter aortic valve replacement (TAVR), whereas severe MR (Grade 4) is seen in 2–5%.1 Here, we review the available literature with regard to assessing MR and AS when both are present, surgical results in patients with concomitant AS and MR, the effects of MR on TAVR patient outcomes, and the effects of TAVR on MR severity. Our aim is to provide assistance with decisions to treat patients with either a higher-risk double-valve procedure or a simpler, but perhaps incomplete, single-valve option.

Patients presenting with multivalvular disease (MVD) are common and often present with heterogeneous valve defects. The Euro Heart Survey and the EURObservational Research Program Valvular Heart Disease Registry demonstrated that one-fifth of patients with native valve disease have MVD, with AS and MR being the most common association.2 The 2021 European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) guidelines recommend that patients presenting with severe primary MR, undergo mitral valve surgery at the time of surgical aortic valve replacement (SAVR).3 In patients with severe secondary MR, surgery may also be considered in the presence of

significant annular dilatation and marked left ventricle (LV) enlargement.

In high-risk or inoperable patients with severe AS and severe MR, combined (or more often sequential) transcatheter aortic valve implantation (TAVI) and transcatheter edge-to-edge repair (TEER) may be feasible, but there is insufficient experience to allow robust recommendations.3 The 2020 American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines on MVD stated that, overall, patients with severe AS and severe primary MR are best treated with SAVR and mitral valve surgery unless the surgical risk is high or prohibitive.4 If there is a high or prohibitive surgical risk, a staged procedure with TAVI followed by mitral TEER can be effective.4 If there is severe AS and severe secondary MR, either SAVR and mitral valve surgery or a staged approach with TAVI followed by mitral TEER are options.4

Assessment of Valvular Lesions in the Setting of Multiple Valve Disease

Evaluation of the severity of valvular lesions is an obvious critical step in patient management. Only with precise diagnosis can clinicians provide accurate guidance and treatment options. In the setting of MVD, identification of the most significant or clinically relevant valvular lesions is paramount in the search for the most appropriate treatment. Although there are clear recommendations from international societies for the diagnosis of severe AS and MR, the hemodynamic and structural consequences of MVD often blur the evaluation of a single valvular lesion.5

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Mitral Regurgitation Associated With Severe Aortic Stenosis Although rheumatic disease has historically been the most frequent cause of MVD, a shift towards degenerative disease is seen in developed countries.6

Assessment of Mitral Regurgitation in the Presence of AS

A transthoracic echocardiogram (TTE) remains the cornerstone of valvular disease diagnosis. A TTE provides insights into the cause of MR, as well as quantitative and semiquantitative assessment of MR severity.

MR etiology, reliably identified with TTE and/or transesophageal echocardiography, can be divided in primary (or degenerative/organic), secondary (or functional), or mixed.7 Degenerative MR is associated with calcification of the mitral apparatus, ruptured chordae, flail leaflets, myxomatous degeneration, or a combination of these findings. However, secondary MR is common in AS patients in whom a high prevalence of coronary artery disease, LV remodeling, and/or AF result in mitral leaflet tethering, annular dilation, or both. The potential of MR regression after relief of AS seems greater when MR is functional.7–9 The severity of MR is typically assessed with TTE using semiquantitative Doppler color flow jet area and quantitative measures such as vena contracta, proximal isovelocity surface area, and regurgitant volume or fraction. The increased systolic LV pressure inherent to severe AS results in a higher systolic transmitral gradient, which consistently increases the color flow jet area, resulting in an overestimation of MR.10 In addition, left atrial enlargement cannot be used as a surrogate to diagnose severe MR when AS-induced LV hypertrophy is present. Although AS added to MR does increase regurgitant flow at any orifice area, estimated regurgitant orifice area and vena contracta are less affected by higher velocities than color flow jet area and should be relied upon in the presence of AS.11 A high color flow jet area but small vena contracta and/or estimated regurgitant orifice area in the setting of AS probably reflects nonsignificant MR. Regurgitant volume and fraction can reliably assess MR severity in the presence of AS, but degenerative changes in the mitral annulus can lead to imprecise mitral inflow orifice estimation.12 Cardiac magnetic resonance is emerging as a reliable tool to assess MR, providing quantification of regurgitation volume based on LV volumes and aortic flow quantification.13 However, this volumetric method is of limited value when both the aortic and mitral valves are regurgitant.13

Assessment of Aortic Stenosis in the Presence of MR

MR reduces forward flow, resulting in lower transvalvular aortic velocity and gradient, even more so when AF occurs. Not only does paradoxical low-flow severe AS present commonly with severe MR, but also the afterload reduction provided by MR can shadow early detection of LV systolic dysfunction. In the absence of high velocity, TEE diagnosis of severe AS relies on calculation of the aortic valve area (AVA), which may be imprecise due to operator-dependent, technically limited estimation of the outflow tract area. TTE or transesophageal echocardiography planimetry of the aortic valve is of limited value if MR is severe and forward driving pressure is reduced.3 Aortic valve calcium scores from multidetector CT (MDCT) are strong predictors of severe AS with most discriminative cut-off scores for severe AS of >2,000 arbitrary units (AU) in men and >1,200 AU in women.3,14 Aortic valve calcium scores are highly reproducible and should be used when uncertainty remains after echocardiographic assessment. Alternatively,

3D measurements of the non-circular outflow tract using 3D echocardiography or MDCT associated with conventional Doppler flow quantification represents an intriguing method that could provide an accurate calculation of the AVA.15 However, current TEE-based threshold for severity (AVA <1 cm2 or indexed AVA <0.6 cm2/m2) may not apply to this method when most 3D-derived measurements result in a larger outflow tract area than that provide by 2D TEE.15 Right and left heart catheterization is recommended when TEE is nonconclusive in the setting of MVD.15 However, the intricacies of MVD also apply to invasive evaluation. Measurement of cardiac output using thermodilution is unreliable in the presence of severe tricuspid regurgitation or very low output, and an estimate of oxygen consumption is used in the Fick method. In addition, the Gorlin formula for calculation of valve areas cannot be used for valves that are both stenotic and regurgitant. Therefore, heart catheterization should be performed meticulously and the results interpreted with caution in patients with MVD. For patients who can safely exercise, hemodynamic evaluation at a higher-flow state can provide discriminatory, yet poorly proven information.5 When stress induces changes that are a hallmark for a specific lesion, such as a high gradient for AS or markedly increased pulmonary arterial pressure for MR, clinicians may be tipped toward the culprit lesion.5 With all the limitations surrounding typical TEE evaluation of AS and MR in the presence of each other, it is necessary to integrate all information.

Using unconventional assessment tools may also provide useful additional information.

Surgical Management and Outcomes of Combined Aortic and Mitral Valve Disease

Combined surgical procedures on multiple valves are associated with increased operative risk. Risk stratification models provide mortality estimates only for specified procedures and, for example, the Society of Thoracic Surgeons (STS) risk assessment tool, namely the Predicted Risk of Mortality (PROM), does not include estimates for concomitant aortic and mitral valve surgery.16 The 2008 STS registry unadjusted short-term mortality for all isolated valve procedures was 3.4%, whereas in-hospital morbidity rates ranged from 0.3% for deep sternal wound infection to 11.8% for prolonged ventilation.16 However, 2013 data from the STS show perioperative mortality after aortic and mitral valve operation almost threefold higher (9.4%) than that after isolated aortic valve replacement (AVR; 3.2%).17 In 2016, outcomes of left-sided valve replacement with modern prostheses in patients from a large single center study were published.18 In that study, in which the mean (±SD) age of patients was 74 ± 7 years, the mean (±SD) 30-day survival rate for patients with combined AVR and mitral valve replacement (MVR) was 92.8 ± 1.6%, compared with rates of 97.3 ± 0.4% and 95.1 ± 1.2% for those with isolated AVR and isolated MVR, respectively.18 The mean (±SD) 10-year survival rates for patients with AVR+MVR, AVR, and MVR were 22.1 ± 7.1%, 42.1 ± 1.5%, and 33.9 ± 4.7%, respectively.18 The decision to operate on the mitral valve in the setting of severe AS depends on the severity and etiology of MR. In symptomatic patients with severe AS, valve replacement (conventional or percutaneous) is the treatment of choice, whereas in patients with severe MR, valve repair is generally favored over replacement if feasible, especially among patients with organic disease.19,20 In a large multicenter retrospective study, mitral

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Mitral Regurgitation Associated With Severe Aortic Stenosis

However, the management of moderate MR at the time of SAVR is controversial.23 Studies focusing on MR evolution following surgical AVR are rare. In one retrospective study, moderate functional MR improved in 66% of patients after isolated AVR.24 The presence of congestive heart failure, an enlarged left atrium, and the degree of postoperative aortic insufficiency were independent predictors of lack of improvement. In the PARTNER trial, 59 of the 299 high-risk patients who underwent isolated SAVR had moderate (90.5%) or severe (9.5%) MR.25 The overall mortality rate at 2 years was significantly higher among patients with moderate or severe MR (49.1% versus 27.9%; p<0.01), an association that remained significant after multivariate analysis (HR 1.77; 95% CI [1.17–2.68]).25 A meta-analysis of 17 studies and more than 3,000 patients published in 2011 confirmed that moderate–severe MR regurgitation adversely affects both early and late mortality following isolated AVR for severe AS despite MR regression in 60% of patients, reverse remodeling, and a reduction in LV end-diastolic diameter.26 In that meta-analysis, the overall unadjusted 30-day mortality was 5%, significantly lower (OR 0.41; 95% CI [0.24–0.72]) in patients without significant MR and remained significant when only patients with functional MR were analyzed.26 Although the authors suggested that concomitant mitral intervention should be considered in the presence of moderate MR, independent of etiology, the added risk of double-valve surgery was not taken into account in that review and the absence of adjustment for baseline characteristics limits the value of such a statement.

In contrast, a small, single-center, high-risk patient cohort of 43 patients with severe AS and significant MR undergoing combined AVR and mitral valve surgery suggests there may be no added benefit to mitral surgery.27 In that study, the mean (±SD) age was 80 ± 6 years, and the mean STS PROM was 10.1 ± 6.4%. Perioperative morbidity was 30% and the mortality rate at 6 months and 1 and 2 years was 25%, 35%, and 45%, respectively.27 Because the prognosis of the 43 patients in that study was similar to that of high-risk patients undergoing isolated TAVR, the authors concluded that, in such high-risk patients, there is no added benefit to a doublevalve surgery.27

Impact and Evolution of Significant MR After TAVR

Although surgical data are scarce on the prognostic role of MR and the fate of untreated MR after relief of AS, the TAVR literature offers significant insights, because concomitant moderate or severe MR in patients undergoing TAVR has been reported to occur in approximately 20–30% of patients.25,28–31 The prevalence of significant MR decreases as patient risk profile improves, as evidenced by the proportion of patients with at least

Figure 1: Prevalence of Moderate to Severe Mitral Regurgitation in the PARTNER Trials Mitral insufficiency prevalence in the PARTNER trials 25 20 Prevalence

valve repair (compared to MVR) was associated with lower perioperative mortality, improved survival, and better preservation of postoperative LV function.21 Although patients who underwent MVR were older and at higher risk, the performance of mitral valve repair was independently associated with lower mortality after adjustment for baseline characteristics. In addition, in the 2013 STS registry publication, perioperative mortality was 5.7% for MVR versus 1.6% for mitral valve repair.17 Among patients with severe functional MR of ischemic etiology, a multicenter randomized clinical trial revealed no significant differences in LV reverse remodeling or survival at 2 years among patients randomized to repair versus replacement.22 However, MR recurred more frequently in the repair group, leading to more heart failure-related adverse events and cardiovascular admissions.22 There is a general consensus that, for patients undergoing SAVR, a double-valve operation is indicated in the presence of severe MR.

15 10 5 0 PARTNER 1A

TAVI = transcatheter aortic valve implantation.

PARTNER 2A

PARTNER 3

Trials TAVI

Surgery

moderate MR in the different PARTNER trials (Figure 1). Correlations between functional MR and comorbidities and referral bias probably combine to explain this finding.

However, there are significant limitations that limit the strength of the available data:

• Severe MR is an exclusion criterion from TAVR randomized clinical trials.

• Quantitative MR evaluation is not reported in the vast majority of publications.

• Studies comparing outcomes of patients with and without MR have

dichotomized patients based on different cut-off values for significant MR and include a small proportion of patients with truly severe MR, ranging from 2% to 9%, resulting in heterogeneity between studies and conflicting results.

• Modern TAVR devices and techniques may limit the generalization of older studies.

Baseline MR as a Predictor of Adverse Outcomes After TAVR

Multiple retrospective analyses and four meta-analyses have focused on the prognostic impact of significant MR after TAVI. The larger and most recent meta-analysis reported on 21 studies and more than 30,000 patients.31 Unadjusted short-term (RR 1.46; 95% CI [1.30–1.65]) and longterm (1–4 years in most studies included in the meta-analysis; RR 1.40; 95% CI [1.18–1.65]) mortality was higher for patients with MR.31 However, patients with significant MR presented with more comorbidities at baseline, including well-known adverse event predictors such as a higher STS score and lower ejection fraction (EF). Hence, 16 of 21 studies with 27,777 patients found no association between MR and mortality after adjusting for baseline variables. Interestingly, no interaction was found between studies that used MR Grade ≥2 or ≥3 as the dichotomization cutoff.31 However, a publication from the STS/ACC Transcatheter Valve Therapy Registry (TVT Registry) on TAVR procedures performed in 2012–13 suggests that the effect of MR on prognosis increases with MR severity (30-day unadjusted HR for mortality 1.27 and 1.84 for moderate and severe MR, respectively; 1-year unadjusted HR for mortality 1.30 and 1.46, respectively).32 After adjustment for baseline variables, HRs were no longer significant for mortality, but remained significant for the combined endpoint of mortality and heart failure hospital admissions.32 This gradual correlation between MR severity and 1- and 2-year mortality was corroborated by a recent single-center study.1

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Mitral Regurgitation Associated With Severe Aortic Stenosis Table 1: Survival After Transcatheter Aortic Valve Replacement According to Significant Mitral Regurgitation at Baseline in Selected Studies of High-risk Patients Data Source

Sample Patients with Size (n) Significant MR (%)

MR Grade Used Follow-up for Comparison Duration

% Patients Surviving with Significant MR

% Patients p-value Surviving with No Significant MR

TVT Registry32 (2012–13)

11,104

36.8

All grades

1 year

73.7

79

<0.0001

PARTNER 1A

331

19.6

<2 versus ≥2

2 years

63.0

67.8

NS

Spanish registry (2007–15)

1,140

15.9

<3 versus ≥3

6 months

65.0

89.8

<0.001

Italian CoreValve registry7 (2007–11)

1,007

33.4

<2 versus ≥2

1 year

75.0

83.9

0.02

25 8

MR = mitral regurgitation; TVT = transcatheter valve therapy.

Earlier and smaller meta-analyses found similar effects of MR on 30-day and 1-year mortality.29–31 Baseline MR etiology did not have an effect on post-TAVR outcomes. In one of these publications that included 8,015 patients, significant MR at baseline persisted as a 1-year predictor of mortality after adjustment for baseline characteristics.30 Moreover, one retrospective multicenter study reported a threefold (35% versus 10.2%) increase in 6-month mortality in high-risk patients with significant MR despite no difference in baseline STS score or LVEF.8 That study is an outlier with regard to the level of effect of MR on prognosis, which could be related to methodological factors, including a more stringent (MR ≥3) definition of significant MR and the use of an echocardiographic core laboratory.

The association between significant preprocedural MR and mortality seems ever greater in the low-EF, low-gradient, severe AS. One study found that 1-year mortality was 3.5-fold higher in low-EF, low-gradient AS patients with moderate or severe MR than in low-EF, low-gradient AS patients who did not have significant MR (11.5% versus 38.1%, respectively; adjusted HR 3.27; 95% CI [1.31–8.15]; p=0.011).33 Despite this prognostic impact of significant baseline MR, high-risk patients with significant MR who undergo TAVR still derive benefit from the procedure, with acceptable mid-term survival (Table 1), improved quality of life, and New York Heart Association class in most patients.34,35

Changes in MR After TAVR

The etiology of MR in TAVR patients is more frequently reported as degenerative (approximately 50%) than functional (±30%), or mixed (±20%) in most publications. Improvement in MR of at least one grade is steadily reported in 50–60% of patients after TAVR.28–31 Such a low figure may be surprising given that AS relief uniformly leads to lower systolic LV pressure and transmitral gradient and probably underlines limitations associated with MR grading and/or lack of quantitative measurements.

MR worsens after TAVR in approximately 2–7% of patients.36 Many studies have aimed to identify clinical and anatomical factors that could predict MR improvement after TAVR. Table 2 presents the most frequently reported factors associated with MR improvement or lack of thereof. Degenerative MR, severity of mitral annular, and/or leaflet calcifications, as well as the presence of AF, were most often linked to persistent MR after TAVR.1,8,9,13,25,29,30,32,35,37,47–49 Some studies associated the use of a self-expandable transcatheter heart valve with more persistent MR after TAVR.29,30,37 Possible explanations for this include more residual aortic regurgitation contributing to LV volume overload, low implantation interacting with the mitral valve apparatus, and a higher likelihood of conduction defects. Transcatheter heart valve

iterations limiting paravalvular regurgitation and reliance on higher implantation probably mitigate these findings in the current era.

In a recent single-center study, Mauri et al. identified several anatomical factors associated with MR persistence after TAVR and created a “mitral score” (Table 3) to predict MR improvement.1 In their cohort, this score was highly discriminant for both MR persistence (ranging from 10.5% to 94.4%; AUC 0.816; p<0.001) after TAVR and overall prognosis (2-year mortality for score ≤4 versus >4, 47.8% versus 31.9%, respectively; HR 2.12; 95% CI [1.06–4.26]; log-rank p=0.030) following TAVR. Interestingly, baseline Grade 4 MR was the single most important predictor of persistent MR after TAVR.1 Although such a tool could be useful for patient assessment, to our knowledge external validation has yet to be published.

Impact of Residual MR on Prognosis After TAVR

MR regression is frequent after successful TAVR and may be attributed to several physiological changes, including lower transmitral systolic gradient, favorable LV remodeling, and regression of LV hypertrophy and end-diastolic volume leading to reduced tethering forces on the mitral leaflets. Many studies have assessed the impact of decreasing MR on prognosis, with the overwhelming majority finding that MR regression is associated with better prognosis.1,28,32,37,38 MR improvement to ≤2 often results in survival rates similar to the overall population. For example, in a recent single-center study of 677 consecutive TAVR patients, significant (≥3) MR at baseline was associated with lower 2-year survival (57.7 versus 74.4%; p<0.001), with those who experienced MR regression more likely to survive than those who did not (74.0% versus 54.1%; HR 2.02; 95% CI [1.43–2.86]).39 Patients with MR regression had an overall prognosis similar to the overall cohort (2-year survival 74.0% versus 77.8%, respectively).39 Data from the TVT Registry, SWEDEHEART, and other studies also suggest residual significant MR after TAVR is associated with worse outcomes, including increased deaths and heart failure admissions after adjustment for baseline variables.32,37 The adverse effect of MR seems gradual with increasing MR grade.38 One meta-analysis evaluated the impact of residual MR on survival and found higher mortality when MR persisted (RR 1.48; 95% CI [1.31–1.68]; p<0.00001).28 To our knowledge, only one study of 1,110 patients, including 157 with significant (MR ≥3), concluded that regression of MR, seen in approximately 60% of patients, was not associated with survival benefit.8 In summary, there is clear evidence that significant MR is associated with increased risk of acute and longer-term adverse events. However, it remains uncertain how much of this difference is attributable to MR or when MR is only a marker of worse prognosis. Significant MR improves at least one grade in approximately half the patients after TAVR, which can

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Mitral Regurgitation Associated With Severe Aortic Stenosis be predicted from clinical and anatomical variables. Lack of MR regression is linked to poorer prognosis.

Table 2: Predictor of Mitral Regurgitation Fate After Transcatheter Aortic Valve Replacement

Percutaneous Treatment of MR After TAVI

Factors

MR improvement

Lack of improvement

Clinical

Low ejection fraction13,47 Non-severe (<4) MR1

AF9,29,32,35 Pulmonary hypertension (sPAP >55–60 mmHg)35 Significant aortic regurgitation after TAVR37,48 Low body surface area32 Coronary artery disease29 CoreValve (versus BEV)30,49

Anatomical

Functional MR8,35 Greater tenting area47 Greater tenting height47

Mitral annular calcifications8,47 Leaflet calcifications8 Larger mitral annular diameter (<32–35 mm)1,8 Increased LVEDD25,32 Prior aortic valve procedure32

Percutaneous mitral valve repair using the MitraClip (Abbott Vascular) is associated with improved outcomes compared with conservative therapy in patients with symptomatic severe MR who are deemed high risk or inoperable.40 TAVI patients who remain symptomatic due to significant MR could potentially profit from a staged percutaneous procedure to treat MR. This may be a particularly attractive option for the subset of patients with low-gradient severe AS and moderate to severe primary MR, who tend to have a particularly high mortality after TAVR.33,36 When percutaneous treatment of AS and MR is contemplated, it is generally accepted that staging procedures, with TAVR first, is the most appropriate strategy. First, MR reduction in the setting of untreated severe AS is associated with a marked increase in afterload, which is likely to be poorly tolerated in patients who often have failing LV function, discouraging a strategy where the mitral valve would be addressed first. In addition, although single-stage TAVR with the MitraClip is possible, symptomatic improvement, MR reduction, and reverse remodeling of the LV after AS is relieved may mitigate the indication for a mitral intervention.

BEV = balloon expandable valve; LVEDD = left ventricular end diastolic diameter; MR = mitral regurgitation; sPAP = systolic pulmonary artery pressure; TAVR = transcatheter aortic valve replacement.

Table 3: Mitral Score to Predict Regression to Mitral Regurgitation Grade ≤2 Item

Points

The first description of the MitraClip device being inserted as a staged procedure after TAVR with the Edwards and Medtronic devices was in 2011.41 Since then, three single-center series of patients undergoing staged TAVR and percutaneous edge-to-edge repair have been published, for a total of 37 cases with functional or degenerative MR.42–44 Procedural success was uniformly high, ranging from 91% to 100%. However, only two-thirds of patients survived to 1 year in two of those publications, with modest or no symptomatic improvement in most patients.42,43 The third publication only reported symptoms improvement at baseline and after both procedures, but a 100% survival at 6 months.44

MR grade ≥4 at baseline

3

Extent of annulus calcification Mild/unilateral Moderate

1 3

Severe/circular

5

Dimension of mitral valve annulus <32 mm ≥32 mm

0 −2

Transcatheter mitral valve replacement (TMVR) seems closer than ever to enter clinical practice. However, as of now, there is little evidence for the use of mitral transcatheter valves in the mixed valvular disease population other than anecdotal, yet successful, cases of TAVR combined with mitral valve-in-valve implantation. A US National Registry publication (2014–18) identified that 0.1% of all TAVR patients underwent either mitral edge-toedge repair (n=110) or TMVR (n=98) either as a combined or staged procedure.45 Compared with isolated TAVR, there was a fivefold increase in in-hospital death among patients undergoing TAVR and a mitral valve procedure (mortality 10.8% and 13.3%, with adjusted ORs of 3.87 and 4.34 for edge-to-edge repair and TMVR, respectively).45 Morbidity was also significantly more prevalent in patients undergoing aortic and mitral valve procedures in that publication.45 However, in another publication, a series of 12 high-risk patients with previous surgical AVR were treated with the Tiara (Neovasc) transcatheter valve via a transapical approach.46 Procedural success was 100%, with no death, MI, stroke, or major bleeding at 30 days. MR was eliminated in all 12 patients immediately after implantation. The authors of that study concluded that TMVR with the Tiara valve in high-risk patients with severe MR and previous AVR was technically feasible and safe.46

performed first, with reassessment of MR and symptoms after complete patient recovery prior to the decision to undertake TMVR.

Based on these data in a small number of patients, transcatheter doublevalve implantation seems currently best limited to highly selected patients and performed as staged procedures. Given that, in most cases, AS carries heavier prognostic implication, we believe TAVR should be

MR = mitral regurgitation. Source: Mauri et al.1 Reproduced with permission from Springer Nature.

Management Strategy for Patients with Severe AS and Significant MR

Management strategies in patients with concomitant severe AS and significant MR should be based on a thorough clinical and anatomical assessment where age, risk profile, patient preferences, MR severity, and potential for regression after isolated SAVR or TAVR are evaluated. Current guidelines recommend the evaluation of patients in specialized heart valve centers when valve intervention is needed so that the risks and benefits of a surgical versus transcatheter procedure can be discussed by a multidisciplinary team.47 Moreover, patients with truly severe MR are underrepresented in the available literature, limiting generalization of data to this subset of patients.

Figure 2 presents a proposed algorithm of treatment for patients with concomitant AS and MR. Moderate MR does not represent an indication for therapy; we suggest most patients should be evaluated and treated with the most appropriate AS therapy, SAVR or TAVR, according to the risk profile and anatomic specificities. When the surgical option is selected, mitral surgery may be considered when the MR is organic or with a low potential for improvement.

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Mitral Regurgitation Associated With Severe Aortic Stenosis Figure 2: Management of Severe Aortic Stenosis Requiring Surgery With Concomitant Mitral Regurgitation Severe symptomatic AS (Careful clinical and functional evaluation Investigation may include TEE, MDCT, stress test Heart team discussion)

Surgical risk

MR severity

MR mechanism

None–mild

Moderate

Severe

Functional

Organic

High

Low

Likelihood of improvement

Treatment

High

Low–intermediate

SAVR

Double-valve procedure

None–mild

Moderate

TAVR or SAVR (if CI to TAVR)

TAVR

Severe

High

Low

TAVR

Medical treatment or TAVR and consider percutaneous edge-to-edge repair

*This algorithm requires validation by further studies. AS = aortic stenosis; CI = contraindication; MDCT = multidetector CT; MR = mitral regurgitation; SAVR = surgical aortic valve replacement; TAVR = transcatheter aortic valve replacement; TEE = transesophageal echocardiography. Source: Nombela-Franco et al.48 Adapted with permission from Elsevier.

Patients with Grade ≥3 MR are likely to derive benefit from mitral valve surgery when the risk and functional status are appropriate. Low- and intermediate-risk patients with reasonable life expectancy should be considered for double-valve surgery. In our experience, high-risk patients with severe MR represent the more challenging cases for the heart team and have the worse prognosis, regardless of treatment allocation. The added risk of double-valve surgery seems to negate its benefits. In this population of patients, TAVR may become the most reasonable option, more so when the potential for MR regression is real.

However, the risk profile should not dichotomize patients. Some higher-risk patients, such as those with technical challenges with severe organic MR, may derive long-lasting benefit of mitral operation and should, at the very least, be presented with all the options. At the end of the spectrum, although significant MR should not, by itself, discount high-risk patients from TAVR, the lower likelihood of symptomatic improvement and long-term survival should be considered, along with the clinical and functional status, and some patients will best be managed conservatively. In our opinion, most high-risk, elderly patients with non-valvular functional limitations and severe AS along with Grade ≥3 MR should be treated medically.

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Staged percutaneous procedures remain a technically feasible and expensive option that have so far met with modest clinical success.

Staged percutaneous procedures are probably best reserved for highly selected, symptomatic patients at high risk for surgery, yet having the potential for significant, long-term improvements in quality of life.

Conclusion

For patients with MVD, assessment should include an extensive clinical examination, a thorough anamnesis, and a comprehensive echocardiographic analysis while taking the effects of the various valve pathologies into account. Risk assessment should be done by a heart team in consideration of patients’ comorbidities and treatment goals (survival and improved quality of life). To date, surgical strategies have been the gold standard and remain so in low- and intermediate-risk patients, yet interventional treatment modalities may offer various advantages for high-risk patients. The decision to address AS and MR at the same time or in staged procedures remains at the discretion of the heart team according to which valve is the most significant. Re-evaluation should then be done of the remaining valve pathologies and the clinical status of the patient.

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