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Volume 15 • 2020

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Editor-in-Chief Simon Kennon Interventional Cardiologist and TAVI Operator, Barts Heart Centre, St Bartholomew’s Hospital, London, UK

Deputy Editors Joost Daemen

Darren Mylotte

Nicolas M Van Mieghem

Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands

Galway University Hospitals, Galway, Ireland

Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands

Angela Hoye

University Hospital of Wales, Cardiff, UK

Andrew SP Sharp

Castle Hill Hospital, Hull, UK

Editorial Board Mirvat Alasnag

Swedish Heart and Vascular Institute, Seattle, WA, US

Fernando Alfonso

Philippe Garot

Elmir Omerovic

Sahlgrenska University Hospital, Gothenburg, Sweden

Institut Cardiovasculaire Paris-Sud – Hôpital Privé Jacques Cartier (Ramsay Générale de Santé), Massy, France

Peter O’Kane

London Chest Hospital, Barts Health NHS Trust, London, UK

Raban Jeger

Crochan J O’Sullivan

Eduardo Arias

Kathleen E Kearney

Hospital Universitario de La Princesa, Madrid, Spain

Andrew Archbold

National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico

Antonious Attallah

University Hospital Basel, Switzerland

Jaffar Khan

Ascension St. John Hospital, Detroit, MI, US

Rodrigo Bagur

Won Keun Kim

Marco Barbanti

Ferrarotto Hospital, Catania, Italy

Jonathan Byrne

King’s College Hospital, London, UK

Antonio Colombo

EMO Centro Cuore Columbus, Milan, Italy

Pierluigi Costanzo

St Michael Hospital/University of Toronto, Toronto, Canada

Carlo Di Mario

Careggi University Hospital, Florence, Italy

Mauro Echavarría-Pinto Hospital General ISSSTE Querétaro, México

Eric Eeckhout

Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Tom Ford

Gosford Public Hospital, New South Wales, Australia

Royal Bournemouth Hospital, Bournemouth, UK Triemli Hospital, Zurich, Switzerland

Liesbeth Rosseel

University of Washington Heart Institute, Seattle, WA, US National Heart, Lung and Blood Institute, Washington, DC, US

London Health Sciences Centre, London, Ontario, Canada

Cover image © Adobe Stock

Sameer Gafoor

King Fahd Armed Forces Hospital, Jeddah, Saudi Arabia

Kerckhoff Heart Center, Bad Nauheim, Germany

Tim Kinnaird

Galway University Hospitals, Galway, Ireland

Fadi J Sawaya

American University of Beirut Medical Center, Beirut, Lebanon

Alexander Sedaghat

University of Bonn, Bonn, Germany

James Spratt

St George’s University Hospital NHS Trust, London, UK

University Hospital of Wales, Cardiff, UK

Ajay Kirtane

Columbia University Medical Center and New York-Presbyterian Hospital, New York, US

Azeem Latib

Montefiore Medical Center, New York, NY, US

Didier Locca

Lars Søndergaard

Rigshospitalet – Copenhagen University Hospital, Copenhagen, Denmark

Gregg Stone

Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, US

Corrado Tamburino

Lausanne University Hospital, Lausanne, Switzerland

Ferrarotto & Policlinico Hospital and University of Catania, Catania, Italy

Mamas A Mamas

Luca Testa

Hannah McConkey

Renu Virmani

University of Keele, Keele, Staffordshire, UK St Thomas’ Hospital, London, UK

Roxana Mehran

Mount Sinai Hospital, New York, US

Thomas Modine

Department of Cardiology, IRCCS Policlinico San Donato, San Donato Milanese, Italy CVPath Institute, MD, US

Simon Walsh

Belfast Health and Social Care Trust, Belfast, UK

Nina C Wunderlich

Cardiovascular Center Darmstadt, Darmstadt, Germany

CHRU de Lille, Lille, France

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Cardiology

Lifelong Learning for Cardiovascular Professionals © RADCLIFFE CARDIOLOGY 2020

Contents

An Extended Statement by the British Cardiovascular Intervention Society President Regarding the COVID-19 Pandemic Nick Curzen DOI: https://doi.org/10.15420/icr.2020.10

Anticoagulation after Transcatheter Aortic Valve Implantation: Current Status Antonio Greco and Davide Capodanno DOI: https://doi.org/10.15420/icr.2019.24

Precision Medicine in Interventional Cardiology Thijmen W Hokken, Joana M Ribeiro, Peter P De Jaegere and Nicolas M Van Mieghem DOI: https://doi.org/10.15420/icr.2019.23

Diagnostic Angiograms and Percutaneous Coronary Interventions in Pregnancy Phyo Htet Khaing, Gill Louise Buchanan and Vijay Kunadian DOI: https://doi.org/10.15420/icr.2020.02

Why, When and How Should Clinicians Use Physiology in Patients with Acute Coronary Syndromes?

Roberto Scarsini, Dimitrios Terentes-Printzios, Giovanni Luigi De Maria, Flavio Ribichini and Adrian Banning DOI: https://doi.org/10.15420/icr.2019.26

Coronary Physiology Derived from Invasive Angiography: Will it be a Game Changer?

Lavinia Gabara, Jonathan Hinton, Julian Gunn, Paul D Morris and Nick Curzen DOI: https://doi.org/10.15420/icr.2019.25

Emerging Role of Large-bore Percutaneous Axillary Vascular Access: A Step-by-step Guide Kathryn Dawson, Tara L Jones, Kathleen E Kearney and James M McCabe DOI: https://doi.org/10.15420/icr.2019.08.R2

Antegrade Chronic Total Occlusion Strategies: A Technical Focus for 2020 Calum Creaney and Simon J Walsh DOI: https://doi.org/10.15420/icr.2020.05

Chimney Stenting During Transcatheter Aortic Valve Implantation Liesbeth Rosseel, Michael Rosseel, Brian Hynes, Xavier Armario Bel, Emily Crilly and Darren Mylotte DOI: https://doi.org/10.15420/icr.2020.08

Management of Valvular Disease During Pregnancy: Evolving Role of Percutaneous Treatment Chiara Fraccaro, Noemie Tence, Giulia Masiero and Nicole Karam DOI: https://doi.org/10.15420/icr.2020.06

Intraventricular Conduction Disturbances After Transcatheter Aortic Valve Implantation Shu-I Lin, Mizuki Miura, Ana Paula Tagliari, Ying-Hsian Lee, Shinichi Shirai, Rishi Puri, Francesco Maisano and Maurizio Taramasso DOI: https://doi.org/10.15420/icr.2020.07

Corrigendum to: Management of Tricuspid Regurgitation: The Role of Transcatheter Therapies Maurizio Taramasso, Christelle Calen, Andrea Guidotti, Shingo Kuwata, Hector Rodriguez Cetina Biefer, Fabian Nietlispach, Michel Zuber and Francesco Maisano DOI: https://doi.org/10.15420/icr.2020.22

Cardioprotection for Acute MI in Light of the CONDI2/ERIC-PPCI Trial: New Targets Needed Joel P Giblett and Heerajnarain Bulluck DOI: https://doi.org/10.15420/icr.2020.01

ISCHEMIA Trial and the Significance of MI Eduardo A Arias, FĂŠlix Damas-de los Santos and Heriberto Ontiveros-Mercado DOI: https://doi.org/10.15420/icr.2020.15

Patent Foramen Ovale Closure: State of the Art Joel P Giblett, Lynne K Williams, Stephen Kyranis, Leonard M Shapiro and Patrick A Calvert DOI: https://doi.org/10.15420/icr.2019.27

Management of Acute Coronary Syndromes During the Coronavirus Disease 2019 Pandemic: Deviations from Guidelines and Pragmatic Considerations for Patients and Healthcare Workers Henry Seligman, Sayan Sen, Sukhjinder Nijjer, Rasha Al-Lamee, Piers Clifford, Amarjit Sethi, Nearchos Hadjiloizou, Raffi Kaprielian, Punit Ramrakha, Michael Bellamy, Masood A Khan, Jaspal Kooner, Rodney A Foale, Ghada Mikhail, Christopher S Baker, Jamil Mayet, Iqbal Malik, Ramzi Khamis, Darrel Francis and Ricardo Petraco DOI: https://doi.org/10.15420/icr.2020.21

Corrigendum to: Intraventricular Conduction Disturbances After Transcatheter Aortic Valve Implantation Shu-I Lin, Mizuki Miura, Ana Paula Tagliari, Ying-Hsiang Lee, Shinichi Shirai, Rishi Puri, Francesco Maisano and Maurizio Taramasso DOI: https://doi.org/10.15420/icr.2020.33

Iterative Improvement and Marginal Gains in Coronary Revascularisation: Is Robot-assisted Percutaneous Coronary Intervention the New Hope?

Kalpa De Silva, Aung Myat, Julian Strange and Giora Weisz DOI: https://doi.org/10.15420/icr.2020.24

Š RADCLIFFE CARDIOLOGY 2020

Guest Editorial

An Extended Statement by the British Cardiovascular Intervention Society President Regarding the COVID-19 Pandemic Nick Curzen Wessex Cardiothoracic Unit, Southampton University Hospital, Southampton, UK

Disclosure: The author has no conflicts of interest to declare.

Citation: Interventional Cardiology Review 2020;15:e01. DOI: https://doi.org/10.15420/icr.2020.10 Correspondence: Nick Curzen, D Level East Wing, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK. E: nick.curzen@uhs.nhs.uk 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 noncommercial purposes, provided the original work is cited correctly.

Further to the statement that was released to members of the British Cardiovascular Intervention Society (BCIS) on 17 March 2020 about the coronavirus disease 2019 (COVID-19) pandemic,1 I have now been offered this opportunity to expand and update on the advice and comments in that original document in the light of recent developments, particularly with regard to personal protective equipment (PPE) and our recent guidance about cath lab procedures.

protecting staff and patients, many of which are incompatible, but which are considered non-negotiable. I will address this issue in detail below, in the light of recent PHE updated guidelines about general PPE, and the statement about specific cardiology procedures that was released a few days ago by the presidents of the British Cardiovascular Society (BCS), BCIS and the Heart Rhythm Society (HRS), and which are endorsed by PHE and the chief medical officers.

Members of the BCIS, along with their colleagues and patients, are facing the COVID-19 pandemic in an atmosphere of unparalleled stress and uncertainty about how we will be able to maintain the highest standards of clinical care.

Clinical Decisions and Choice of Case Management

As a group, our reaction to the challenges thrown at us by COVID-19 needs to be reasoned, calm, positive and energetic.

As before, the hottest issues remain: • What is the appropriate nature and application of PPE? • Are there some categories of patient who should not be offered treatment that we would normally consider (e.g. out of hospital cardiac arrest ventilated patients) or who should be offered alternatives (e.g. thrombolysis instead of primary percutaneous coronary intervention [PCI] for ST-elevation MI [STEMI]) to preserve cath lab access?

• What happens if a cath lab loses the ability to provide emergency cover?

It remains inappropriate for BCIS to attempt to provide proscriptive universal guidance concerning these and other contentious issues, for a number of reasons.

Firstly, there are a number of policies already laid down at a national level by NHS England, Public Health England (PHE) and the Department of Health, and by individual Trusts. Secondly, our understanding of the effects of this pandemic is evolving in a dynamic fashion, and there are significant differences in local Trust resources and logistical factors which may well shape the development of local policies. Finally, in some areas, particularly PPE, individual operators and centres have rapidly formed very strong views about the best algorithms for

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The presidents of BCS and BCIS have released a joint statement of support and advice to our members, and have contributed to an NHS England statement about recommendations for ongoing cardiology activities.2,3 Consistent with these guidelines, BCIS recommends that all our members follow some general principles, outlined here.

• Members should adopt, and comply with, national and local policies for testing, self-isolation and PPE compliance (see below).

• Members should develop local plans for possible scenarios in which their cath lab cannot provide emergency cover, whether due to staff absence or inadequate facilities/resources. We suggest that clinical leads/senior cath lab staff have discussions across local networks regarding potential cross cover for emergency patients between local centres, in case this becomes necessary.

• Be cautious about the implications of changing treatment pathways as a reflex response to this crisis. To this end, the NHS England guidance continues to recommend primary PCI for STEMI and angiography with a view to revascularisation for all non-ST-elevation MI (NSTEMI) patients, except perhaps the lowest risk group. This advice is based upon the assumption that the access to the cath lab and its specialised staff will remain stable. Clearly, in circumstances in which lab access is compromised by staff shortage or case load, hard alternative choices will need to be made. But the fact is that primary PCI for STEMI is associated with the best outcome for these patients, with the lowest mortality, fewest complication rates and shortest hospital stay. The same is true of a high-risk NSTEMI case.

Making a rapid diagnosis using angiography and providing effective revascularisation, as appropriate, is again associated with a shorter admission, with a much lower reinfarction and subsequent revascularisation rate. By contrast, deferring NSTEMI patients may

© RADCLIFFE CARDIOLOGY 2020

BCIS COVID-19 Statement

1.

2.

•

•

simply be deferring subsequent acute events and requirement for revascularisation. Having said that, the threshold for accepting patients for these procedures may have to change. This is going to be a matter of skill and judgement by experienced interventional cardiologists. The very elderly and comorbid patient cohort may not be included in this type of cath lab activity, given their increased risks and lower likelihood of benefit. Two examples highlight these points: Providing thrombolysis may seem like a good way of reducing demand upon cath labs, but what happens to the 25% of such patients who do not reperfuse? They then represent a major, and delayed, emergency dilemma. Even those patients who are successfully thrombolysed have a mandate to undergo angiography with or without revascularisation within 24 hours, according to international guidelines. The average length of stay for a primary PCI patient will be less than for a thrombolysed patient, given the higher likelihood of complications, and this may well lead to a higher overall exposure of NHS staff to the patient.

Not offering emergency angiography to ventilated out of hospital cardiac arrest patients with ST elevation. Consider the 45-year-old who has cardiac arrest at the gym – it is unlikely that most of us would not want to offer cath lab access to them, so make such blanket policies only with great care. Therefore, we recommend a case-by-case approach.

Members should reconsider the appropriate balance between PCI and coronary artery bypass grafting, as well as transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement.

As the NHS England document recommends, limited access to operating theatres and intensive care beds should push our balance of decision-making towards PCI and TAVI, respectively. This can still be based upon sound and considered decision-making processes involving discussion with colleagues and assessment of all available options. Unfortunately, we all need to remember that the option of ‘no intervention’ will necessarily become an important and useful one in our armoury during this crisis.

Members should continue to provide clinical expertise, skilful judgement, calm leadership and dignified assurance.3

Personal Protective Equipment The early variation in practices around the UK for PPE at all stages of patient contact was pretty alarming at the beginning of this crisis, but is becoming more uniform as NHS England catches up with the rapid spread of the virus and lessons learned from other countries. All patient exposure should now be associated with some form of PPE according to the latest national advice, a policy welcomed almost universally.

However, for BCIS members, it is the optimal PPE for cath lab procedures, especially primary PCI for STEMI, that has raised most anxiety and contention. I have been involved with Simon Ray (BCS President), Alistair Slade (President Elect, HRS) and Nick Linker (National Clinical Director for Heart Disease) and a number of others around the UK, with the aim of providing some definitive recommendations about optimal PPE for such cases. These recommendations were released a few days ago,4 and have been endorsed by NHS England and PHE, as being complementary to their recent updated general PPE guidance. I am pleased to reproduce the 1.

2.

British Cardiovascular Intervention Society. Statement by BCIS regarding the Covid-19 pandemic. BCIS, 17 March 2020. https://www.bcis.org.uk/news/statement-by-bcis-regardingthe-covid-19-pandemic/ (accessed 1 April 2020).

British Cardiovascular Intervention Society. Cardiology services during the Covid-19 pandemic. BCIS. 23 March 2020. https://

INTERVENTIONAL CARDIOLOGY REVIEW

3.

Table 1: Personal Protective Equipment in the Cath Lab BCIS/BCS/HRS/PHE Recommendations For primary PCI and other situations where the patient is admitted directly to the lab or via a resuscitation area in a haemodynamically unstable state, the default is that the first operator, assistant and others with direct patient contact (within 1 metre) should wear type 2 PPE. Note 1. It may well be the case that in many catheter labs, every member of staff will be within 1 metre of the patient at some point during the case.

Note 2. If some members of staff are not wearing type 2 PPE and there is a cardiac arrest, those staff should leave the lab immediately and only return if wearing full PPE.

For patients admitted to the lab already intubated or where there is felt to be a very high risk of arrest with prolonged resuscitation, then all those in the lab to wear type 2 PPE. For other situations the cath lab, when deemed low risk of AGP, can be regarded as an inpatient area or operating theatre with suspected or confirmed COVID-19 cases, and type 1 PPE is recommended for all those with direct patient contact.

AGP = aerosol generating procedure; COVID-19 = coronavirus disease 2019; PCI = percutaneous coronary intervention; PPE = personal protective equipment.

important part of this cath lab PPE guidance here. Our recommendations are shown in Table 1.

This guidance adopts an approach in which the PPE strategy is dependent upon both (a) the location in which patient contact occurs and (b) the likelihood that the contact will involve an aerosol generating procedure (AGP).

For cardiology this applies to any procedure requiring or likely to require resuscitation for cardiac arrest involving CPR ± intubation and to transoesophageal echocardiography. These procedures require disposable gloves, fluid resistant gowns, a filtering face piece respirator and eye/face protection wherever they are performed (termed type 2 PPE). Other procedures require disposable gloves, plastic apron (when not scrubbed), fluid resistant surgical mask and eye protection (termed type 1 PPE).

Ward environments are covered within the PHE guidance.

For cath lab procedures the PHE guidance can be applied to the individual case by the assessment of the senior clinician, together with senior cath lab staff, taking into account (a) the likelihood that the patient has the virus and (b) the chance the procedure will be AGP.

Conclusion We will all continue to face the challenges offered up to us by this pandemic in a professional and dignified manner. Colleagues must be allowed choice and judgement in circumstances when so much of what we are being asked to decide upon comes down to individual interpretation and analysis of scant data.

Furthermore, our decisions about a clinical scenario on any given day may need to be modified by the rapidly changing nature of this outbreak in our individual centres.

I wish all BCIS members the strongest personal support on behalf of myself and the members of BCIS Council.

www.bcis.org.uk/news/cardiology-services-during-the-covid19-pandemic/ (accessed 1 April 2020).

NHS England. Clinical guide for the management of cardiology patients during the coronavirus pandemic. NHS England. 20 March 2020. https://www.england.nhs.uk/coronavirus/ wp-content/uploads/sites/52/2020/03/specialty-guide-

4.

cardiolgy-coronavirus-v1-20-march.pdf (accessed 1 April 2020).

British Cardiovascular Intervention Society. Public Health England (PHE) PPE Guidelines. BCIS. 6 April 2020. https://www. bcis.org.uk/news/public-health-england-phe-ppe-guidelines/ (accessed 8 April 2020).

Structural

Anticoagulation after Transcatheter Aortic Valve Implantation: Current Status Antonio Greco and Davide Capodanno Division of Cardiology, CAST, PO G Rodolico, Policlinico-Vittorio Emanuele University Hospital, University of Catania, Catania, Italy

Abstract Transcatheter aortic valve implantation (TAVI) is the standard of care for symptomatic severe aortic stenosis. Antithrombotic therapy is required after TAVI to prevent thrombotic complications but it increases the risk of bleeding events. Current clinical guidelines are mostly driven by expert opinion and therefore yield low-grade recommendations. The optimal antithrombotic regimen following TAVI has yet to be determined and several randomised controlled trials assessing this issue are ongoing. The purpose of this article is to critically explore the impact of antithrombotic drugs, especially anticoagulants, on long-term clinical outcomes following successful TAVI.

Keywords Antithrombotic therapy, aortic stenosis, bleeding, cardiovascular events, direct oral anticoagulants, non-vitamin K oral anticoagulants, transcatheter aortic valve implantation, vitamin K antagonists Disclosure: DC receives speakers’ honoraria from Bayer, AstraZeneca and Daiichi Sankyo. AG has no conflicts of interest to declare.

Received: 5 October 2019 Accepted: 27 January 2020 Citation: Interventional Cardiology Review 2020;15:e02. DOI: https://doi.org/10.15420/icr.2019.24 Correspondence: Davide Capodanno, CAST, AOU Policlinico-Vittorio Emanuele, PO Rodolico, Ed 8, Via Santa Sofia 78, Catania, Italy.

E: dcapodanno@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 noncommercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve implantation (TAVI) is a valuable treatment option for patients with severe symptomatic aortic stenosis.1 Its use is supported by the results of multiple randomised controlled trials (RCTs) exploring the entire surgical risk spectrum, including inoperable, high-risk, intermediate risk and low risk patients. 2–8 TAVI is associated with a small but not negligible complication rate that exceeds that observed for percutaneous coronary intervention by approximately 10-fold and strongly impacts on overall morbidity, mortality and costs.9–12 Thrombotic events are a major concern during and after TAVI procedures and are associated with various factors, including procedure-related and valve-related factors.13,14 The typical TAVI population is highly comorbid and several coexisting conditions (e.g.

AF) may enhance the individual’s risk of thrombosis.15 The multifactorial mechanism behind thrombotic events after TAVI suggests the need for adequate antithrombotic therapy, including antiplatelet and/or anticoagulant agents.16 However, the prescription of multiple antithrombotic drugs is not desirable in the older population that is currently offered TAVI, since any benefits may be outweighed by an increased propensity to bleed, which is a risk after TAVI irrespective of a patient’s background and adjunctive pharmacotherapy.11 Importantly, a large proportion of TAVI patients have comor­bidities requiring longterm oral anticoagulation (OAC) or dual antiplatelet therapy (DAPT), which makes it difficult to balance the risks of ischaemia and bleeding for subsequent drug selection.13 Since the current evidence is not conclusive and recommendations are mostly supported by expert opinion, uncertainties about optimal antithrombotic therapy after TAVI remain.17 The purpose of this article is

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to critically explore the role of antithrombotic therapy after TAVI, focusing mainly on anticoagulant therapy and its connection with clinical and pathophysiological effects in patients with and without a long-term indication for OAC.

Complications of TAVI Despite consistent improvements in patient and device selection, technical and procedural performance and clinical management, TAVI is still fraught with risk. Both thrombotic and bleeding complications may occur, which have a strong impact on early and long-term clinical outcomes.9

Thrombotic Events Definitions of thrombotic events following TAVI have been standardised by the Valve Academic Research Consortium (VARC) and updated VARC-2 consensus.18,19 Cerebrovascular events, AF and valve thrombosis account for the majority of thrombotic complications associated with TAVI and are the reason that antithrombotic therapy with antiplatelets and/or OAC is recommended (Figure 1).

High concentrations of tissue factor and thrombin surrounding degenerative aortic stenosis leaflets contribute to local inflammation and thrombogenicity. The exposure of diseased leaflets and irregular blood flow around the device strongly increase the periprocedural prothrombotic environment associated with TAVI.20 Thrombotic risk is also enhanced by coexisting conditions. Approximately 70% of TAVI patients suffer from coronary artery disease, which increases the risk of subsequent ischaemic events.2–8,21 Peripheral artery disease and extracranial carotid artery stenosis occur in 24–48% and 30% of patients, respectively.22,23 AF also plays a major role, as it has a detrimental impact

© RADCLIFFE CARDIOLOGY 2020

Anticoagulation after Transcatheter Aortic Valve Implantation on cardiovascular and cerebrovascular events (CVEs), mortality and length of hospitalisation and affects one-third of TAVI patients, presenting as a new-onset condition in about 36% of individuals.24–26

Figure 1: Impact of Antiplatelet and Anticoagulant Strategies on the Prevention and Treatment of the Main Thrombotic Complications after Transcatheter Aortic Valve Implantation

MI

Cerebrovascular Events CVEs are a major concern for TAVI patients and include VARC-2-defined stroke and transient ischaemic attack.19 Based on their timing, these events may be classified as acute (within 24 hours; about 50% of CVEs), subacute (1–30 days) and late (>30 days).33 It should be highlighted that the incidence of CVEs has remained substantially unchanged in recent decades, signalling the need for further improvements in this field.

Across TAVI landmark studies, the 30-day stroke incidence ranges between 0.6% and 6.7%, increasing to 1.2–10.6% at 1 year.2–8,21 The mechanism underpinning CVEs following TAVI is multifactorial. It includes valve-related flow turbulence, vessel wall disruption, metallic frame exposure (which in turn induces platelet activation) and patientrelated prothrombotic factors, irrespective of the valve type (balloonor self-expandable) or procedural approach (transfemoral or transapical).34 Other patient-related factors, such as AF, periprocedural hypotension or hypoperfusion, should be considered determinants of CVEs.35 The acute events seem to be slightly different: thrombi derive from the interaction between the device and the calcified aortic valve, with debris dislodgment due to the placement of wires and catheters, pre- and post-dilatation.36,37 Interestingly, neuroimaging studies have demonstrated the appearance of silent cerebral lesions with embolic features following TAVI in up to two-thirds of patients.38,39 Their clinical and prognostic significance is still unknown and will probably be ascertained once TAVI is offered to a younger population. However, embolic cerebral protection devices are available and preliminary studies have demonstrated a reduction in total lesion burden without stroke or survival benefits.40,41

Leaflet Thrombosis The European Society of Cardiology (ESC), European Association of Percutaneous Cardiovascular Interventions and European Association for Cardio-Thoracic Surgery published a joint consensus statement to standardise the definition of bioprosthetic valve dysfunction (BVD), an all-encompassing term including all factors underlying bioprosthesis failure.42 In this instance, bioprosthetic valve thrombosis refers to a spectrum of abnormalities ranging from minimal hypo-attenuating leaflet thickening (HALT) to clinically overt obstructive thrombosis.43,44 Epidemiological characteristics of this phenomenon are hard to assess because there is high heterogeneity in definitions and diagnostic imaging used in various studies.45 Two registries established a higher

INTERVENTIONAL CARDIOLOGY REVIEW

Anticoagulant therapy

Leaflet Thrombosis

tic bo s m on ro ti th lica VI p TA com

MI is modestly frequent after TAVI, occurring in up to 5.1% of patients at 30 days, and has a detrimental impact on long-term outcomes.27 TAVI patients are usually screened for coronary artery disease and eventually treated, but whether complete revascularisation before TAVI reduces ischaemic events and improves clinical outcomes is still matter of debate. Current knowledge is based on small observational trials and their meta-analyses, therefore the evidence is of poor quality.28–32 Myocardial injury may also result from other causes, including tissue compression, hypoperfusion or direct cardiac injury in cases of transapical access.13

MI

Antiplatelet therapy

TAVI = transcatheter aortic valve implantation.

prevalence of leaflet thrombosis among TAVI patients compared to those undergoing surgical aortic valve replacement.46,47 Recently, the imaging sub-study of the Placement of AoRTic TraNscathetER Valves (PARTNER) 3 trial confirmed this finding. HALT was found to have an incidence of approximately 10% at 30 days, increasing up to 24% at 1 year.48 Interestingly, HALT minimally affects transvalvular gradients, does not cause clinical adverse events, and spontaneously resolves in half of cases without any need for OAC.48 A recent meta-analysis of one RCT and 17 observational trials found that, whereas clinically apparent thrombosis is very rare (0.48% per year), subclinical leaflet thrombosis is common (16.32% per year).49 Importantly, leaflet thrombosis seems to lead to an increased risk of further thrombotic events, probably due to the distal embolisation of microthrombi;49 unfortunately, current data are too sparse to draw a final conclusion.

Diagnosis of leaflet thrombosis is made based on haemodynamic (e.g. increased mean trans-prosthetic gradient, new/worsened intraprosthetic regurgitation), imaging (leaflet thickening or reduced motion) and therapeutic ex juvantibus (improvement on anticoagulant therapy) criteria.42 The assumed pathophysiological mechanisms of leaflet thrombosis include reduced blood flow between the Valsalva sinuses and bioprosthetic leaflets, tissue fissuring, endothelium exposure and incomplete prosthesis expansion or apposition, which in turn delays the process of endothelisation.50,51 Several factors are independent predictors of leaflet thrombosis: body mass index >30 kg/m2, large valve diameter (>28 mm), balloon-expandable prostheses, valve-in-valve procedure and single antiplatelet therapy (SAPT) administration.52,53 Interestingly, in comparison with OAC, SAPT and DAPT are less effective on these thrombi in many cases because they develop in a low shear-stress setting that often involves thrombinmediated processes rather than platelet aggregation (Figure 1).13 Knowledge of subclinical leaflet thrombosis is scarce and controversial but it seems to be a potential concern in relation to clinical outcomes and long-term valve durability.13,43 OAC has exhibited good efficacy in the prevention and treatment of subclinical and clinical leaflet thrombosis. However, since the association between subclinical leaflet thrombosis and clinical outcome is unclear, no recommendations can

Structural be made for routine pharmacological prevention.13 The imaging substudy of the Medtronic Evolut Transcatheter Aortic Valve Replacement Low Risk Patients trial (NCT02701283) will further elucidate this topic.8

Bleeding Events A major concern during and after TAVI is bleeding events. These are ranked in severity from minor to major and life-threatening according to the VARC-2 consensus scale19 and are more specifically defined by the Bleeding Academic Research Consortium.54 A rough but essential distinction exists on the basis of the bleeding site; there are two classes of events with different incidences, clinical features and prognostic implications, namely access-related and non-access-related bleeding.18,19,54 A further criterion, similar to CVEs, considers the timing of bleeds, which may be split into periprocedural, early (within the first month) and late.

Periprocedural bleeding mainly results from access-site complications arising from mechanical causes (e.g. large delivery sheaths in patients with peripheral artery disease and vascular calcifications) and may be predicted by several parameters, including sheath-to-femoral artery ratio and femoral artery calcium score.55,56 A small proportion of periprocedural bleeds is due to cardiac structural damage leading to pericardial tamponade, especially during surgical repair of the apex using the transapical approach.57 Late bleeds (>30 days) are mainly non-access-related and involve other systems (gastrointestinal, genitourinary, neurological).9 Access-site events occur almost entirely within the first month (periprocedural and early); whereas nonaccess-site bleeds have an initial peak and then continue to accrue over time.9 When assessing the characteristics of bleeding events, two limitations should be acknowledged. First, despite the efforts that have gone into producing consensus documents, the definitions of bleeds, timing of assessment and event adjudication are heterogeneous among TAVI trials and registries.18,19,54 Second, initial TAVI trials included older and frailer patients with a higher inherent bleeding risk, resulting in an increased event rate.58 Taking these aspects into account, life-threatening or major bleeding rates have been reported to be between 2.4% and 41.7% at 30 days and between 3.2% and 46.1% at 1-year follow-up.2–8,21 Notably, regardless of the aetiology, both acute and late bleeding are associated with poor clinical outcomes and increased mortality rate.9,10,12 In addition, bleeds may be augmented by coexisting conditions, such as older age, frailty, fall risk, renal failure, liver disease, malignancy, anaemia and coagulation disorders, as well as by AF and antithrombotic therapy.59–64 Finally, a periprocedural thrombo-inflammatory state and reduced platelet turnover in the older patient may act synergistically, resulting in transient thrombocytopenia in 69–87% of TAVI patients, signalling severe impairment of general homeostasis.65–67 Gastrointestinal bleeding associated with aortic stenosis is due to the shear stress and flow turbulence across the stenotic aortic valve, which may cause the cleavage of high-molecular-weight multimers of von Willebrand factor, a coagulation protein responsible for haemostasis.

This condition, known as Heyde’s syndrome or acquired von Willebrand factor disease type 2A, prolongs the adenosine diphosphate closure time and leads to a tendency to bleed.68 Interestingly, this condition may also develop as a result of a moderate-to-severe paravalvular leak after TAVI, and a prolonged adenosine diphosphate closure time (>180 seconds) was shown to be predictive of significant aortic regurgitation and higher 1-year mortality rate following TAVI.69 The role of paravalvular

leak as a surrogate predictor for bleeding tendency and mortality following TAVI is still unclear.70 Finally, strategies aiming to reduce the bleeding rate following TAVI include technological improvement, reduction in sheath size, optimal patient selection, choice of access route and the use of percutaneous closure devices. Increase in the operator’s experience also reduces the chances of bleeds following TAVI.

Antithrombotic Therapy Following TAVI As larger RCTs are still awaited, current guidelines are based on observational studies and expert opinion (Table 1).71 The American Heart Association/American College of Cardiology guidelines recommend: • life-long acetylsalicylic acid (ASA) (class IIa, level of evidence B); • the consideration of DAPT with clopidogrel on top of ASA for the first 6 months (class IIb, level of evidence C); and • the consideration of a vitamin K antagonist (VKA) with a target international normalised ratio of 2.5 in the first 3 months in patients at low bleeding risk (class IIb, level of evidence B).72,73 The attitude is slightly different on the other side of the Atlantic, where the ESC recommends lifelong SAPT after an initial DAPT for 3–6 months (class IIa, level of evidence C) and starting with SAPT as a more conservative option for high bleeding risk patients (class IIb, level of evidence C).74 Finally, lifelong OAC is recommended only for patients who have other indications for anticoagulation (class I, level of evidence C).74 The Canadian Cardiovascular Society recommends lifelong SAPT with ASA, preceded by a short 1–3 month course of DAPT.75 OAC should be reserved for patients with coexisting indications for long-term anticoagulation in which adding antiplatelet therapy is controversial.

Interestingly, triple therapy is generally not recommended owing to the inherent high risk of bleeding in this population.75 Many of the societal guidelines do not issue specific recommendations for patients requiring long-term OAC, rendering this specific subgroup a residual field of uncertainty. Interestingly, a joint consensus document from the European Heart Rhythm Association and ESC Working Group on Thrombosis suggested that AF patients who undergo TAVI should receive OAC alone or a double therapy (OAC plus SAPT) if coronary artery disease coexists, or OAC alone if it does not.76 Unfortunately, OAC alone might not be enough to prevent stroke in such patients due to the various mechanisms underpinning thrombi formation, thus the dilemma continues.

Anticoagulant Therapy after Transcatheter Aortic Valve Implantation The optimal antithrombotic strategy following TAVI is matter of debate. On the basis of the mechanisms surrounding thrombotic complications, both antiplatelet agents and OACs deserve consideration (Figure 1), with triple therapy representing a very questionable option.13,77 Up to two-thirds of patients currently receive a combination of OAC and antiplatelet therapy, but this seems to lead to a substantial increase in the composite of major or life-threatening bleeding.78 This practice is derived from analogy with percutaneous coronary intervention, considering the lack of high-grade guideline recommendations and the high prevalence of coronary or peripheral artery disease among TAVI patients.14

INTERVENTIONAL CARDIOLOGY REVIEW

Anticoagulation after Transcatheter Aortic Valve Implantation Table 1: Societal Guideline Recommendations Patients

Recommendations

Class of Level of Recommendation Evidence

American Heart Association/American College of Cardiology Guidelines (2019)89 Patients without coexisting indication for long-term anticoagulation

Patients with coexisting indication for long-term anticoagulation

Aspirin 75–100 mg daily is reasonable in all patients with a bioprosthetic aortic valve.

IIa

B

Clopidogrel 75 mg daily may be reasonable for the first 6 months after TAVI in addition to life-long aspirin 75–100 mg daily.

IIb

C

Anticoagulation with a VKA to achieve an INR of 2.5 may be reasonable for at least 3 months after TAVI in patients at low risk of bleeding.

IIb

B-NR

No specific recommendations have been given.

Canadian Cardiovascular Society Position Statement (2012)75 Patients without coexisting indication for long-term anticoagulation

Low-dose aspirin is recommended along with 1–3 months of a P2Y12 inhibitor.

Patients with coexisting indication for long-term anticoagulation

The need for adjunctive antiplatelet agents is controversial and triple therapy should be avoided unless definite indications exist.

Expert consensus

European Society of Cardiology/European Association of Percutaneous Cardiovascular Interventions Guidelines (2017)74 Patients without coexisting indication for long-term anticoagulation

Patients with coexisting indication for long-term anticoagulation

Dual antiplatelet therapy should be considered for the first 3–6 months after TAVI, followed by life-long single antiplatelet therapy.

IIa

C

Single antiplatelet therapy may be considered after TAVI in high bleeding risk patients.

IIb

C

Life-long oral anticoagulation is recommended for patients with surgical or transcatheter implanted bioprostheses who have other indications for anticoagulation.

I

C

INR = international normalised ratio; TAVI = transcatheter aortic valve implantation; VKA = vitamin K antagonist.

Current knowledge on OAC in patients who have undergone TAVI is largely confined to VKA and stems from observational trials (Figure 2).79–83 To assess this issue in a more careful and comprehensive way, it is useful to make specific considerations after splitting patients receiving TAVI into two groups, i.e. with and without a coexisting indication for OAC.

Patients with a Coexisting Indication for Anticoagulation The most frequent indication for long-term anticoagulation is AF, followed by mechanical valve prostheses, deep vein thrombosis/pulmonary embolism, left ventricular thrombi, pulmonary hypertension or clotting disorders.84 How to treat these conditions after TAVI is an area of uncertainty and data from trials and registries are controversial.85–88 Importantly, when AF or other comorbidities require OAC, the antithrombotic regimen should rely on more specific recommendations.89 A large European and Canadian TAVI registry questioned the efficacy and safety of adding antiplatelet therapy to OAC: after a 13-month follow-up, there was no between-group difference in stroke, major cardiovascular events and death, while patients on dual or triple therapy experienced significantly more major or life-threatening bleeds.85 The large prospective FRANCE TAVI registry showed OAC at discharge to be an independent predictor of 3-year mortality;88 whereas a few observational studies have confirmed the safety and efficacy of OAC, either with VKA or a direct oral anticoagulant (DOAC).86,87 Further insights may come from ongoing investigations (Figures 3 and 4). The Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic Valve Implantation (POPular-TAVI; NCT02247128) is a large multicentre open-label RCT questioning the value of adding 3 months of clopidogrel to single antithrombotic therapy (SAPT or

INTERVENTIONAL CARDIOLOGY REVIEW

OAC, as indicated) with respect to the co-primary endpoints of 1-year free from any or non-procedural bleeding; the results are expected in 2020.90,91 The multicentre open-label Clopidogrel Omission After Transcatheter Aortic Valve Replacement (CLOE) trial has a similar design to POPularTAVI. It will enrol up to 4,000 TAVI patients to explore the role of routine clopidogrel (at least 6 months) on top of SAPT or OAC, as indicated, after TAVI to determine its effect on efficacy (composite of death, MI, stroke and valve thrombosis) and safety (major and life-threatening bleeding) endpoints.

The Anticoagulation Alone Versus Anticoagulation and Aspirin Following Transcatheter Aortic Valve Interventions (AVATAR; NCT02735902) trial is expected finish in April 2020.92 It has recruited TAVI patients with an underlying indication for long-term OAC and is investigating the 12-month net clinical benefit of OAC monotherapy with VKA or DOAC versus double therapy with aspirin plus OAC. Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation (ENVISAGE-TAVI AF; NCT02943785) is an open-label RCT enrolling up to 1,400 AF-TAVI patients and is comparing edoxaban 60 mg to VKA in terms of net adverse events and major bleeds up to 3-year follow-up. Notably, antiplatelet therapy – either SAPT or DAPT – may be administered at the investigator’s discretion in both the experimental and control arms.

The final data are due to be collected in May 2020.93,94 The Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis (ATLANTIS; NCT02664649) trial is a multicentre openlabel RCT including 1,510 all-comers and is structured into two strata: the first comparing apixaban 5 mg to VKA in patients with indications

Structural Figure 2: Published Studies Evaluating Anticoagulant Therapy in Transcatheter Aortic Valve Implantation Patients D’Ascenzo et al. (n=1,210)

Salinas et al. (n=34)

Varshney et al. (n=241)

Jochheim et al. (n=962)

Figini et al. (n=360) Vavuranakis et al. (n=80)

AUREA (n=123) R

2012

2013

2014

2015

2016

2017

2018

R

Geis et al.

(N=167) Czerwinska-Jelonkiewicz et al. (n=83)

Poliacikova et al. (n=171)

Abdul-Jawad et al. (n=621)

2019

Holy et al. (n=514)

GALILEO (n=1,644)

The size of circles reflects the magnitude of the studies. R = randomised. Sources: Salinas et al. 2012.79; Figini et al. 2013.80; Poliacikova et al. 2013.81; Czerwinska-Jelonkiewicz et al. 2013.82; Vavuranakis et al. 2015.83; Abdul-Jawad et al. 2016.85; Geis et al. 2017.86; AUREA (NCT03557242)105; Dangas et al. 2019.106; Jochheim et al. 2019.110D’Ascenzo et al. 2017.125; Holy et al. 2017.126; Varshney et al. 2017.127

Figure 3: Design of Ongoing Trials Involving Transcatheter Aortic Valve Implantation Patients with a Long-term Indication for Oral Anticoagulation Antithrombotic therapy duration (months) 0

3

6

12

0

ATLANTIS

Treatment

1,510 patients undergoing successfull TAVI

R VKA

1

r

d fo Nee C OA

R

Apixaban VKA

1

No n for eed OA C

Apixaban

1 R

Treatment

SAPT/DAPT

1 Follow-up

12 months

0

1

1,400 AF patients undergoing successfull TAVI

1

3

6

Up to 13 months

APT

VKA APT

Control

Follow-up

12

Antithrombotic therapy duration (months) 36

0

1

Edoxaban

R 1

12

Treatment

Antithrombotic therapy duration (months)

Treatment

6

Control

Follow-up

ENVISAGE-TAVI AF

3

Control

ASA

Control

1

1

VKA

1

AVATAR 170 patients requiring long-term OAC undergoing successfull TAVI

1

Antithrombotic therapy duration (months)

POPular-TAVI 1,000 patients undergoing successfull TAVI

r d fo Nee C OA

R

Treatment

1 Control

No n for eed OA C

1 R

Treatment

1 Control

36 months

Follow-up

1

3

6

12

VKA VKA Clopidogrel

ASA ASA Clopidogrel

12 months

APT = antiplatelet therapy; ASA = acetylsalicylic acid; DAPT = dual antiplatelet therapy; OAC = oral anticoagulation; R = randomised; SAPT = single antiplatelet therapy; TAVI = transcatheter aortic valve implantation; VKA = vitamin K antagonist.

INTERVENTIONAL CARDIOLOGY REVIEW

Anticoagulation after Transcatheter Aortic Valve Implantation for OAC; and the second evaluating apixaban 5 versus SAPT or DAPT in patients without the need for OAC. The primary endpoint is a composite of death, MI, stroke, systemic embolism, intracardiac or bioprosthetic thrombus, any episode of deep vein thrombosis or pulmonary embolism, or life-threatening or major bleeding at 12 months. The study results are expected to be published in 2020.95,96

Transcatheter Heart Valve Dysfunction in Low Risk Transcatheter Aortic Valve Replacement (LRT; NCT03557242) is exploring the add-on effect of VKA in low-risk TAVI patients taking ASA who have no reason for OAC administration, in terms of clinical outcomes and valve deterioration.105 The registry arm is implementing the same study design in patients requiring OAC.

Importantly, current considerations apply to contemporary (high-tointermediate surgical risk) population and bioprostheses, needing a careful reappraisal of their external validity when TAVI will be offered to lower-risk and younger patients (with a subsequent decrease in CVE rates) and aortic bioprostheses will go through further improvements as expected.14

The Global Study Comparing a rivAroxaban-based Antithrombotic Strategy to an antipLatelet-based Strategy After Transcatheter aortIc vaLve rEplacement to Optimize Clinical Outcomes (GALILEO) was the first to evaluate the role of a DOAC in TAVI patients not requiring OAC. This open-label trial randomised 1,644 patients to a DOAC-based strategy with long-term low-dose rivaroxaban 10 mg once daily (plus ASA for the first 3 months) or standard 3-month DAPT (ASA plus clopidogrel) followed by SAPT with ASA. The efficacy and safety outcomes were studied for both regimens.20,106 This trial was prematurely halted in August 2018 by the Data and Safety Monitoring Board due to safety concerns arising from an interim analysis as the rivaroxaban-based regimen had higher rates of thromboembolic events, bleeding and all-cause death.

Patients without a Coexisting Indication for Anticoagulation The use of anticoagulants following TAVI is based on a lesson from surgical valve replacement; however, while mechanical prostheses always necessitate long-term anticoagulation, this requirement has been overcome by modern bioprosthetic valves.97 While OAC is the standard of care for clinical or subclinical bioprosthetic leaflet thrombosis,49 its role in the prevention of stroke following TAVI is less clear. Although the prevailing mechanism of CVEs after TAVI is unknown, the rationale for using OAC relies on the knowledge that platelet activation and coagulation are highly interdependent and that thrombin plays a central role in both pathways.98 A recent analysis of the PARTNER 2 cohort strongly questioned the efficacy of OAC alone for preventing stroke after TAVI in these patients, showing that OAC without antiplatelets did not reduce the risk of stroke, probably due to platelet activation being triggered by the stent and increased thrombogenicity arising from endothelium exposure.99 Furthermore, antiplatelet therapy may disrupt the diffuse inflammatory and antithrombotic environment, acting as a substrate for stroke in patients with aortic stenosis.100

Recently, the GALILEO-4D sub-study demonstrated that dual pathway inhibition (rivaroxaban 10 mg plus ASA) is more effective than DAPT (ASA plus clopidogrel) in preventing subclinical leaflet abnormalities as documented using 4D CT.107 However, these results should be cautiously interpreted due to the higher risk of adverse outcomes found with the rivaroxaban-based strategy in the parental trial.

The FRANCE-TAVI registry has recently demonstrated the paradoxical effect of OAC monotherapy, which reduced BVD but independently increased the risk of death.88 A further consideration is that VKA may enhance the calcification of native and bioprosthetic leaflets, inhibiting a matrix vitamin K-dependent protein, thus leading to BVD.101 This represents an additional concern about the long-term use of VKA, whose benefit-to-risk ratio may worsen over time because the prevention of BVD becomes less relevant as time passes (BVD occurs mostly in the first 2 years) and bleeding risk increases with age.101

In conclusion, while European guidelines did not provide specific recommendations supporting anticoagulant pathways in patients without a coexisting indication for OAC, American guidelines were published at a time when new evidence from large registries and the AUREA and GALILEO trials that showed a definite increase in the bleeding rate without significant benefits with OAC, was not available.

The Dual Antiplatelet Therapy Versus Oral Anticoagulation for a Short Time to Prevent Cerebral Embolism After TAVI (AUREA; NCT01642134) trial compared VKA to DAPT (ASA plus clopidogrel) in terms of new ischaemic and haemorrhagic cerebral lesions on 6-day and 3-month identified using diffusion-weighted magnetic resonance.102 No differences were noted between the two regimens with regards to new cerebral lesions or clinical events (death, stroke and major bleeding).103 It should be noted that the above results (PARTNER 2 sub-analysis, FRANCE-TAVI registry and AUREA) were obtained in the context of predominant VKA use, while the role of DOAC-based strategies is uncertain.104 Several RCTs exploring the role of OAC in TAVI patients who do not require it are ongoing (Figure 4). The randomised Strategies to Prevent

INTERVENTIONAL CARDIOLOGY REVIEW

Finally, among 220 patients otherwise not requiring OAC, the open-label Anticoagulant Versus Dual Antiplatelet Therapy for Preventing Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement (ADAPT-TAVR; NCT03284827) trial is comparing the effects of 6 months of edoxaban to DAPT with ASA plus clopidogrel on leaflet thrombosis assessed by 4D CT.108 The results are expected in December 2020.

If Using an Anticoagulant, Which One is Best?

Since numerous concerns about OAC seem to derive from the prevailing use of VKA, several investigations have compared DOAC to VKA in terms of efficacy and safety among TAVI patients. 87,109,110 Previous studies had rendered controversial results, probably due to the lack of randomisation and the small sample sizes. A recent multicentre non-randomised registry of TAVI patients requiring OAC compared a DOAC-based strategy (mostly rivaroxaban or apixaban) to a standard VKA strategy. While there was no difference in 30-day efficacy and safety outcomes (except a higher rate of non-disabling stroke with DOAC), the DOAC group had an increased rate of the 1-year composite endpoint of all-cause death, any stroke or MI without a corresponding decrease in bleeding. This is striking, because OAC was indicated for the prevention of AF-related stroke, for which DOAC are superior to VKA.111,112 Similar worries arose from the GALILEO trial, which was prematurely halted due to DOACrelated safety concerns.106 In spite of a clear superiority of DOAC

Structural Figure 4: Design of Ongoing Trials Involving TAVI Patients without a Long-term Indication for Oral Anticoagulation Antithrombotic therapy duration (months) 0

1

6

Antithrombotic therapy duration (months) 12

ATLANTIS

Treatment

1,510 patients undergoing successfull TAVI

ASA

1

Clopidogrel

Control

1

r

d fo Nee AC O

R

3

6

12

Apixaban

1

R

220 patients undergoing successfull TAVI

0

Edoxaban

1

ADAPT-TAVR

3

Treatment

VKA

1 Control

No n for O eed AC

1 R

Apixaban

Treatment

1

SAPT/DAPT

Control

6 months

Follow-up

Follow-up

Up to 13 months

Antithrombotic therapy duration (months)

Antithrombotic therapy duration (months) 0

1

3

6

0

12

1

3

1

LRT 300 low-risk TAVI patients

Treatment

ASA

R In

1

di

ca tio

nf or

POPular-TAVI

VKA

1,000 patients undergoing successfull TAVI

Control OA C

1 Registry arm

Follow-up

r d fo Nee AC O

R

Treatment

1 Control

No n for O eed AC

VKA Clopidogrel

ASA

1 R

Treatment

ASA

1 VKA

Control

Follow-up

30–45 days

12

VKA

1 VKA

6

Clopidogrel

12 months

ASA = acetylsalicylic acid; DAPT = dual antiplatelet therapy; OAC = oral anticoagulation; R = randomised; SAPT = single antiplatelet therapy; TAVI = transcatheter aortic valve implantation; VKA = vitamin K antagonist.

over VKA for stroke prevention in the AF population, their administration to TAVI patients is currently not supported by strong evidence and the choice of the OAC regimen, if any, is empirical.

increases bleeding risk.121,122 The AVATAR trial and the OAC subgroups of the POPular-TAVI and CLOE trials will provide some answers on the benefit-to-risk ratio of combination therapy including antiplatelets and OACs in patients undergoing TAVI.14,90,92

Special Subsets The subject of antithrombotic therapy following TAVI may be more challenging than usual in certain subgroups who present other indications for antithrombotic drugs or display specific features influencing the ischaemia-to-bleeding risk trade-off. 13 All demographic (age, gender, race), clinical (comorbidities) and procedural (technical skills and requirements) characteristics should be taken into account when dealing with this issue. 113–116 Notably, several strategies could be applied to reduce the predominant risk profile in an individual patient, for instance the assessment of ontreatment platelet reactivity to tailor antithrombotic therapy to a patient’s response.117

Patients Requiring Antiplatelet Therapy after Transcatheter Aortic Valve Implantation The main independent indication for antiplatelet therapy is chronic coronary syndrome, which affects up to 40% of TAVI patients, followed by acute coronary syndrome, peripheral artery disease and large aortic arch atheroma.118–120 In these patients, routine administration of OAC should be avoided. In the most complex scenario of patients in whom the absolute indications for antiplatelets and OAC merge, the matter becomes convoluted. As a rule, in AF patients with chronic coronary syndrome or peripheral artery disease the addition of antiplatelets to OAC should be discouraged, since this strategy does not appear to reduce the risk of ischaemic events but significantly

Patients at High Bleeding Risk: When Less is More The management of this subgroup is very perplexing, since the adverse effects of antithrombotic drugs can easily overcome the intended benefits. Only ESC yielded a specific recommendation for this cohort, suggesting a SAPT (class IIb, level of evidence C).74 A typical high bleeding risk setting is outlined by the need for triple antithrombotic therapy (e.g. an AF patient who experiences acute coronary syndrome):123 importantly, since the primary aim is to reduce the adjunctive bleeding risk from antithrombotic drugs, left atrial appendage occlusion may be a valuable option. This is currently being evaluated among high bleeding risk TAVI patients.124 Importantly, this choice may represent more than an alternative to OAC, even in AF patients who have previously experienced major or life-threatening bleeding or an ischaemic stroke while on OAC.120

Conclusion OAC is currently the standard treatment for leaflet thrombosis and represents a valuable option for ischaemia prevention among TAVI patients. However, all antithrombotic therapies should be weighted according to a patient’s thrombotic and bleeding risk profiles and comorbidities.

Current evidence is from the high- to intermediate-risk TAVI population, which is expected to significantly change in the next few years. The

INTERVENTIONAL CARDIOLOGY REVIEW

Anticoagulation after Transcatheter Aortic Valve Implantation treatment of younger and healthier patients will soon reduce the burden of complications and the net benefit of antithrombotic regimens will likely vary accordingly.

Two questions remain unanswered: 1) what is the best antithrombotic regimen and duration in TAVI patients; and 2) are DOACs non-inferior or

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Al-Azizi K, Hamandi M, Mack M. Clinical trials of transcatheter aortic valve replacement. Heart 2019;105(Suppl 2):S6–9. https://doi.org/10.1136/heartjnl-2018-313511; PMID: 30846518.

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97. An K, Belley-Cote E, Um K, et al. Antiplatelet therapy versus anticoagulation after surgical bioprosthetic aortic valve replacement: a systematic review and meta-analysis. Thromb Haemost 2019;119:328–39. https://doi.org/10.1055/ s-0038-1676816; PMID: 30616247.

98. Weitz J. Insights into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome. Thromb Haemost 2014;112:924–31. https://doi.org/10.1160/TH14-030265; PMID: 25030773.

99. Kosmidou I, Liu Y, Alu MC, et al. Antithrombotic therapy and cardiovascular outcomes after transcatheter aortic valve replacement in patients with atrial fibrillation. JACC Cardiovasc Interv 2019;12:1580–9; PMID: 31439338.

100. Parolari A, Loardi C, Mussoni L, et al. Nonrheumatic calcific aortic stenosis: an overview from basic science to pharmacological prevention. Eur J Cardiothoracic Surg 2009;35:493–504. https://doi.org/10.1016/j.ejcts.2008.11.033; PMID: 19162497.

101. Pibarot P, Mazer CD, Verma S. Should bioprosthetic aortic valves be routinely anticoagulated? Insights from PARTNER and beyond. J Am Coll Cardiol 2019;74:1201–4. https://doi. org/10.1016/j.jacc.2019.07.018; PMID: 31466617.

102. Dual Antiplatelet Therapy Versus Oral Anticoagulation for a Short Time to Prevent Cerebral Embolism After TAVI (AUREA), NCT01642134. https://clinicaltrials.gov/ct2/show/NCT01642134 (accessed 19 February 2020).

103. Diaz VAJ. Short-course dual antiplatelet therapy versus oral anticoagulation to prevent cerebral embolism after transcatheter aortic valve replacement. Presented at TCT 2019, San Francisco, CA, 28 September 2019.

104. Mazer CD, Bhatt DL, Verma S. Anticoagulation following TAVR. J Am Coll Cardiol 2019;73:22–8. https://doi.org/10.1016/j. jacc.2018.11.012; PMID: 30621947.

105. Strategies to Prevent Transcatheter Heart Valve Dysfunction in Low Risk Transcatheter Aortic Valve Replacement (LRT), NCT03557242. https://clinicaltrials.gov/ct2/show/NCT03557242 (accessed 19 February 2020).

106. Dangas GD, Tijssen JGP, Wöhrle J, et al. A controlled trial of rivaroxaban after transcatheter aortic-valve replacement. N Engl J Med 2019;382:120–9. https://doi.org/10.1056/ NEJMoa1911425; PMID: 31733180.

107. De Backer O, Dangas GD, Jilaihawi H, et al. Reduced leaflet motion after transcatheter aortic-valve replacement. N Engl J Med 2020;382:130–9. https://doi.org/10.1056/NEJMoa1911426; PMID: 31733182.

108. Park S-J. Anticoagulant Versus Dual Antiplatelet Therapy for Preventing Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement, ADAPT-TAVR, NCT03284827. https://clinicaltrials.gov/ct2/show/NCT03557242 (accessed 19 February 2020).

109. Seeger J, Gonska B, Rodewald C, et al. Apixaban in patients with atrial fibrillation after transfemoral aortic valve replacement. JACC Cardiovasc Interv 2017;10:66–74. https://doi. org/10.1016/j.jcin.2016.10.023; PMID: 27916486.

110. Jochheim D, Barbanti M, Capretti G, et al. Oral anticoagulant type and outcomes after transcatheter aortic valve replacement. JACC Cardiovasc Interv 2019;12:1566–76. https:// doi.org/10.1016/j.jcin.2019.03.003; PMID: 31202946.

111. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955–62. https://doi.org/10.1016/S01406736(13)62343-0; PMID: 24315724.

112. 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.

113. Yoon S-H, Ohno Y, Araki M, et al. Comparison of aortic root anatomy and calcification distribution between Asian and Caucasian patients who underwent transcatheter aortic valve implantation. Am J Cardiol 2015;116:1566–73. https://doi. org/10.1016/j.amjcard.2015.08.021; PMID: 26428022.

114. Wang T-Y, Gracia E, Callahan S, et al. Gender disparities in management and outcomes following transcatheter aortic valve implantation with newer generation transcatheter valves. Am J Cardiol 2019;123:1489–93. https://doi. org/10.1016/j.amjcard.2019.01.048; PMID: 30782416.

115. Greco A, Capodanno D, Angiolillo DJ. The conundrum surrounding racial differences on ischaemic and bleeding risk with dual anti-platelet therapy. Thromb Haemost 2019;119:9–13. https://doi.org/10.1055/s-0038-1676612; PMID: 30597496.

116. Capodanno D, Greco A. Risk stratification for bleeding in the elderly with acute coronary syndrome: not so

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Anticoagulation after Transcatheter Aortic Valve Implantation simple. Thromb Haemost 2018;118:949–52. https://doi. org/10.1055/s-0038-1649519; PMID: 29847837.

117. Capodanno D, Greco A. Platelet function testing after transcatheter aortic valve implantation. Thromb Haemost 2018;118:1681–5. https://doi.org/10.1055/s-0038-1672215; PMID: 30273951.

118. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC). Eur Heart J 2020;41:407–77. https://doi.org/10.1093/ eurheartj/ehz425; PMID: 31504439.

119. Stefanini GG, Stortecky S, Meier B, et al. Severe aortic stenosis and coronary artery disease. EuroIntervention 2013;9(Suppl):S63–8. https://doi.org/10.4244/EIJV9SSA12; PMID: 24025960.

120. Nijenhuis VJ, Brouwer J, Søndergaard L, et al. Antithrombotic therapy in patients undergoing transcatheter aortic valve implantation. Heart 2019;105:742–8. https://doi.org/10.1136/

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heartjnl-2018-314313; PMID: 30867148.

121. Lamberts M, Gislason GH, Lip GYH, et al. Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant. Circulation 2014;129:1577–85. https://doi.org/10.1161/CIRCULATIONAHA.113.004834; PMID: 24470482.

122. Aboyans V, Ricco J-B, Bartelink M-LEL, et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Eur Heart J 2018;39:763–816. https://doi.org/10.1093/eurheartj/ ehx095; PMID: 28886620.

123. 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.

124. WATCHMAN for Patients With Atrial Fibrillation Undergoing

Transcatheter Aortic Valve Replacement (WATCH-TAVR), NCT03173534. https://clinicaltrials.gov/ct2/show/NCT03173534 (accessed 19 February 2020).

125. D’Ascenzo F, Benedetto U, Bianco M, et al. Which is the best antiaggregant or anticoagulant therapy after TAVI? A propensity-matched analysis from the ITER registry. The management of DAPT after TAVI. EuroIntervention 2017;13:e1392-1400. https://doi.org/10.4244/EIJ-D-17-00198; PMID: 28870875.

126. Holy EW, Kebernik J, Allali A, et al. Comparison of dual antiplatelet therapy versus oral anticoagulation following transcatheter aortic valve replacement: A retrospective singlecenter registry analysis. Cardiol J 2017;24:649-659. https://doi. org/10.5603/CJ.a2017.0050; PMID: 28497845.

127. Varshney A, Watson RA, Noll A, et al. Impact of antithrombotic regimen on mortality, ischemic, and bleeding outcomes after transcatheter aortic valve replacement. Cardiol Ther 2018;7:7177. https://doi.org/10.1007/s40119-018-0111-4; PMID: 29779200.

Expert Opinion

Precision Medicine in Interventional Cardiology Thijmen W Hokken,1 Joana M Ribeiro,1,2 Peter P De Jaegere1 and Nicolas M Van Mieghem1 1. Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands; 2. Department of Cardiology, Centro Hospitlar and Universitário de Coimbra, Coimbra, Portugal

Abstract Precision medicine has recently become widely advocated. It revolves around the individual patient, taking into account genetic, biomarker, phenotypic or psychosocial characteristics and uses biological, mechanical and/or personal variables to optimise individual therapy. In silico testing, such as the Virtual Physiological Human project, is being promoted to predict risk and to test treatments and medical devices. It combines artificial intelligence and computational modelling to select the best therapeutic option for the individual patient.

Keywords Precision medicine, computational modelling, heart team Conflicts of interest: The authors have no conflicts of interest to declare.

Received: 23 September 2019 Accepted: 31 January 2020 Citation: Interventional Cardiology Review 2020;15:e03. DOI: https://doi.org/10.15420/icr.2019.23 Correspondence: Nicolas M Van Mieghem, Department of Interventional Cardiology, Thoraxcenter, Erasmus MC, Office Nt 645, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. E: n.vanmieghem@erasmusmc.nl 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 noncommercial purposes, provided the original work is cited correctly.

Evidence-based medicine is the foundation of contemporary clinical practice and results in better clinical outcomes than experience-based medicine.1 Meta-analyses of homogenous randomised controlled clinical trials are the pinnacle of evidence-based medicine and the backbone of the highest recommendations in clinical guidelines.

These randomised trials pertain only to the selected patients who meet the predefined inclusion/exclusion criteria but are applied as a onesize-fits-all approach in guidelines. Medical advances are rapidly continuing, with a plethora of medical and device concepts emerging for any given condition in any given patient becoming hard to capture in formal treatment guidelines. Furthermore, patient preference and shared decision-making have recently gained a higher profile.

Precision medicine is the new paradigm and is focused on the needs of an individual patient. It was recently defined as “treatments targeted to the needs of an individual patient on the basis of genetic, biomarker, phenotypic or psychosocial characteristics that distinguish a given patient from another patient with similar clinical presentation.”2,3 Computational modelling may assist precision medicine by integrating individual patient data (the phenotype) to stratify risk and potentially identify more precise therapeutic solutions and simulate the effects of a therapy in the individual person of interest.2,3 In short, the paradigm is shifting from the average to the individual person of interest.4

Precision Medicine in Practice Precision medicine relies on biological, mechanical and personal variables to optimise individual therapy (Figure 1). Examples of precision medicine in interventional cardiology are the multidisciplinary heart team, the systematic use of intravascular imaging for left main stem

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stenting and plaque modification technology. The heart team is a tool to integrate multiple perspectives from different disciplines that are involved in the management of a patient.

The consensus of the heart team is personalised and therefore specific to the individual patient, but may vary from one heart team to another.

Heart team decision-making reflects geographical variability and local institutional expertise. Some institutions may favour a surgical approach, while others may be oriented more towards interventional cardiology. More recently, the value of patient preference was added to the mix and may further determine treatment strategy selection and complement precision medicine.

Interventionists have a wide array of tools and techniques at their disposal and need to figure out their optimal implementation to justify financial cost, procedural time and clinical benefit. Arguably, systematic use of intravascular imaging would make more sense in left main percutaneous coronary intervention (PCI) than in a type A lesion in the mid segment of a right coronary artery. A more specific example is plaque modification of calcified coronary lesions. Rotational and orbital atherectomy, Shockwave intravascular lithotripsy (Shockwave Medical) or an arsenal of compliant, semi-compliant and high-pressure balloons can be used for this purpose. Specific plaque characteristics can mean one technology is favoured over another.

Additional intravascular imaging with intravascular ultrasound (IVUS) or optical coherence tomography optimises clinical outcomes. IVUS assesses plaque composition and distribution before PCI and identifies abnormalities such as underexpansion, malposition or edge dissections after PCI.5 These quantitative and qualitative

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Precision Medicine characteristics may guide targeted, patient-tailored device selection and result in optimal lesion preparation and stent deployment with proper expansion and apposition.

Future of Computational Modelling Through sophisticated algorithms, computational modelling allows a virtual reality representation to be created so clinicians can appreciate and simulate therapeutic strategies that relate uniquely to one particular patient. The rapid development of computational modelling may provide new possibilities to predict the risk of developing certain diseases, test new therapeutic treatments, improve medical device safety and select the best therapeutic options for individual patients.6 In silico testing, where computational modelling and artificial intelligence are combined, is an interesting new development. The Virtual Physiological Human (VPH) project is an example of this concept and started in 2005 with three objectives: introduce patient-specific modelling to support medical decision; apply in silico clinical trials to test new treatments and duplicate the robustness of clinical trials with large samples in a virtual clinical trial (its main objective); and introduce patient-specific, real-time simulations to devise tailored treatment for the individual patient.6,7 In the in silico test environment, approximately nine of 10 novel drugs entering Phase I clinical trials seem to fail. The beauty of in silico trials is that they are able to evaluate positive effects and drug toxicity precluding animal testing and reducing cost and time.8 VPH models can incorporate numerous patient-specific variables, such as lifestyle, medical history, physical examination, diagnostic tests and genetics to make reliable predictions.2 VPH might be used to predict the risk of developing certain conditions and determine which treatment should be used and when it should be started to prevent diseases on an individual level.

There are numerous challenges to implementing these models in the medical practice. Before making a patient-specific model that works in clinical practice, several issues need to be addressed. First are the granularity and type of data to be used. Computational modelling can process huge numbers of variables and irrelevant variables may camouflage underlying relationships and pollute the model. The use of existing knowledge of relevant variables based on evidence-based research should guide this selection.2,4 Second is the validation of patient-specific models before implementation in clinical practice. This validation process requires the model be tested in a properly sized patient sample.4 Machine learning, big data and artificial intelligence may help to optimise these processes.6 The VPH approach requires pathophysiological processes to be described in quantitative terms. In the first 10 years of the VPH project, the most popular targets were organ systems with clear biophysical characterisations, such as the cardiovascular system. This focus led to developments in computational modelling that may catalyse precision medicine.

Two examples of the application of computational modelling in contemporary interventional cardiology derived from in silico trials are HeartFlow FFRCT (HeartFlow) and FEops HEARTguide (FEops).

HeartFlow FFRCT generates a person-specific 3D model of the coronary arteries from static coronary CT images and simulates pressure,

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Figure 1: Pathway of Precision Medicine

Local expertise

Geographic variability

Individualised therapy

Personalised advice

Heart team

Patient preference

Risk stratification

Computational modelling

External data

Patient characteristics

Clinical measurements

Genetic

Psychosocial characteristics

Patient

This pathway involves patient characteristics, consisting of genetic data, psychosocial characteristics and clinical data. The heart team in conjunction with the individual’s personal preference formulates device tailored to the patient.

velocity and blood flow to predict the fractional flow reserve. With this technique, it becomes possible to determine coronary physiology and thus the functional importance of a particular stenosis in the coronary arterial tree. Computational modelling is used to compare a patientunique CT scan with a database of CT scans to determine the clinical importance of the stenosis and thereby show non-invasively whether PCI would be effective.9 With further iterations, prediction of the effect of coronary stenting, including residual coronary flow after PCI, should be possible. This technique may also allow patients with vulnerable plaques to be identified, in whom PCI might have prophylactic benefit.10 The FEops HEARTguide integrates CT imaging with tissue and device characteristics to simulate device-host interactions and predict calcium displacement, device deformity, residual periprosthetic leak and occurrence of conduction abnormalities secondary to focal pressure phenomena in patients who undergo transcatheter aortic valve implantation for severe aortic stenosis.11,12 Computational modelling may help to identify and select the best device for any specific anatomy whether it is in the coronary or structural heart space. These technologies may prove invaluable for patient-tailored device selection and treatment in future.

Conclusion Precision medicine reconciles evidence-based medicine with the growing armamentarium of medical options and technologies. As randomised trials remain the pinnacle of evidence-based medicine and backbone of contemporary clinical practice, physicians need to figure out how to implement the best clinical option for each individual patient.

Precision medicine is being increasingly adopted in contemporary clinical practice, but has numerous layers. Further refinement by advanced computational modelling in concert with artificial intelligence and computer learning will be a prelude to the medicine of the future.

Expert Opinion 1.

2.

3.

4.

5.

Kirchhof P, Sipido KR, Cowie MR, et al. The continuum of personalized cardiovascular medicine: a position paper of the European Society of Cardiology. Eur Heart J 2014;35:3250–7. https://doi.org/10.1093/eurheartj/ehu312; PMID: 25148837.

Konig IR, Fuchs O, Hansen G, et al. What is precision medicine?

Eur Respir J 2017;50:1700391. https://doi.org/10.1183/ 13993003.00391-2017; PMID: 29051268.

Jameson JL, Longo DL. Precision medicine – personalized, problematic, and promising. N Engl J Med 2015;372:2229–34. https://doi.org/10.1056/NEJMsb1503104; PMID: 26014593.

Gray RA, Pathmanathan P. Patient-specific cardiovascular computational modeling: diversity of personalization and challenges. J Cardiovasc Transl Res 2018;11:80–8. https://doi. org/10.1007/s12265-018-9792-2; PMID: 29512059.

Papaioannou TG, Kalantzis C, Katsianos E, et al. Personalized assessment of the coronary atherosclerotic arteries by intravascular ultrasound imaging: hunting the vulnerable

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plaque. J Pers Med 2019;9:1. https://doi.org/10.3390/ jpm9010008; PMID: 30682871.

Morrison TM, Pathmanathan P, Adwan M, et al. Advancing regulatory science with computational modeling for medical devices at the FDA’s Office of Science and Engineering Laboratories. Front Med (Lausanne) 2018;5:241. https://doi. org/10.3389/fmed.2018.00241; PMID: 30356350.

Viceconti M, Hunter P. The virtual physiological human: ten years after. Annu Rev Biomed Eng 2016;18:103–23. https://doi.org/10.1146/annurev-bioeng-110915-114742; PMID: 27420570.

Qian T, Zhu S, Hoshida Y. Use of big data in drug development for precision medicine: an update. Expert Rev Precis Med Drug Dev 2019;4:189–200. https://doi.org/10.1080/23808993.2019.16 17632; PMID: 31286058.

Liyanage L, Lee NJ, Cook T, et al. The impact of gender on cardiovascular system calcification in very elderly patients

with severe aortic stenosis. Int J Cardiovasc Imaging 2016;32:173–9. https://doi.org/10.1007/s10554-015-0752-5; PMID: 26319217.

10. Dugas CM, Schussler JM. Advanced technology in interventional cardiology: A roadmap for the future of precision coronary interventions. Trends Cardiovasc Med 2016;26:466–73. https://doi.org/10.1016/j.tcm.2016.02.003; PMID: 27020905.

11. de Jaegere P, Rocatello G, Prendergast BD, et al. Patientspecific computer simulation for transcatheter cardiac interventions: what a clinician needs to know. Heart 2019;105(Suppl 2):s21–7. https://doi.org/10.1136/ heartjnl-2018-313514; PMID: 30846521.

12. Cahill TJ, Chen M, Hayashida K, et al. Transcatheter aortic valve implantation: current status and future perspectives. Eur Heart J 2018;39:2625–34. https://doi.org/10.1093/eurheartj/ehy244; PMID: 29718148.

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Coronary

Diagnostic Angiograms and Percutaneous Coronary Interventions in Pregnancy Phyo Htet Khaing,1 Gill Louise Buchanan2 and Vijay Kunadian1,3 1. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 2. North Cumbria Integrated Care NHS Foundation Trust, Cumbria, UK; 3. Cardiothoracic Centre, Freeman Hospital, Newcastle Upon Tyne, UK

Abstract Cardiovascular disease is the leading indirect cause of maternal mortality in the UK. Pregnancy increases the risk of acute MI (AMI) by threeto fourfold secondary to the profound physiological changes that place an extra burden on the cardiovascular system. AMI is not always recognised in pregnancy and there is concern among both clinicians and patients regarding catheter-based interventions due to fears of foetal irradiation and risks to the foetus. This article evaluates the current state of knowledge on AMI in pregnancy with particular emphasis on pregnancy-associated spontaneous coronary artery dissection and percutaneous coronary intervention as the revascularisation procedure for AMI. Special considerations that must be made in patients requiring percutaneous coronary intervention for pregnancy-associated spontaneous coronary artery dissection and the current recommendations on arterial access, methods of minimising radiation and stent selection are discussed.

Keywords Pregnancy-associated spontaneous coronary artery dissection, acute MI in pregnancy, percutaneous coronary intervention in pregnancy, ionising radiation exposure, stent in pregnancy Disclosure: The authors have no conflicts of interest to declare.

Received: 31 January 2020 Accepted: 2 April 2020 Citation: Interventional Cardiology Review 2020;15:e04. DOI: https://doi.org/10.15420/icr.2020.02 Correspondence: Vijay Kunadian, Translation and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, 4th Floor William Leech Building, Newcastle-upon-Tyne NE2 4HH, UK. E: vijay.kunadian@newcastle.ac.uk 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 noncommercial purposes, provided the original work is cited correctly.

Many profound physiological changes take place in the cardiovascular system during pregnancy to meet the increased metabolic demands of both the mother and foetus. Such changes include an increase in circulating blood volume and cardiac output and decreases in systemic vascular resistance, blood pressure and hypercoagulation.1,2 The increase in circulatory burden during pregnancy and the postpartum period can unmask pre-existing undiagnosed cardiac disease, cause the deterioration of known heart disease or lead to the development of a new one.1 Cardiovascular disease in pregnancy is an increasingly important cause of maternal morbidity and mortality.3 The latest report from the Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK (MBRRACE-UK) showed that cardiac disease is the leading indirect cause of maternal deaths up to 6 weeks after the postpartum period.4 This report is supported by the Confidential Enquiries into Maternal and Child Health (CEMACH) finding that in the UK, the overall rate of mortality secondary to cardiac disease has risen from 7.3 per million births in the 1982–1984 triennium to 22.7 per million births in the 2003–2005 triennium.5 Despite this increase, data from the MBRRACE-UK report showed that 90% of pregnant women who died between 2014 and 2016 did not have a pre-existing cardiac condition.4 It appears that the major part of this increase is attributable to acquired cardiac disease, with one-third of these deaths being secondary to acute MI (AMI) or ischaemic heart disease.4 Understandably, there is concern among cardiologists and obstetricians

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regarding the treatment of AMI in pregnancy, especially percutaneous coronary intervention (PCI). This article will focus on AMI in pregnancy and PCI in detail.

Acute MI in Pregnancy AMI in pregnancy leads to poor maternal and foetal outcomes, and the mortality rate is twice as high in cases where AMI occurs during the peripartum period.6 The incidence of coronary artery disease (CAD) in women of child-bearing age is currently low and AMI is quite uncommon in this population (3–100 per 100,000 deliveries).7 Interestingly, a large UK-based study recently demonstrated that prior hypertensive disorders of pregnancy, such as gestational hypertension and eclampsia, were associated with increased arterial stiffness and a longterm risk of a range of cardiovascular diseases, including CAD.8 Thus, there is a possibility for the incidence of CAD in women of child-bearing age to increase in future with the increasing incidence of hypertensive disorders of pregnancy.8 Despite the low CAD rate, pregnancy increases the risk of AMI by threeto fourfold compared to non-pregnant women of similar age (Table 1).9 This risk is age-related, being 30 times higher for women >40 years of age compared with women aged <20 years.10 Over the past two decades, there has been an increase in the use of fertility therapy, such as in vitro fertilisation, particularly among older women.11 Fertility therapy often involves repeated cycles of high-dose

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Coronary Table 1: Current Knowledge Regarding Acute MI and Percutaneous Coronary Intervention in Pregnancy Current Knowledge

Gaps in Knowledge

Areas of Future Research

• Pregnancy increases the risk of acute MI by three- to fourfold, yet • Optimal management of P-SCAD. • Registered clinical studies and collaborative the diagnosis is not suspected as often as it should be. research worldwide to establish large SCAD • Optimal type of stent during PCI for both databases.

• P-SCAD is the most common cause of acute MI in pregnancy and P-SCAD and STEMI. it tends to occur mainly in late pregnancy and the early • Prospective randomised controlled trials • Safety data on use of PY212 inhibitors in postpartum period. investigating the optimal management pregnancy post PCI. (including both medical and coronary • PCI is not contraindicated in pregnancy and should be performed • Duration of antiplatelet therapy in interventional strategies) for SCAD and P-SCAD when clinically indicated. pregnancy post PCI. are required.

• Although the radiation dose used in PCI is significantly less than • Optimal management of acute MI • Due to the rarity of coronary embolism and that reported to be harmful, efforts should be made to keep the secondary to coronary embolism and coronary artery vasospasm, international dose as low as possible. coronary artery vasospasm. collective research efforts should be made to • There are no current recommendations on the optimal establish large population databases on these management of P-SCAD, coronary embolism and coronary artery conditions. vasospasm in pregnancy.

PCI = percutaneous coronary intervention; P-SCAD = pregnancy-associated spontaneous coronary artery dissection; SCAD = spontaneous coronary artery dissection; STEMI = ST-elevation MI.

MI with Obstructive Coronary Arteries ST-elevation in MI in Pregnancy

Figure 1: Acute MI in Pregnancy

Acute MI in pregnancy

MI with obstructed coronary arteries

MI with non-obstructed coronary arteries

ST-elevation MI (STEMI) in pregnant women involves the anterior wall in 70–80% of cases.18 In more than half of cases, reduction of left ventricular ejection fraction to <40% was observed, leading to a high incidence of heart failure, cardiogenic shock and ventricular arrhythmias.18 Diagnostic criteria are the same as for patients who are not pregnant and are based on clinical symptoms, ECG changes and an increase in troponin levels.19,20 It should be noted that ST elevation is not seen in normal pregnancy and warrants urgent attention.19 STEMI in pregnant women should be managed in the same way as in nonpregnant women. Given the high mortality associated with STEMI in pregnancy, the European Society of Cardiology (ESC) recommends primary PCI as the preferred reperfusion therapy.13

Non-ST-elevated MI in Pregnancy STEMI

NSTEMI

P-SCAD*

Coronary embolism

Coronary vasospasm

*The most common cause of acute MI in pregnancy. NSTEMI = non-ST-elevation MI; P-SCAD = Pregnancy-associated spontaneous coronary artery dissection; STEMI = ST-elevation MI.

hormonal stimulation protocols and superovulation itself is prothrombotic;12,13 therefore, it is plausible that in vitro fertilisation and other fertility therapy techniques contribute to cardiovascular risk.12 However, a recent systematic review and meta-analysis reported no increased risk of developing an acute cardiac event following fertility therapy.12 This finding is supported by a large population-based Canadian study involving 6,979 women, where the authors concluded that successful fertility therapy was not associated with an increased risk of cardiovascular disease in later life.11 Overall, the incidence of AMI is higher in multigravidas and during the third trimester.6 Pregnant women with AMI during the postpartum period tend to be younger than those experiencing AMI during the antepartum or peripartum periods.14 Aside from traditional cardiovascular risk factors, other risk factors specific to pregnancy include pre-eclampsia, the presence of prosthetic valves, anaemia and thrombophilia.15,16 Despite the increased risk of AMI in pregnancy, one US-based study found that of 859 patients presenting with AMI during pregnancy and the postpartum period, only 45% had undergone cardiac catheterisation.17 The authors highlighted that the diagnosis of AMI is not suspected as often as it should be and that there is a general reluctance of physicians to intervene.17

Similarly to STEMI, there are no differences in diagnostic criteria between pregnant and non-pregnant patients presenting with non-STelevation MI (NSTEMI). It is important to note that ST segment depression and T-wave inversion can be a normal variant seen in pregnancy.19 Both the American Heart Association and ESC guidelines recommend that myocardial revascularisation with PCI be reserved for pregnant women with NSTEMI who are unstable or present with serious complications unresponsive to medical therapy.13,21

MI with Non-obstructive Coronary Arteries In pregnancy, causes of MI with non-obstructive coronary arteries (MINOCA) include spontaneous coronary artery dissection (SCAD), coronary embolism and severe coronary artery vasospasm (Figure 1).22 While pregnancy-associated SCAD (P-SCAD) is more common, there are a few case reports of AMI secondary to coronary embolism and coronary artery vasospasm.22–25

P-SCAD In the general population, the majority of AMI occurs as a result of coronary atherosclerosis, typically leading to STEMI or NSTEMI. In pregnancy, SCAD is the most common cause of AMI and tends to occur mainly in late pregnancy or during the early postpartum period.7,18,20 Although previously considered rare, it has recently become clear that SCAD is an important and underdiagnosed cause of AMI in women.26,27 P-SCAD makes up <10% of the total number of SCAD cases.26,27

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Diagnostic Angiograms and PCI in Pregnancy In the past, SCAD was frequently reported as a disorder mostly affecting women with no risk factors for cardiovascular disease. However, a recent study has demonstrated that conventional cardiovascular risk factors, such as hypertension, dyslipidaemia and smoking, are not uncommon in patients presenting with SCAD.28 P-SCAD is most frequent during the first postpartum month, but cases have been reported during early pregnancy and up to 18 months postpartum.29,30 It has been suggested that this might be related to cardiac stress secondary to rapid post-delivery uterine contraction and the return of a copious volume of blood to the systemic circulation.31,32 Most patients tend to have a history of multiple pregnancies.29,32 Although the association is unclear, there is a potential link with arterial degeneration, which could be compounded by multiple pregnancies.33 Studies have shown that SCAD is not benign and can have complications such as life-threatening ventricular arrhythmias and sudden cardiac death.30 P-SCAD patients can have a more severe clinical presentation, such as acute heart failure and multivessel dissections, than patients with non-pregnancy-associated SCAD.32 Additionally, it has significant reported recurrence of ~10% at 3-year follow-up and major adverse cardiovascular event rates.34,35 In a recent Canadian prospective cohort study of 236 SCAD patients, the rate of recurrent MI was 19.1%, recurrent SCAD was 12.7%, stroke or transient ischaemic attack was 1.3% and mortality was 1.7% at a median 2.3-year follow-up.36 Thus, women of child-bearing age with a history of SCAD should be carefully counselled regarding the risk of recurrent events.

Pathophysiology It is rare for patients with SCAD to have recognised hereditary connective tissue disorders, such as Marfan syndrome and vascular Ehlers-Danlos syndrome.34,37 With SCAD, there is sudden disruption of the coronary artery wall, resulting in separation of the inner intimal lining from the outer vessel wall, leading to an intramural haematoma (Figure 2), or rupture of the vasa vasorum, leading to intramural haematoma.30 This can cause luminal compression and obstruction and, if the haematoma expands, can cause propagation of the dissection plane.30,38 Typically, patients with SCAD have fragile arterial walls with no atheroma or calcification to limit the propagation of dissection, which means the dissections tend to be more extensive.30 There have been several proposals in the literature regarding the pathophysiology of P-SCAD. Although the exact mechanism is undetermined, the proposals focus on hormonal and haemodynamic changes as possible causes. These changes include excess progesterone leading to structural weakening of the vessel wall and consecutive shearing stress secondary to increased cardiac output and circulatory volume.18,29,39

Figure 2: Pathological Mechanisms Underlying Spontaneous Coronary Artery Dissection A

B

C

D TL FL

IH

A: Normal coronary artery. B: Sudden intimal tear in the coronary wall, resulting in blood flow under the tunica intima (blue arrow). C: This can cause accumulation and propagation of blood forming a false lumen in the tunica media (red arrow). D: This results in an intramural haematoma, which can cause luminal compression and obstruction leading to acute MI. FL = false lumen; IH = intramural haematoma; TL = true lumen.

‘clicking’ sensation in the chest.29,32 Most patients have elevated troponin levels, although it has been observed that there is a wide variation in the rise in troponin I.42 Coronary angiography is the first-line diagnostic imaging method in SCAD due to its wide availability.43,44 It is of vital importance that extra care is taken, as there is a risk of iatrogenic extension of the dissection.45 When there is diagnostic uncertainty, intracoronary imaging using optical coherence tomography and intravascular ultrasound can allow detailed visualisation of the arterial wall.43,44 Another study has shown that in P-SCAD there are more frequent findings of left ventricular ejection fraction ≤35%, and patients are more likely to experience SCAD affecting the left main or multiple vessels.32 There are multiple reports that the left anterior descending artery is the most frequently affected vessel.17,29,46 The haemodynamic and anatomical differences between the right and left coronary arteries could explain this finding. For instance, the left anterior descending artery is subjected to increased torsion force during the cardiac cycle due to a higher number of branches than the right coronary artery.7,47

Management Optimal management of P-SCAD is controversial. Generally, the ‘conservative if possible’ approach is preferred; both recent European and US consensus statements emphasise a preference for a conservative approach.43,44 In the majority of cases, arteries affected by SCAD heal spontaneously and studies have suggested that revascularisation is associated with a high failure rate.38,48,49 Additionally, PCI for SCAD has an increased risk of extending the dissection and requiring emergency surgery.29,38 However, the lack of randomised controlled trials means there is no specific recommendation; the decision ultimately depends on the clinical presentation, extent of coronary artery dissection and size of myocardium at risk. Nevertheless, in patients with ongoing or recurrent ischaemia, haemodynamic instability or isolated left main dissection, it has been suggested that PCI should be performed if the anatomy is suitable.50

Coronary Embolism Clinical Presentation and Diagnosis The clinical presentation of P-SCAD is dependent on the extent and rate of dissection as well as the degree of myocardial ischaemia.40 Patients can present with STEMI, but may also have more serious presentations, such as cardiogenic shock or pericardial tamponade.29 Tamponade could result from direct extension of the dissection into the pericardial space, rupture of infarcted myocardium or from postinfarction pericarditis.41 Clinical symptoms of P-SCAD include chest pain, dyspnoea, diaphoresis, nausea, vomiting and a ‘popping’ or

INTERVENTIONAL CARDIOLOGY REVIEW

Hypercoagulable states, such as pregnancy, increase the risk of embolic disease.51 Thus, despite its rarity, coronary embolism is an important condition to be aware of as a cause of MINOCA during pregnancy. ST segment elevation can be seen on ECG in the majority of patients presenting with coronary embolism.52 The diagnosis is challenging, but clinical suspicion should be increased in patients with predisposing conditions, such as AF, right-to-left cardiac shunt, prosthetic heart valves and antiphospholipid syndrome as well as a low likelihood of CAD.53 Typically, coronary embolism affects the left

Coronary coronary system as the left main artery is larger than the right coronary artery and receives a greater proportion of blood flow, making it more likely to receive emboli.54 There are three types of coronary embolism: direct, paradoxical and iatrogenic.55 Direct coronary emboli typically arise from the left atrial appendage, left ventricle or aortic and mitral valves.55 Pregnant women with mechanical prosthetic valves are particularly vulnerable as the valves themselves are thrombogenic and it is difficult to achieve adequate anticoagulation.25 This is evident in the case reports of AMI in pregnancy secondary to thromboembolism originating from prosthetic valves.23,25 Paradoxical emboli originate from the venous system and usually pass through a patent foramen ovale, an atrial septal defect or pulmonary arteriovenous malformations.

Pregnancy is associated with a fourfold increased risk of venous thromboembolism, but the incidence of paradoxical coronary embolism is unknown.24,55 One case has reported on coronary embolism in pregnancy secondary to a paradoxical embolus, but the patient was a factor V Leiden carrier.24 With the increased use of coronary angiograms, valvuloplasty and other invasive coronary interventions, iatrogenic coronary embolism is currently the most common cause of embolism in the coronary arteries.52,54 Possible mechanisms for this may be the formation of clots in catheters, accidental introduction of air during invasive procedures and, on rare occasions, embolisation of friable calcific valvular material from the aortic valve into the coronary arteries during such procedures.52,55 At present, there is no consensus regarding the optimal management of AMI secondary to coronary embolism due to its rarity. Various attempts to treat the condition have been described in numerous case reports using intracoronary thrombolysis, aspiration catheter and ballooning and/or stenting, with varying success.25 Large populationbased studies in this area are required to obtain further knowledge (Table 1).

Coronary Artery Vasospasm AMI secondary to coronary artery vasospasm in pregnancy is very rare.22 One case has been reported in the literature where a woman in her 38th week of pregnancy presented with sudden severe substernal central chest pain and ST-elevation.22 According to the ESC consensus document on vasospastic angina, coronary artery spasm is defined as transient total or subtotal coronary artery occlusion (>90% constriction) with angina and ischaemic ECG changes either spontaneously or in response to a provocative stimulus, such as acetylcholine and hyperventilation.56 Diagnosis of coronary artery spasm itself is challenging and often requires provocative testing with intracoronary acetylcholine during invasive coronary angiography, where >90% vasoconstriction is the angiographic threshold to diagnose inducible spasm.56 Smoking is a risk factor and East Asians could potentially be predisposed to coronary vasospasm.56,57 In cases of recent STEMI requiring reperfusion therapy, it has been reported that Japanese patients had hyper-reactive vessels compared to white patients.57

and thromboxane.16 Other suggested causes of coronary vasospasm in pregnancy include enhanced vascular reactivity to angiotensin II and noradrenaline, renin release and angiotensin production due to decreased uterine perfusion in the supine position, and the use of ergot derivatives to control pregnancy-related haemorrhage.9,58â&#x20AC;&#x201C;61 AMI can result from significant occlusions secondary to prolonged and intense coronary vasospasm or if there is coronary vasospasm with superimposed thrombosis.52,62 Vasodilators, such as calcium channel blockers and nitroglycerin, are used to treat it, but little has been published regarding diagnostic strategies and therapeutics (Table 1).22

Percutaneous Coronary Intervention in Pregnancy Any procedure involving radiation can cause concern for both the healthcare professional and the pregnant woman, and this can influence decision-making regarding PCI. Pregnancy is not a contraindication for PCI; as a life-saving procedure it should be performed when necessary. Management should be determined by a multidisciplinary team consisting of cardiologists, obstetricians, anaesthesiologists and neonatologists, and patients should be treated in an intensive care unit that can provide meticulous maternal monitoring and obstetric care.9,13 Based on ESC guidelines, the best time to perform any PCI procedure is after the fourth month during the second trimester.13 The reasoning behind this is mainly due to the completion of foetal organogenesis, inactive state of the foetal thyroid and the small uterine volume at this time, allowing a greater distance between the foetus and chest than in the later months of pregnancy.

Arterial Access The latest ESC guidelines recommend that the radial approach by an experienced operator is preferable.13 Femoral artery entry allows direct pelvic radiation, which could theoretically increase the dose absorbed by the foetus. Additionally, there are more technical challenges associated with the femoral approach, due to the presence of the enlarged uterus and difficulties in positioning the woman.19 A recent meta-analysis of randomised controlled trials on radial versus femoral access for PCI in STEMI patients showed that the radial approach is favourable as it is associated with decreased bleeding complications, reduced length of hospital stay and improved patient comfort.63

Ionising Radiation Exposure Concern regarding PCI in pregnancy usually stems from the risks associated with foetal exposure to ionising radiation. The dose of radiation absorbed and stage of pregnancy can determine the potential risks that ionising radiation exposure poses to the foetus.13,64 The highest levels of risk are during organogenesis and the early foetal period; the risk decreases as pregnancy progresses from the second trimester.65,66 ESC guidelines recommend that during cardiac catheterisation, the mean radiation the unshielded abdomen is exposed to should be 1.5 mGy, where <20% reaches the foetus.13 This dose is far lower than doses reported to be associated with foetal malformation, growth restriction or abortion (>50 mGy).67,68

Use of Iodinated Contrast Agents During Pregnancy One of the proposed mechanisms for coronary vasospasm is endothelial dysfunction, as it promotes coronary vasoconstriction.15 In pregnancy, pre-eclampsia is a strong risk factor as it causes systemic endothelial dysfunction due to imbalance in the secretion of endothelin

Iodinated contrast material can cross the placenta and enter the foetus;69 however, it has not been reported to cause teratogenic effects.70 Another concern is the potential risk of foetal congenital hypothyroidism.71 A 2010 study showed that there is no serious risk of

INTERVENTIONAL CARDIOLOGY REVIEW

Diagnostic Angiograms and PCI in Pregnancy neonatal hypothyroidism secondary to iodinated contrast agents, but there is a gap in the literature regarding this.72

Figure 3: Special Considerations for Percutaneous Coronary Intervention and Methods to Minimise Radiation in Pregnancy

Methods to Minimise Radiation Although the mother can be reassured that the risk of radiation to the foetus is small, procedures should follow the radiation dose to be ‘as low as reasonably achievable’ principle (Figure 3). In order to achieve this, the ESC recommends the following manoeuvres: • Use echo guidance when possible.

• Place the source as distant as possible from the patient and the receiver as close as possible.

• Use only low-dose fluoroscopy.

• Favour anteroposterior projections.

• Avoid direct radiation of the abdominal region.

• Collimate as tightly as possible to the area of interest.

• Minimise fluoroscopy time.

• Use an experienced cardiologist.13 Abdominal shielding is of limited benefit as the dose absorbed by the foetus is the result of internal scatter from thoracic tissues rather than direct foetal irradiation from the X-ray beam.13,73

PCI in P-SCAD: • Consider femoral access • Consider risk of iatrogenic dissection and extension of dissections • Confirm true lumen using IVUS/OCT guidance • Consider long stents Minimising radiation during PCI: • Use echo guidance when possible • Place the source as distant as possible from the patient and the receiver as close as possible • • • • • • •

Use low-dose fluoroscopy Minimise fluoroscopy time Favour anteroposterior projections Avoid direct radiation of the abdomen Collimate as tightly as possible to the area of interest Tilt the patient to the left to reduce inferior vena cava compression Have a peripartum caesarean section kit to hand

Other techniques suggested to minimise radiation to the patient include using a lower frame rate (7.5 frames/s), using wedge filters, changing the projection frequently to distribute radiation and opening the iris on the television camera, which allows a lower increase in beam intensity.74,75

Pregnancy is not a contraindication for PCI, and in pregnancy-associated spontaneous coronary artery dissection, special considerations should be taken before performing PCI due to the fragility of the arteries. The radiation dose should be kept as low as possible in order to minimise risks to the foetus. IVUS = intravascular ultrasound; OCT = optical coherence tomography; PCI = percutaneous coronary intervention; P-SCAD = pregnancy-associated spontaneous coronary artery dissection.

Stent Selection

Secondary Prevention Post-PCI

The type of stent deployed requires careful consideration, as this affects the duration of antiplatelet therapy after implantation.19 Baremetal stents are commonly employed for STEMI in pregnancy, especially in the third trimester.19 This allows for interruption of dual antiplatelet therapy at the time of delivery, reducing potential bleeding complications.

ESC guidelines state that low-dose aspirin appears to be safe, but that clopidogrel should only be used when essential and for the shortest possible duration.7,13 Generally, little is known regarding P2Y12 inhibitors in pregnancy and, as such, use of P2Y12 inhibitors other than clopidogrel is not recommended.13 No complications have been reported so far in stented pregnant women treated with aspirin and clopidogrel, but breastfeeding is currently not recommended in women taking antiplatelet medications other than low-dose aspirin.13 There are currently no specific recommendations regarding the duration of antiplatelet therapy in pregnancy, but there is a suggestion in the ESC guidelines that the duration of dual antiplatelets for second- or thirdgeneration drug-eluting stents can be shortened in pregnant women.13 An algorithm for the pharmaceutical management of AMI during pregnancy has been published.81

New-generation drug-eluting stents are recommended for patients with STEMI who are not pregnant in the 2017 AMI STEMI guidelines, because trials have demonstrated that they are superior to bare-metal stents in patients with AMI, even with the use of short-duration dual antiplatelet therapy.76–78

Special Considerations in P-SCAD Typically, the arteries in SCAD are prone to iatrogenic dissections and extension of dissections during PCI due to the fragility of the arterial walls.79 It is vital that PCI is undertaken cautiously using meticulous techniques. It may be challenging for the coronary guidewire to enter the true lumen; however, the true lumen can be confirmed using intravascular ultrasound or optical coherence tomography before angioplasty or stenting.29,50 Due to the extensive nature of the dissections, long stents are often necessary despite the increased risk of restenosis.29,50 It is important to note that there is a risk of late stent thrombosis due to the chance of stent malposition after natural resorption of the intramural haematoma.50 Despite radial access being favourable in both STEMI and NSTEMI, femoral access is preferred in PCI for SCAD.50 This is because the radial approach has been associated with higher iatrogenic dissection rates.42,80 However, due to a lack of randomised data, there is no specific recommendation for P-SCAD (Table 1).

INTERVENTIONAL CARDIOLOGY REVIEW

Timing and Mode of Delivery in Acute MI ESC guidelines advise that the treatment of STEMI/NSTEMI should not be delayed for delivery.13 In an acute situation, the priority is to stabilise and treat the mother. The timing and mode of delivery (vaginal or elective caesarean section) must be decided based on maternal cardiac status and gestational age.13,20 Although neither mode of delivery is associated with a higher mortality, there is agreement in the literature that vaginal delivery is preferred as there are greater risks associated with anaesthesia and surgery.9,13,20 Based on the ESC guidelines, delivery should ideally be postponed for at least 2 weeks post-AMI as there is increased risk of maternal mortality during this period.13,20 It is critical that the multidisciplinary team, consisting of a cardiologist, obstetrician, anaesthetist and neonatologist, are involved in decisionmaking regarding treatment and delivery for a good outcome. Postdelivery, maternal monitoring should take place in a high-dependency or intensive care unit.20

Coronary Conclusion Pregnancy increases the risk of AMI and its occurrence is likely to increase with the continuing trend of childbearing at older ages. SCAD is the most common cause of AMI presenting during pregnancy. A conservative approach is generally preferred in P-SCAD but PCI needs to be performed in specific cases for revascularisation. Special considerations should be taken into account before performing PCI due to the fragility of the arteries. According to the latest guidelines, PCI is the recommended strategy for revascularisation in pregnant women presenting with STEMI. Strategies to minimise the radiation

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50. Saw J, Mancini GBJ, Humphries KH. Contemporary review on spontaneous coronary artery dissection. J Am Coll Cardiol 2016;68:297–312. https://doi.org/10.1016/j.jacc.2016.05.034; PMID: 27417009.

51. Ashrafi R, Curtis SL. Heart disease and pregnancy. Cardiol Ther 2017;6:157–73. https://doi.org/10.1007/s40119-017-0096-4; PMID: 28681178.

52. Mirza A. Myocardial infarction resulting from nonatherosclerotic coronary artery diseases. Am J Emerg Med 2003;21:578–84. https://doi.org/10.1016/S0735-6757(03)001049; PMID: 14655241.

53. Denas G, Jose SP, Bracco A, et al. Antiphospholipid syndrome and the heart: a case series and literature review. Autoimmun Rev 2015;14:214–22. https://doi.org/10.1016/j. autrev.2014.11.003; PMID: 25461836.

54. Dagre A, Kouris N, Olympios C. Coronary artery disease: Not always the case for ST-elevation myocardial infarction. J Invasive Cardiol 2012;24:E142–4. PMID: 22781484.

55. Raphael CE, Heit JA, Reeder GS, et al. Coronary embolus: an underappreciated cause of acute coronary syndromes. JACC Cardiovasc Interv 2018;11:172–80. https://doi.org/10.1016/j. jcin.2017.08.057; PMID: 29348012.

56. Beltrame JF, Crea F, Kaski JC, et al. International standardization of diagnostic criteria for vasospastic angina.

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59. Nisell H, Hjemdahl P, Linde B. Cardiovascular responses to circulating catecholamines in normal pregnancy and in pregnancy‐induced hypertension. Clin Physiol 1985;5:479–93. https://doi.org/10.1111/j.1475-097X.1985.tb00779.x; PMID: 4053528.

60. Sasse L, Wagner R, Murray FE. Transmural myocardial infarction during pregnancy. Am J Cardiol 1975;35:448–52. https://doi.org/10.1016/0002-9149(75)90040-5; PMID: 115003.

61. Lin YH, Seow KM, Hwang JL, Chen HH. Myocardial infarction and mortality caused by methylergonovine. Acta Obstet Gynecol Scand 2005;84:1022. https://doi.org/10.1111/j.0001-6349.

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62. Tun A, Khan IA. Myocardial infarction with normal coronary arteries: the pathologic and clinical perspectives. Angiology 2001;52:299–304. https://doi.org/10.1177/ 000331970105200501; PMID: 11386379.

63. Karrowni W, Vyas A, Giacomino B, et al. Radial versus femoral access for primary percutaneous interventions in ST-segment elevation myocardial infarction patients: a metaanalysis of randomized controlled trials. JACC Cardiovasc Interv 2013;6:814–23. https://doi.org/10.1016/j.jcin.2013.04.010; PMID: 23968700.

64. American College of Radiology. ACR–SPR practice parameter for imaging pregnant or potentially pregnant adolescents and women with ionizing radiation. 2013. Reston, VA: American College of Radiology, 2015.

65. Ray JG, Vermeulen MJ, Bharatha A, et al. Association between MRI exposure during pregnancy and fetal and childhood outcomes. JAMA 2016;316:952–61. https://doi.org/10.1001/

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67. Pieper PG, Hoendermis ES, Drijver YN. Cardiac surgery and percutaneous intervention in pregnant women with heart disease. Neth Heart J 2012;20:125–8. https://doi.org/10.1007/ s12471-012-0244-3; PMID: 22351585.

68. Gjelsteen AC, Ching BH, Meyermann MW, et al. CT, MRI, PET, PET/CT, and ultrasound in the evaluation of obstetric and gynecologic patients. Surg Clin North Am 2008;88:361–90. https://doi.org/10.1016/j.suc.2008.01.005; PMID: 18381118.

69. Webb JAW, Thomsen HS, Morcos SK; Members of Contrast Media Safety Committee of European Society of Urogenital Radiology. The use of iodinated and gadolinium contrast media during pregnancy and lactation. Eur Radiol 2005;15:1234–40. https://doi.org/10.1007/s00330-004-2583-y; PMID: 15609057.

70. Wagner LK, Applegate K; American College of Radiology. ACR practice guideline for imaging pregnant or potentially pregnant adolescents and women with ionizing radiation. American College of Radiology Practice Guideline. Reston, VA: American College of Radiology, 2011.

71. Thomsen HS. European Society of Urogenital Radiology (ESUR) guidelines on the safe use of iodinated contrast media. Eur J Radiol 2006;60:307–13. https://doi.org/10.1016/j.ejrad.2006.

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72. Bourjeily G, Chalhoub M, Phornphutkul C, et al. Neonatal thyroid function: Effect of a single exposure to iodinated contrast medium in utero. Radiology 2010;256:744–50. https:// doi.org/10.1148/radiol.10100163; PMID: 20634430.

73. Dauer LT, Thornton RH, Miller DL, et al. Radiation management for interventions using fluoroscopic or computed tomographic guidance during pregnancy: a joint guideline of the Society of Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe with Endorsement by the Canadian Interventional Radiology Association. J Vasc Interv Radiol 2012;23:19–32. https://doi. org/10.1016/j.jvir.2011.09.007; PMID: 22112899.

74. Vijayalakshmi K, Kelly D, Chapple CL, et al. Cardiac catheterisation: Radiation doses and lifetime risk of malignancy. Heart 2007;93:370–1. https://doi.org/10.1136/ hrt.2006.098731; PMID: 17322516.

75. Kuba K, Wolfe D, Schoenfeld AH, Bortnick AE. Percutaneous coronary intervention in pregnancy: Modeling of the fetal absorbed dose. Case Rep Obstet Gynecol 2019;2019:8410203. https://doi.org/10.1155/2019/8410203; PMID: 31360566.

76. 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 2017;39:119–77. https://doi. org/10.1093/eurheartj/ehx393; PMID: 28886621.

77. Räber L, Kelbæk H, Ostojic M, et al. Effect of biolimus-eluting stents with biodegradable polymer vs bare-metal stents on cardiovascular events among patients with acute myocardial infarction: the COMFORTABLE AMI randomized trial. JAMA 2012;308:777–87. https://doi.org/10.1001/jama.2012.10065; PMID: 22910755.

78. Sabate M, Cequier A, Iñiguez A, et al. Everolimus-eluting stent versus bare-metal stent in ST-segment elevation myocardial infarction (EXAMINATION): 1 year results of a randomised controlled trial. Lancet 2012;380:1482–90. https://doi. org/10.1016/S0140-6736(12)61223-9; PMID: 22951305.

79. Macaya F, Salinas P, Gonzalo N, et al. Spontaneous coronary artery dissection: contemporary aspects of diagnosis and patient management. Open Heart 2018;5:e000884. https://doi. org/10.1136/openhrt-2018-000884; PMID: 30487978.

80. Prakash R, Starovoytov A, Heydari M, et al. TCT-386 Iatrogenic catheter-induced dissection during angiography of patients with spontaneous coronary artery dissection. J Am Coll Cardiol 2015;66:B155–6. https://doi.org/10.1016/j.jacc.2015.08.1002.

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Coronary

Why, When and How Should Clinicians Use Physiology in Patients with Acute Coronary Syndromes?

Roberto Scarsini,1,2 Dimitrios Terentes-Printzios,1 Giovanni Luigi De Maria,1 Flavio Ribichini2 and Adrian Banning1,3 1. Oxford Heart Centre, NIHR Biomedical Research Centre, Oxford University Hospitals, Oxford, UK; Division of Cardiology, Department of Medicine, University of Verona, Verona, Italy; 3. Division of Cardiovascular Medicine, BHF Centre of Research Excellence, University of Oxford, Oxford, UK

Abstract Current data support the use of coronary physiology in patients with acute coronary syndrome (ACS). In patients with ST-elevation MI, the extent of myocardial damage and microvascular dysfunction create a complex conundrum to assimilate when considering clinical management and risk stratification. In this setting, the index of microcirculatory resistance emerged as an accurate tool to identify patients at risk of suboptimal myocardial reperfusion after primary percutaneous coronary intervention who may benefit from novel adjunctive therapies. In the context of non-ST-elevation ACS, coronary physiology should be carefully interpreted and often integrated with intracoronary imaging, especially in cases of ambiguous culprit lesion. Conversely, the functional assessment of bystander coronary disease is favoured by the available evidence, aiming to achieve complete revascularisation. Based on everyday clinical scenarios, the authors illustrate the available evidence and provide recommendations for the functional assessment of infarct-related artery and non-culprit lesions in patients with ACS.

Keywords Acute coronary syndromes, coronary physiology, fractional flow reserve, index of microcirculatory resistance, microvascular resistance, MI, ST-segment elevation Disclosure: RS has served on an advisory board for Abbott. AB has received institutional funding for an interventional fellowship from Boston Scientific.

All other authors have no conflicts of interest to declare.

Received: 19 November 2019 Accepted: 13 January 2020 Citation: Interventional Cardiology Review 2020;15:e05. DOI: https://doi.org/10.15420/icr.2019.26 Correspondence: Roberto Scarsini, Oxford Heart Centre, Oxford University Hospitals, Headley Way, Oxford OX3 9DU, UK. E: roberto.scarsini@ouh.nhs.uk 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.

Acute coronary syndromes (ACS) encompass a wide spectrum of clinical presentations that range from ST-elevation MI (STEMI) to non-ST-elevation MI and unstable angina. These conditions are life threatening and remain a source of high morbidity and mortality. Unfortunately, despite major accomplishments worldwide in timely reperfusion with percutaneous coronary intervention (PCI), an important residual risk of future cardiovascular events and mortality persists.1 Numerous methods have been proposed to provide individualised management in patients with ACS. In the past 20 years, there has been an exponential increase in the application of epicardial functional indices (e.g. fractional flow reserve [FFR]) and microvascular indices (e.g. index of microcirculatory resistance [IMR]). The initial proof-of-concept validation for these indices was performed in patients with chronic coronary syndromes (CCS) and then, based on these initial positive results, further application in patients with ACS has been attempted.

Although evidence supporting the use of coronary physiology guidance in ACS management is increasing, caution should be exercised in the interpretation of coronary physiology indices in this setting, given their potential pitfalls. This article summarises the evidence of the role of the main coronary physiology indices in ACS, focusing on five different clinical practice scenarios: STEMI with disease only in the infarctrelated artery (IRA), STEMI with multivessel disease (MVD), non-ST-

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elevation ACS (NSTE-ACS) with unclear culprit lesion and MVD, NSTEACS with well-defined culprit lesion and MVD, and MI with non-obstructive coronary artery disease (MINOCA).

ST-elevation MI: The Infarct-related Artery Usually, in STEMI undergoing primary PCI (PPCI), the IRA can be easily identified because of its acute angiographic characteristics, compatible with the clinical presentation. In this particular scenario, there is no need for physiological guidance to decide whether revascularisation is necessary. Moreover, the accuracy of epicardial functional indices such as FFR may be hampered by the significant degree of microvascular dysfunction observed in nearly 50% of cases, as discussed in detail below (Figure 1).

Nevertheless, coronary physiology can still play an important role in the assessment of the downstream microcirculatory function of the IRA, providing prognostically relevant information and identifying patients at high risk of suboptimal reperfusion who are eligible for additional novel therapies. The IMR, a pressure wire thermodilutionderived index supported by a large body of evidence, is the index of choice to assess the microvascular function in the IRA because of its ability to offer a reasonable compromise between accuracy and feasibility.2 In patients with STEMI, a cut-off value of IMR â&#x2030;Ľ40 has been associated with poor prognosis and more extensive myocardial injury.3

Š RADCLIFFE CARDIOLOGY 2020

Coronary Physiology in Acute Coronary Syndromes Microvascular Damage in the STEMI Infarct-related Artery Within less than an hour of ischaemia in the territory of the IRA, oedema develops from structural alterations to cardiomyocytes, resulting in cardiomyocyte death after the first 3 hours. PCI is able to restore coronary blood flow in the IRA but may also have detrimental effects on the microcirculation, causing dislodgement of atherothrombotic debris and distal embolisation.3 Although endothelial cells are more resilient to ischaemia than cardiomyocytes, prolonged ischaemia eventually also results in endothelial dysfunction.

As a consequence, capillary permeability is initially increased with oedema formation. Furthermore, endothelial dysfunction leads to impaired vasomotion, stasis and release of deleterious substances such as vasoconstrictors, inflammatory cytokines and reactive oxygen species. The final consequences of these processes are microvascular obstruction (MVO) and haemorrhage.4 It is well established that intramyocardial haemorrhage (IMH) and MVO are closely associated. However, IMH reflects a more irreversible degree of myocardial damage than MVO, which can instead shrink and eventually resolve at follow-up. MVO assessed by cardiovascular MRI (CMR) is an independent predictor of worse outcome regardless of infarct size, and patients with larger MVO are more likely to develop heart failure, leading to an increase in mortality. Thus, MVO represents a potential therapeutic target.

Invasive coronary physiology, and specifically IMR, predict the occurrence of MVO and provides important information regarding a patient’s prognosis and management, especially when CMR is unavailable or impractical.5

Temporal Changes in Coronary Physiology in the Infarct-related Artery Cuculi et al. assessed the changes in coronary physiology over time after STEMI.6 In that study, 43 STEMI patients underwent physiological assessment of the IRA at the time of the PPCI, at day 1 and at the 6-month follow-up. Notably, the resting coronary flow, estimated via thermodilution, did not change over time after STEMI. Conversely, the hyperaemic coronary flow increased significantly at follow-up (coronary flow reserve [CFR] 1.8 ± 0.9 versus 3.1 ± 1.1; p<0.001). Consistently, IMR decreased progressively after STEMI, being 37.0 ± 22.3 after PPCI, 30.6 ± 21.4 at day 1 and 24.0 ± 22.0 at 6 months (p=0.002).

Interestingly, the epicardial coronary physiology in the IRA also showed significant variations over time. In particular, FFR decreased from 0.93 ± 0.06 after PPCI to 0.92 ± 0.06 at day 1 and 0.89 ± 0.06 at 6 months (p<0.001). In contrast, resting coronary physiology estimated by the baseline ratio of distal coronary pressure (Pd) to aortic pressure (Pa) did not change significantly over time (after PPCI: 0.96 ± 0.04; day 1: 0.95 ± 0.05; 6 months: 0.96 ± 0.04; p=0.22).6 Notably, FFR variations over time were significant in patients with evidence of MVO at CMR (mean FFR 0.94 ± 0.04 versus 0.88 ± 0.06; p=0.006), but not in patients without MVO (0.94 ± 0.05 versus 0.93 ± 0.04; p=0.21; Figure 2).6 These interesting findings suggest that the coronary microcirculation generally recovers after STEMI in the IRA and tends to normalise 6 months after STEMI. The hyperaemic response to adenosine is blunted in the IRA, especially in patients with evidence of MVO.

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Figure 1: Potential Limitations of Fractional Flow Reserve in Patients with Acute Coronary Syndrome MVO at MRI

Limitations of FFR in ACS

False negative 1. Significant microvascular dysfunction 2. Severe hypotension – unproportional flow to pressure gradient

ACS = acute coronary syndrome; FFR = fractional flow reserve; MVO = microvascular obstruction.

Therefore, the reliability of FFR in the acute phase of STEMI is questionable in the territory of the IRA. Whether the new adenosinefree indices can be used in the IRA in the setting of a recent STEMI is not clear, and further studies are needed.

Prognostic Value of Coronary Physiology After STEMI An increasing body of evidence provides insights into the prognostic value of invasive physiology assessed at the time of PPCI with regard to acute and final infarct size, MVO, residual systolic function and clinical outcome after STEMI. IMR at completion of PPCI has been associated with the extent of MVO (rho=0.29, p=0.002) and infarct size in the subacute phase after STEMI (rho=0.21, p=0.03) and at the 6-month follow-up (rho=0.43, p=0.001).5 In addition, post-PCI IMR ≥40 has been associated with higher risk of mortality and readmission for heart failure.7 Moreover, IMR ≥40 has shown excellent performance in predicting major in-hospital cardiac complications after PPCI (area under the curve [AUC] 0.90; 95% CI [0.85–0.93]). 8 In addition, when measured before stenting, IMR can detect patients at high risk of suboptimal myocardial reperfusion who are candidates for additional therapies.9 A preserved vasodilatory capacity, reflecting an intact and functional coronary microvasculature, is an important predictor of myocardial functional recovery at 6 months after STEMI. The resistive reserve ratio (RRR) has been proposed to assess the vasodilatory capacity of the coronary circulation, and is calculated as the ratio between the baseline microcirculatory resistance (BMR) and the hyperaemic microcirculatory resistance expressed as IMR.10 Recently, it was demonstrated that RRR had incremental prognostic value in a small cohort of STEMI patients undergoing PPCI. In particular, patients with impaired RRR (<1.98) at completion of PPCI showed larger MVO (3.5 [0.0–5.9]; p=0.026), larger infarct size at 6 months (22.7 [10.2–35.0] versus 8.8 [6.9–12.3]; p=0.006) and a lower myocardial salvage index (34.0 [22.0–59.2] versus 53.2 [37.7–71.0]; p=0.032) than patients with preserved RRR.11 Numerous strategies have been developed to prevent or reduce the severity of microcirculatory dysfunction and MVO in patients with STEMI. In particular, the efficacy of intracoronary fibrinolytic therapy in STEMI patients after PPCI has been investigated, with controversial results.

Coronary Figure 2: Effect of Microvascular Obstruction on the Microcirculation and Fractional Flow Reserve After ST-segment Elevation MI

PPCI

Day 1

6 months

Oedema + Necrosis +

Scar +

No MVO

Vasodilation +++

Vasodilation +++

FFR

FFR

CFR

CFR

IMR

IMR

Oedema ++ Necrosis ++

Scar ++

MVO

Vasodilation +/–

Vasodilation ++

FFR appears

FFR

CFR

CFR

IMR

IMR

After restoring epicardial coronary artery patency by stenting, the presence of MVO detected by cardiac MRI is associated with a blunted capacity for vasodilation. This can be measured as a low CFR or a high IMR and results in an apparently higher FFR. Recovery of myocardial function with improved capacity for vasodilation is reflected by increased CFR; this results in a lower measured FFR at 6 months. In patients without MVO, vasodilatory function is relatively preserved acutely and temporal changes in FFR are less evident. Changes in CFR are represented by arrows: single arrows indicate some response; double arrows indicate a marked response; and triple arrows indicate maximum response. CFR = coronary flow reserve; FFR = fractional flow reserve; IMR = index of microcirculatory resistance; MVO = microvascular obstruction; PPCI = primary percutaneous coronary intervention. Source: Cuculi et al. 2014.6 Used with permission from Elsevier.

Sezer et al. studied the effects of adjunctive low-dose intracoronary streptokinase given after PPCI in 41 STEMI patients.12 Of note, the treatment was effective in reducing IMR (16.29 ± 5.06 versus 32.49 ± 11.04; p<0.001) and increasing CFR (2.01 ± 0.57 versus 1.39 ± 0.31; p=0.002) compared with controls.12

In a larger study, patients who received adjunctive intracoronary streptokinase after PPCI demonstrated smaller infarct size (22.7% versus 32.9%; p=0.003) and better left ventricle ejection fraction (LVEF; 57.2% versus 51.8%, p=0.018) compared with controls.13

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Coronary Physiology in Acute Coronary Syndromes Conversely, McCartney et al. recently reported that patients who were randomised to receive low-dose intracoronary alteplase after PPCI did not differ from controls in terms of MVO at CMR (estimated difference 0.29%; 95% CI [−0.76–1.35%]; p=0.74) and presented similar clinical outcomes.14

4 to 128 days). However, the Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Non Culprit Lesions in Patients With ST-segment Elevation Myocardial Infarction (WAVE) study also showed no significant variations in FFR in the non-culprit artery, even though the follow-up period was limited to 5–8 days after STEMI.21

Among the procedural techniques available to reduce microvascular and myocardial injury after STEMI, pressure-controlled intermittent coronary sinus occlusion (PiCSO; Miracor Medical) has been reported by us to reduce IMR (24.8 [18.5–35.9] versus 45.0 [32.0–51.3]; p<0.001) and infarct size at 6 months after STEMI (26% [20.2–30.0] versus 33.0% [28.0– 37.0]; p=0.006) compared with controls.9 Intermittent occlusion of the coronary sinus allows redistribution of the coronary blood flow in underperfused areas when the balloon is inflated and washing out of cellular debris and oedema fluid on balloon release, leading to relief of MVO.

Recently, a substudy of the Reducing MicroVascular Dysfunction in Revascularized STEMI Patients by Off-target Properties of Ticagrelor (REDUCE-MVI) trial demonstrated that CFR measured in the nonculprit vessel significantly increases (2.9 ± 1.4 versus 4.1 ± 2.2; p<0.001) and the IMR tends to decrease 1 month after the index procedure (18.0 [13.5–27.0] versus 14.5 [11.0–21.0]; p=0.6).22 Interestingly, the authors of that study observed a blunted hyperaemic response to adenosine in the acute phase of STEMI measuring Pd variations and RRR (3.4 ± 1.7 versus 5.0 ± 2.7; p<0.001). Consistent with these observations, FFR decreased significantly in the nonculprit vessel at the 1-month follow-up (0.88 ± 0.07 versus 0.86 ± 0.09; p=0.001), maintaining a classification agreement of 80.8% between the acute phase and follow-up assessment.

Further details regarding available pharmacotherapy and procedural techniques to prevent and treat microcirculatory impairment in STEMI have been reported elsewhere.15

STEMI with Multivessel Disease: The Non-culprit Artery More than 50% of patients presenting with STEMI have MVD.16 Recent evidence supports complete revascularisation compared with a culpritonly approach in patients with STEMI and MVD. The Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Early PCI for STEMI (COMPLETE) trial demonstrated a significant benefit in terms of cardiovascular death and MI in a large population of STEMI patients who underwent complete revascularisation (HR 0.74; 95% CI [0.60–0.91]; p=0.004).17 The functional assessment of non-culprit lesions has been questioned because of concerns related to the status of the microvasculature in remote myocardial territories, with potential detrimental effects on the reliability of FFR or the instantaneous wave-free ratio (iFR). Numerous studies have addressed this question, and they generally favour the use of physiology to guide revascularisation of the non-culprit.

Fractional Flow Reserve and Instantaneous Wave-free Ratio Assessment of the Non-culprit Lesion The Primary PCI in Patients With ST-elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization (DANAMI-3-PRIMULTI) and Comparison Between FFR Guided Revascularization Versus Conventional Strategy in Acute STEMI Patients With MVD (CompareAcute) trials demonstrated the efficacy of FFR-guided complete revascularisation in patients presenting with STEMI.18,19 Interestingly, in the CompareAcute trial, functional assessment of the non-culprit lesions was performed during the PPCI procedure, whereas in the DANAMI-3-PRIMULTI trial the assessment was performed before discharge in a staged manner. Notably, both trials demonstrated the superiority of FFR-guided complete revascularisation compared with the culprit-only approach (Table 1).

The feasibility of FFR assessment of non-culprit lesions in patients with acute MI was assessed by Ntalianis et al.20 In that study, the authors found no overall significant difference in FFR values at follow-up compared with the acute phase. However, the heterogeneity of the study population has to be taken into consideration when interpreting the results, particularly with regard to the mixed clinical presentation (both STEMI and NSTE-ACS) and the time of follow-up (ranging from

INTERVENTIONAL CARDIOLOGY REVIEW

Notably, a blunted haemodynamic response detected in the non-culprit artery was associated with larger infarct size and worse LVEF after STEMI.22 If the reduced hyperaemic flow in the IRA can be explained primarily by the presence of infarct-related microvascular injury, this phenomenon is less well characterised in the non-culprit artery. It is known that the sensitivity of purinergic adenosine receptors is reduced in the remote myocardium in the acute phase of STEMI. Moreover, increased neurohumoral activation and extravascular compression secondary to myocardial oedema may play a role in the acute blunted hyperaemic response to adenosine.23,24 Nevertheless, Mejía-Rentería et al. recently observed that the hyperaemic flow was preserved in the subacute phase of MI, supporting the use of FFR in this setting.25 Notably, IMR (15.6 [10.4–21.8] versus 16.7 [11.6–23.6]; p=0.56) and RRR (3.1 ± 2.1 versus 3.7 ± 2.2; p=0.12) were similar in non-culprit lesions compared with a matched cohort of stable patients, whereas CFR was lower in the non-culprit lesions (1.77 [1.25–2.76] versus 2.44 [1.63–4.00]; p=0.018). Interestingly, the reduction in CFR was primarily driven by an increase in resting coronary flow (rest mean transit time 0.58 s [0.32–0.83] versus 0.65 s [0.39–1.20]; p=0.045).25 This observation may have implications for adenosine-free ischaemic indices in non-culprit vessels.

In particular, a tendency for overestimation of lesion severity was observed in the Nonculprit Stenosis Evaluation Using iFR in Patients with STEMI (iSTEMI) study using iFR. Notably, a similar trend was observed in different clinical settings where baseline coronary flow is markedly increased.26,27 In the iSTEMI study, the classification agreement between the acute phase and follow-up iFR values was modest (78%) and inferior compared with that for FFR.28 Conversely, in the study by van der Hoeven et al., iFR presented a similar classification agreement between acute and 30-day assessment to that obtained for FFR (82.2%).22 In conclusion, FFR-guided assessment and treatment of non-culprit lesions is supported by pathophysiological and randomised data. Less extensive experience supports the use of iFR in this clinical scenario, but iFR guidance of non-culprit lesions in a practice similar to the DANAMI-3-PRIMULTI and CompareAcute trials will require additional research and, ideally, a randomised control trial.21,22,28,29

Coronary Table 1: Non-culprit Lesion Functional Assessment in Patients with Acute MI Study

Sample size

STEMI or NSTE-ACS

Main findings

Ntalianis et al.20

101 patients, 112 lesions

STEMI and NSTE-ACS

Overall, FFR does not change when measured in the acute phase and at follow-up in non-culprit lesions

DANAMI-3-PRIMULTI18

627 patients

STEMI

FFR-guided complete revascularisation (assessment before discharge) reduces the composite of cardiac death, MI and ischaemia-driven revascularisation at 27 months (HR 0.56; 95% CI [0.38–0.83]; p=0.004)

Compare-Acute19

885 patients

STEMI

FFR-guided complete revascularisation (assessment during PPCI) reduces the composite of cardiac death, MI and ischemia-driven revascularisation at 12 months (HR 0.35; 95% CI [0.22–0.55]; p<0.001)

WAVE (Musto et al.21)

50 patients, 66 lesions

STEMI

No significant variations in FFR values between the acute and subacute phases (5–8 days)

Choi et al.29

100 patients

STEMI and NSTE-ACS

FFR decrease with worsening of lesion severity is similar in non-culprit artery and stable CAD

Van der Hoeven et al.22

73 patients

STEMI

Overall, FFR decreases from the acute phase to the 30-day follow-up (0.88 ± 0.07 versus 0.86 ± 0.09; p=0.001) 80.8% classification agreement between the acute phase and 30-day follow-up

WAVE (Musto et al.21)

50 patients, 66 lesions

STEMI

No significant variations in FFR values between the acute and subacute phases (5–8 days) iFR has high accuracy in identifying abnormal FFR ≤0.80 in the non-culprit lesion (AUC 0.95)

iSTEMI (Thim et al.28)

120 patients, 157 lesions

STEMI

78% classification agreement between acute and follow-up iFR Negative predictive value of negative iFR in the acute phase is 89% The time interval from acute to follow-up iFR affects the classification agreement

Indolfi et al.45

52 patients, 78 lesions

STEMI and NSTE-ACS

iFR has good accuracy (agreement 79.5%, AUC 0.86) in predicting FFR ≤0.80 iFR in non-culprit ACS has comparable diagnostic accuracy compared with stable CAD

Choi et al.29

100 patients

STEMI and NSTE-ACS

iFR decrease with worsening of lesion severity is similar in non-culprit artery and stable CAD

Van der Hoeven et al.22

73 patients

STEMI

Overall iFR did not change at the 30-day follow-up (0.93 ± 0.07 versus 0.94 ± 0.06; p=0.12) 82.0% classification agreement between the acute phase and 30-day follow-up

1. 31 patients

STEMI

QFR is highly reproducible in the non-culprit lesion (r=0.98)

2. 45 patients

STEMI

QFR has high accuracy in predicting FFR ≤0.80 (AUC 0.96)

3. 110 patients

STEMI

Patients with QFR ≤0.80 in non-culprit arteries are at increased risk of MACE (HR 2.3; 95% CI [1.2–4.5]; p=0.01)

iSTEMI (Sejr-Hansan et al.32)

103 lesions

STEMI

QFR has 84% classification agreement with FFR in the non-culprit lesion and 74% classification agreement with iFR

Lauri et al.31

82 patients, 91 lesions

STEMI

QFR has comparable high accuracy in non-culprit lesion and stable CAD (AUC 0.91) The accuracy of QFR is higher out of the 0.75–0.85 ‘grey zone’

FFR

iFR

QFR Spitaleri et al.30

ACS = acute coronary syndrome; AUC = area under the curve; CAD = coronary artery disease; FFR = fractional flow reserve; iFR = instantaneous wave-free ratio; NSTE = non-ST-elevation; PPCI = primary percutaneous coronary intervention; QFR = quantitative flow ratio; STEMI = ST-elevation MI.

Angiography-derived Functional Assessment of the Non-culprit Lesion Recently, the quantitative flow ratio (QFR), a novel angiography-derived index, has been proposed to functionally assess non-culprit lesions in ACS patients. QFR in the non-culprit lesion has demonstrated high reproducibility between the acute and sub-acute phases of STEMI (r=0.98; 95% CI [0.96–0.99]; mean difference 0.004 [−0.027–0.34]) and high accuracy (AUC 0.96; 95% CI [0.89–0.99]) in predicting an abnormal FFR value (≤0.80).30

Similarly, Lauri et al. demonstrated the feasibility of performing QFR analysis retrospectively in patients with STEMI undergoing PPCI.31 In that study, the authors observed a high accuracy of QFR (AUC 0.91; 95% CI [0.85–0.97]) in predicting an abnormal FFR (≤0.80), especially when QFR is out of a receiver operating characteristic (ROC)-defined grey zone (0.75–0.85). When a hybrid QFR–FFR approach was used, measuring FFR only when QFR is in the grey zone, an overall 96.7% classification agreement was obtained, avoiding further invasive diagnostic procedures in the non-culprit vessels in 58.5% of patients.32

INTERVENTIONAL CARDIOLOGY REVIEW

Coronary Physiology in Acute Coronary Syndromes Figure 3: Use of Coronary Physiology in Different Clinical Scenarios in Patients with Acute Coronary Syndrome Coronary physiology in ACS

STEMI

Infarct-related artery

MINOCA

NSTE

Non-culprit

Non-culprit

Multivessel disease and ambiguous culprit lesion

?CFR/IMR risk stratification

IMR for risk stratification

FFR ≤0.80 or iFR <0.89

FFR >0.80 or iFR ≥0.89

Treat

Defer

Imaging (OCT or IVUS)

FFR ≤0.80 or iFR <0.89

FFR >0.80 or iFR ≥0.89

Presence of plaque instability signs

Treat

Defer

Physiology Non-culprit

FFR ≤0.80 or iFR <0.89

FFR >0.80 or iFR ≥0.89

Treat

Imaging (OCT or IVUS)

Presence of plaque instability signs

Yes

No

Treat

Defer

Yes

No

Treat

Physiology

ACS = acute coronary syndrome; CFR = coronary flow reserve; FFR = fractional flow reserve; iFR = instantaneous wave-free ratio; IMR = index of microcirculatory resistance; IVUS = intravascular ultrasound; MINOCA = MI with non-obstructive coronary artery disease; NSTEMI = non-ST segment elevation MI; OCT = optical coherence tomography; STEMI = ST-elevation MI.

A post hoc analysis of the iSTEMI study revealed good accuracy of QFR in predicting an abnormal FFR (84%; 95% CI [76–90]) in the non-culprit artery and moderate accuracy compared with an abnormal iFR (74%; 95% CI [65–83]).32 Notably, Spitaleri et al. showed that patients with untreated non-culprit lesions with QFR ≤0.80 were at higher risk of adverse clinical events (HR 2.3; 95% CI [1.2–4.5]; p=0.01).30 Angiographyderived indices, and in particular QFR, may find a role in the simplification of ACS management, and further randomised data are warranted to confirm these preliminary findings.

NSTE-ACS with Clear Culprit Lesion and Multivessel Disease In presence of a clear infarct-related lesion and bystander MVD, the same information reported for the STEMI non-culprit lesions can be applied to NSTE-ACS patients. In particular, FFR and iFR have been used in this setting with favourable outcomes and should be considered in the presence of angiographic intermediate lesions (Figure 3).

Microvascular Vasodilatory Capacity and Hyperaemic Physiology in NSTE-ACS The question of a reliable achievable maximal hyperaemia in patients with NSTE-ACS has been explored by Layland et al. using thermodilutionderived RRR.10 Notably, the vasodilatory response of the coronary microcirculation was comparable between patients with NSTE-ACS and

INTERVENTIONAL CARDIOLOGY REVIEW

stable coronary artery disease (RRR 2.5 [1.6–3.9] versus 2.8 [1.7–4.8]; p=0.61). These findings confirm the preserved capacity of the coronary microcirculation to achieve maximal hyperaemia in NSTE-ACS and are reassuring about the reliability of hyperaemic physiology in NSTE-ACS.10 The Fractional Flow Reserve Versus Angiography in Guiding Management of Optimize Outcomes in Non-ST-Elevation Myocardial Infarction (FAMOUS-NSTEMI) trial demonstrated the safety and feasibility of FFR measurements in NSTE-ACS.33 An interesting FAMOUSNSTEMI substudy demonstrated that FFR has a 92% diagnostic accuracy (positive predictive value 76%, negative predictive value 97%) in detecting significant perfusion abnormalities in matched territories at stress CMR (AUC 0.93; 95% CI [0.90–0.99]).34 IMR has been less extensively studied in the NSTE-ACS setting compared with STEMI. In the study of Layland et al., pre-PCI IMR values in NSTE-ACS patients did not differ significantly from those in stable angina patients (22.73 ± 11.36 versus 18.26 ± 9.15; p=0.1), but were significantly lower than in STEMI IRA (22.73 ± 11.36 versus 36.51 ± 35.7; p=0.01).10 Murai et al. investigated the prognostic value of post-PCI coronary physiology in 83 patients with NSTE-ACS. Notably, IMR and CFR <2, but not FFR, were significantly associated with major adverse cardiac events (MACE) at 20.7 months of follow-up.35 Multivariate analysis revealed that high IMR was an independent predictor of MACE in this NSTE-ACS cohort (HR 1.03; 95% CI [1.01–1.05]; p=0.001).35

Coronary NSTE-ACS with Ambiguous Culprit Lesion and Multivessel Disease When coronary intervention is deferred based on coronary physiology, patients presenting with ACS have a higher risk of MACE at follow-up than stable coronary artery disease patients.36,37 The Fractional flow reserve versus Angiography for Multivessel Evaluation (FAME) trial enrolled 328 patients with NSTE-ACS, of whom 150 were randomised to FFR-guided PCI. Notably, the risk of MACE at 2 years was higher in the ACS group than stable patients (21.3% versus 16.4).36 Recently, a combined analysis of the Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation (DEFINE-FLAIR) and Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome (iFR SWEDEHEART) trials confirmed that the ACS presentation was associated with a higher incidence of MACE at 1 year in 2,130 patients with coronary lesions deferred based on ‘negative’ values of iFR or FFR (for stable coronary artery disease presentation, HR 0.61; 95% CI [0.38–0.99]; p=0.04).37 It remains unclear whether this higher rate of events registered in patients with ACS is related to an intrinsic higher risk in ACS patients or whether it reflects a ‘false negative’ physiological assessment.

In the setting of NSTE-ACS, the culprit lesion is often less obvious than in STEMI, especially when there are no specific angiographic features (e.g. intracoronary thrombus, ulceration, dissection), ECG changes or regional wall motion abnormalities. In this clinical scenario, a few aspects can be considered in the assessment of intermediate coronary lesions in patients with NSTE-ACS and ambiguous culprit plaque or artery.

In the IRA, postulating a plaque rupture and a preserved conduit vessel luminal area, FFR and iFR results may be above the ischaemic thresholds, even in case of an intact downstream microvasculature.

Conversely, in case of extreme ACS-related microvascular dysfunction, physiological indices may be falsely elevated even in case of flowlimiting intraluminal disease.38 In patients with ACS, the optimal FFR cut-off for treatment deferral has been questioned, observing that the rate of MI or target vessel failure was 12.8% per year when FFR was 0.75–0.80, 10.0% per year when FFR was 0.80–0.85 and 6.2% per year for FFR values >0.90. Notably, such a trend was not observed in patients with stable angina.39 Given the theoretical limitations of FFR and iFR in case of an acute plaque event, physiology should be integrated with intracoronary imaging to detect the presence of plaque rupture, erosion or intracoronary thrombus. In particular, optical coherence tomography (OCT) or intravascular ultrasound (IVUS) should be considered as the first choice to guide revascularisation in case of uncertainty regarding the IRA in the setting of NSTE-ACS. If functional assessment by means of FFR or iFR is preferred by the operators, imaging should still be considered in the case of a borderline or negative result (FFR >0.80 or iFR ≥0.89; Figure 3).

angiography, so that the direct cause for the clinical syndrome is not evident.40 MINOCA is not an uncommon condition and has been reported in 5–15% of patients with suspected MI admission. MINOCA encompasses a wide variety of aetiological mechanisms that could be differentiated into epicardial and microvascular. Regional wall motion abnormalities limited to a single coronary artery territory suggest an epicardial mechanism that is caused primarily by coronary plaque disease, spasm or dissection. Conversely, regional wall motion abnormalities extending to more than one epicardial coronary artery territory suggest a microvascular mechanism that is primarily caused by takotsubo syndrome, myocarditis, coronary microvascular spasm and coronary embolism.

Data on the role of coronary physiology in MINOCA are scarce and stem from small pilot studies and case reports.

During the acute phase of takotsubo syndrome, significant microcirculatory dysfunction with a global distribution pattern has been described, with a tendency towards normalisation during the recovery phase. Possible underlying mechanisms of the temporary disrupted perfusion and myocardial stunning include diffuse vasoconstriction due to catecholamine-induced alpha-adrenoceptor stimulation in resistance arteries, as well as endothelial dysfunction and inflammation.41–43 Although there is currently no clinical indication for coronary physiology assessment in MINOCA, it is possible that the assessment of microvascular dysfunction may lead to a better risk stratification and personalised treatment. 44 Understanding coronary physiology in MINOCA and implementation of targeted therapies to improve prognosis represent important challenges for future dedicated research.

Conclusion Coronary physiology provides useful information in guiding the management of patients with ACS, as summarised in Figure 3. There is usually no need for epicardial functional assessment of the IRA in STEMI. Moreover, a significantly impaired microcirculatory function is detected in more than 50% of STEMI patients, limiting the value of FFR or iFR in the IRA. Conversely, IMR has emerged as an important tool to stratify the clinical risk of adverse events or adverse left ventricle remodelling in STEMI. In addition, increasing data suggest a potential role of IMR in identifying patients who may benefit from additional therapies on top of standard approaches with stenting to prevent suboptimal myocardial reperfusion.

MI with Non-obstructive Coronary Artery Disease

In the setting of NSTE-ACS, physiology should be integrated with intracoronary imaging in the case of an ambiguous IRA (Figure 3), and OCT or IVUS should be used to detect signs of plaque instability in case of ‘negative’ functional assessment. Conversely, an increasing body of evidence supports the use of coronary physiology in the nonculprit lesion of both STEMI and NSTE-ACS, and complete revascularisation is recommended by the latest European Society of Cardiology guidelines.1

MINOCA is the term currently used to describe patients presenting with clinical features of an acute myocardial injury but with no evidence of obstructive coronary artery disease on coronary

Finally, coronary physiology assessment in patients with MINOCA represents an interesting field for future dedicated research.

INTERVENTIONAL CARDIOLOGY REVIEW

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Coronary

Coronary Physiology Derived from Invasive Angiography: Will it be a Game Changer?

Lavinia Gabara,1,2 Jonathan Hinton,1,2 Julian Gunn,3,4 Paul D Morris3,4 and Nick Curzen1,2 Coronary Research Group, University Hospital Southampton NHS Foundation Trust, UK; Faculty of Medicine, University of Southampton, UK 3. Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, UK; Insigneo Institute of In Silico Medicine, Sheffield, UK

Abstract There is a large body of evidence suggesting that having knowledge of the presence and extent of coronary atheroma and whether it is causing downstream myocardial ischaemia facilitates optimal diagnosis and management for patients presenting with chest pain. Despite this, the use of coronary pressure wire in routine practice is surprisingly low and routine assessment of all diseased vessels before making a bespoke management plan is rare. The advent of angiogram-derived models of physiology could change diagnostic practice completely. By offering routine assessment of the physiology of all the major epicardial coronary vessels, angiogram-derived physiology has the potential to radically modify current practice by facilitating more accurate patient-level, vessel-level, and even lesion-level decision-making. In this article, the authors review the current state of angiogram-derived physiology and speculate on its potential impact on clinical practice.

Keywords Computational fluid dynamics, coronary artery disease, microvascular physiology, coronary modelling, physiology, fractional flow reserve, virtual fractional flow reserve, chronic coronary syndrome, angiography-derived physiology Disclosure: NC reports grants, personal fees and non-financial support from HeartFlow; grants, personal fees and non-financial support from Boston Scientific; grants, personal fees and non-financial support from Haemonetics; and grants from Beckmann Coulter that are unrelated to this article. All other authors have no conflicts of interest to declare.

Received: 28 October 2019 Accepted: 27 January 2020 Citation: Interventional Cardiology Review 2020;15:e06. DOI: https://doi.org/10.15420/icr.2019.25 Correspondence: Nick Curzen, Wessex Cardiothoracic Centre, University Hospital Southampton NHS Trust, Southampton SO16 6YD, UK. E: nick.curzen@uhs.nhs.uk 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 noncommercial purposes, provided the original work is cited correctly.

The optimal assessment and management of patients presenting with recent onset chest pain is achieved by acquiring information about the coronary anatomy and physiology, enabling decisions to be made based upon evidence of ischaemia at a patient-level and at lesion-level.

There are robust data indicating that the visual assessment of stenosis severity alone does not provide enough information upon which to base decisions about revascularisation.1,2 The addition of an assessment of vessel physiology in the form of indices derived from invasive pressure wire, such as fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR), allows for more accurate identification of lesions causing myocardial ischaemia that facilitates personalised management of coronary disease.3–7 Despite this evidence, which has resulted in international guidelines recommending the routine use of FFR and iFR, the uptake in clinical practice has been inexplicably low.8–12 Potential reasons for this reduced rate of adoption include increased procedural time, concerns about the added procedural risks, technical uncertainty about pressure wire drift or damping, increased costs, the requirement for patient counselling before the procedure and, perhaps most importantly, the need for experienced operators.13 Some of these factors have driven the evolution of invasive physiological methodology. Specifically, concern about preparation time, side-effects, additional costs and availability have led to the

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development of invasive adenosine free, non-hyperaemic methods in addition to iFR, such as distal coronary pressure to aortic pressure ratio (Pd/Pa), diastolic pressure ratio (dPR/DPR), resting full-cycle ratio (RFR), diastolic hyperaemia-free ratio (DFR) and contrast FFR.14–16 These indices have been shown to correlate closely with the gold standard FFR and iFR, but they all require an intracoronary pressure wire.17,18 In parallel, there have been important advances in methods that derive anatomical and physiological information from computational or mathematical modelling. By applying computational fluid dynamics (CFD) to the raw data from the CT coronary angiogram, FFR can be predicted in all major epicardial vessels to produce FFRCT noninvasively and this technology has been developed by HeartFlow (Redwood City, CA, US). Subsequent to clinical validation and cost efficacy studies, this technique has been approved by the National Institute for Health and Care Excellence (NICE) and is the subject of an Innovation and Technology Payment programme from NHS England to encourage its uptake in clinical practice.19–21 The aim of this technology is to reduce unnecessary invasive coronary angiography in patients presenting with chest pain. The next challenge is how to increase the use of physiological coronary assessment for those patients who do make it to the catheter laboratory.

© RADCLIFFE CARDIOLOGY 2020

Coronary Physiology Derived from Invasive Angiography

Angiography-derived Physiology Systems Virtual Fractional Flow Reserve The original computed or virtual FFR (vFFR) model was modelled using the VIRTUheart software devised by a team at University of Sheffield (UK). This used rotational coronary angiography and a Philips 3D workstation to reconstruct the 3D coronary artery anatomy in silico.

After reconstruction, mathematical boundary conditions were assigned (representing the physiological conditions which bound the reconstructed 3D domain) at the inlet and outlet. CFD simulation was then performed by Ansys CFX to yield the vFFR result. vFFR showed a diagnostic accuracy of 94% to predict physiological significance in a modest cohort of 19 patients – with 13 of them also having percutaneous coronary intervention (PCI) with post-stenting cases. However, performing the full 3D, time-dependent (or transient) 3D CFD required >24 hours of computing time.22 The Fast Virtual Fractional Flow Reserve Based Upon Steady-State Computational Fluid Dynamics Analysis (VIRTU-Fast) study, from the same University of Sheffield researchers, demonstrated a ‘pseudotransient’ or paired steady-state analysis, that accelerated processing to 189 seconds with <1% error relative to fully transient CFD.23 This >500-fold CFD acceleration method was then incorporated into their proprietary VIRTUheart workflow. The same study included a sensitivity analysis which investigated the sensitivity of vFFR relative to model inputs, that is, markers of stenosis geometry, proximal pressure and microvascular resistance. This analysis demonstrated that accurate vFFR computation was heavily dependent upon the tuning of the boundary condition of the distal vessels – the values used to represent microvascular resistance in an individual case.

The group now model vFFR using two image projections ≥30° apart from standard multiplanar angiography. CFD computation time was reduced further to a mean of 95 seconds while achieving excellent accuracy, specificity and sensitivity (93%, 92% and 100%, respectively).

In addition, a virtual stenting tool enables operators to assess the physiological impact of multiple alternative stenting strategies to identify which approach offers the maximum physiological benefit relative to the length of stent deployed virtually, hence potentially allowing a real-time PCI planner (Figure 2). Results correlated closely with the invasively measured post-PCI FFR (r=0.80).24 There are certain limitations of this technique. First, the studies only included a small number of cases all recruited in elective, stable circumstances (Table 3). Complex coronary anatomies including total occlusion and coronary artery bypass grafts (CABG) were excluded.

Second, applying a ‘one size fits all’ approach to tuning the models (i.e. reflecting the microvascular resistance or hyperaemic flow on an individual case basis) results in error in cases where these parameters are different from population-averaged values.25 Hence results may prove to be different in patients with scarring, previous infarcts or left ventricular hypertrophy, for example. However, this is a universal challenge for virtual physiology modelling and highlights the difficult

INTERVENTIONAL CARDIOLOGY REVIEW

Figure 1: The Evolution of Angiography-derived Parameters Over Time Philips/VIRTUHeart

Pie Medical Imaging

Medis Medical Imaging

CathWorks

105% Accuracy versus invasive FFR

Several research teams have developed systems (Figure 1 and Table 1) that derive physiological data from invasive angiographic images resulting in simulated physiological indices that are surrogates of invasively measured FFR. This review describes the currently available systems offering computed coronary physiology derived from angiography and discusses the potential value of these tools in the clinical assessment of patients.

100% 95% 90% 85% 80% 2012

2013

2014

2015

2016

2017

2018

2019

2020

Year of Publication Colour-coded by 3D quantitative coronary angiography software provider and study size.

FFR = fractional flow reserve.

choice of assumptions that need to be made when constraining the mathematics and tuning the boundary conditions.

Virtual Functional Assessment Index and Virtual Distal Coronary to Aortic Pressure Ratio Papafaklis et al. developed a simplified approach for virtual functional assessment of coronary stenoses from routine angiographic data using the Caas Workstation Quantitative Coronary Analysis (QCA)-3D from Pie Medical Imaging (Maastricht, the Netherlands) to recreate coronary geometry. Further processing involves steady-flow CFD analysis using flow rates of 1 and 3 ml/s, corresponding to the average flow at rest and during hyperaemia.

The pressure gradients at these two flow rates were calculated from the difference of the average pressure at the inlet and outlet and a ratio of Pd/Pa was derived. The average computed pressure ratio over this flow range was named the virtual functional assessment index (vFAI). This model was studied retrospectively in a multicentre cohort of 120 patients and 139 vessels. It demonstrated that, for an optimum vFAI value of 0.82, the ability to discriminate ischaemiaproducing lesions was very good with the area under the receiver operating characteristic curve (AUC) 92% (95% CI: [86–96%]), and the correlation with invasive FFR was reasonable (r=0.78). Diagnostic accuracy, sensitivity and specificity were 88%, 90% and 86%, respectively.26 The virtual resting Pd/Pa with an optimal cut-off ≤0.94 performed less well when correlated to invasive FFR (r=0.69).27 A limitation of this system is that the processing was 15 minutes per vessel, which is not ideal for the workflow in a typical catheterisation laboratory. In addition, vFAI is entirely a function of the geometry of the stenosis. It cannot be a surrogate for FFR because FFR is a measure of the pressure gradient in the context of patient-specific, microvascular, physiology. It is therefore likely to be less accurate in patients with microvascular disease, scar or increased myocardial mass.

Vessel Fractional Flow Reserve Using the same Caas Workstation QCA-3D, Masdjedi et al. have proposed a new method for simulating FFR from conventional angiography. The 3D coronary reconstruction is processed semiautomatically based on two angiographic projections. The boundaries were defined as a constant parabolic flow incorporating the measured aortic pressure at the inlet and stress-free (zero pressure) at the outlet approximating the coronary wall as rigid and the blood as Newtonian fluid. The pressure drop is then calculated based on physical laws

Coronary Table 1: Studies Including Virtual Parameters Derived from Angiography and Outcomes Compared to Invasive Fractional Flow Reserve 3D Software Provider

Parameter

Study

Patients Vessels Design (n) (n)

Accuracy Sensitivity Specificity Correlation (r)

Philips 3D QCA

Virtual FFR

VIRTU 1 201322

19

35

Prospective, single centre

97%

86%

100%

0.84

VIRTU Fast 201723

20

73

Prospective, single centre

*100%

*100%

*100%

0.99

Gosling et al. 201924

54

58

Prospective, single centre

93%

92%

100%

0.87

vFAI

Papafaklis et al. 201426

120

139

Retrospective, multi-centre

88%

90%

86%

0.78

Resting Pd/Pa

Papafaklis et al. 201827

120

139

Retrospective, multi-centre

84.9%

90.4%

81.6%

0.69

Vessel FFR

FAST 201928

100

n/a

Retrospective, single centre

n/a

n/a

n/a

0.89

FFR-QCA

Tu et al. 201429

68

77

Retrospective, multi-centre

88%

78%

93%

0.81

QFR

FAVOR 201630

73

84

Prospective, multi-centre

86%

74%

91%

0.77

FAVOR II China 201731

308

328

Prospective, multi-centre

92%

94%

91%

0.86

WIFI-II 201833

191

292

Prospective, multi-centre

83%

77%

86%

0.70

FAVOR II Europe-Japan 201832

329

319

Prospective, multi-centre

87%

86%

86%

0.83

VIRTUheart workflow

Caas QCA-3D Pie Medical Imaging

Medis Medical Imaging

Siemens

FFRangio

Tröbs et al. 201634

73

100

Retrospective, single-centre

90%

79%

94%

0.85

CathWorks

FFRangio

Pellicano et al. 201735

184

203

Prospective, multi-centre

93%

88%

95%

0.88

Kornowski et al. 201836

53

60

Prospective, single centre

95%

86%

100%

0.91

FAST-FFR 201937

301

319

Prospective, multi-centre

92%

94%

91%

0.80

*The 100% accuracy, sensitivity and specificity of virtual FFR in the VIRTU Fast trial should not be interpreted as clinical accuracy given the study was aimed at testing an accelerated computational fluid dynamics method and not a true marker of accuracy when deployed clinically. FFR = fractional flow reserve; Pd/Pa = distal coronary pressure to aortic pressure; QCA = quantitative coronary analysis; QFR = quantitative flow ratio; vFAI = virtual functional assessment index.

incorporating viscous resistance and separation loss effects resulting in a parameter named vessel-FFR (commonly given the acronym vFFR, not to be confused with virtual FFR described above, which is computed via a different method). This algorithm was then retrospectively applied to a cohort of 100 patients with an intermediate degree of stenosis in the Fast Assessment of STenosis severity (FAST) study that found a good correlation between the offline simulated vessel FFR and invasive FFR (r=0.89; p<0.001). Bland Altman limits of agreement were impressive at ± 0.03.28 Departing from CFD using Navier-Stokes equations and instead using simplified haemodynamic laws renders much faster analytical results, reported as ‘instantaneous’ by the authors. However, it should be noted that this technique required manual input for the 3D reconstruction and the time that this took was not quantified. In addition, several assumptions are required when the mathematics are simplified. This again highlights the challenges of incorporating patientspecific parameters into the solution, particularly regarding either hyperaemic flow and/or microvascular resistance. Finally, these results were collected retrospectively in a small cohort of selected patients and without involving a core lab. It will be interesting to see if the high levels of diagnostic accuracy and relatively narrow limits of agreement

are reproduced in larger multicentre trials when the tool is used by others. Some of these limitations may be addressed in the FAST-II study (NCT03791320), a prospective multicentre observational trial using this technique which was aiming to finish recruiting at the end of 2019.

Quantitative Flow Ratio This model was initially based upon two angiography projections during rest and at least one additional projection obtained during hyperaemia which were further processed using QAngio XA 3D prototype by Medis Medical Imaging (Leiden, the Netherlands) to generate the 3D QCA. The steady-state CFD analysis was then performed using the hyperaemic flow velocity derived from thrombolysis in MI (TIMI) frame count at the boundaries. The parameter that resulted, initially named FFRQCA, took 10 minutes per vessel and showed good correlation (r=0.81; p<0.001) with invasive FFR in a cohort of 68 patients and 77 vessels.29 The main drawback of this initial method was the need to use adenosine for hyperaemia. A unique benefit in this approach was that it incorporated a surrogate of patient-specific flow velocity from TIMI frame counting the progress of the contrast through the artery being studied. Other models must assume this value based on less specific markers.

INTERVENTIONAL CARDIOLOGY REVIEW

Coronary Physiology Derived from Invasive Angiography Subsequently, however, this approach was modified such that the flow velocity was frame-counted under resting conditions and an assumption/prediction was then made about what the velocity would be if hyperaemia was induced. Thus, the hyperaemic adenosine model quantitative flow ratio (aQFR) was replaced with the contrast quantitative flow ratio (cQFR). This was validated in the Diagnostic Accuracy of Fast Computational Approaches to Derive Fractional Flow Reserve from Diagnostic Coronary Angiography (FAVOR) pilot study involving a cohort of 73 patients and 84 vessels. The cQFR (or simply QFR from here on) showed good accuracy compared with invasive FFR (86%).30 Three further prospective multicentre trials validated the method in Asia and Europe and included more than 800 patients in total (Table 1 and Figure 3).31–33 A major benefit of computed FFR is that it may reduce procedure time relative to invasive FFR with QFR processing time being 5 minutes compared with measuring invasive FFR, which took 7 minutes.31 For speed and computational simplicity, CFD equations were replaced with equations based upon the laws of Bernoulli and Poiseuille. QFR was derived from relatively few parameters such as vessel geometry, assumptions on flow through a stenosis and vessel tapering in relation to side branch, thus generating a calculation of function based primarily upon anatomy. Not all vessels are currently suitable for this approach with a 6–31% reported attrition rate.32,33

Figure 2: Case Study of a Left Anterior Descending Artery Lesion Pre- and Post-Percutaneous Coronary Intervention (Left Panels) and Pre- and Post-Virtual Stenting (Right Panels) A

B stenosis

Virtual stenosis

FFR 1.00 0.95 0.90 0.85 0.80 0.75

vFFR 0.75

FFR 0.77

0.70 0.65 0.60

C

D Virtual stent

stent

FFR 1.00 0.95 0.90 0.85 0.80

FFR 0.88

vFFR 0.88

0.75 0.70 0.65

0.60 The FFR and VFFR show close agreement. FFR = fractional flow reserve; vFFR = virtual fractional flow reserve. Source: Gosling et al. 2019.24 Reproduced with permission from Elsevier.

FFRangio (Siemens) Another technique, termed FFRangio, was developed in collaboration with Siemens Healthcare GmbH (Frochheim, Germany), which provided the 3D reconstruction software and the CFD modelling prototype. The boundaries of the 3D model were personalised by using the blood pressure measured at the tip of the catheter and heart rate. FFRangio required only 40 seconds per vessel mean calculation time and, using the same 0.80 cut-off, reached a 90% agreement with invasive FFR in deciding whether a lesion was significant or not. The Bland Altman limits of agreement were excellent at ±0.04. The limitations of this technique so far are similar to those of other systems. Validation data are based on a limited number of patients included in the retrospective study (73 patients, 100 vessels).34 Additional drawbacks were loss of data from the final analysis due to motion artefacts, elements of the workflow requiring manual input and estimating microvascular resistance. To date there have been no further published trials using Siemens software.

FFRangio (CathWorks) FFRangio is now a CathWorks Ltd (Kfar Saba, Israel) registered trademark which has developed a proprietary method for computing the ’functional angiogram’ of the entire coronary tree. The basis is similar to other methods in that it constructs the 3D coronary model from single plane angiographic projections, initially requiring at least three, rather than two, projections. This model applies a serial resistance model based purely on the anatomical features of lesions (such as length and diameter) to calculate resistance, while neglecting entrance effects and rheology particularities. Pellicano et al. validated the technique in a prospective, blinded, multicentre trial including 184 patients using the offline version and reporting a 93% accuracy compared with invasive FFR.35 Kornowski et al. prospectively tested FFRangio online in a cohort of 53 patients and 60 vessels and obtained excellent concordance with FFR (AUC 0.95) within 10 minutes.36 Recently, Fearon et al. have published the results of the FAST-FFR trial, which is a prospective, multicentre

INTERVENTIONAL CARDIOLOGY REVIEW

international trial including 301 patients and 319 vessels employing an updated version of the proprietary technology from CathWorks, requiring only two angiographic projections for the 3D reconstruction.

In the per vessel analysis, the results were encouraging, with sensitivity and specificity at 94% and 91%, respectively, and an overall accuracy at 92% using invasive pressure wire as the reference. The 99% success rate of the device was particularly impressive.37 The main advantage of this model lies in generating a complete and accurate 3D reconstruction, including the branches (down to 0.5mm), coupled with a short processing time. However, once again, there are considerable assumptions in the mathematical solution that may compromise the model’s ability to accurately characterise haemodynamic flow and translesional pressure dynamics.

Potential Advantages of Angiographyderived Physiology The ability to assess the physiology of all epicardial coronary branches and potentially intervenable lesions directly from the invasive angiogram could be a game-changer for personalised patient management. Given the extensive data that support the clinical value of knowing the anatomical atheroma burden, but also lesion-level ischaemic potential, deriving functional data from the anatomy, without needing to use an invasive pressure wire at all, let alone in multiple vessels, could facilitate achieving this management paradigm. While different systems are competing for this role, they all have the major advantage of not requiring a pressure wire or adenosine. This resolves the key limitations of invasive FFR: the cost and time associated with pressure wire use and adenosine administration, as well as the required technical expertise and potential complications when passing an intracoronary wire. Furthermore, these models offer the potential for global assessment of all major vessels in a single analysis thereby providing a more comprehensive assessment and reducing the operator bias that affects use of invasive pressure wire. Typically, operators interrogate lesions with 50–70% stenosis, but not those with

Coronary Figure 3: Case Study of Intermediate Left Anterior Descending Artery Stenosis Demonstrating Close Correlation Between QFR (Left Panels) and Invasive FFR (Right Panels)

Contrast QFR

1

QFR

0.8 0.6 0.4 0.2 0 0

10

20

30 40 Position (mm)

50

60

70

A III

AI

1.0 0.9 0.8 0.7 0.6 0.5

A II

QFR = 0.83

A IV

Contrast QFR

1

QFR

0.8 0.6 0.4 0.2 0 0

10

20

30 Position (mm)

40

50

60

B III

BI

1.0 0.9 0.8 0.7 0.6 0.5

QFR = 0.72

B II

B IV

FFR = fractional flow reserve; QFR = quantitative flow reserve. Source: Xu et al. 2017.31 Reproduced with permission from Elsevier.

30–50% or 70–90% stenosis, despite a wealth of data reporting that these categories also comprise anatomy-physiology discordant cases (Figure 4).38 The 3D reconstruction of the coronary arteries is based upon two 2D projections acquired during routine coronary angiography.37 Computation appears to be operator-independent and highly reproducible, with accuracies between 83 and 95% compared with invasive FFR (Table 1).9,28,29 Furthermore, a meta-analysis including 13

studies with most, but not all, of the methods described above, and a total of 1,842 vessels demonstrated a good pooled diagnostic accuracy when compared with invasive FFR using the 0.8 cut-off (AUC 0.84; 95% CI [0.66–0.94]). The pooled sensitivity for detecting a significant coronary stenosis was 89% (95% CI [83–94%]) and the pooled specificity was 90% (95% CI [88–92%]), without any significant difference between calculation methods (CFD versus mathematical), software or analysis type (offline versus online).39 However, diagnostic accuracy is a function of model accuracy as well as the clinical case mix included in a

INTERVENTIONAL CARDIOLOGY REVIEW

Coronary Physiology Derived from Invasive Angiography

Processing time for all models has been reduced so they could be integrated into the workflow of a typical catheterisation laboratory.

Finally, some of these systems simulate and predict the physiological outcome of alternative PCI strategies in real time, enabling the identification and selection of the optimal revascularisation approach.24

Limitations of Angiography-derived Physiology Methodologically, key challenges remain in adequately representing patient-specific physiology. Specifically, this means tuning models with artery-specific data that reflect microvascular resistance or hyperaemic flow. Both parameters vary in health and disease and are difficult to measure invasively, let alone predict non-invasively. Without adequate physiological ‘tuning’, these models are little more than a sophisticated QCA, dependent only on stenosis geometry, ignoring the very things that make FFR superior to diagnostic angiography. The whole point of FFR is that it reports the significance of a lesion, and thus the potential benefit of PCI, in the context of the patient’s microvascular resistance.

Failure to reflect this in computed FFR would represent a retrograde step in clinical assessment, not an advance.

A further limitation is that, despite impressive diagnostic accuracy, the confidence intervals for these tools remain wide for borderline FFR cases. In addition, all these methods rely upon good quality angiography, in which clear, unobstructed, high contrast images with minimal overlap, panning or excessive magnification (cutting off proximal or distal vessel) are recorded. Furthermore, some need an ECG signal to identify diastole. An invasive pressure wire examination on the other hand, requires less angiographic precision. Also, the segmentation step when the downloaded angiographic images are reconstructed into a 3D in silico anatomical model, requires considerable practice, time and skill, because manual corrections are often required.40 In terms of validation, all methods have been compared only with a dichotomised application of invasive FFR, with its inherent shortcomings when considering there is a continuum of risk associated with reduced coronary flow and there is a lack of prospective outcome studies (Table 1). Furthermore, studies include mostly stable angina and intermediate lesions within 30–90% (Table 3), excluding chronic total occlusion, proximal left main and right coronary artery and side branch stenosis.31,33 A number of studies have included patients with previous MI or revascularisation and others have included acute coronary syndromes.13,26,27,37 Work is under way to investigate the role of QFR in assessing non-culprit lesions in ST-elevation MI (STEMI) patients (Non Culprit Functional Evaluation With 3D Angio QFR in STEMI PCI Procedure [NCT02998853]), which has assumed increased importance since the recently reported Complete Versus Culprit-Only Revascularization Strategies to Treat Multivessel Disease After Early PCI for STEMI (COMPLETE) trial.41 Some of these techniques have been validated using higher than standard temporal resolution (15–30 frames/s), thus increasing the

INTERVENTIONAL CARDIOLOGY REVIEW

Figure 4: Scatter Plot Showing Relationship Between Angiographic Stenosis Grade and Fractional Flow Reserve Readings for All Measurements.2

1.0 0.8 FFR

particular study. For the same virtual physiology model, diagnostic accuracy will appear high in studies with comparatively fewer patients around the 0.80 threshold, but far worse if the opposite is true. A better statistical test to characterise the accuracy of the model is a Bland Altman plot with ±95% limits of agreement (± 1.96 SD). From this perspective all methods are comparable with mean differences between -0.01 and +0.05 and SD between ± 0.03 and ± 0.08 (Table 2).

0.6 0.4 0.2

0–30%

31–50%

51–70%

>70%

Stenosis classification on angiography FFR = fractional flow reserve. Source: Curzen et al. 2014.2 Reproduced with permission from Wolters Kluwer Health.

Table 2: Quantitative Diagnostic Accuracy Parameter Study vFFR

Mean difference AUC (± 1.96 SD)

VIRTU 1 201322 VIRTU-FAST 2017

0.02 (SD 0.08) 23

NA NA

Gosling et al. 201924 (post-PCI cases)

0.01 (SD 0.03)

NA

vFAI (cut off 0.82)

Papafaklis et al. 201426

−0.00 (SD 0.08)

0.92; 95% CI [0.86–0.96]

Vessel FFR

FAST 201928

0.01 (SD 0.03)

0.93; 95% CI [0.88–0.97]

FFR-QCA

Tu et al. 201429

0.00 (SD 0.06)

0.93; 95% CI [0.86–0.99]

cQFR

Tu et al. 201429

0.00 (SD 0.05)

0.92; 95% CI [0.84-0.97]

QFR

FAVOR pilot 201630

−0.01 (SD 0.06)

0.96; 95% CI [0.94–0.98]

WIFI-II 201833

0.01 (SD 0.08)

0.86; 95% CI [0.81–0.91]

FAVOR II E/J 201832

−0.01 (SD 0.06)

0.92; 95% CI [0.89–0.96]

FFRangio (Siemens)

Tröbs et al. 201634

0.05 (SD 0.04)

0.93; 95% CI [NA]

FFRangio (CathWorks)

Pellicano et al. 201735

0.00 (SD 0.05)

0.97; 95% CI [NA]

Kornowski et al. 201836 NA

0.95; 95% CI [NA]

FAST-FFR 201937

0.94; 95% CI [0.91–0.97]

NA

AUC = area under the curve; FFR = fractional flow reserve; NA = not available; PCI = percutaneous coronary interventions; QCA = quantitative coronary analysis; QFR = quantitative flow ratio; vFAI = virtual functional assessment index; vFFR = virtual FFR.

radiation exposure for patients and operators.29,34,35 Not all angiograms are suitable for computational analysis because this requires optimal coronary opacification, a lack of overlapping vessels and excellent views of the lesion in at least two projections. It is estimated that up to one-third of standard angiograms may be unsuitable, although operators may improve their technique to meet modelling demands in selected patients.33

Coronary Table 3: Clinical and Angiographic Inclusion Criteria Per Virtual Physiology Method and Study.

Parameter

Study

Clinical Presentation

Virtual FFR

VIRTU 1 201322 VIRTU Fast 2017

vFAI

23

Previous MI

Previous stenting

Previous Visual stenosis CABG diameter (DS%)

Stable CAD Unstable ACS

NSTEMI STEMI

+

−

−

−

−

+

−

NA

+

−

−

−

+

NA

−

All except CTO

Gosling et al. 201924

+

−

−

−

NA

+

−

30–90%

Papafaklis et al. 201426

+

+

+

−

+

+

+

30–70%

28

+

+

+

−

NA

−

−

30–70%

+

−

−

−

NA

−

−

40–70%

Vessel FFR

FAST 2019

FFR-QCA

Tu et al. 201429 FAVOR 2016

30

+

−

−

−

+

+

+

30–80%

FAVOR II China 201731

+

+

−

−

+

+

+

30–90%

WIFI-II 201833

+

−

−

−

NA

NA

NA

30–90%

FAVOR II Europe-Japan 201832

+

−

−

−

NA

+

+

FFRangio (Siemens)

Tröbs et al. 201634

+

−

−

−

+

+

+

50–90%

FFRangio (CathWorks)

Pellicano et al. 201735

+

−

−

−

+

+

−

50–90%

Kornowski et al. 201836

+

+

+

−

NA

NA

NA

NA

+

+

+

−

+

+ (>12 months)

−

NA

QFR

FAST-FFR

37

ACS = acute coronary syndrome; CABG = coronary artery bypass graft; CAD = coronary artery disease; CTO = chronic total occlusion; FFR = fractional flow reserve; NA = not applicable; NSTEMI = non-ST-elevation MI; QCA = quantitative coronary analysis; QFR = quantitative flow ratio; STEMI = ST-elevation MI; vFAI = virtual functional assessment index.

Regulatory Approval vFFR (CAAS workstation) was the first method to translate into practice after receiving US Food and Drug Administration (FDA) market clearance in March 2018 followed by CE mark in Europe. FFRangio was granted FDA market clearance in December 2018. It has a CE mark in Europe and Medical Devices and Accessories (AMAR) approval in Israel and Pharmaceuticals and Medical Devices Agency (PMDA) approval in Japan. QAngio XA 3D/QFR was CE marked in Europe as a class IIa device in 2017. It was reviewed by NICE in the Medtech innovation briefing, in which the specialist panel saw this technology as “potentially replacing FFR and iFR… could also reduce other functional tests… and FFRCT”.42 Formal guidance is expected at the end of 2020.43 In May 2019, the FDA granted QAngio XA 3D/QFR market clearance.

Conclusion Significant steps have been made in developing angiography-derived coronary physiology tools which compare favourably to the gold standard

1.

2.

3.

4.

5.

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Pijls NHJ, van Schaardenburgh P, Manoharan G, et al.

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invasive FFR. Three methods are already available on the market and others have shown encouraging prospects. Although there are still methodological challenges to be negotiated, all techniques allow the assessment of the functional significance of stenoses in all epicardial coronary vessels without any additional risk. Furthermore, they offer the possibility of virtual pull-back at multiple levels in the coronary tree, thus providing a more comprehensive assessment at lesion-specific, as well as vessel-specific level. This could represent the dawn of a new era in which the gold standard invasive FFR is replaced by computed algorithms that simulate physiology comprehensively throughout the epicardial coronary tree in real time in the catheterisation laboratory. Such an approach could prove particularly useful for non-PCI centres that undertake diagnostic angiography. Furthermore, some systems may allow real-time stenting procedure planning facilitating bespoke treatment algorithms for patients. However, more clinical data, including randomised trials, demonstrating prognostic clinical benefit are required before any of these methods make their way into routine practice.

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Leone AM, Campo G, Gallo F, et al. Adenosine-free indexes vs. fractional flow reserve for functional assessment of coronary stenoses: systematic review and meta-analysis. Int J Cardiol 299:93–9. https://doi.org/10.1016/j.ijcard.2019.07.035; PMID: 31378379. van’t Veer M, Pijls NHJ, Hennigan B, et al. Comparison of different diastolic resting indexes to iFR: are they all equal?

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Structural

Emerging Role of Large-bore Percutaneous Axillary Vascular Access: A Step-by-step Guide Kathryn Dawson,1 Tara L Jones,2 Kathleen E Kearney1 and James M McCabe1 1. Division of Cardiology, Department of Medicine, University of Washington Heart Institute, Seattle, WA, US; 2. Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, US

Abstract Advances in transcatheter structural heart interventions and temporary mechanical circulatory support have led to increased demand for alternative sites for large-bore vascular access. Percutaneous axillary artery access is an appealing alternative to femoral access in patients with peripheral arterial disease, obesity or for prolonged haemodynamic support where patient mobilisation may be valuable. In particular, axillary access for mechanical circulatory support allows for increased mobility while using the device, facilitating physical therapy and reducing morbidity associated with prolonged bed rest. This article outlines the basic approach to percutaneous axillary vascular access, including patient selection and procedure planning, anatomic axillary artery landmarks, access techniques, sheath removal and management of complications.

Keywords Large-bore access, alternative access, axillary artery access, haemodynamic support, structural heart intervention Disclosure: JM has received research and consulting funding from Abiomed. KK has received consulting funding from Teleflex. All other authors have no conflicts of interest to declare.

Received: 13 September 2019 Accepted: 2 April 2020 Citation: Interventional Cardiology Review 2020;15:e07. DOI: https://doi.org/10.15420/icr.2019.22 Correspondence: James M McCabe, 3rd Floor, 1959 NE Pacific St, Seattle, WA 98195, US. E: jmmccabe@cardiology.washington.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 noncommercial purposes, provided the original work is cited correctly.

Advances in transcatheter structural heart interventions and temporary mechanical circulatory support (MCS) have led to increased demand for alternative sites for large-bore vascular access.1 Percutaneous axillary artery (AA) access is an appealing alternative to standard femoral access when the patient has iliofemoral peripheral arterial disease (PAD), obesity or there is an expected device duration >24–48 hours. In the case of prolonged haemodynamic support, AA access for MCS device insertion allows for increased mobility while the device is in place, facilitating physical therapy and reducing morbidity associated with prolonged bed rest.2 Transaxillary access is now the most common alternative access site for transcatheter aortic valve replacement (TAVR) with balloon-expandable valves, with high rates of procedural success and similar outcomes whether a surgical or a percutaneous approach is taken.1 Historically, upper extremity large-bore arterial access required surgical cutdown to access the subclavian or axillary artery. A fully percutaneous approach has now been demonstrated and offers potential advantages of local anaesthesia and rapid access in an emergency, whereas surgical access typically requires a multidisciplinary approach potentially including anaesthesia, interventional cardiology and the cardiothoracic surgery team.1,3,4 A percutaneous approach targets the distal first or proximal second segment of the axillary artery, where it is compressible against the second rib. The selection of a surgical versus percutaneous approach should be determined by operator comfort the level of experience at the setting regarding management before and after the procedure.

Access at: www.ICRjournal.com

Initial concerns regarding the safety of percutaneous AA access have not borne out in clinical practice.4–6 Cadaveric and clinical experiences demonstrate compressibility and when coupled with contemporary vascular closure devices, reliable haemostasis has been demonstrated without surgical cutdown after large-bore AA.7 This article outlines the basics of our approach to large-bore percutaneous subclavian and axillary vascular access, including patient selection and procedure planning, anatomic AA landmarks to guide access, access techniques, sheath removal and the management of complications.

Patient Selection and Pre-procedure Planning Experience with AA access and several patient characteristics must be considered when selecting the site for large-bore access. Patients with significant iliofemoral PAD are the main candidates when an alternative access site is required and a centre is beginning to use the procedure.

CT imaging in multiple TAVR populations has shown that the AA is often relatively spared from atherosclerosis in patients with severe iliofemoral PAD, but even a simple evaluation for pulses, blood pressure discrepancies and duplex ultrasound can be useful in the initial assessment for possible PAD in the upper extremity.8,9 AA access may also be advantageous in patients with obesity where the depth of the AA may be less challenging than the depth of the femoral artery (FA), depending on habitus. Additional clinical assessment for all patients should include anticoagulation status, the patient’s ability to cooperate during the procedure and other clinical characteristics that may affect

© RADCLIFFE CARDIOLOGY 2020

Step-by-step Percutaneous Axillary Access the ability to access the axillary space, such as musculoskeletal deformities from previous injury, post-surgical changes or a permanent pacemaker/defibrillator. Factors that should be considered in laterality choice include the patient’s dominant hand, presence of a patent internal mammary artery graft and existing pacemaker or defibrillator.

In these circumstances, contralateral AA access is preferred though ipsilateral access is not an absolute contraindication.

After careful clinical assessment, pre-procedural imaging is strongly advised. CT angiography (CTA), ideally with 3D reconstruction, is the preferred modality and should be performed in all patients. This allows for complete assessment of vessel calibre, degree of PAD, vessel tortuosity and angle of entry to the aorta. A vessel diameter of ≥6 mm is recommended to ensure adequate distal perfusion for indwelling devices, although ≥5.5 mm has also been suggested.8 Calcified vessels are more prone to dissection or distal embolisation and can lead to challenges deploying closure devices at the time of explant.10 For this reason, heavy calcification of the AA warrants additional consideration before large-bore access, aided by a detailed ultrasound assessment at the location of calcium within the arterial wall at the target site. The angle of take-off from the aorta and course of the innominate and left subclavian arteries and tortuosity should be considered when choosing laterality as these factors can affect the deliverability of the device (Figure 1). Angulation of the branch vessel to the aorta of <90° requires retroflexion of the device upon entry to the aorta and can pose significant challenges for delivery into the left ventricle. Keep in mind that CTA imaging is often performed with the patient’s arms above their head, which may create the appearance of a hinge point in the second segment of the AA that may be misread as a significant stenosis. Regardless, this location is often distal to the recommended access site.

Figure 1: Angulation of Branch Vessel Entry to Aorta

Angle of <90° requires retroflexion of the device upon entry to the aorta and can pose significant challenges for delivery into the left ventricle.

Figure 2: Anatomic Landmarks of the Upper Extremity

Superior thoracic artery

Image guidance with point-of-care vascular ultrasound and/or direct peripheral angiography is also encouraged during the procedure and may be the only imaging performed in more urgent clinical scenarios.

However, each of these modalities have limitations, which must be understood and a limited pre-procedural evaluation should be reserved for more experienced operators. While point-of-care ultrasound is strongly encouraged to assist with access, the assessment of vessel calibre compared with dedicated vascular ultrasound equipment is suboptimal. Additionally, point-of-care ultrasound does not allow evaluation of the more proximal vessel or aortic arch angles. Direct peripheral angiography provides adequate assessment of the aortic arch angles, though provides only a 2D assessment with limited evaluation of vessel calcification.

Anatomic Landmarks The AA originates as a continuum of the subclavian artery as it crosses beneath the clavicle lateral to the first rib and terminates in the brachial artery as it crosses the inferior border of the teres minor attachment to the humerus (Figure 2). Branches off the AA include the highest thoracic, lateral thoracic, anterior circumflex humeral, posterior circumflex humeral, thoracoacromial and subscapularis arteries which often provide collateral flow distal to the access point for indwelling devices.2 Access is typically obtained in the first segment of the AA to allow for vascular compression against the second rib and to avoid many of the branch vessels, although the skin puncture is performed more distally to allow for a shallow angle of entry.11 Injury to the brachial plexus is also more easily avoided in this region as the nerve bundle travels cephalad to the AA and can be identified on ultrasound.12

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Subclavian artery

Thoracoacromial artery

1

Lateral thoracic artery

2

Posterior circumflex humeral artery

First rib 3

Anterior circumflex humeral artery

Brachial artery

Pectoral branch Clavicular branch Acromial branch Deltoid branch

Subscapular artery Thoracodorsal artery

Circumflex scapular artery

Source: Hapugoda 2019.17 Reproduced with permission from Radiopaedia.

Access Technique There are various iterations of AA access technique.3,6,9,11,13 Here, we review the key steps for successful percutaneous AA access. As discussed above, pre-procedural imaging with CTA or a combination of ultrasound and fluoroscopically guided access are critical aspects for procedural success.

Prior to AA puncture, femoral or ipsilateral radial arterial access is obtained using a standard 5 Fr or 6 Fr catheter in order to perform AA angiography. The FA is generally preferred in our practice, as antegrade

Structural Figure 3: Fluoroscopic Images from Percutaneous Axillary Transcatheter Aortic Valve Replacement

Following peripheral angiography and fluoroscopic AA mapping, the proximal segment of the AA should be identified on ultrasound with respect to the subclavian vein and brachial plexus (Figure 4). This is the preferred segment for percutaneous access due to compressibility and there being fewer adjacent structures. If the vein appears on top of the artery, tilting the ultrasound probe laterally away from the sternum and clavicle will demonstrate that the AA runs cephalad to the vein more laterally at the optimal puncture site. The thoracoacromial branch of the AA may also be seen and therefore avoided when using ultrasound to facilitate access. Once the access segment is identified, use ultrasoundguided micropuncture technique at a shallow angle of entry (about 30°) to access the AA near the lateral border of the second rib on fluoroscopy. Based on our experience, the skin entry point is usually just medial to and at the inferior aspect of the deltopectoral groove.

A shallow angle of entry is of the utmost importance to allow largebore device delivery and avoid kinking of the sheath as it advances under the clavicle. This also minimises protuberance of an indwelling system and tension on the arteriotomy site and leads to less oozing around the device with longer-term use.

Once acceptable access is obtained, the micropuncture should be upsized to a 6 or 8 Fr arteriotomy over a standard 0.035 inch J-tipped wire. This will facilitate placement of one or two 6 Fr Perclose ProGlide devices (Abbott Vascular), depending on anticipated arteriotomy size, which are used to ‘pre-close’ the arteriotomy and facilitate haemostasis at the time of explant. If two Perclose devices are required, we recommend the sutures be deployed at minimal angulation – at 11.30 and 12.30 positions rather than the classic 10 o’clock and 2 o’clock – as a milder degree of angulation is better tolerated in the AA. Once the vessel has been pre-closed, the 6 or 8 Fr sheath can be inserted and a standard diagnostic catheter and a stiff 0.035 inch wire are used to traverse the aorta and aortic valve. Following acceptable positioning of the stiff 0.035 inch wire placement in the desired location, the largebore sheath can be delivered in standard fashion with manual pressure or internal balloon tamponade used for haemostasis between dilators where required.

Removal and Closure

A: 0.018 inch safety wire in the axillary artery; B: AA angiography. Arrow indicates vessel access point.

angiography will provide superior visualisation of the arterial structure.

The FA also allows the ability to upsize the sheath, offering a broader range of bailout strategies when necessary. Following FA or radial artery access, a spring-coil tipped 0.018 inch wire is advanced across the AA to the brachial artery in the case of FA access or into the ascending aorta in the case of radial access. This serves as a fluoroscopic marker of the AA and is used to map the arterial course on the skin using the lung fields and the lateral border of the second rib as fluoroscopic landmarks, noting that the AA typically runs cephalad to the deltopectoral groove (Figure 3). The 0.018 inch wire is also used as a safety wire, allowing for prompt advancement of a balloon should vessel tamponade be necessary.

When AA access is used for procedural indications such as transcatheter structural heart interventions or haemodynamic support during protected percutaneous coronary interventions (PCIs), the sheath can be removed at the end of the case and the Perclose sutures tightened in the usual fashion. When closure is delayed, as in cases of prolonged haemodynamic support, the patient is brought back to the cardiac catheterisation lab and 6 Fr FA access is obtained to facilitate angiography and bailout strategies at the time of explant if possible.

Baseline angiography of the subclavian artery is performed before device removal to evaluate vessel patency, distal flow to the ipsilateral arm and thrombus at the insertion site.9 Depending on the device and sheath in the place from the AA, reestablishing wire access through the arteriotomy may require specific tips beyond the scope of this article.14 Nevertheless, re-establishing wire access for any closure device beyond manual pressure should be considered optimal care. Internal balloon tamponade for a dry field closure is also best practice, particularly when an operator is unfamiliar with the procedure. This can be performed with a peripheral balloon sized 1:1 with the distal subclavian (typically 6–8 mm) and inflated to no more than nominal pressures.

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Step-by-step Percutaneous Axillary Access Figure 4: Ultrasound Imaging of the Axillary Artery in Relation to the Axillary Vein and Brachial Plexus (Arrows)

Figure 5: Fluoroscopic Image of Occlusive Thrombus Within the Axillary Artery after Impella Explant

A

B

especially in the setting of prolonged device implantation. Maintaining the initial insertion angle and a mild degree of cranial-medial tension on the sheath can limit minor bleeding. If needed, the Perclose sutures placed during the initial insertion can be tightened (‘cinched’ around the indwelling device) to achieve haemostasis. More clinically significant bleeding complications include the development of a hematoma, which invariably occurs along the pectoralis or lateral chest wall. The AA, at the point of optimal entry is not intrathoracic and occult thoracic bleeding is not a feature of arteriotomy bleeding from the AA. Branchial plexus complaints are rare and appear more likely to be related to external compression from the development of haematoma rather than the initial access, highlighting the importance of effective haemostasis. Early multicentre data following axillary Impella (Abiomed) implantation reported bleeding and haematoma in 6% of patients which is consistent with findings from other large-bore access registries.7

A: With colour Doppler. B: Without colour Doppler. A = artery; V = vein.

Bleeding from inadequate haemostasis at the time of explant is often visualised by invasive angiography. Balloon tamponade performed via FA or ipsilateral radial access or manual pressure are typically sufficient to achieve adequate haemostasis should the closure devices fail, particularly in conjunction with reversal of any anticoagulation. Covered stents can be deployed but are rarely needed and are associated with unclear long-term durability. As such, covered stents are reserved for severe refractory bleeding.

When feasible, our favoured approach is to ‘pre-close’ the arteriotomy using the Perclose ProGlide device at the time of device implantation.

Using this technique, sutures can be tightened at the time of device removal to facilitate vessel closure. In the absence of a pre-closure, vascular closure devices can be deployed at the time of device removal although it is often more difficult. Suture-mediated closure remains the most common form of haemostasis, however, vascular plugs, or a combination of suture and vascular-plug-mediated closure have been described and can be used at the discretion of the operator.15 The primary advantage of a suture-mediated vascular closure device is maintenance of wire position in the vessel to allow for additional haemostasis options if necessary as well as not necessitating a foot plate within the vessel. Once adequate haemostasis is achieved, final angiography of the subclavian and axillary artery is performed using a standard catheter through the FA sheath to ensure vessel patency, adequate haemostasis and absence of obstructive thrombus.

Laminar thrombus formation around the indwelling device is a more frequent complication in the case of prolonged indwelling devices, though distal flow to the extremity is often preserved via robust collateralisation, and thus this is primarily a radiographic rather than a clinically apparent phenomenon.2 It is our practice that if occlusive thrombus is observed (Figure 5), balloon angioplasty and, occasionally, thrombectomy may be required if the thrombus is displaced distally and becomes occlusive. In the case of non-occlusive thrombus noted on angiography with in-line perfusion to the extremity, the patient can be treated with 48–72 hours of unfractionated heparin with regular neurovascular examinations.

Management of Complications As with any large-bore arterial device, bleeding complications can occur. Mild bleeding around the arteriotomy site is not uncommon,

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It is worth emphasising that two recent studies demonstrated higher stroke rates in patients undergoing TAVR via an AA approach compared

Structural with the high and intermediate risk cohorts in the Placement of AoRTic TraNscathetER Valves (PARTNER) II trial.1,16 It remains unclear if this is due to patient-related factors, including peripheral vascular disease requiring alternative access, or crossing the head and neck vessels, and interestingly it was not associated with mortality.1 Further investigation into the mechanism and risk of stroke with surgical and percutaneous AA approaches, including indwelling devices, is warranted.

Conclusion Percutaneous AA access carries unique advantages of improving mobility in patients with indwelling mechanical support devices and avoiding suboptimal or hostile iliofemoral arteries in the case of PAD. The AA may be limited by size in certain patients and pre-procedural

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McCabe J, Kearney K. Percutaneous axillary artery access best practices. In: Shroff A, Pinto D, eds. Vascular Access, Management and Closure Best Practices. Washington DC, US: Society for Cardiovascular Angiography & Interventions, 2019;92–6.

Kearney K, Atkins BZ, McCabe JM. Chapter 4: Axillary access for impella catheter placement. In: A Practical Handbook for Impella Catheter Use. San Diego, US: Elsevier, 2018;1–17.

Cheney AE, McCabe JM. Alternative percutaneous access for large bore devices. Circulation Cardiovasc Interv 2019;12:3610705. https://doi.org/10.1161/ CIRCINTERVENTIONS.118.007707; PMID: 31167600.

McCabe J, Khaki A, Nicholson W, et al. TCT-99 safety and

imaging is required in some form to assess for adequate size, atherosclerotic burden, and inhospitable angulation with the aortic arch. The rapid growth and evolution of transcatheter structural heart interventions and temporary MCS devices requiring large-bore arterial access continues to drive a need for ‘alternative’ access sites. AA access as described here is a teachable technique and it is a powerful skill to have while striving to provide the best care for patients. While this review provides a basic outline of the necessary steps for success, the importance of operator comfort and experience cannot be overstated. Before initiating a fully percutaneous AA access programme, seeking advice from someone with more experience or attending a dedicated hands-on programme is strongly encouraged to ensure good outcomes with early practice.

efficacy of percutaneous axillary artery access for mechanical circulatory support with the Impella© devices: an initial evaluation from the axillary access registry to monitor safety (ARMS) multicenter registry. J Am Coll Cardiol 2017;70:B43. https://doi.org/10.1016/j.jacc.2017.09.1123.

8. Arnett DM, Lee JC, Harms MA, et al. Caliber and fitness of the axillary artery as a conduit for large-bore cardiovascular procedures. Catheter Cardiovasc Interv 2018;91:150–6. https:// doi.org/10.1002/ccd.27416; PMID: 29130612.

9. Tayal R, Iftikhar H, LeSar B, et al. CT angiography analysis of axillary artery diameter versus common femoral artery diameter: implications for axillary approach for transcatheter aortic valve replacement in patients with hostile aortoiliac segment and advanced lung disease. Int J Vasc Med 2016;3:36107055. https://doi.org/10.1155/2016/3610705; PMID: 27110403.

10. Généreux P, Webb JG, Svensson LG, et al. Vascular complications after transcatheter aortic valve replacement: insights from the PARTNER (Placement of AoRTic TraNscathetER Valve) trial. J Am Coll Cardiol 2012;60(12):1043– 52. https://doi.org/10.1016/j.jacc.2012.07.003; PMID: 22883632.

11. Mathur M, Krishnan SK, Levin D, et al. A step-by-step guide to fully percutaneous transaxillary transcatheter aortic valve replacement. Structural Heart 2017;1:209–15. https://doi.org/ 10.1080/24748706.2017.1370156.

12. Lapegue F, Faruch-Bilfeld M, Demondion X, et al.

Ultrasonography of the brachial plexus, normal appearance and practical applications. Diagn Interv Imag 2014;95:259–75. https://doi.org/10.1016/j.diii.2014.01.020; PMID: 24603038.

13. Schäfer U, Ho Y, Frerker C, et al. Direct percutaneous access technique for transaxillary transcatheter aortic valve implantation: ‘The Hamburg Sankt Georg approach’. JACC Cardiovasc Interv 2012;5:477–86. https://doi.org/10.1016/j. jcin.2011.11.014; PMID: 22625184.

14. Tongers J, Flierl U, Sieweke JT, et al. Safe exchange of a transfemoral Impella pump. Cardiovasc Revasc Med 2018;20:827–8. https://doi.org/10.1016/j.carrev.2018.12.006; PMID: 30651215.

15. Harris E, Warner CJ, Hnath JC, et al. Percutaneous axillary artery access for endovascular interventions. J Vasc Surg 2018;68:555–9. https://doi.org/10.1016/j.jvs.2017.11.066; PMID: 29398309.

16. Gleason TG, Schindler J, Hagberg RC, et al. Subclavian/axillary artery access for self-expanding transcatheter aortic valve replacement renders equivalent outcomes as transfemoral.

Ann Thorac Surg 2018;105:477–83. https://doi.org/10.1016/j. athoracsur.2017.07.017; PMID: 29100645.

17. Hapugoda S. Axillary Artery (Illustrations). 2019. https:// radiopaedia.org/cases/axillary-artery-illustrations?lang=gb (accessed 26 April 2020).

INTERVENTIONAL CARDIOLOGY REVIEW

Coronary

Antegrade Chronic Total Occlusion Strategies: A Technical Focus for 2020 Calum Creaney and Simon J Walsh Department of Cardiology, Belfast Health and Social Care Trust, Belfast, UK

Abstract Chronic total occlusions (CTOs) are common in patients with ischaemic heart disease. In many countries, patients with CTOs are underserved by percutaneous coronary intervention (PCI). One of the barriers to CTO PCI is the technical challenges of these procedures. Improvements in technique and dedicated devices for CTO PCI, combined with advances in procedural strategy, have resulted in a dramatic increase in procedural success and outcomes. Antegrade wiring (AW) is the preferred initial strategy in short CTOs, where the proximal cap and course of the vessel is understood. For many longer, more complex occlusions, AW has a low probability of success. Dissection and re-entry techniques allow longer CTOs and those with ambiguous anatomy to be crossed safely and efficiently, and CTO operators must also be familiar with these strategies. The CrossBoss and Stingray system is currently the primary targeted re-entry device used during antegrade dissection and re-entry (ADR), and there continues to be an evolution in its use to increase procedural efficiency. In contrast to older ADR techniques, targeted re-entry allows preservation of important side-branches, and there is no difference in outcomes compared to intraplaque stenting.

Keywords Chronic total occlusion, antegrade wiring, antegrade dissection and re-entry, intracoronary imaging Disclosure: SJW is a consultant to Abbott, Boston, Medtronic and Teleflex. CC has no conflicts to declare.

Received: 25 February 2020 Accepted: 24 April 2020 Citation: Interventional Cardiology Review 2020;15:e08. DOI: https://doi.org/10.15420/icr.2020.05 Correspondence: Calum Creaney, Department of Cardiology, Belfast Health and Social Care Trust, Belfast, UK. E: calum.creaney@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 noncommercial purposes, provided the original work is cited correctly.

There has been rapid development in the techniques used for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) over the past decade, with success rates in experienced centres now exceeding 90%.1 This is in part due to advances in devices and techniques for CTO crossing, but also an improved understanding of strategy. The development of the ‘hybrid algorithm’ has improved success rates, safety and efficiency of these procedures across many countries (Figure 1).1–5

The Proximal Cap

Registries consistently show that antegrade wiring (AW) is the most common strategy for crossing CTOs, particularly those of lower complexity.1,5 However, it is important to understand that to safely achieve a high success rate in CTO PCI, expertise in dissection and reentry techniques (DART) and retrograde approaches are also required.

This review will provide a contemporary update on antegrade techniques for CTO PCI.

The shape of the cap is important: a tapered proximal cap may offer lower resistance to wire passage, and AW is more likely to be successful than in a CTO with a blunt proximal cap.7 The presence of a side-branch at a blunt proximal cap is common in long-duration CTOs. This may cause guidewires to deflect into the side-branch, making AW more challenging.

Angiographic Assessment and Strategy Selection A detailed understanding of the coronary anatomy is fundamental to successful CTO procedures. Some of the necessary information can be gained from a pre-procedure diagnostic angiogram, but dual catheter angiography is essential (with the exception of ipsilateral collaterals or bridging) to provide information about collateral filling, lesion length and vessel course. When acquiring dual catheter images, a wide field of view should be used, the camera should not pan and the run should be long enough to allow accurate assessment of collateral channels.

When interpreting the angiogram, there are a number of features that require assessment, and in turn help to guide procedural strategy.

© RADCLIFFE CARDIOLOGY 2020

If the proximal cap is ambiguous (i.e. its location or the course of the vessel after the occlusion is uncertain), this is a point of jeopardy during the case. Adjunctive imaging with intravascular ultrasound (IVUS) should be considered to resolve anatomical ambiguity (Figure 2).

Coronary CT can also provide information on location and morphology of the proximal cap, as well as lesion length, calcification and tortuosity.6

The Chronic Total Occlusion Body Lesion length progressively increasing >20 mm makes intimal wire passage less likely and increases procedure duration.8 This will lead many operators to DART procedures primarily. A heavy burden of calcification and vessel tortuosity are additional features that confer complexity and make it more likely that DART may be required.1,5

The Distal Cap and Landing Zone The vessel beyond the distal cap and before the origin of a major sidebranch is known as the distal landing zone (LZ), referring to the area for potential re-entry during antegrade dissection and re-entry (ADR).

If the distal cap is at or near a bifurcation of a significant side-branch, the chance of dissection extending across the branch and causing

Access at: www.ICRjournal.com

Coronary Figure 1: The Hybrid Chronic Total Occlusion Algorithm

Dual injection

1. Ambiguous proximal cap 2. Poor distal target 3. Good interventional collaterals 4. Major side-branch at distal cap

NO

<20 mm

Antegrade wire escalation

YES

Antegrade

Cross NO

>20mm

Antegrade dissection re-entry

Cross YES

>20 mm

Cross NO

Cross YES

Cross NO

Retrograde dissection re-entry

Cross YES

Retrograde

<20mm

Cross NO

Retrograde wire escalation

Cross YES

Source: Vascular Perspectives. Reproduced with permission from Vascular Perspectives.

Figure 2: Use of Intravascular Ultrasound to Resolve Proximal Cap Ambiguity

Operators should be mindful that retrograde procedures are associated with increased complications from the procedure (although selection bias may contribute to this observation) and the risk associated with perforation is highest when using epicardial collateral channels.3,10

IVUS catheter

Procedural Setup CTO

Proximal cap External elastic lamina at bifurcation Open side-branch A side-branch at the proximal cap can be used to deliver an IVUS catheter which can reveal the location of the proximal cap. CTO = chronic total occlusion; IVUS = intravascular ultrasound. Source: Vascular Perspectives. Reproduced with permission from Vascular Perspectives.

occlusion is increased, making ADR a less favourable strategy.

Similarly, inadvertent extraplaque wire passage at the distal cap during AW can have the same effect. If there is a heavily diseased LZ in close proximity to a major bifurcation, a primary retrograde strategy is indicated, provided this can be achieved safely.

Collateral Supply Collateral vessels supplying the distal vessel facilitate visualisation of the distal target during antegrade procedures, and also open the possibility of a retrograde approach. The source of the collateral should first be identified, and then the course of the collateral considered (epicardial or septal). The diameter of the collateral, tortuosity and angle of entry and exit from vessels are other important features in determining whether the collaterals are suitable for use as a retrograde conduit.9 When visualisation of a collateral channel is challenging, selective imaging using a microcatheter may be considered.

With advances in equipment and technique, most CTO procedures can now be carried out through 7 French guide catheters. There has recently been a move towards bilateral radial access. The use of appropriately sized catheters, which provide a high degree of passive support, (typically Voda Left, XB or Extra Back-Up curves for the left coronary, and Amplatz Left or 3D curves for the right coronary) has little downside, while having the advantage of avoiding the morbidity and mortality of vascular complications from femoral access.11 In the Registry of CrossBoss and Hybrid procedures in France, the Netherlands, Belgium and United Kingdom (RECHARGE), 24% of cases were performed using only radial access. This had no impact on procedural success compared with transfemoral access, irrespective of lesion complexity.12 After engagement of the donor guide, we recommend that a workhorse wire should routinely be placed in the donor vessel. This maintains the catheter position, allows easy engagement and disengagement and importantly also expedites treatment of any donor vessel injury (which can cause rapid deterioration in the context of a contralateral CTO).

Antegrade Wiring AW is a technique where a guidewire penetrates the proximal cap of the CTO and aims to remain intraplaque before entering the distal true lumen. In reality, the wire often passes in and out of the vessel extraplaque during AW, often unrecognised angiographically.13â&#x20AC;&#x201C;15 AW is most likely to be successful where there is a clear, tapered proximal cap and the occlusion is short (<20 mm). Where these conditions are not met, a primary AW strategy may still be appropriate, but operators should understand that the probability of successfully completing the

INTERVENTIONAL CARDIOLOGY REVIEW

Antegrade CTO Strategies procedure is lower and should remain flexible to changing to an alternative strategy if progress is not being made.

Table 1: Commonly Used Guidewires for Chronic Total Occlusion Percutaneous Coronary Intervention

Initial Wire Selection

Wire Properties

Examples

Low-gram weight, tapered tip, polymer jacket

Fighter (Boston Scientific) Palpate proximal cap, loose Fielder XT, Fielder XTA, tissue tracking within CTO Fielder XTR (Asahi Intecc) body. Knuckle wire

Medium-gram weight, polymer jacket

Pilot 200 (Abbott) Gladius (Asahi Intecc) Crosswire NT (Terumo) Raider (Teleflex)

Palpate proximal cap, tracking within more resistant CTOs. Knuckle wire. Less likely to exit in tortuosity and ambiguity

Medium-gram weight, no polymer jacket

Gaia 2, Gaia 3, Gaia Next (Asahi Intecc) Judo 3, Judo 6 (Boston Scientific)

Crossing CTO body in more mature resistant lesions.

Tactile feedback and torque transmission help in understood anatomy

High-gram weight, tapered, no polymer jacket

Confianza Pro12, Astato Penetration wires for 8/20 & 8/40 (Asahi Intecc) focused crossing of highly Pro Via 15 (Medtronic) resistant segments Progress 200T (Abbott) Hornet 14 (Boston Scientific)

Dedicated knuckle wire

Gladius MG (Asahi Intecc) Crossing long segments efficiently using blunt dissection, with a low risk of perforation

AW has traditionally been described as an escalation of wire tip load until the lesion is crossed. While this is effective for crossing some CTOs, it is more efficient to select wires based on their suitability for a particular task within the procedure. It should also be noted that any wire should be used in combination with a microcatheter. Various microcatheters are available, although a comprehensive overview of their properties and application is beyond the scope of this article.

A knowledge of guidewires, their individual properties and the tasks they are used for is therefore fundamental to AW success. A detailed description of each wire is outside the scope of this review, but it is helpful to group CTO lesion crossing wires into categories based on their properties and functions. Some newer guidewires are outlined in Table 1.

With this understanding, the choice of initial wire for AW should be dictated by the anatomy of the CTO, in particular the proximal cap. If the cap is tapered, a low- or medium-tip load wire with a polymer jacket is a good choice, as the cap is likely to be of relatively low resistance and these wires can track loose tissue within the CTO body with a relatively low risk of exiting the vessel.

Factors that should prompt consideration of a penetration wire are: • Blunt proximal cap – in longer-duration CTOs, the proximal cap tends to be blunt due to prolonged exposed to systemic arterial pressure, causing formation of dense fibrous tissue.

• Heavy calcification at the proximal cap.

• Presence of a side-branch or bridging collaterals at the proximal cap that often cause softer, jacketed wires to prolapse or deflect away from the cap.

A penetration wire (i.e. a Confianza Pro 12; Asahi Intecc) is well suited to crossing a short occlusion, with a blunt cap and with little tortuosity in the CTO body. It is important to understand that penetration wires can easily exit the vessel architecture, and are therefore not suitable for crossing long CTO segments, especially where the course of the vessel is ambiguous or there is established within-CTO tortuosity.

Crossing the Chronic Total Occlusion Body Once a penetration wire has crossed the proximal cap, it is safest to advance the microcatheter into the CTO and exchange for a less penetrative wire, unless the CTO segment is very short and straight.

This principle of exchanging wires based on CTO resistance is known as ‘escalation/de-escalation’, and the overriding principle is of safety, provided that progress is being made.

Before advancing a microcatheter (or other equipment) over a wire, the position of the wire must be confirmed. Medium- and high-gram weight wires, especially those without polymer jackets, can exit the vessel architecture. Wire exit on its own is usually of little clinical consequence; however, advancement of secondary equipment beyond the adventitia will usually lead to significant perforation.

Wire position can be confirmed by taking a number of orthogonal views to check the wire is within the vessel architecture in all projections, and

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Collateral crossing wires Sion, Sion Black, Suoh03 for retrograde (Asahi Intecc) procedures Samurai RC (Boston Scientific)

Function

Low tip load, highly torquable and flexible shafts to adapt to channel shapes

Guidewires are classified by their properties, which determine the function of the wire within a CTO procedure. CTO = chronic total occlusion.

is seen to be ‘dancing’ in synchrony with the vessel. A retrograde contrast injection from the donor guide can also be helpful. Antegrade injections are less likely to provide additional information and may hinder attempts at DART if there has been extraplaque wire passage.

Once the wire position has been confirmed in the distal true lumen, the microcatheter should be advanced beyond the distal cap and the wire exchanged for a workhorse wire, which can then be used for the remainder of the procedure.

There are a number of other wires that have specific functions within CTO procedures. When starting a knuckle to facilitate dissection, a softor medium-tip load polymer jacketed wire is usually used, although dedicated knuckle wires are now coming into routine use (Table 1).

Antegrade Dissection and Re-entry ADR is a technique where the guidewire and/or equipment intentionally pass into a dissection plane before re-entering the distal vessel lumen at or beyond the distal cap. The technique has two main indications, first as a primary strategy for crossing long or complex CTOs, and secondly as a bailout following inadvertent extraplaque wire passage during AW that cannot be resolved.

Wire-based Re-entry Techniques Many AW procedures (~10%) may represent a form of inadvertent ADR, although the wire typically regains the true lumen close to the distal cap.13

Coronary Figure 3: Stingray LP Balloon

A A

0.014" (0.36 mm) hydrophiliccoated Stingray guidewire 0.014" (0.36 mm) hydrophiliccoated Stingray guidewire

0.014" (0.36 mm) and 0.018" (0.46 mm) Guidewire compatible 0.014" (0.36 mm) and 0.018" (0.46 mm) Guidewire compatible

6 Fr (2.0 mm) Guide catheter 6compatible Fr (2.0 mm) Guide catheter compatible

180° opposed and offset exit ports for selective guidewire re-entry 180° opposed and offset exit ports for selective guidewire re-entry

B B Low resistance in SIS Low resistance in SIS

Co-axial force is redirected by the perpendicular access This facilitates successful re-entry port of the Stingray balloon Co-axial force is redirected by the perpendicular access This facilitates successful re-entry A. Stingray LP balloon. B. Stingray LP balloon positioned at distal cap allowing targeted re-entry to distal lumen. SIS = Subintimal space. port of the Stingray balloon Source: Vascular Perspectives. Reproduced with permission from Vascular Perspectives.

Subintimal tracking and re-entry (STAR) was the first dedicated ADR technique to be described.16 This involves passage of a looped or ‘knuckled’ guidewire into a dissection plane and advancing it until it enters the distal lumen, often at the site of a bifurcation, risking loss of branches. The mini-STAR technique is when an attempt is made to wire the occlusion as far as possible before entering a dissection plane,17 thereby theoretically minimising the length of extraplaque wire passage. Mini-STAR does not overcome the fundamental downside of STAR: that re-entry cannot be controlled.

The medium- and long-term outcomes from these techniques are poor,18–20 and at present, they are only used in two circumstances: when a guidewire inadvertently re-enters the lumen close to the distal cap during ADR or as a bailout manoeuvre as part of an investment or CTO body modification procedure that aims to facilitate a later second attempt.1 Limited antegrade subintimal tracking and re-entry uses targeted reentry by advancing a microcatheter within a dissection plane and attempting wire-based re-entry beyond the distal cap.21 The subintimal wire is exchanged for a penetration wire with a large primary bend, and this is directed towards the true lumen to re-enter. This technique is also not reproducible and has largely been abandoned since the development of dedicated re-entry equipment for ADR. Another non-targeted technique for ADR has recently been reported.22 Antegrade fenestration and re-entry (AFR) causes disruption within the vessel extraplaque by inflation of a 1:1-sized balloon through the

CTO segment. This aims to create tears within the vessel media, thus allowing a soft polymer wire to cross fenestrations and reach the distal true lumen. The experience of this technique is largely confined to a single centre with six successful cases reported so far. Given the established role of ballooning the subintimal space for investment and a lack of reliable ability to re-enter the distal true lumen in a long experience of these procedures,1 extensive data about the reproducibility of AFR and longer-term outcomes will be required.

Most likely, STAR and AFR will be reserved for bailout manoeuvres when targeted re-entry cannot be facilitated by targeted ADR or retrograde procedures.

Device-based Re-entry Techniques The CrossBoss and Stingray system (Boston Scientific) continues to form the mainstay of targeted re-entry devices. The CrossBoss is a blunt tipped dissection catheter that will track through intimal plaque or create a controlled extraplaque dissection that facilitates delivery of the Stingray LP balloon beyond the distal cap (Figure 3).

The ReCross device (IMDS) is an over-the-wire, modified dual-lumen microcatheter. It has two exit ports close to the distal end of the device, oriented at 180o from each other, thereby providing some degree of control in guidewire redirection (Figure 4). At present, experience with the device is limited, with no published case series.

A primary ADR procedure is typically applied to cross long and/or ambiguous CTOs where the proximal cap is well defined and there is

INTERVENTIONAL CARDIOLOGY REVIEW

Antegrade CTO Strategies an LZ proximal to important side-branches. 23 After crossing the proximal cap, a balloon in the vessel extraplaque is used to introduce a guide catheter extension as a standard step. The Trapliner (Teleflex) allows the most efficient exchange of equipment for ADR, while also preventing haematoma formation. A knuckle wire and microcatheter can then be advanced across the CTO segment. When approaching the LZ, many operators will use the CrossBoss to create a smaller dissection plane for the last 20–30 mm to minimise haematoma formation. The Stingray LP balloon is then delivered, inflated and the correct orientation for re-entry found on fluoroscopy. Wire choice for re-entry has evolved since the introduction of the device; the Stingray wire has a small microbarb at the tip. This is helpful for reentry when the balloon is close to a healthy distal LZ. However, in the presence of a large burden of atheroma between the balloon and lumen, it may be less effective. In this circumstance, many operators prefer a tapered penetration wire (i.e. Confienza Pro 12 or Astato 8/20 [Asahi Intecc] or Hornet 14 [Boston Scientific]). After re-entry to the distal true lumen and removal of the Stingray LP, the penetration wire is exchanged for a workhorse wire via a microcatheter to safely complete the procedure.

When the wire inadvertently passes into a dissection plane and beyond the distal cap during AW, we advocate an early switch in strategy to bailout ADR, if the anatomy is suitable. In this setting, the CrossBoss is often not required. The antegrade microcatheter can be advanced to the LZ and a MIRACLEbros 12 wire (Asahi Intecc) used to deliver the Stingray LP balloon or ReCross for re-entry. By minimising the steps in the procedure, this increases procedural efficiency without compromising safety.

Figure 4: ReCross Device Radiopaque atraumatic tip

Exit marker at 95 cm and 105 cm

Hub stylet lumen

Removable stylet

Exit port stylet lumen

1 Exit port tip lumen Hydrophilic coating

Reinforced shaft Usable length: 140 cm

Distal tip exit port

Stylet lumen exit port

Hub tip lumen

2

3

1. The ReCross dual-lumen over-the-wire microcatheter. 2. ReCross device with wires exiting from distal tip exit port and stylet exit port. 3. ReCross device in vessel extraplaque with wire directed from proximal exit port into distal true lumen. Source: Interventional Medical Device Solutions. Reproduced with permission from Interventional Medical Device Solutions.

Figure 5: Balloon-assisted Subintimal Entry 1

2 BASE technique

Troubleshooting During Antegrade Dissection and Re-entry

“BASE + power knuckle”

Troubleshooting CTO lesions is an important skillset. In the following section, we describe some common challenges during ADR and how these can be resolved.

+

Impenetrable Proximal Cap With impenetrable proximal caps or unresolvable anatomical ambiguity, one solution is the use of balloon-assisted subintimal entry (BASE) and a parallel anchor (power knuckle; Figure 5).24 A balloon, sized 1:1 with the vessel, is inflated proximal to the CTO to create intimal disruption. A microcatheter is then positioned alongside and the balloon inflated to trap the microcatheter. This increases support and allows passage of the knuckle wire into a dissection plane.

When a side-branch is present at the proximal cap, a modification of this technique (side-BASE) can be used.25 A blocking balloon is positioned in the side-branch causing deflection of the knuckle wire into a dissection plane (Figure 5).

Equipment Enters a Side-branch When advancing a knuckle or CrossBoss, it is important to confirm it is moving in synchrony and in plane with the main vessel architecture.

If this is not the case, the most likely explanation is passage into a side-branch. This can be resolved by retracting the equipment and redirecting a wire past the side-branch before advancing the CrossBoss or microcatheter over the wire until it is beyond the sidebranch. At this point, blunt dissection can be resumed. If this is not successful, a dual-lumen catheter or a blocking balloon placed in the side-branch can aid redirection.

INTERVENTIONAL CARDIOLOGY REVIEW

3

S-BASE technique

1. BASE. A balloon inflated proximal to the CTO creates intimal disruption and allows subintimal passage of a wire; 2. The use of a parallel anchor (power knuckle) to facilitate BASE; 3.

Side-BASE. A blocking balloon is used to facilitate subintimal entry when there is a side-branch at the proximal cap. BASE = balloon-assisted subintimal entry; CTO = chronic total occlusion.

Source: Vascular Perspectives. Reproduced with permission from Vascular Perspectives.

Haematoma at the Landing Zone Extraplaque haematoma at the LZ is a common failure mode of ADR. The use of a guide catheter extension within the proximal CTO to prevent inflow, avoiding extensive dissection beyond the distal cap with knuckled wires, and/or using the CrossBoss close to the LZ, all help reduce haematoma formation. Additionally, we recommend routinely aspirating from the end hole of the Stingray balloon prior to attempting the puncture.

Coronary The subintimal transcatheter withdrawal technique can also be used to reconstitute the LZ when there is reduced filling due to haematoma. 26 With the Stingray balloon in place, a second wire is advanced into the vessel extraplaque, and an over-the-wire 1:1-sized balloon is delivered and inflated, blocking any inflow to the vessel. A syringe is then used to aspirate haematoma via the tip of the over-the-wire balloon, and puncture re-attempted after the distal vessel reconstitutes.

The Role of Intracoronary Imaging There is now clear evidence that the routine use of intravascular imaging significantly reduces target vessel failure in non-occlusive disease.27,28 IVUS is preferred over optical coherence tomography for CTO PCI, as it avoids the need for high-pressure contrast injection, which can create and propagate dissection. Many operators will be familiar with the use of IVUS for stent sizing, identifying stent LZ and assessing stent apposition and expansion, and this is invaluable in optimising results in CTO PCI. We advocate the liberal use of IVUS during CTO PCI, stent deployment and optimisation to maximise procedural durability.

In addition, IVUS can determine the course of the wire through different vascular compartments. It is important to know where the wire is in the false lumen and how this relates to side-branches that need to be preserved. This is particularly important in ADR when the site of reentry is close to a major bifurcation. If a wire has crossed a side-branch in a dissection plane, stenting will result in loss of that branch, and potentially procedural MI.

Complications and Outcomes Following ADR Contemporary registries show low complication rates from CTO PCI.1,3,29 When comparing complications between different strategies,

1.

Wilson WM, Walsh SJ, Yan AT, et al. Hybrid approach improves success of chronic total occlusion angioplasty. Heart 2016;102:1486–93. https://doi.org/10.1136/ heartjnl-2015-308891; PMID: 27164918.

2. Brilakis ES, Grantham JA, Rinfret S, et al. A percutaneous treatment algorithm for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2012;5:367–79. https://doi. org/10.1016/j.jcin.2012.02.006; PMID: 22516392.

3. Tajti P, Karmpaliotis D, Alaswad K, et al. The hybrid approach to chronic total occlusion percutaneous coronary intervention: update from the PROGRESS CTO Registry. JACC Cardiovasc Interv 2018;11:1325–35. https://doi.org/10.1016/j.jcin.2018.02.036; PMID: 29706508.

4. Pershad A, Eddin M, Girotra S, et al. Validation and incremental value of the hybrid algorithm for CTO PCI. Catheter Cardiovasc Interv 2014;84:654–9. https://doi.org/10.1002/ccd.25370; PMID: 24403122.

5. Maeremans J, Walsh S, Knaapen P, et al. The hybrid algorithm for treating chronic total occlusions in Europe: the RECHARGE Registry. J Am Coll Cardiol 2016;68:1958–70. https://doi. org/10.1016/j.jacc.2016.08.034; PMID: 27788851.

6. Opolski MP, Achenbach S. CT angiography for revascularization of CTO: crossing the borders of diagnosis and treatment. JACC Cardiovasc Imaging 2015;8:846–58. https://doi.org/10.1016/j. jcmg.2015.05.001; PMID: 26183556.

7. Dong S, Smorgick Y, Nahir M, et al. Predictors for successful angioplasty of chronic totally occluded coronary arteries.

J Interv Cardiol 2005;18:1–7. https://doi.org/10.1111/ j.1540-8183.2005.00390.x; PMID: 15788046.

8. Morino Y, Abe M, Morimoto T, et al. Predicting successful guidewire crossing through chronic total occlusion of native coronary lesions within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan) score as a difficulty grading and time assessment tool. JACC Cardiovasc Interv 2011;4:213–21. https:// doi.org/10.1016/j.jcin.2010.09.024; PMID: 21349461.

9. McEntegart MB, Badar AA, Ahmad FA, et al. The collateral circulation of coronary chronic total occlusions.

EuroIntervention 2016;11:e1596–603. https://doi.org/10.4244/ EIJV11I14A310; PMID: 27056120.

10. 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,

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17.

18.

there is a higher rate of perforation and major adverse cardiovascular events (MACE) in patients treated with DART, and especially retrograde procedures, compared to AW.3,29,30 This reflects the increased complexity of CTOs that require the application of DART, including longer lesions, higher Japanese CTO scores and an increased proportion of post-coronary artery bypass graft cases.

The higher rate of target vessel failure with STAR has led to some concern that stenting extraplaque in the vessel leads to poorer outcomes than intraplaque stenting.18,19 Modern ADR using targeted re-entry, with a focus on preserving all important side-branches, is a different procedure. There is no evidence to suggest that this has any adverse long-term clinical consequences.13,29–31 Vessel healing and stent coverage appears to be unaffected by extraplaque stenting on optical coherence tomography follow-up in the largest series reported to date.13 It is unsurprising that more complex lesions that require DART and longer stent lengths are associated with an increase in both target vessel revascularisation and MACE.13 This is true of every PCI, and is due to the disease burden and stent length more so than the technique that is applied during the case.

Conclusion Advances in equipment and technique have undoubtedly led to improvements in the field of CTO PCI, and operators must familiarise themselves with these to achieve good outcomes for patients. It is equally important to understand when to use each of these within a case, as developments in procedural strategy have had the biggest impact in improving outcomes from CTO PCI. AW remains the predominant strategy for crossing short CTOs of lower complexity.

However, many CTOs can only be opened with a dissection-based strategy, and ADR offers a safe and efficient means to achieve this when used in appropriately selected cases.

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.

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.

Bakker EJ, Maeremans J, Zivelonghi C, et al. Fully transradial versus transfemoral approach for percutaneous intervention of coronary chronic total occlusions applying the hybrid algorithm: insights from RECHARGE Registry. Circ Cardiovasc Interv 2017;10:e005255. https://doi.org/10.1093/eurheartj/ ehx504.P4219; PMID: 28851720.

Walsh SJ, Hanratty CG, McEntegart M, et al. Intravascular healing is not affected by approaches in contemporary CTO PCI: the CONSISTENT CTO study. JACC Cardiovasc Interv 2020;13:1448–57. https://doi.org/10.1016/j.jcin.2020.03.032; PMID: 32553333.

Song L, Maehara A, Finn MT, et al. Intravascular ultrasound analysis of intraplaque versus subintimal tracking in percutaneous intervention for coronary chronic total occlusions and association with procedural outcomes. JACC Cardiovasc Interv 2017;10:1011–21. https://doi.org/10.1016/j. jcin.2017.02.043; PMID: 28521919.

Muhammad KI, Lombardi WL, Christofferson R, Whitlow PL. Sub-intimal guidewire tracking during successful percutaneous therapy for chronic coronary total occlusions: insights from an intravascular ultrasound analysis. Catheter Cardiovasc Interv 2012;79:43–8. https://doi.org/10.1002/ccd.23139; PMID: 21542105.

Colombo A, Mikhail GW, Michev I, et al. Treating chronic total occlusions using sub-intimal tracking and re-entry: the STAR technique. Catheter Cardiovasc Interv 2005 64:407–11. https:// doi.org/10.1002/ccd.20307; PMID: 15789384.

Galassi AR, Tomasello SD, Costanzo L, et al. Mini-STAR as bailout strategy for percutaneous coronary intervention of chronic total occlusion. Catheter Cardiovasc Interv 2012;79:30– 40. https://doi.org/10.1002/ccd.22998; PMID: 21956876.

Godino C, Latib A, Economou FI, et al. Coronary chronic total

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occlusions: mid-term comparison of clinical outcome following the use of the guided-STAR technique and conventional anterograde approaches. Catheter Cardiovasc Interv 2012;79:20–7. https://doi.org/10.1002/ccd.23058; PMID: 21805559.

Valenti R, Vergara R, Migliorini A, et al. Predictors of reocclusion after successful drug-eluting stent-supported percutaneous coronary intervention of chronic total occlusion.

J Am Coll Cardiol 2013;61:545–50. https://doi.org/10.1016/j. jacc.2012.10.036; PMID: 23273395.

Galassi AR, Boukhris M, Tomasello SD, et al. Long-term clinical and angiographic outcomes of the mini-STAR technique as a bailout strategy for percutaneous coronary intervention of chronic total occlusion. Can J Cardiol 2014;30:1400–6. https:// doi.org/10.1016/j.cjca.2014.07.016; PMID: 25442438.

Michael TT, Papayannis AC, Banerjee S, Brilakis ES. Subintimal dissection/reentry strategies in coronary chronic total occlusion interventions. Circ Cardiovasc Interv 2012;5:729–38. https://doi.org/10.1161/CIRCINTERVENTIONS.112.969808; PMID: 23074346.

Carlino M, Azzalini L, Mitomo S, Colombo A. Antegrade fenestration and re-entry: a new controlled subintimal technique for chronic total occlusion recanalization. Catheter Cardiovasc Interv 2018;92:497–504. https://doi.org/10.1002/ ccd.27470; PMID: 29314567.

Walsh SJ, Cosgrove C, Spratt JC, Hanratty CG. A technical focus on antegrade dissection and re-entry for coronary chronic total occlusions: a practice update for 2019. Korean Circ J 2019;49:559–67. https://doi.org/10.4070/kcj.2019.0160; PMID: 31243929.

Vo MN, Karmpaliotis D, Brilakis ES. “Move the cap” technique for ambiguous or impenetrable proximal cap of coronary total occlusion. Catheter Cardiovasc Interv 2016;87:742–8. https://doi. org/10.1002/ccd.26079; PMID: 26332640.

Roy J, Hill J, Spratt C. The “side-BASE technique”: combined side branch anchor balloon and balloon assisted sub-intimal entry to resolve ambiguous proximal cap chronic total occlusions. Catheter Cardiovasc Interv 2018;92:E15–9. https:// doi.org/10.1002/ccd.27422; PMID: 29266669.

Smith EJ, Di Mario C, Spratt JC, et al. Subintimal TRAnscatheter Withdrawal (STRAW) of hematomas compressing the distal true lumen: a novel technique to facilitate distal reentry during

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Antegrade CTO Strategies recanalization of chronic total occlusion (CTO). J Invasive Cardiol 2015;27:E1–4. PMID: 25589704.

27. Zhang J, Gao X, Kan J, et al. Intravascular ultrasound versus angiography-guided drug-eluting stent implantation: the ULTIMATE trial. J Am Coll Cardiol 2018;72:3126–37. https://doi. org/10.1016/j.jacc.2018.09.013; PMID: 30261237.

28. Hong SJ, Mintz GS, Ahn CM, et al. Effect of intravascular ultrasound-guided drug-eluting stent implantation: 5-year follow-up of the IVUS-XPL randomized trial. JACC Cardiovasc

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Interv 2020;13:62–71. https://doi.org/10.1016/j.jcin.2019.09.033; PMID: 31918944.

29. 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.

30. Wilson WM, Walsh SJ, Bagnall A, et al. One-year outcomes after successful chronic total occlusion percutaneous coronary intervention: the impact of dissection re-entry

techniques. Catheter Cardiovasc Interv 2017;90:703–12. https://doi.org/10.1002/ccd.26980; PMID: 28296045.

31. Kawasaki T, Abe M, Sakuada M, Kishi K. Promus stent treatment of chronic total occlusions using two different recanalization techniques in Japan – J Proctor registry: a multicenter registry to evaluate clinical outcome of drug eluting stent in subintimal area after CTO revascularization using antegrade or retrograde approach. J Am Coll Cardiol 2013;61(Suppl 10):e1692. https://doi. org/10.1016/S0735-1097(13)61692-7.

Structural

Chimney Stenting During Transcatheter Aortic Valve Implantation Liesbeth Rosseel,1 Michael Rosseel,2 Brian Hynes,1 Xavier Armario Bel,1 Emily Crilly1 and Darren Mylotte1 1. Department of Cardiology, Galway University Hospital, Galway, Ireland; 2. Department of Cardiology, ASZ Hospital Aalst, Aalst, Belgium

Abstract Acute coronary artery obstruction is a rare but life-threatening complication of transcatheter aortic valve implantation. In patients at risk of coronary artery obstruction, pre-emptive coronary artery protection with a coronary wire, balloon or stent provides a bailout treatment option.

The authors describe the steps involved in performing chimney stenting and summarise the short- and long-term outcome data associated with this technique.

Keywords Transcatheter aortic valve implantation, surgical aortic valve replacement, coronary artery obstruction, chimney stenting, dual antiplatelet therapy, MI Disclosure: The authors have no conflicts of interest to declare.

Received: 16 March 2020 Accepted: 24 April 2020 Citation: Interventional Cardiology Review 2020;15:e09. DOI: https://doi.org/10.15420/icr.2020.08 Correspondence: Liesbeth Rosseel, Galway University Hospital, Newcastle Rd, Galway H91 YR71, Ireland. E: liesrosseel@outlook.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 noncommercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve implantation (TAVI) has emerged as a safe and effective strategy for the treatment of symptomatic and severe aortic valve stenosis (AS).1 The choice between a transcatheter or surgical approach is no longer dependant on the estimated surgical risk, but rather the institutional heart team’s assessment of medical comorbid illnesses and frailty, individual cardiac and vascular anatomic characteristics, the patient’s preferences and local experience. The major advantages of TAVI with regard to surgical aortic valve replacement (SAVR) include a less invasive approach with rapid recovery and lower risk of short-term death and stroke.1 SAVR, in contrast, is less dependent on vascular, aortic root or valve anatomy, and is associated with a lower risk of post-procedural paravalvular leak or the requirement for a permanent pacemaker.1 In addition, TAVI presents a risk for acute or subacute coronary artery obstruction (CAO), a rare but devastating and life-threatening complication.

Coronary artery protection with an option to perform ‘chimney stenting’ is an important and ever more frequently used technique that can mitigate against CAO during TAVI. In this article, we describe the risk factors associated with CAO, the procedural steps to perform coronary protection and chimney stenting and discuss the available literature on this topic.

Coronary Artery Obstruction in Transcatheter Aortic Valve Implantation Acute CAO is defined as a new complete or partial obstruction of one or both coronary ostia during a TAVI procedure.2 This complication typically manifests as abrupt haemodynamic instability with rapid progression to cardiogenic shock and ventricular arrhythmias.

The incidence of acute CAO during TAVI in native aortic valves is relatively low (<1%) but occurs three- to fourfold times more frequently after valve-in-valve (VIV) procedures (2.3–3.5%).3–6 Obstruction of one or both coronary arteries is usually caused by direct coverage of the ostia by displaced (bulky) native leaflet tissue that is pushed aside by

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the frame of the expanded transcatheter heart valve (THV). In case of VIV procedures, it is the displacement of the bioprosthetic leaflet tissue that can cover the coronary ostia. Displaced leaflets, native or prosthetic, can also reduce coronary flow towards the sinus of Valsalva (SOV) when pushed into contact with the sinotubular junction. It is rather uncommon that components of the THV itself (e.g. skirt, commissural posts) directly obstruct the coronary ostia; however, this should be suspected in the setting of shallow aortic sinuses. Coronary dissection, haematoma or embolisation of thrombotic or degenerative material are alternative, less-common mechanisms of CAO. Acute CAO has a major effect on morbidity and mortality after TAVI. The 30-day mortality of acute CAO is high, ranging between 8% and 41% for TAVI in native AS and up to 53% in cases of VIV.3,4,6 The type of coronary revascularisation, and hence the rapidity of restoration of coronary blood flow, appears to be an important determinant of outcome after CAO. A multicentre registry reported a 30-day mortality of 22% in patients successfully treated with percutaneous coronary intervention (PCI), 50% in patients who were treated with urgent coronary bypass grafting (CABG) and a striking 100% 30-day mortality among patients with unsuccessful PCI.3 Recently, delayed CAO has been reported as a rare cause of MI after TAVI, associated with similarly high in-hospital mortality rates (50%).7 In these cases, CAO occurs after the patient has left the catheterisation laboratory after TAVI and is categorised as either early (0–7 days) or, less frequently, late (>7days) presentation after the index procedure.7 Clinicians should be aware that similar risk factors as for acute CAO are associated with the early type of delayed CAO. Further stent expansion or thromboembolic phenomena occurring in shallow and overfilled SOV are presumed factors for the occurrence of early delayed CAO. In cases of late delayed CAO, occurring months to years after the

© RADCLIFFE CARDIOLOGY 2020

Chimney Stenting in TAVI Figure 1: Risk Factors for Coronary Artery Obstruction During Transcatheter Aortic Valve Implantation

A: 1, coronary height <10 mm relative to the annular plane; 2, width of the sinus of Valsalva <28 mm; 3, severity of leaflet calcification and its distribution relative to the coronary ostia; 4, leaflet thickness and its distribution relative to the coronary ostia; 5, length of the leaflet compared to the height of the coronary ostia; 6, sinotubular junction height and width relative to virtual transcatheter heart valve. B,C: Virtual transcatheter valve (purple dashed lines) to coronary ostium distance ≤4 mm. B: Stented bioprosthetic valve design with leaflets mounted externally of the stent frame. C: Stentless bioprosthetic valve design. The blue solid lines represent bioprosthetic leaflets.

procedure, mechanisms related to endothelialisation, fibrosis and thrombosis are presumed to cause this late complication.

Risk Factors for Acute Coronary Artery Obstruction Risk factors for acute CAO during TAVI have been identified and include female sex, coronary height <10 mm from the annular plane and SOV <28 mm.3,4,8 However, a systematic review of acute CAO cases reported between 2002 and 2012 showed approximately 60% with left coronary artery (LCA) height >10 mm, and most patients with acute CAO in observational trials had an LCA height of <12 mm or SOV <30 mm.3,4 These data suggest higher cut-off values may be more accurate, but also that other risk factors may be involved. Potential adverse anatomical features that should be assessed during preprocedural planning include the severity of valve calcification, the distribution of bulky calcifications and thickened leaflet tissue, the length of the native leaflets relative to ostial height of the coronaries or the height and width of the sinotubular junction.

Not surprisingly, in the available registries, patients with CAO less frequently had a history of CABG.3,4 At the same time, this may be cause of underreporting of the true prevalence of CAO in these registries, because CAO symptoms may have been obscured by ‘graft protection’.

For VIV procedures, additional risk factors include the treatment of surgical bioprostheses with externally mounted leaflets, stentless bioprosthetic valves, patients with a virtual transcatheter valve to coronary ostium distance <4 mm, or those with a virtual transcatheter to sinus tubular junction distance <4 mm (Figure 1).6

Strategies in At-risk Patients When patients are identified to be at an increased risk of CAO during TAVI, a robust discussion in the institutional heart team is essential. In

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such cases, SAVR may be a more appropriate treatment strategy. In cases where a surgical approach is not feasible, several procedural techniques can be considered to reduce the risk of CAO during TAVI. Some observational data suggest a higher risk of CAO with balloonexpandable (BE) than self-expandable (SE) THVs.3,4 Although it has been suggested this may be explained, in part, by differences in frame characteristics, it should be mentioned that the manufacturer of SE CoreValve rules out specific recommendations regarding SOV diameter and coronary height, with these recommendations not provided by the manufacturer of the BE Edwards valves. Therefore, it is not generalisable that SE THVs should be preferred above BE THVs in patients at risk of CAO. Conversely, a recapturable THV system provides the advantage of assessing CAO before final deployment of the valve. For example, the Lotus Edge (Boston Scientific) THV allows thorough assessment of implantation position, function, sealing and relationship to the coronary arteries prior to release. If malposition or CAO is observed, the prosthesis can simply be recaptured and repositioned or removed (Figure 2A). No other currently commercially available THV system can be assessed while fully deployed and in position before final release.

Other THVs have been designed to clamp native or bioprosthetic aortic valve leaflets to ‘anchor’ this tissue to the THV device and potentially reduce the risk of CAO. For example, the ACURATE Neo (Boston Scientific) THV system is designed such that the upper crown ‘engages’ leaflet tissue and pushes it down in the direction of the annulus (Figure 2B). A trial in 30 patients at high risk of acute CAO (mean ± standard deviation left main height 10.8 ± 1.5 mm and shallow SOV with an SOV:annulus ratio 1.8 ± 0.8 mm) showed no acute CAO after transapical implantation of the ACURATE Neo THV system.9 The JenaValve (JenaValve Technology) is another second-generation THV that has a clipping mechanism to grasp the native leaflets and attaches them to the THV device (Figure 2C). Data on the rate of CAO with the most recent version of the JenaValve system are not yet available.

Structural Figure 2: Strategies to Lower the Risk of Coronary Artery Obstruction

A

B

C

A: Complete deployment and assessment of a fully functional transcatheter heart valve (THV) provides an opportunity to assess coronary flow before the final release of the THV (LOTUS Edge).

B,C: THV designs that clamp the native or bioprosthetic aortic valve leaflet to anchor this tissue to the THV device. B: Arrows indicate the upper crown of the ACURATE neo system that engages leaflet tissue and pushes it down in an annular direction. C: Arrows indicate the clamping mechanism of the JenaValve system, which attaches the leaflet tissue to the THV device itself.

Figure 3: Schematic Principle of the Bioprosthetic or Native Aortic Scallop Intentional Laceration to Prevent Iatrogenic Coronary Artery Obstruction (BASILICA) During TAVI Technique

Figure 4: Schematic Overview of Risk Assessment and Strategy for Coronary Artery Obstruction

Assess risk of CAO TAVI • • • • •

VIV

Female Coronary height ≤10 mm SOV ≤28 mm Leaflet length relative to coronary height Calcific masses/leaflet thickness and distribution

• Stented valve with leaflets mounted exteriorly • Stentless valve design • VTC ≤4 mm

Reconsider SAVR

Preventive measures during TAVI

Retrievable THV

A: Native or bioprosthetic leaflets are split percutaneously by electrocauterisation along the dashed lines. B: The leaflets can be splayed once the transcatheter heart valve is being deployed, thus avoiding coronary obstruction.

Bioprosthetic or Native Aortic Scallop Intentional Laceration to Prevent Iatrogenic Coronary Artery Obstruction (BASILICA) during TAVI is a contemporary method to decrease the risk of acute CAO. In this technique, native or bioprosthetic leaflets that risk CAO are intentionally sliced using transcatheter electrocauterisation. This enables the leaflets to splay once the THV is being deployed, and hence maintain blood flow into the SOV and coronaries (Figure 3).10 A prospective single-arm study in 30 patients (57% VIV) at high risk of CAO demonstrated this technique to be successful in 93% of patients, with no cases of CAO or reintervention after 30 days.11 Three patients (10%) had neurological events (one disabling stroke, two non-disabling stroke). In 43% of patients, cerebral protection was provided. This procedure was tolerated haemodynamically in most patients (93%). In cases when haemodynamic instability appeared, this resolved immediately after completion of THV deployment. Primary reports appear to show acceptable safety of BASILICA, but this needs

Avoid oversizing

Tailor THV type

BASILICA

Coronary artery protection ± chimney stenting

BASILICA = Bioprosthetic or native Aortic Scallop Intentional Laceration to prevent Iatrogenic Coronary Artery obstruction during TAVI; SAVR = surgical aortic valve replacement; SOV = sinus of Valsalva; TAVI = transcatheter aortic valve implantation; THV = transcatheter heart valve; VIV = valve-in-valve; VTC = virtual transcatheter valve to coronary ostium distance.

confirmation in larger trials. This technique is currently not widely available outside expert centres.

Despite these aforementioned strategies to avoid CAO, patients at risk of CAO continue to present for TAVI. In such cases, prophylactic coronary protection with a wire, balloon or stent should be considered as a facilitatory step in case bailout ‘chimney’ or ‘snorkel’ stenting is required to manage acute CAO. This technique has been successfully described in case reports and small case series.12–14 A coronary balloon or stent premounted on the protective 0.014" guidewire can be parked distally in the coronary artery, retrieved proximally and deployed with rapid restoration of coronary flow in case of acute CAO. We consider pre-emptive coronary protection in all at-risk patients as described in Figure 4.

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Chimney Stenting in TAVI Figure 5: Procedural Steps for Coronary Protection and Chimney Stenting A

B

C

D

E

F

G

H

I

J

A: The aortic valve is crossed with a stiff wire. B and C: The guide catheter is engaged towards the coronary of interest and the coronary wire with a balloon/stent is advanced distally. D: The guide catheter is disengaged away from the aortic valve. E: If needed, the aortic valve is predilated, with or without concomitant contrast dye injection to estimate coronary flow repercussion.

F: The transcatheter heart valve (THV) is deployed and coronary patency is assessed. G: In case of (impending) coronary artery obstruction, the coronary stent is retracted and deployed within the proximal part of the coronary artery, extending above the displaced leaflet tissue and/or stent frame. H: If post-procedural dilatation of the THV is required, a ‘kissing balloon’ technique can be considered. I: Chimney stent expansion is assessed and, if needed, post-chimney stent-dilatation is performed.

Coronary Protection and Chimney Stenting Figure 5 illustrates the steps used for coronary protection and chimney stenting, and a case example is shown in Figure 6. Coronary artery protection during TAVI usually necessitates the use of an additional arterial access for guide catheter engagement of the at-risk coronary artery. Alternatively, the retracted guide catheter can be used for contrast dye injections while deploying the THV, in lieu of a pigtail catheter and subsequently avoiding an extra arterial access.15 Ideally, Judkins left/right or multipurpose guiding catheters are chosen because they are easier to back up into the aorta during THV deployment and can be repositioned towards the coronary ostium once the THV is deployed. Other guiding catheters can also be used successfully (Ikari, EBU or AL1), but may be more difficult to reposition after THV implantation. Because of the risk of haemodynamic instability after balloon aortic valvuloplasty (BAV), we prefer to have the coronary protection kit in situ prior to BAV. The coronary guide catheter should be engaged, with delivery of a coronary guide wire distal in the vessel under appropriate heparinisation (activated clotting time >250 s). The guide catheter is then retracted into the ascending aorta once a premounted balloon or stent over the protective wire is positioned distal in the coronary vessel. The decision to premount a balloon or stent on the coronary guide wire depends on the anatomical characteristics of the aortic root and the perceived risk of CAO. Although a guide wire-only strategy saves time and money, it can be difficult to advance a coronary stent alongside the deployed THV (and displaced native leaflets) due to obstructing calcification or jailing of the safety wire between the aortic wall and the THV frame. In two observational trials, a 10–20% rate of failure to deploy a stent occurred in cases where stenting was attempted for the treatment of CAO during

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TAVI.3,4 A more recent registry of patients who underwent chimney stenting for established or impending CAO showed that the absence of a coronary protective wire was associated with increased rates of death, cardiogenic shock or MI.14 It is therefore suggested that a protective coronary guide wire with a premounted coronary stent is positioned distally in the coronary vessel prior to THV deployment.

If acute CAO is evident after BAV or THV deployment (i.e. chest pains, reduced coronary blood flow, ST-segment changes, ventricular arrhythmias, haemodynamic instability), immediate restoration of coronary flow is crucial and the parked balloon/stent can be deployed as described below. If, however, there is no clinical evidence of acute CAO but the angiographic appearance is suspicious for impending CAO (e.g. evidence of leaflet tissue directly in front of the coronary ostium with or without reduced coronary flow), coronary stenting should still be considered. Indeed, the presence of a coronary protection wire can provide false reassurance that CAO is not imminent by keeping displaced leaflet tissue away from the coronary ostium and maintaining normal coronary blood flow. In such cases, withdrawal of the wire can precipitate acute CAO and readvancement of the wire can be challenging. Moreover, a recent report on delayed coronary obstruction after TAVI reported that 23.7% of cases of delayed CAO had coronary protection during their index TAVI procedure.7 Conversely, a retrospective registry that included 93 at-risk patients who had a coronary protective wire but no final coronary stenting during TAVI showed a considerable risk (4.3%) for definite delayed CAO and demonstrated a high mortality rate in those patients (three of four with a fatal outcome).16 Intravascular ultrasound assessment of the coronary ostium and the adjacent aortic sinus can be an additional tool in such cases to determine the proximity of displaced

Structural Figure 6: Case Example, Valve-in-valve Procedure in a Patient at Risk of Coronary Artery Obstruction of the Left Coronary Artery A

B

D

E

junction. Alternatively, the stent can be positioned at the level of the coronary ostium, while the THV is being deployed. This latter strategy can be used when a very high risk of CAO is anticipated and the risk of stent displacement or guide wire loss during THV deployment is low, or if there are concerns for the development of ischaemia with the stent placed deeper in the coronary artery.

After the stent is retrieved to the desired position, it should be inflated to high pressure (12 atm). The stent balloon can then be partially retracted for repeat inflation at higher pressure in order to flare the proximal portion of the stent. Importantly, the deflated stent balloon should not be withdrawn out of the coronary stent frame before THV function has been assessed because, in case post-dilation of the THV is required, a ‘kissing balloon’ technique can be used to avoid crushing of the chimney stent, as re-engagement of the balloon into the chimney stent can be challenging (Figure 5H). Compression or recoil of the implanted coronary stent by the expanded THV and displaced native leaflets has been reported.4,16 In such cases, a second stent can be implanted to improve stent expansion. Here, intravascular imaging can facilitate decision making if any further optimisation of the chimney stent(s) is needed.

Long-term Outcome of a Chimney Stent

C

F

A: 23 mm Evolut R (Medtronic) transcatheter heart valve implantation for the treatment of a degenerated 23 mm Mitroflow (Sorin) surgical bioprosthesis with leaflets sutured ´outside´ stent. Left coronary artery height = 11.7 mm. B: Virtual transcatheter valve to coronary ostium distance distance to left coronary artery = 3.9 mm. C: High take-off of the right coronary artery at 17.6 mm. D: Coronary protection with a guide wire and 4.0 x 12 mm balloon. E: balloon dilatation for the treatment of acute coronary occlusion post-transcatheter heart valve deployment. F: Delivery of a 4.0 x 26 mm Xience Alpine (Abbott Vascular) drug-eluting stent through a guide extension catheter according to chimney stent technique.

leaflet tissue or calcifications to the coronary ostium, especially when there is doubt as to the need for stenting based on angiographic images only.12,16,17 A low threshold for stent deployment should be contemplated in these high-risk patients. Conversely, if there are no suggestions for impeding coronary flow or CAO after THV deployment, the coronary stent can be cautiously retracted.

If established or impending CAO occurs, the parked stent can simply be retracted and deployed. The coronary stent width should be selected according to the preprocedural CT analysis or angiographic assessment.

The length of the stent length should be long enough so it has sufficient length to anchor in the proximal portion of the coronary artery and extend above the anticipated obstructive factor. If CAO is expected to be caused by displacement of bulky leaflet tissue, the stent length should be adjusted to extend above these obstructive leaflets; alternatively, if it is anticipated that the CAO is caused by closure of the entire sinus due to contact between the THV frame and the sinotubular junction, the stent chosen should extend above the sinotubular

Some specific concerns regarding long-term outcomes of chimney stenting need to be recognised. First, in a milieu of turbulent flow and calcific debris, a stent protruding far into the aorta that has not been apposed to the coronary artery wall over a length of several millimetres could, theoretically, be at considerable higher risk of chimney stent failure, including thrombosis or restenosis. Second, there are no available data to guide the intensity or duration of antiplatelet therapy.

This requires careful consideration in patients who have an increased bleeding risk due to their comorbidities. Individualisation of antiplatelet therapy is mandatory, with most centres suggesting 3–9 months of dual antiplatelet therapy. The third concern relates to future access to the coronary circulation for routine management of stable or unstable coronary artery disease. This access is expected to be extremely challenging in this patient cohort. One study suggested easier reaccess in BE THV systems because the THV frame, and subsequently the chimney stent length protruding in the aorta, are both shorter.14 To date, no long-term follow-up or data on systematic imaging with coronary CT or angiography of chimney stents are available. However, recently the results of two retrospective registries have been published, collecting data on patients who received chimney stenting with clinical follow-up for up to 3 years.14,16 In the International Chimney Registry, a retrospective observational trial collecting data on 60 patients who were treated with chimney stenting for established or impeding CAO, there was a stent failure rate of 5.3% after a median follow-up of 612 days (interquartile range 405–842 days).14 Data on 236 at-risk patients undergoing TAVI with coronary protection wire were collected in the Coronary Protection to Prevent Coronary Obstruction During TAVR (COPROTAVR) registry.15 In that trial, 143 patients (60.6%) received coronary stenting (79% chimney stenting, 21% ostial stenting). After a 3-year follow-up, clinical outcome was generally favourable in patients treated with stenting (cardiac mortality 7.8%, MI 9.8%, stroke 5.4%).

Although the occurrence of stent thrombosis was low (0.9%), it was fatal in all cases. No cases of in-stent restenosis were observed. In the group of stented patients, in three of four patients with MI who underwent angiography no coronary artery disease could be identified.

It is not clear whether an underlying thromboembolic source, triggered

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Chimney Stenting in TAVI by the protruding stent, for this latter finding should be considered.

These trials are the first to suggest acceptable mid-term safety of chimney stenting. However, these retrospective data in a relatively small set of patients should be interpreted with caution. Therefore, we discourage the use of chimney stenting as a first-line strategy in younger patients or in those with advanced coronary artery disease, and chimney stenting should only be effectuated as a bailout option for impending or established CAO.

Future Perspective Few registries have retrospectively collected data on this subject, demonstrating that chimney stenting is an effective bailout strategy for the acute management of CAO during TAVI, but long-term outcomes remain unclear. A prospective international registry collecting data on patients who are at risk of CAO or have developed CAO during TAVI is

1.

2.

3.

4.

5.

6.

7.

Cahill TJ, Chen M, Hayashida K, et al. Transcatheter aortic valve implantation: current status and future perspectives. Eur Heart J 2018;39:2625–34. https://doi.org/10.1093/eurheartj/ehy244; PMID: 29718148.

Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcathter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. Eur J Cardiothorac Surg 2012;42:545–60. https://doi. org/10.1093/ejcts/ezs533; PMID: 23026738.

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.

Ribeiro HB, Nombela-Franco L, Urena M, et al. Coronary obstruction following transcatheter aortic valve implantation: a systematic review. JACC Cardiovasc Interv 2013;6:452–61. https://doi.org/10.1016/j.jcin.2012.11.014; PMID: 23602458.

Dvir D, Leipsic J, Blanke P, et al. Coronary obstruction in transcatheter aortic valve-in-valve implantation. Preprocedural evaluation, device selection, protection, and treatment.

Circulation: Cardiovasc Interv 2015;8:e002079. https://doi. org/10.1161/CIRCINTERVENTIONS.114.002079; PMID: 25593122.

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

Jabbour RJ, Tanaka A, Finkelstein A, et al. Delayed coronary

INTERVENTIONAL CARDIOLOGY REVIEW

in development. Such data are needed to improve current risk models and enable the development of new tools to better predict the occurrence of CAO. Further experience with new techniques, such as BASILICA or THV design innovation, will also be required to mitigate the risk of coronary occlusion and the requirement for chimney stenting.

Conclusion Acute CAO during TAVI is a rare but life-threatening complication. In most cases, risk factors for CAO can be identified. In patients at risk of CAO, upfront coronary protection with a coronary guide wire and the use of a premounted stent are suggested. Chimney stenting is performed as a bailout treatment for the restoration of coronary flow in case of impending or established CAO. The long-term performance of chimney stenting remains unclear.

obstruction after transcatheter aortic valve replacement. J Am Coll Cardiol 2018;17:1513–24. https://doi.org/10.1016/j. jacc.2018.01.066; PMID: 29622157.

8. Holmes DR Jr, Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/ STS expert consensus document on transcatheter aortic valve replacement: developed in collaboration with the American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. Ann Thorac Surg 2012;93:1340–95. https://doi.org/10.1016/j.athoracsur.2012.01.084; PMID: 22300625.

9. Chu MW, Bagur R, Losenno KL, et al. Early clinical outcomes of a novel self-expanding transapical transcatheter aortic valve bioprosthesis. J Thorac Cardiovasc Surg 2017;153:810–18. https://doi.org/10.1016/j.jtcvs.2016.11.054; PMID: 28073571.

10. 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-inhuman. JACC Cardiovasc Interv 2018;11:677–89. https://doi. org/10.1016/j.jcin.2018.01.247; PMID: 29622147.

11. 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.

12. Abramowitz Y, Chakravarty T, Jilaihawi H, et al. Clinical impact

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of coronary protection during transcatheter aortic valve implantation: first reported series of patients. EuroIntervention 2015;11:572–81. https://doi.org/10.4244/EIJV11I5A112; PMID: 26390518.

Yamamoto M, Shimura T, Kano S, et al. Impact of preparatory coronary protection in patients at high anatomical risk of acute coronary obstruction during transcatheter aortic valve implantation. Int J Cardiol 2016;217:58–63. https://doi. org/10.1016/j.ijcard.2016.04.185; PMID: 27179209.

Mercanti F, Rosseel L, Neylon A, et al. Chimney stenting for coronary occlusion during transcatheter aortic valve replacement: insights from the Chimney Registry. JACC Cardiovasc Interv 2020;13:751–61. https://doi.org/10.1016/j. jcin.2020.01.227; PMID: 32192695.

Palmerini T, Chakravarty T, Saia F, et al. Coronary protection to prevent coronary obstruction during aortic valve replacement: a multicenter international registry. JACC Cardiovasc Interv 2020;13:739–47. https://doi.org/10.1016/j.jcin.2019.11.024; PMID: 32061608.

Spina R, Khalique O, George I, Nazif T. Acute left main stem coronary occlusion following transcatheter aortic valve replacement in a patient without recognized coronary obstruction risk factors: a case report. Eur Heart J Case Rep 2018;2:yty112. https://doi.org/10.1093/ehjcr/yty112; PMID: 31020188.

Kubo S, Fuku Y, Shimamoto T, et al. Leaflet protrusion into left main coronary artery detected by intravascular ultrasound after transcatheter aortic valve implantation with SAPIEN 3.

Eur Heart J Cardiovasc Imaging 2017;18:608. https://doi. org/10.1093/ehjci/jew341; PMID: 28180241.

Catheter-based Interventions in Pregnancy

Management of Valvular Disease During Pregnancy: Evolving Role of Percutaneous Treatment Chiara Fraccaro,1 Noemie Tence,2 Giulia Masiero1 and Nicole Karam2 1. Interventional Cardiology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy; 2. Medico-Surgical Heart Valve Unit, Georges Pompidou European Hospital, University of Paris, Paris, France

Abstract Valvular heart disease (VHD) is encountered in approximately 1% of pregnancies, significantly increasing both maternal and foetal risk.

Rheumatic VHD remains the most common form in non-Western countries, whereas congenital heart disease dominates in the Western world. The risk of complications varies according to the type and severity of the underlying VHD. Moreover, pregnancy is a hypercoagulable state associated with increased risk of thromboembolism. The authors review the main VHDs encountered during pregnancy, and suggest management strategies based on the 2018 European Society of Cardiology recommendations for the management of pregnant women with VHD, providing an overview of classical and new transcatheter structural therapeutic options with a special focus on radiation exposure and anticoagulation drug management.

Keywords Transcatheter structural interventions, pregnancy, rheumatic heart disease, mitral stenosis, aortic stenosis Disclosure: NK has received consultant fees from Abbott Vascular and a research grant from Edwards Lifesciences. All other authors have no conflicts of interest to declare.

Received: 28 February 2020 Accepted: 11 May 2020 Citation: Interventional Cardiology Review 2020;15:e10. DOI: https://doi.org/10.15420/icr.2020.06 Correspondence: Chiara Fraccaro, Interventional Cardiology Unit, Department of Cardiac, Thoracic, Vascular Science and Public Health, University of Padua, Via Giustiniani 2, 35128 Padua, Italy. E: chiarafraccaro980@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 noncommercial purposes, provided the original work is cited correctly.

Valvular heart disease (VHD) is encountered in approximately 1% of pregnancies, significantly increasing both maternal and foetal risk.1,2 Rheumatic VHD remains the most common form in non-Western countries, whereas congenital heart disease dominates in the Western world.3,4 As increasing numbers of women with congenital heart disease are reaching childbearing age, the prevalence of women of childbearing age with significant cardiac pathology is also increasing.5 Other causes of VHD in younger women include myxomatous mitral valvular disease (mitral valve prolapse), prior endocarditis, valvular disease associated with systemic disorders (Marfan’s syndrome, systemic lupus erythematosus, inflammatory vascular disorders) and radiation-induced valvular disease.6 Pregnant women with VHD are at risk of cardiac decompensation due to the haemodynamic changes that occur during pregnancy, including increases in heart rate, stroke volume and cardiac output (CO).3 The risk of complications varies according to the type and severity of the underlying VHD. However, stenotic valve lesions are generally less well tolerated during pregnancy than regurgitant lesions, because increased CO increases the transvalvular gradient by approximately 50%, mainly between the first and second trimesters, worsening the prognosis of the patient and the foetus.7,8 Moreover, pregnancy is a hypercoagulable state associated with an increased risk of thromboembolism.9 The management of VHD is particularly challenging in pregnant women because both the maternal and foetal prognoses are at stake, and need

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to be taken into account.10 In this article, we review the main VHDs that are encountered during pregnancy, and suggest management strategies based on the 2018 European Society of Cardiology (ESC) recommendations for the management of pregnant women with VHD.11 We also provide an overview of classical and new transcatheter structural therapeutic options, with a special focus on radiation exposure and anticoagulation drug management.

Prevention and Risk Assessment European guidelines recommend performing a risk assessment in all women with known cardiac diseases of childbearing age before conception using the modified WHO (mWHO) classification of maternal cardiovascular risk in order to plan the appropriate management (Table 1).11 VHD in pregnant women is heterogeneous and its management varies from simple surveillance (mWHO Class I) to contraindication or termination of pregnancy (mWHO Class IV).11 The current ESC guidelines introduced the notion of the pregnancy heart team. Any women with a moderate or high risk of complications during pregnancy (mWHO Class II–III and above) should be referred to for prepregnancy counselling and management during pregnancy and around delivery in order to anticipate and potentially avoid complications.11 The pregnancy heart team is a multidisciplinary team composed of at least a cardiologist, an obstetrician and an anaesthesiologist, all with expertise in the management of high-risk pregnancies in women with

© RADCLIFFE CARDIOLOGY 2020

Transcatheter Structural Interventions in Pregnancy Table 1: Maternal Valvular Heart Diseases Stratified According to the Modified WHO Classification mWHO Mitral classification

Aortic

Tricuspid

Pulmonary

Class I

Small MV prolapse, trivial MR

Trivial AR

Mild TR

Mild PS and PR

Class II

Mild MR

Mild AS and AR

Mild TS, Moderate TR

Moderate PS and PR

Class II–III

Class III

Class IV

Moderate MR, mild MS

Moderate AS and AR

Mild LV impairment (EF >45%)

Mild LV impairment (EF >45%)

Mild LV impairment (EF >45%)

Severe PR Mild LV impairment (EF >45%)

Severe MR, moderate MS

Severe asymptomatic AS, severe AR

Severe TR and TS

Severe PS

Moderate LV impairment (EF 30–45%)

Moderate LV impairment (EF 30–45%)

Moderate LV impairment (EF 30–45%)

Moderate LV impairment (EF 30–45%)

Mechanical valve

Mechanical valve

Mechanical valve

Mechanical valve

Severe MS

Severe symptomatic AS

Pulmonary arterial hypertension

Pulmonary arterial hypertension

Pulmonary arterial hypertension

Pulmonary arterial hypertension

Severe systemic ventricular dysfunction (EF <30% or NYHA Class III–IV)

Severe systemic ventricular dysfunction (EF <30% or NYHA Class III–IV)

Severe systemic ventricular dysfunction (EF <30% or NYHA Class III–IV)

Severe systemic ventricular dysfunction (EF <30% or NYHA Class III–IV)

AR = aortic regurgitation; AS = Aortic stenosis; EF = ejection fraction; LV = left ventricular; MR = mitral regurgitation; MS = mitral stenosis; MV = mitral valve; mWHO = Modified WHO; NYHA = New York Heart Association; PR = pulmonary regurgitation; PS = pulmonary stenosis; TR = tricuspid regurgitation; TS = tricuspid stenosis.

heart disease in an expert centre. Other additional experts may be involved where appropriate, such as geneticists, cardiothoracic surgeons, paediatric cardiologists, pneumologists, foetal medicine specialists, neonatologists, haematologists and nurse specialists.

Figure 1: Percutaneous Mitral Balloon Valvuloplasty Using the Inoue-Balloon Catheter (Toray)

All patients with high-risk VHD (mWHO Class IV) should be counselled against pregnancy or considered for prepregnancy interventions, particularly if the valve lesion is amenable to percutaneous intervention or surgical repair.11

Indications for Cardiac Interventions Indications for intervention (surgical or transcatheter) do not differ between women who contemplate pregnancy and other patients. The only exception to this rule in the field of VHD is women with at least moderate mitral stenosis (MS) who want to become pregnant; in these women, preventive percutaneous treatment should be considered regardless of symptoms (Class IIA, level of evidence [LOE] C).

If an intervention is required during pregnancy, cardiac surgery should be avoided if possible due to the significant risk of cardiopulmonary bypass for the foetus, related to non-pulsatile blood flow and reduced uteroplacental flow.12,13 Coronary bypass surgery or valvular surgery may be considered during pregnancy only when conservative and medical therapy has failed, and in situations that threaten the mother’s life or that are not amenable to percutaneous treatment, which remains the first choice (Class IIb, LOE C).11 To date, an urgent or emergency structural intervention during pregnancy, could be required in the following clinical scenarios: • Patients with high-risk VHD (mWHO Class IV) that was unknown at the time of conception (the incidence of this phenomenon is increasing due to migration flows) and when pregnancy interruption is refused.

• Patients with lower risk VHD, haemodynamic instability and refractory symptoms despite optimal medical therapy.

• Patients with acute onset of severe VHD during pregnancy (i.e. acute severe mitral regurgitation due to chordal rupture).

INTERVENTIONAL CARDIOLOGY REVIEW

Percutaneous Mitral Balloon Valvuloplasty for Mitral Stenosis Percutaneous mitral balloon valvuloplasty (PMBV) for the treatment of selected patients with rheumatic MS was developed by Inoue et al. in 1984 and has revolutionised the treatment of this disorder (Figure 1).14,15 Rheumatic valvular disease is the most common cause of MS among women of childbearing age, particularly in low- to middle-income countries, but also in the developed world. Congenital heart disease (parachute mitral valve) is a less common cause of MS. In pregnant women with MS, the increase in CO combined with a decrease in filling time due to increased heart rate can result in increased left atrial pressures, risk of AF and pulmonary oedema.16,17 Pregnancy in women with MS is associated with increased maternal morbidity and

Catheter-based Interventions in Pregnancy Table 2: Contraindications to Percutaneous Mitral Balloon Valvuloplasty • Mitral valve area >1.5 cm2, except where the symptoms cannot be explained otherwise and the anatomy is favourable • Presence of a left atrial thrombus • Presence of a more than mild mitral regurgitation • Presence of severe or bicommissural calcification • Absence of commissural fusion • Presence of severe concomitant aortic valve disease, or severe combined tricuspid stenosis and regurgitation requiring surgery • Presence of concomitant coronary artery disease requiring bypass surgery

Figure 2: Percutaneous Balloon Aortic Valvuloplasty in a Case of Aortic Stenosis

mitral regurgitation), such as percutaneous transeptal mitral valve implantation in mitral annular calcification (valve-in-MAC) or transcatheter dedicated mitral valve implantation.21,22 However, data and experience are lacking regarding the use of these techniques in pregnant women.

Transcatheter Balloon Aortic Valvuloplasty for Aortic Stenosis Congenital bicuspid aortic valve disease is the most common cause of aortic stenosis (AS) among women of childbearing age.23 Rheumatic heart disease is a less common cause of AS and is generally associated with rheumatic MS. All women with severe symptomatic AS should have a valve intervention before pregnancy because of the high risk of obstetric and foetal or neonatal complications.24 If AS is diagnosed, or becomes symptomatic, during pregnancy, valve intervention may be needed before delivery in case of refractory symptoms. In this context, and considering the high foetal risk of surgery, transcatheter balloon aortic valvuloplasty (BAV) can be undertaken by an experienced operator, depending on the exact morphology of the congenitally abnormal aortic valve (Figure 2).24,25 If the valve has clear commissures, is not thickened or calcified and is not regurgitant, cautious BAV, ideally with an undersized balloon to avoid aortic regurgitation, may provide a small increase in valve area, sufficient to allow the pregnancy to progress. However, compared with MS, data on BAV in pregnancy are scarce.26 When a BAV is considered by the pregnancy heart team, an associated aortopathy or aortic coarctation should be excluded, and the size of the ascending aorta should be always taken in account given the risk of aortic dissection.27 In addition, the feasibility of rescue surgical or percutaneous valve replacement should be confirmed before planning the intervention because emergency aortic valve replacement could be needed if severe aortic regurgitation develops.

Transcatheter Aortic Valve Replacement

adverse foetal outcome. Accordingly, if severe MS is recognised before pregnancy, PMBV is recommended before conception, especially when the valve area is <1.0 cm2, if valve morphology is favourable for intervention, even if the patient is asymptomatic.11 If MS is recognised during pregnancy and haemodynamic compromise persists (New York Heart Association [NYHA] Class III/IV and/or pulmonary artery systolic pressure ≥50 mmHg) despite appropriate medical treatment (beta-blockers and diuretics), PMBV may be needed antenatally and is usually performed, unless contraindicated, during the second trimester (after the 20th week of pregnancy) in experienced centres.8 PBMV performed either before or during pregnancy seems to lead to equivalent maternal and foetal outcomes.18 PBMV was found to be superior to open mitral valve commissurotomy because it is a minimally invasive interventional procedure performed under local anaesthesia with significantly fewer foetal complications and reduced foetal and neonatal mortality compared with open surgery.19 PBMV is performed through percutaneous transvenous femoral access and requires transeptal puncture. Nonetheless, PBMV could be contraindicated in particular situations (Table 2).20 Other transcatheter technologies are being developed for patients with severe MS who are not eligible for PBMV due to unfavourable anatomy (e.g. very high Wilkins score or more than mild

In patients with severe AS refractory to medical therapy, with unsuccessful BAV or associated aortic regurgitation, a transcatheter aortic valve replacement (TAVR) procedure, particularly through a femoral approach, seems to be a promising alternative to open heart surgery due to the perceived high likelihood of success with lower procedural risk for both the mother and foetus (Figure 3). Several transcatheter prostheses are now approved for clinical use, including in low-risk patients. However, experience with TAVR during pregnancy is still anecdotal, and key to the success of this procedure is a caseby-case evaluation and discussion by the heart team.2,8 Preprocedural assessment, which implies contrast medium injection and radiation, should be performed with caution, and transoesophageal echography could help assess valve size and anatomy while avoiding radiation and contrast medium. The other main difficulty in young women is the absence of calcification in this age group, which may preclude optimal positioning and stability of the prosthetic valve. Moreover, the risk of heart block and the need for a pacemaker should be carefully evaluated and discussed with the patient, as well as the lack of robust data about long-term durability of transcatheter prostheses in such young patients.

Percutaneous Mitral Valve Repair Acute mitral regurgitation, due, for example, to a ruptured chord, is not well tolerated during pregnancy. In addition, chronic mitral regurgitation can become symptomatic during pregnancy. In case of refractory symptoms despite diuretic therapy, transcatheter mitral valve repair (edge-to-edge repair or annuloplasty) could, theoretically, be an intriguing solution, reducing maternal and foetal risk by

INTERVENTIONAL CARDIOLOGY REVIEW

Transcatheter Structural Interventions in Pregnancy avoiding extracorporeal circulation, even though no data have been published so far. As noted above, transcatheter mitral valve replacement is a solution under investigation but, to date, no data are available in pregnant women.22 All these procedures are generally performed under general anaesthesia, through transapical or transvenous femoral access followed by transeptal puncture, and with transoesophageal ultrasound guidance.29,30

Figure 3: Transcatheter Valve Implantation of a Balloon-expandable Device in the Aortic Position

Transcatheter Valve-in-Valve Implantation in Degenerated Bioprosthesis Until few years ago, the treatment of bioprosthesis degeneration leading to severe stenosis or regurgitation was a real challenge in pregnant women with symptoms refractory to medical therapy. In fact, redo open heart surgery was the only therapeutic option.

The recent widespread use of transcatheter valve-in-valve procedures has provided an important alternative option in these cases, with high procedural success rates and very low risk with respect to surgical redo. Therefore, despite the small amount of data during pregnancy, the valve-in-valve procedure already seems to be the optimal therapy for symptomatic pregnant women with severe bioprosthesis dysfunction in aortic and other anatomical locations.31–34 However, there are no data regarding the safety and durability of such a procedure in young women. Moreover, due to the high prevalence of small aortic root anatomies in young women, the risk of prosthesis–patient mismatch in case of valve-in-valve implantation should be carefully evaluated.35 Again, contrast medium and radiation should be used with caution during pregnancy (see below).

Considerations Regarding Radiation Exposure The general principles for imaging during pregnancy are similar to imaging in the general population, with the goal of keeping radiation exposure as low as reasonably achievable. As obvious ethical issues prohibit researching on the foetus, most of the data on the effect of radiation on the foetus derives from observations made of victims of high-level radiation exposure.

The effect of radiation exposure during pregnancy depends on both radiation dose and the gestational age of the foetus. By the second trimester of pregnancy, organogenesis is complete and the foetal thyroid is still inactive. Accordingly, if an intervention is absolutely necessary, the best time is after the fourth month in the second trimester. Moreover, in the second trimester, the uterine volume is still small, so there is a greater distance between the foetus and the chest than in later months; therefore, there is no reason to postpone a necessary intervention until later. According to the Centers for Disease Control and Prevention, a foetal radiation dose <50 mGy is considered safe and harmless. Higher doses, especially doses >150 mGy, may result in adverse effects, including miscarriage, growth reduction, IQ reduction and severe mental retardation.36 Interestingly, the majority of diagnostic studies performed during pregnancy are below the toxicity threshold. However, every effort must be made to minimise radiation exposure by weighting the risk versus benefit of each intervention, referring these patients to experienced interventional cardiologists and adopting radiation reduction measures (Table 3).11,37,38 It is essential to remember that catheter-based diagnostic and interventional studies should not be avoided for fear of radiation exposure, especially when these studies can dramatically change maternal and foetal management and improve outcomes.

INTERVENTIONAL CARDIOLOGY REVIEW

Table 3: Measures Aiming to Reduce Radiological Exposure to the Foetus During Catheter-based Diagnostic and Interventional Studies • Use only low-dose fluoroscopy (pulse fluoroscopy instead of continuous fluoroscopy) • Minimise fluoroscopy time (last image hold rather than full exposure) • Place the X-ray source as distant as possible from the patient and the detector as close as possible • Favour anteroposterior projections • Collimate as tightly as possible to the area of interest • Avoid direct radiation of the abdominal region • Use echo guidance when possible • Prefer radial approach when possible • Shield the abdomen if it does not interfere with an optimal intervention

In particular, current evidence suggests that a single cardiovascular imaging study during pregnancy is safe and should be undertaken at all times when clinically justified.

Considerations Regarding Anticoagulation Therapy During Pregnancy Oral Anticoagulants Direct oral anticoagulants (DOACs) are contraindicated throughout pregnancy;39 thus, vitamin K antagonists (VKAs) remain the most effective anticoagulant regimen. However, VKAs cross the placenta and their use in the first trimester can result in embryopathy (limb defects and nasal hypoplasia) in 0.6–10% of cases.40 Moreover, as described in the Registry of Pregnancy and Cardiac Disease (ROPAC),41 the use of VKAs versus heparin in the first trimester was associated with a higher rate of miscarriage (28.6% versus 9.2%, respectively; P<0.001) and late foetal death (7.1% versus 0.7%, respectively; P=0.016). This risk seems to be dose dependent, and recent reviews suggest that is <1% with low-dose warfarin (<5 mg daily).42–44 Apart from this risk of embryopathy that is limited to the first trimester, the use of VKAs in the second and third trimesters can lead to a 0.7–2% risk of foetopathy (e.g. ocular and

Catheter-based Interventions in Pregnancy central nervous system abnormalities and intracranial haemorrhage).40 Moreover, VKAs must be discontinued before vaginal delivery because of the risk of foetal intracranial bleeding.40

Unfractionated Heparin Unfractionated heparin (UFH) does not cross the placenta, so its use in Weeks 6–12 is safe, and almost eliminates the risk of embryopathy when replacing VKAs.3 However, foetopathy has also been described with UFH throughout pregnancy, so its use during the second and third trimesters is not recommended.43 The main disadvantages of UFH are the higher risks of osteoporosis and thrombocytopenia, requiring platelet counts every 2–3 days.45 Therefore, the use of UFH is limited to the acute treatment of massive pulmonary emboli and around the time of delivery, when the ability to reverse anticoagulation urgently using protamine is advantageous. UFH remains the preferred antithrombotic regimen in the catheterisation laboratories during catheter-based interventions, where UFH has to be given intravenously at a dose of 40–70 U/kg targeting an activated clotting time of 250 s (200–300 s) or an activated partial thromboplastin time twice that of normal.

Low-molecular-weight Heparin The efficacy and safety of several low-molecular-weight heparin (LMWH) preparations have been well demonstrated in pregnant women.46,47 The main advantage of LMWH is its safety in weeks 6–12, when its use instead of VKAs almost eliminates the risk of embryopathy; in addition, no case of foetopathy has been described with LMWH throughout pregnancy.43,44 Moreover, in contrast to UFH, heparin-induced thrombocytopenia is markedly lower with LMWH, as is heparin-induced osteoporosis.45 Conversely, monitoring is essential to maintain a certain therapeutic anti-Factor Xa level, in particular in patients with mechanical valves or when pulmonary embolism has occurred in women receiving prophylactic doses of LMWH.48 Considering this unfavourable pharmacokinetic feature, LMWH should be switched to intravenous UFH 36 hours before the induction of labour or when caesarean delivery is planned in order to reduce haemorrhagic complications.

hypercoagulable state and is expected to further increase the risk of thromboembolic events. Therefore, immediate anticoagulation is required in all patients with MS and AF. The suggested regimen in such cases is LMWH at therapeutic doses in the first trimester and VKAs with the usual target international normalised ratio (INR; or LMWH) for the second and third trimesters. These patients should then be converted to continuous infusion of UFH before planned delivery.11 Cardioversion seems safe in all phases of pregnancy, but the choice to do it depends on the tolerance of the patient and on the severity of the underlying valve disease.51

Mechanical Heart Valves Anticoagulation of mechanical heart valves is also a challenge in pregnant patients, and current evidence, even though randomised studies are lacking, tends to indicate that VKAs with a strictly controlled INR are the safest treatment to avoid valve thrombosis throughout pregnancy. For example, VKAs should be continued throughout pregnancy and replaced by UFH at 36 weeks of gestation, particularly when the required VKA dose is low (warfarin <5 mg/day, phenprocoumon <3 mg/day or acenocoumarol <2 mg/day), because of the low risks of embryopathy, foetopathy (<2%) and foetal loss (<20%) and because VKAs are the most effective regimen to prevent valve thrombosis.

When a higher dose of VKAs is required, discontinuation of VKAs between weeks 6 and 12, and replacement with adjusted-dose intravenous UFH or LMWH twice daily with dose adjustment according to peak anti-Factor Xa levels, should be considered. The use of LMWH remains controversial due to the higher risk of valve thrombosis that is mitigated by a strict control of anti-Factor Xa levels. The treatment must be discussed with the patient and individualised, especially in terms of VKA dosage, according to the stage of pregnancy (with the first trimester to be considered on its own), the patient’s compliance and the type of prosthesis.11,43

Conclusion Fondaparinux Fondaparinux is a direct inhibitor of Factor Xa activity via antithrombin III binding. Given the scarce evidence on the use of fondaparinux in pregnancy, together with possible minor transplacental passage, its use should be limited to cases of documented allergy or adverse response to LMWH. More data are required to assess the risk of congenital malformations with fondaparinux.49,50

Practical Use of Anticoagulation Therapy During Pregnancy Native Valve Disease Systemic embolisation may occur in up to 10–20% of patients with MS, with the highest risk in patients with AF. Pregnancy is associated with a

1.

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In conclusion, VHD is a relatively rare condition in pregnant woman, but should be carefully managed due to the risk of cardiac decompensation and worsening prognoses for both the mother and foetus. A multidisciplinary pregnancy heart team should be involved in any clinical steps, from prepregnancy counselling to management during pregnancy and around delivery, in order to anticipate and potentially avoid complications.

Evolving technologies in the field of interventional cardiology have been developed, allowing, in many cases, a minimally invasive transcatheter treatment of VHD. The risk–benefit ratio for both the mother and foetus must be considered when planning these procedures, and every effort must be made to minimise the risks.

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Thorne S. Pregnancy and native heart valve disease. Heart 2016;102:1410–7. https://doi.org/10.1136/ heartjnl-2014-306729; PMID: 27390366.

Samiei N, Amirsardari M, Rezaei Y, et al. Echocardiographic evaluation of hemodynamic changes in left-sided heart valves in pregnant women with valvular heart disease. Am J Cardiol 2016;118:1046–52. https://doi.org/10.1016/j. amjcard.2016.07.005; PMID: 27506332. van Hagen IM, Thorne SA, Taha N, et al. Pregnancy outcomes in women with rheumatic mitral valve

disease: results from the Registry of Pregnancy and Cardiac Disease. Circulation 2018;137:806–16. https://doi.org/10.1161/CIRCULATIONAHA.117.032561; PMID: 29459466.

9. Kupferminc MJ. Thrombophilia and pregnancy. Reprod Biol Endocrinol 2003;1:111. https://doi.org/10.1186/1477-7827-1111; PMID: 14617365.

10. Elkayam U, ed. Cardiac Problems in Pregnancy. 4th ed. Hoboken, NJ: Wiley-Blackwell, 2020. https://doi.org/10.1002/ 9781119409861.

11. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J 2018;39:3165–241. https://doi.org/10.1093/eurheartj/ehy340; PMID: 30165544.

INTERVENTIONAL CARDIOLOGY REVIEW

Catheter-based Interventions in Pregnancy 12. John AS, Gurley F, Schaff HV, et al. Cardiopulmonary bypass during pregnancy. Ann Thorac Surg 2011;91:1191–6. https://doi. org/10.1016/j.athoracsur.2010.11.037; PMID: 21440145.

13. Parry AJ, Westaby S. Cardiopulmonary bypass during pregnancy. Ann Thorac Surg 1996;61:1865–9. https://doi. org/10.1016/0003-4975(96)00150-6; PMID: 8651812.

14. Inoue K, Owaki T, Nakamura T, et al. Clinical application of transvenous mitral commissurotomy by a new balloon catheter. J Thorac Cardiovasc Surg 1984;87:394–402. https://doi. org/10.1016/S0022-5223(19)37390-8; PMID: 6700245.

15. Lock JE, Khalilullah M, Shrivastava S, et al. Percutaneous catheter commissurotomy in rheumatic mitral stenosis. N Engl J Med 1985;313:1515–8. https://doi.org/10.1056/ NEJM198512123132405; PMID: 4069160.

16. Silversides CK, Colman JM, Sermer M, Siu SC. Cardiac risk in pregnant women with rheumatic mitral stenosis. Am J Cardiol 2003;91:1382–5. https://doi.org/10.1016/S0002-9149(03)003394; PMID: 12767443.

17. Hameed A, Karaalp IS, Tummala PP, et al. The effect of valvular heart disease on maternal and fetal outcome of pregnancy. J Am Coll Cardiol 2001;37:893–9. https://doi.org/10.1016/S07351097(00)01198-0; PMID: 11693767.

18. Sharma JB, Yadav V, Mishra S, et al. Comparative study on maternal and fetal outcome in pregnant women with rheumatic heart disease and severe mitral stenosis undergoing percutaneous balloon mitral valvotomy before or during pregnancy. Indian Heart J 2018;70:685–9. https://doi. org/10.1016/j.ihj.2018.01.018; PMID: 30392507.

19. de Souza JA, Martinez EE, Ambrose JA, et al. Percutaneous balloon mitral valvuloplasty in comparison with open mitral valve commissurotomy for mitral stenosis during pregnancy. J Am Coll Cardiol 2001;37:900–3. https://doi.org/10.1016/S07351097(00)01184-0; PMID: 11693768.

20. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. https://doi.org/10.1093/eurheartj/ ehx391; PMID: 28886619.

21. Guerrero M, Dvir D, Himbert D, et al. Transcatheter mitral valve replacement in native mitral valve disease with severe mitral annular calcification: results from the first multicenter global registry. JACC Cardiovasc Interv 2016;9:1361–71. https://doi. org/10.1016/j.jcin.2016.04.022; PMID: 27388824.

22. Taramasso M, Gavazzoni M, Nickenig G, Maisano F. Transcatheter mitral repair and replacement: which procedure for which patient? EuroIntervention 2019;15:867–74. https://doi. org/10.4244/EIJ-D-19-00743; PMID: 31746753.

23. Silversides CK, Colman JM, Sermer M, et al. Early and intermediate-term outcomes of pregnancy with congenital aortic stenosis. Am J Cardiol 2003;91:1386–9. https://doi. org/10.1016/S0002-9149(03)00340-0; PMID: 12767444.

24. Orwat S, Diller GP, van Hagen IM, et al. Risk of pregnancy in moderate and severe aortic stenosis: from the multinational ROPAC registry. J Am Coll Cardiol 2016;68:1727–37. https://doi. org/10.1016/j.jacc.2016.07.750; PMID: 27737738.

25. Myerson SG, Mitchell ARJ, Ormerod OJM, Banning AP. What is the role of balloon dilatation for severe aortic stenosis during

pregnancy? J Heart Valve Dis 2005;14:147–50. PMID: 15792172.

26. Radford DJ, Walters DL. Balloon aortic valvotomy in pregnancy.

Aust N Z J Obstet Gynaecol 2004;44:577–9. https://doi. org/10.1111/j.1479-828X.2004.00293.x; PMID: 15598301.

27. McKellar SH, MacDonald RJ, Michelena HI, et al. Frequency of cardiovascular events in women with a congenitally bicuspid aortic valve in a single community and effect of pregnancy on events. Am J Cardiol 2011;107:96–9. https://doi.org/10.1016/j. amjcard.2010.08.061; PMID: 21146694.

28. Hodson R, Kirker E, Swanson J, et al. Transcatheter aortic valve replacement during pregnancy. Circ Cardiovasc Interv 2016;9:e004006. https://doi.org/10.1161/ CIRCINTERVENTIONS.116.004006; PMID: 27733429.

29. Biner S, Perk G, Kar S, et al. Utility of combined twodimensional and three-dimensional transesophageal imaging for catheter-based mitral valve clip repair of mitral regurgitation. J Am Soc Echocardiogr 2011;24:611–7. https://doi. org/10.1016/j.echo.2011.02.005; PMID: 21435839.

30. Shiota T. Role of echocardiography for catheter-based management of valvular heart disease. J Cardiol 2017;69:66–73. https://doi.org/10.1016/j.jjcc.2016.09.015; PMID: 27863908.

31. Zhong C, Rokey R, Rolak S, Mesa J. Pregnancy and transcatheter aortic valve replacement in a severely stenotic Freestyle full aortic root stentless bioprosthesis. Catheter Cardiovasc Interv 2020;95:1225–9. https://doi.org/10.1002/ ccd.28481; PMID: 31483554.

32. Berry N, Sawlani N, Economy K, et al. Transcatheter aortic valve replacement for bioprosthetic aortic stenosis in pregnancy. JACC Cardiovasc Interv 2018;11:e161–2. https://doi. org/10.1016/j.jcin.2018.07.046; PMID: 30286865.

33. Herbert KA, Sheppard SM. Not your typical dyspnea of pregnancy: a case report of transcatheter valve-in-valve replacement during pregnancy. A A Pract 2019;12:202–4. https://doi.org/10.1213/XAA.0000000000000884; PMID: 30199399.

34. Chengode S, Shabadi RV, Rao RN, et al. Perioperative management of transcatheter, aortic and mitral, double valvein-valve implantation during pregnancy through left ventricular apical approach. Ann Card Anaesth 2018;21:185–8. https://doi. org/10.4103/aca.aca_157_17; PMID: 29652282.

35. Chhatriwalla AK, Allen KB, Saxon JT, et al. Bioprosthetic valve fracture improves the hemodynamic results of valve-in-valve transcatheter aortic valve replacement. Circ Cardiovasc Interv 2017;10: e005216. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.005216; PMID: 28698291.

36. Yoon I, Slesinger TL. Radiation Exposure In Pregnancy. StatPearls, 2019. https://www.ncbi.nlm.nih.gov/books/NBK551690/ (accessed 9 June 2020).

37. Wieseler KM, Bhargava P, Kanal KM, et al. Imaging in pregnant patients: examination appropriateness. Radiographics 2010;30:1215–29. https://doi.org/10.1148/rg.305105034; PMID: 20833847.

38. Ntusi NAB, Samuels P, Moosa S, Mocumbi AO. Diagnosing cardiac disease during pregnancy: imaging modalities.

Cardiovasc J Afr 2016;27:95–103. https://doi.org/10.5830/CVJA2016-022; PMID: 27213857.

39. Beyer-Westendorf J, Michalski F, Tittl L, et al. Pregnancy outcome in patients exposed to direct oral anticoagulants – and the challenge of event reporting. Thromb Haemost 2016;116:651–8. https://doi.org/10.1160/TH16-04-0305; PMID: 27384740.

40. van Driel D, Wesseling J, Sauer PJJ, et al. Teratogen update: fetal effects after in utero exposure to Coumarins. Overview of cases, follow-up findings, and pathogenesis. Teratology 2002;66:127–40. https://doi.org/10.1002/tera.10054; PMID: 12210474.

41. van Hagen IM, Roos-Hesselink JW, Ruys TPE, et al. Pregnancy in women with a mechanical heart valve: data of the European Society of Cardiology Registry of Pregnancy and Cardiac Disease (ROPAC). Circulation 2015;132:132–42. https:// doi.org/10.1161/CIRCULATIONAHA.115.015242; PMID: 26100109.

42. Hassouna A, Allam H. Limited dose warfarin throughout pregnancy in patients with mechanical heart valve prosthesis: a meta-analysis. Interact Cardiovasc Thorac Surg 2014;18:797– 806. https://doi.org/10.1093/icvts/ivu009; PMID: 24595247.

43. Xu Z, Fan J, Luo X, et al. Anticoagulation regimens during pregnancy in patients with mechanical heart valves: a systematic review and meta-analysis. Can J Cardiol 2016;32:1248.e1–9. https://doi.org/10.1016/j.cjca.2015.11.005; PMID: 26927861.

44. D’Souza R, Ostro J, Shah PS, et al. Anticoagulation for pregnant women with mechanical heart valves: a systematic review and meta-analysis. Eur Heart J 2017;38:1509–16. https://doi. org/10.1093/eurheartj/ehx032; PMID: 28329059.

45. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401–7. https://doi.org/10.1182/ blood-2005-02-0626; PMID: 15811953.

46. Jacobson B, Rambiritch V, Paek D, et al. Safety and efficacy of enoxaparin in pregnancy: a systematic review and metaanalysis. Adv Ther 2020;37:27–40. https://doi.org/10.1007/ s12325-019-01124-z; PMID: 31673991.

47. Lu E, Shatzel JJ, Salati J, Deloughery TG. The safety of lowmolecular-weight heparin during and after pregnancy. Obstet Gynecol Surv 2017;72:721–9. https://doi.org/10.1097/ OGX.0000000000000505; PMID: 29280473.

48. Friedrich E, Hameed AB. Fluctuations in anti-Factor Xa levels with therapeutic enoxaparin anticoagulation in pregnancy. J Perinatol 2010;30:253–7. https://doi.org/10.1038/jp.2009.164; PMID: 19829297.

49. De Carolis S, Di Pasquo E, Rossi E, et al. Fondaparinux in pregnancy: could it be a safe option? A review of the literature. Thromb Res 2015;135:1049–51. https://doi. org/10.1016/j.thromres.2015.04.001; PMID: 25912931.

50. Dempfle C-EH. Minor transplacental passage of fondaparinux in vivo. N Engl J Med 2004;350:1914–5. https://doi.org/10.1056/ NEJM200404293501825; PMID: 15115845.

51. Wang Y-C, Chen C-H, Su H-Y, Yu M-H. The impact of maternal cardioversion on fetal haemodynamics. Eur J Obstet Gynecol Reprod Biol 2006;126:268–9. https://doi.org/10.1016/j. ejogrb.2005.11.021; PMID: 16377063.

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Structural

Intraventricular Conduction Disturbances After Transcatheter Aortic Valve Implantation Shu-I Lin,1 Mizuki Miura,2 Ana Paula Tagliari,2 Ying-Hsian Lee,1 Shinichi Shirai,3 Rishi Puri,4 Francesco Maisano2 and Maurizio Taramasso2 1. Cardiovascular Center, MacKay Memorial Hospital, Taipei, Taiwan; 2. Department of Cardiac Surgery, University Hospital Zurich, Zurich, Switzerland; 3. Department of Cardiology, Kokura Memorial Hospital, Fukuoka, Japan; 4. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, US

Abstract Despite significant improvements in transcatheter aortic valve implantation (TAVI) outcomes, periprocedural conduction disturbances, such as new-onset left bundle branch block (LBBB) and new pacemaker implantation (PMI), remain relatively frequent concerns. The development of periprocedural conduction disturbances can be explained by the proximity between the aortic valve and the conduction system. Although prior studies reported heterogeneity in PMI rates after TAVI, current evidence supports the potentially deleterious consequence of LBBB and PMI, and several predisposing factors have been reported. Therefore, new strategies to avoid conduction disturbances and to improve their management are required, particularly with the current trend to expand TAVI to a low-risk population.

Keywords Transcatheter aortic valve implantation, conduction abnormality, left bundle branch block, pacemaker implantation Disclosure: MM has been a consultant for Japan Lifeline. APT is supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil (Finance Code 001). RP has received consulting fees from Medtronic and has minor equity in Centerline Biomedical. FM has received grant and/or research support from Abbott, Medtronic, Edwards Lifesciences, Biotronik, Boston Scientific Corporation, NVT and Terumo; receives consulting fees and honoraria from Abbott, Medtronic, Edwards Lifesciences, SwissVortex, Perifect, Xeltis, Transseptal Solutions, Cardiovalve and Magenta; has royalty income or intellectual property rights from Edwards Lifesciences; and is a shareholder of Cardiovalve, Cardiogard, Magenta, SwissVortex, Transseptal Solutions, 4Tech and Perifect.

MT is a consultant for Abbott Vascular, Boston Scientific, 4tech and CoreMedic; and has received speaker honoraria from Edwards Lifesciences. All other authors have no conflicts of interest to declare.

Acknowledgements: The authors thank Takeshi Masui for creating Figure 1. SIL and MM contributed equally as first author.

Received: 8 March 2020 Accepted: 9 June 2020 Citation: Interventional Cardiology Review 2020;15:e11. DOI: https://doi.org/10.15420/icr.2020.07 Correspondence: Mizuki Miura, University Heart Center Zurich, Rämistrasse 100, CH-8091, Zurich, Switzerland. E: mizumiura-circ@umin.ac.jp 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 noncommercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve implantation (TAVI) is now established as the standard treatment for symptomatic severe aortic stenosis (AS) in patients at high or prohibitive surgical risk, and the preferred treatment for those at intermediate risk.1 Based on recent trials in low-risk patients, the indications for TAVI are expanding towards the lower-risk classes, and the procedure has even been discussed for younger and asymptomatic patients.2,3 Although a significant reduction in periprocedural morbidity and mortality has been observed for TAVI over the past decade due to better patient selection, device design and operator experience, the occurrence of periprocedural conduction disturbances remains a concern.4 The most common post-TAVI conduction abnormalities are left bundle branch block (LBBB) and high-degree atrioventricular block (HAVB) requiring pacemaker implantation (PMI).5 Although the clinical effects of new-onset LBBB and PMI after TAVI remain controversial, substantial evidence supports an association of these conduction abnormalities with adverse effects.6,7 With an expanding indication for TAVI, the possible deleterious consequences of LBBB and PMI need to be taken

Access at: www.ICRjournal.com

into account and further clarified. We review the current evidence in conduction abnormalities after TAVI and how to manage them.

Mechanisms of Conduction Disturbances in Transcatheter Aortic Valve Implantation The development of periprocedural conduction disturbances can be explained by the proximity of the aortic valve with the conduction system. The atrioventricular (AV) node is located within the triangle of Koch in the right atrium and is in close proximity to the subaortic region and the membranous septum (MS). The AV node continues as the bundle of His and branches into the right and left bundle branch (RBB and LBB, respectively). The bundle of His is located in the MS and the LBB emerges at the level of the non-coronary aortic cusp, just below the posteroinferior MS edge. Thus, the length of the MS is equal to the distance between the aortic annulus and the exit point of the bundle of His.8 This close relationship between the LBB and aortic cusp explains the predisposition to conduction disturbances after TAVI (Figure 1).

Direct mechanical insult to the conduction system due to inflammation, oedema, localised haematoma and ischaemia of surrounding tissue

© RADCLIFFE CARDIOLOGY 2020

Intraventricular Conduction Disturbances After TAVI Figure 1: Anatomical Relationships Between the Aortic Cuspids, Membrane Septum and Conduction System A

B

MS

NCC

RCC

LCC

LBB PB RBB

MS

AVN LBB

A: The penetrating bundle of His emerges at the surface of the left ventricular outflow tract beneath the membrane septum (MS). The length of the MS is equal to the distance between the aortic annulus and bundle of His. B: The left bundle branch emerges beneath the MS and is positioned between the right coronary cusp and non-coronary cusp. AVN = atrioventricular node; LBB = left bundle branch; LCC = left coronary cusp; PB = penetrating bundle; MS = membrane septum; NCC = non-coronary cusp; RBB = right bundle branch; RCC = right coronary cusp.

caused by TAVI was demonstrated by previous studies.9 If a branching bundle of His lies superficially within the left half of the ventricular septum, or the LBB is briefly exposed, the chances of conduction disturbance after TAVI are increased.10

New-Onset Left Bundle Branch Block After Transcatheter Aortic Valve Implantation Incidence New-onset LBB block (LBBB) is the most frequently observed conduction abnormality after TAVI. The incidence of new-onset LBBB varies considerably in previous studies because of differences in the inclusion of transient LBBB, timing of measurement and the type of transcatheter valve. The incidence of new-onset LBBB has been reported to range from 4% to 65% after TAVI with first-generation valves.11–14 The incidence of new-onset LBBB was higher with self-expandable CoreValve devices (Medtronic), with rates ranging from 18% to 65%, than with balloonexpandable SAPIEN/SAPIEN XT devices (Edwards Lifesciences), with rates ranging from 4% to 30%.15 The incidence of new-onset LBBB after TAVI with newer-generation devices ranges from 13% to 78% (Table 1). Similar occurrence rates were reported for SAPIEN 3 (13–22%) and Portico (Abbott Vascular; 28%).2,4,16– 19 The incidence of new-onset LBBB appears to be more frequent for some self-expandable newer-generation devices, such as the Evolut R/ PRO (Medtronic; 44%) and Lotus (Boston Scientific; 74%).20–22

Timing Most of the conduction disturbances after TAVI occur periprocedurally or within the first 24 hours of TAVI, with 90% diagnosed within the first week after the procedure.23 New-onset LBBB can be transient and recover within the first few days. In a previous study, only 52% of patients who developed new LBBB after CoreValve implantation had persistent LBBB at discharge, but this mostly persisted out to 30 days.24 A recent study showed new LBBB after TAVI resolved in 33% of patients at 1-year follow-up, and no clinical or ECG variables predicted LBBB recovery.25 Late-recovery or delayed-onset LBBB after discharge or at

INTERVENTIONAL CARDIOLOGY REVIEW

Table 1: Incidence of New-onset Left Bundle Branch Block Following Transcatheter Aortic Valve Implantation Authors

Mack et al.2 De Torres-Alba et al.

Walther et al.19 20

4

No. Patients

Valve Type

Incidence of New-onset LBBB, n (%)

496

SAPIEN 3

106 (22)

162

SAPIEN 3

21 (13)

187

Portico

53 (28)

225

Evolut R

116 (51)

Rao et al.21

109

Evolut R/PRO

44 (40)

Zaman et al.22

95

Lotus

74 (78)

Chamandi et al.

LBBB = left bundle branch block.

30 days is rare. Delayed-onset LBBB at discharge to 30 days was reported in only 1.8% of patients after SAPIEN valve implantation and in 2.9% of patients at 6 months to 1 year.13

Clinical Outcomes A previous study reported that new-onset LBBB worsened 1-year survival after surgical aortic valve replacement.26 However, the clinical impact of new-onset LBBB after TAVI remains controversial. De Carlo et al. reported that of 275 patients undergoing TAVI, 34.5% developed new LBBB.27 Among patients who did not undergo PMI, 1-year overall survival rates were similar between those who developed new LBBB and those who did not.27 Similar results were reported among 201 Asian patients undergoing TAVI; new-onset LBBB or PMI was not associated with 1-year all-cause and cardiovascular mortality, or with hospitalisation due to heart failure.28 Moreover, in a meta-analysis of 4,756 patients, new-onset LBBB was not associated with a significant increase in all-cause mortality.29 However, that study reported that new LBBB was associated with a higher risk of 1-year cardiovascular mortality and PMI. Data from the Placement of AoRTic TraNscathetER Valve (PARTNER) Trial also showed that new-onset LBBB was associated with increased PMI during hospitalisation (8.3% versus 2.8%; p=0.005)

Structural and from discharge to 1 year (4.7% versus 1.5%; p=0.01).13 In addition, left ventricular ejection fraction (LVEF) declined more and was significantly lower in patients with than without new LBBB (53.4% versus 57.4%; p=0.02).

cardiac monitor device for close follow-up in this group of patients; however, the level of evidence for this measure remains low, and more evidence is still needed to determine which patient profile will benefit more from a prophylactic PMI approach.

Conversely, some studies have demonstrated that new-onset LBBB is an independent predictor of all-cause mortality at more than 2 years of follow-up.30,31 Nazif et al. reported the analysis of 1,179 intermediaterisk patients from the PARTNER II trial and revealed that new-onset LBBB was associated with increased all-cause mortality, cardiovascular mortality, rehospitalisation and new PMI at the 2-year follow-up.32 Similarly, another recent study reported that new-onset LBBB did not increase the risk of long-term all-cause mortality, cardiovascular mortality or rehospitalisation at a median follow-up of 3 years; however, it was associated with higher in-hospital mortality, PMI and lack of LVEF improvement.20 The discrepancy between studies may be explained by differences in patients’ baseline risk, sample size, type of transcatheter heart valve used, application of diagnostic ECG criteria, absence of a standardised definition of new-onset LBBB and the duration of follow-up.

Rodés-Cabau et al. recently proposed a strategy algorithm for the management of patients with new-onset LBBB after TAVI.38 Some characteristics of patients at higher risk were addressed and more aggressive management was recommended. Patients with persistent LBBB at Day 2 with QRS ≤150 ms and PR ≤240 ms could be discharged and continuous ECG monitoring (2–4 weeks) could be considered.

Patients with persistent LBBB at Day 2 with QRS >150 ms or PR >240 ms were at increased risk of delayed HAVB requiring PMI, and continuous ECG monitoring or electrophysiology studies may be considered to guide PMI decision. If further prolongation of the QRS or PR interval (of at least 20 ms) was observed after 24 h, evaluation with electrophysiological studies (followed by continuous ECG monitoring if no PMI) or direct PMI may be considered.

A recent meta-analysis of 12 studies summarised the clinical impact of new LBBB and reported an increased risk of all-cause death at 1-year follow-up in patients with new LBBB (RR 1.32; 95% CI [1.17–1.49]; p<0.001].33 It also demonstrated that the presence of new LBBB after TAVI was associated with a higher risk of 1-year cardiac death (RR 1.46; 95% CI [1.20–1.78]; p<0.001), 1-year heart failure hospitalisation (RR 1.35; 95% CI [1.05–1.72]; p=0.02) and 1-year PMI (RR 1.89; 95% CI [1.58–2.27]; p<0.001).

Management of New-onset Left Bundle Branch Block There are no standard guidelines to manage new-onset LBBB after TAVI. Because of the potential risk of early progression to HAVB (7–16%), monitoring patients with new LBBB with telemetry or daily 12-lead ECG for at least 2 days seems reasonable. Auffret et al. suggested keeping the temporary pacemaker and monitoring those patients with new LBBB in an intensive care unit for at least 24 hours.34 There is still no effective measure to manage patients with new-onset LBBB that lasts 48 hours after TAVI. In a study of 3,726 patients who had undergone TAVI, new-onset LBBB and QRS duration >160 ms at discharge were associated with increased risk of sudden cardiac death.35 Therefore, prophylactic PMI in this setting may be reasonable. A recent study reported that 9% of patients with new-onset LBBB developed advanced conduction disturbances requiring PMI during a 1-year follow-up period.25 In that study, the presence of AF, a longer PR interval at discharge and a longer PR interval change between baseline and discharge were associated with an increased risk of PMI. Close monitoring (i.e. Ziopatch) in this group of patients may be reasonable.

Almeida et al. studied a cohort of 138 patients after TAVI using multidetector CT (MDCT) and demonstrated that implantation depth assessed by MDCT is associated with new-onset conduction disturbances after TAVI.36 Postprocedural MDCT has the possibility of detecting patients at high risk of late-onset conduction disturbances.

A multicentre prospective study evaluated the role of an implantable cardiac monitor during the first year of follow-up in 103 patients with new-onset LBBB after TAVI.37 Significant bradycardia events were reported in 20% of patients and HAVB was observed in 15% of patients.

PMI was required in 10% of patients.37 These data support the use of a

Pacemaker Implantation After Transcatheter Aortic Valve Implantation Incidence Conduction disturbances requiring PMI are the most common complications after TAVI. A meta-analysis reported that among 11,210 patients from 41 studies, 1,917 (17%) underwent PMI after TAVI.39 The incidence of PMI after TAVI ranged from 2% to 51% in individual studies.

Similar to new-onset LBBB, PMI is more frequent with the firstgeneration Medtronic CoreValve than with the Edwards SAPIEN transcatheter heart valve.39,40 An Italian national prospective observational study comparing five leading new-generation TAVI devices reported that the incidence of PMI ranged from 5.6% to 23.2%.41 The five new-generation devices included ACURATE (Boston Scientific), Evolut R/PRO, Lotus/Lotus Edge (Boston Scientific), Portico and SAPIEN 3/SAPIEN 3 Ultra, with the results favouring ACURATE, with the Lotus transcatheter heart valve being associated with a higher rate of PMI. A registry enrolling 1,000 patients undergoing TAVI using a self-expanding ACURATE Neo showed a low rate of new PMI (9.9%), which is lower than rates for SAPIEN 3, Evolut R/PRO and Lotus.21,42–44 Several studies have reported that periprocedural TAVI complications have been significantly reduced with the introduction of newergeneration devices; however, no marked improvement in terms of PMI rate has been reported.45–47 Some studies showed an increased rate of PMI with SAPIEN 3 compared with the older SAPIEN XT (13.6% versus 9.5%; p=0.001).47 In addition, patient surgical risk does not seem to affect the rate of PMI. A multicentre Australian cohort reported that PMI rates were similar among patients with different classes of risk (21%, 27% and 26% in low-, intermediate- and high-risk groups, respectively).48 Conversely, a recent meta-analysis encompassing three randomised studies comparing TAVI to surgical aortic valve replacement in low-risk patients showed that, at 1 year, TAVI was related to a higher PMI risk (RR 3.47; 95% CI [1.33–9.07]; p=0.01).49 Some limitations regarding the evaluation of the incidence of PMI should be considered. Although HAVB is the most common indication for PMI after TAVI, the reported indications for PMI were inconsistent across the studies and may vary according to the operator or hospital criteria, with some institutions having a more aggressive approach than others.

Therefore, the proportion of patients who have undergone ‘prophylactic’ PMI not following the current guidelines is unknown. In addition, the

INTERVENTIONAL CARDIOLOGY REVIEW

Intraventricular Conduction Disturbances After TAVI current trend of shorter postprocedural hospital stay is a factor that can interfere with prophylactic PMI indications, resulting in a shorter period of clinical observation for new-onset conduction disturbances.

Timing and Evolution of High-degree Atrioventricular Block Leading to Pacemaker Implantation After TAVI Similar to new-onset LBBB, TAVI-induced HAVB occurs primarily in the periprocedural phase. A previous study showed that in patients requiring PMI due to HAVB after TAVI, 87% of HAVB occurred in the periprocedural phase.50 Toggweiler et al. studied 1,064 patients undergoing TAVI with CoreValve or SAPIEN XT/SAPIEN 3: 163 patients had new-onset of HAVB, of whom 56% had periprocedural HAVB and 44% had delayed HAVB (defined as not present on the first ECG after TAVI but occurring during 30-day follow-up).51 Among those with delayed HAVB, most events occurred within the first 48 hours and only 2.3% occurred 3–8 days after TAVI. Several lines of evidence support that the risk of late-onset conduction disturbance is low in patients with a normal ECG after TAVI. Independent predictors for late-onset conduction disturbance requiring PMI include pre-existing non-specific intraventricular conduction delay, pre-existing RBB block (RBBB), selfexpandable valves and predilation.52 Most HAVB tends to recover over time. In a study with 234 consecutive patients who underwent TAVI with CoreValve, 27.4% of patients underwent HAVB-related PMI. Half the patients who had an absolute indication for PMI had resolution of the conduction abnormality after 24 hours after TAVI.53 In another study of 1,198 patients who underwent TAVI, only 22.4% of patients who developed HAVB requiring PMI had persistent complete heart block at a follow-up of 73 days.54 Miura et al. provided long-term data on interrogations of the implanted pacemaker due to HAVB after TAVI with balloon-expandable valves: at 6 months and 1 year after PMI, 60% of patients who recovered from bradycardia had a ventricular pacing rate of ≤1.0%.28

Clinical Outcomes Right ventricular (RV) pacing results in inter- and intraventricular desynchrony, with subsequent detrimental effects on cardiac structure and function. Evidence supports RV pacing causing chronic left ventricular (LV) remodelling and, in some cases, possibly leading to adverse clinical outcomes, such as AF, heart failure and death.55–57 However, the clinical impact of PMI after TAVI remains controversial.

A meta-analysis including 7,032 patients reported that periprocedural PMI after TAVI was not associated with an increased risk for all-cause mortality at 1 year.29 In that study, a potentially protective effect of PMI on 1-year cardiac death was observed (RR 0.77; 95% CI [0.58–1.01]; p=0.06) in 4,362 patients following TAVI. This protective effect may be explained by PMI preventing progression towards complete AV block and sudden death. Another multicentre study including 1,629 patients undergoing TAVI reported that 19.8% of patients required PMI.21 After a median follow-up of 4 years, PMI was associated with an increased risk of heart failure rehospitalisation and a lack of LVEF improvement; however, there were no differences in all-cause and cardiovascular mortalities between those with and without PMI.21 In contrast, a negative clinical impact was reported in a cohort of 9,785 patients who underwent TAVI.58 PMI was required in 6.7% after TAVI and was associated with longer lengths of stay in hospital and in the intensive care unit. PMI was also related to higher mortality (24.1% versus 19.6%) and a composite of mortality or heart failure admission

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(37.3% versus 28.5%) at 1 year.58 A recent study reporting long-term follow-up results in a cohort of 1,116 post-TAVI patients showed that PMI was indicated in 13% of patients.59 At the 6-year follow-up, PMI was associated with increased all-cause mortality (57.0% versus 41.7%; p=0.034).59 Faroux et al. conducted a meta-analysis including 21 studies and demonstrated a deleterious effect of PMI on all-cause death (RR 1.17; 95% CI [1.11–1.25]; p<0.001) at the 1-year follow-up.33 That study also showed that PMI increased the risk of heart failure hospitalisation at 1 year (RR 1.18; 95% CI [1.03–1.36]; p=0.02), but had no significant effect on cardiac death at 1 year (RR 0.84; 95% CI [0.67– 1.05]; p=0.13).

The negative effect of RV pacing is related to the percentage of pacing. Only a few studies have reported pacemaker pacing frequency after TAVI; therefore, the clinical impact of PMI becomes hard to demonstrate. In a study of pacemaker dependency after TAVI, Costa et al. reported pacemaker dependency rates of 35.7%, 35.8% and 33.3% at 1, 6 and 12 months, respectively.59 At 6 years, pacemakerdependent patients showed a higher overall mortality than nondependent patients. Conversely, the negative effect of chronic pacing is counterbalanced by the protective effect of PMI against the risk of sudden death. Moreover, most prior studies enrolled TAVI patients who were elderly and vulnerable; thus, reduced life expectancy may limit the appearance of clinical outcome due to chronic pacingrelated ventricular dysfunction.

Management of High-degree Atrioventricular Block The latest European Society of Cardiology guidelines recommend that a period of clinical observation up to 7 days is indicated in order to assess whether HAVB after TAVI is transient and resolves before patients undergo PMI.60 This recommendation is supported by the observation that a significant proportion of HAVB recovers over time.

Considering the potential negative clinical impact of PMI after TAVI and complications associated with pacemakers, such as lead-related damage, pneumothorax, pocket haematoma or pacemaker infection, it is reasonable to have a watchful period before PMI.21,58,59 Conversely, a prolonged observation period with temporary pacemaker increases the risk of patient immobilisation, thromboembolism, catheter-related infection and cardiac perforation.61 However, prior studies showed that most PMI after TAVI occurred within the first 5 days. One reason is the current trend toward minimalist TAVI and the early discharge strategy. A meta-analysis of 1,775 patients comparing clinical outcomes between those with early (≤3 days) and standard discharge after TAVI found no significant differences between the two groups in terms of 30 day mortality and new PMI rates.62 This suggests that a watchful period of 3 days after an HAVB episode may be sufficient in selected patients. Auffret et al. suggested monitoring patients in intensive care units and keeping the temporary pacemaker for 24–48 hours before patients undergo PMI.34 Rodés-Cabau et al. proposed a comprehensive strategy of HAVB management and suggested that a 24-hour observation period following the procedural HAVB episode was a reasonable compromise.38 If HAVB persisted at 24 hours after TAVI, PMI was recommended and, if HAVB recovered, the temporary pacing wire could be removed with telemetry and daily ECG monitoring for one more day. If another episode of HAVB occurred during the 24-hour period, PMI was recommended.38 Patients could be discharged at day 2 after TAVI if there were no other episodes of HAVB and no other features potentially justifying PMI.

Structural Figure 2: ‘Cusp Overlap’ Technique With the Evolut System A

B

C

D

A: A sample case explaining the ‘cusp overlap’ technique. The right and left coronary cusps were overlapped, creating a three-cusp view including the non-coronary cusp. This fluoroscopic angle is usually right anterior oblique and caudal. Implantation was started at a high position at the level of the non-coronary cusp. B: After full deployment, there was asymmetric expansion.

C: Postdilatation. D: Final aortography.

Table 2: Risk Factors For Conduction Disturbances After Transcatheter Aortic Valve Implantation Procedural Factors Intraoperative atrioventricular block CoreValve, Evolut R/PRO, Lotus, Lotus Edge Implantation depth Oversizing of the prosthesis Implantation depth greater than MS length

Clinical Factors Preprocedural conduction abnormalities (especially RBBB) Amount of calcification of aortic valve and LVOT Prior coronary bypass surgery Prior MI Diabetes Age >80 years LVOT = left ventricular outflow tract; MS = membranous septum; RBBB = right bundle branch block.

Predictors of Conduction Disturbances After Transcatheter Aortic Valve Implantation Previous studies reported that predisposing factors for conduction disturbances after TAVI include preprocedural conduction abnormalities, previous coronary artery bypass surgery, diabetes, severity of calcification on the aortic valve, implantation depth, larger valve size, degree of prosthesis overexpansion and the use of a CoreValve system (Table 2).31,63–67 A meta-analysis reported that CoreValve implantation was associated with a 2.5-fold higher risk of PMI, which can be attributed to the greater radial force that exerts significantly more mechanical stress on the conduction system than a balloon-expandable prosthesis.39 Preexisting RBBB was also reported as a strong independent predictor of PMI after TAVI;39 this can be explained by the implanted prosthesis primarily affecting the LBBB and leading to complete AV block when there is a predamaged RBB. Valve oversizing by 10–15% has been associated with a higher risk of PMI after TAVI with first-generation devices.68 The MS length, a surrogate for the distance between the aortic annulus and the penetrating bundle of His, has been identified as a predictor of HAVB and PMI.8 A recent study demonstrated that there was higher risk of HAVB after TAVI when the implantation depth was greater than MS length rather than considering implantation depth

alone.69 Kiani et al. reported on a cohort of 1,266 patients who underwent TAVI with SAPIEN 3.70 In that study, the Emory risk score was proposed and validated on the basis of PMI risk predictors: a history of syncope (1 point), QRS duration ≥138 ms (1 point), pre-existing RBBB (2 points) and a degree of valve oversizing ≥16% (1 point). Patients with higher risk scores were more likely to require PMI after TAVI.70

Strategy to Prevent Pacemaker Implantation Preprocedural evaluation is important to prevent PMI. The presence of predisposing factors for PMI (Table 2), including baseline RBBB, may inform the need for careful procedural planning and continued observation for conduction deficits after the procedure.

The variables that can be controlled during the procedure are the depth of implantation, the choice of a self- or balloon-expandable valve and avoiding an oversized valve. Jilaihawi et al. suggested using an anatomically guided approach for device positioning based on the CT-determined MS length.69 This minimally higher depth of implantation approach reduced the rate of new PMI after placement of a selfexpandable valve to only 3% in that study cohort. In terms of the procedure itself, Tang et al. suggested using the ‘cusp overlap’ fluoroscopy view to guide implantation of self-expandable valves.71 A coplanar projection by overlapping the right and left coronary cusp offers several advantages: the delivery catheter more centred across the aortic valve and an en face view of non-coronary cusp (NCC) enable higher valve implantation with a lower risk of device embolisation (Figure 2). In addition, some centres have recently tried to perform high implantations using the radiolucent marker of the SAPIEN 3 (Figure 3a, blue line) instead of centre maker (Figure 3a, green line). In the case of nominal volume or overfilling, the top of the radiolucent marker was used to align the bottom of the NCC (Figure 3a, yellow arrow) and implant the SAPIEN 3. In the case of underfilling, the bottom of the radiolucent maker (Figure 3a, red arrow) was used to align the bottom of NCC and implant the SAPIEN 3. With this strategy, higher implantation is achieved (Figures 3b and 3c), which minimises the rate of PMI.

Choice of Pacemaker New LBBB after TAVI is associated with a decline in LV function, particularly in patients with pre-existing LV dysfunction.13 Biventricular pacing was demonstrated to have a beneficial effect on patients with HAVB and LV dysfunction.72 Previous case reports showed resynchronisation therapy improved the LV function of patients with chronic LV dysfunction developing persistent LBBB after TAVI.73,74 This

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Intraventricular Conduction Disturbances After TAVI Figure 3: High Implantation Technique for the SAPIEN 3 B

A

C

A: A sample case explaining the technique using a radiolucent marker (blue). The central marker is green. Yellow and red arrows indicate the top and bottom of the radialucent marker, respectively. B: Demonstration of optimal positioning of the SAPIEN 3. In this case, the annulus area calculated by CT was 624 mm2 and CT showed a moderately calcified type 1 bicuspid aortic valve. We decided to implant a 29 mm SAPIEN 3 with 3 ml underfilling. CT analysis indicated that the annulus in this case was between a 26 mm and 29 mm SAPIEN 3 and bicuspid aortic valve, suggesting to the operators that the SAPIEN 3 was not expanding fully and that the bottom of the SAPIEN 3 was not moving up so much. Thus, the SAPIEN 3 was implanted using the bottom of the radialucent marker. C: Final aortography.

strategy seems reasonable in select cases, but more evidence is needed to confirm the timing of implantation and potential clinical impact.

A previous study suggested that periodic examination and adjustment of pacemaker settings minimised the risk of long-term pacing in patients requiring PMI after TAVI.75 Prior studies also showed pacemaker dependency after TAVI was not so high.28,59 Thus, leadless pacemakers may contribute to less morbidity in these patients. Currently there is little evidence concerning the use of leadless pacemakers in patients after TAVI. A case report described the leadless pacemaker as an alternative choice for patients with conduction disturbances after TAVI to minimise procedural-related damage, especially for old and frail patients.76

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Conclusion Conduction disturbances remain a challenge even in the contemporary TAVI era. Most common conduction disturbances are new-onset LBBB and HAVB requiring PMI. These complications may portend a negative clinical impact on patients. Several predictors of conduction disturbances after TAVI have been reported previously. Efforts should be made to mitigate the risk of conduction disturbances after TAVI by considering preprocedural risk assessment, periprocedural planning, device selection and implantation technique. Further prospective studies are needed to define the optimal watchful period before PMI and to identify specific patients who may benefit from prophylactic and leadless PMI.

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2018;107:60–9. https://doi.org/10.1007/s00392-017-1158-2; PMID: 28963581.

55. Delgado V, Tops LF, Trines SA, et al. Acute effects of right ventricular apical pacing on left ventricular synchrony and mechanics. Circ Arrhythm Electrophysiol 2009;2:135–45. https:// doi.org/10.1161/CIRCEP.108.814608; PMID: 19808458.

56. Prinzen FW, Augustijn CH, Arts T, et al. Redistribution of myocardial fiber strain and blood flow by asynchronous activation. Am J Physiol 1990;259:H300–8. https://doi. org/10.1152/ajpheart.1990.259.2.H300; PMID: 2386214.

57. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003;107:2932–7. https://doi. org/10.1161/01.CIR.0000072769.17295.B1; PMID: 12782566.

58. Fadahunsi OO, Olowoyeye A, Ukaigwe A, et al. Incidence, predictors, and outcomes of permanent pacemaker implantation following transcatheter aortic valve replacement: analysis from the U.S. Society of Thoracic Surgeons/American College of Cardiology TVT Registry. JACC Cardiovasc Interv 2016;9:2189–99. https://doi.org/10.1016/j.jcin.2016.07.026; PMID: 27832844.

59. Costa G, Zappulla P, Barbanti M, et al. Pacemaker dependency after transcatheter aortic valve implantation: incidence, predictors and long-term outcomes. EuroIntervention

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Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on Cardiac Pacing and Resynchronization Therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013;34:2281–329. https://doi.org/10.1093/eurheartj/eht150; PMID: 23801822.

Metkus TS, Schulman SP, Marine JE, et al. Complications and outcomes of temporary transvenous pacing: an analysis of >360,000 patients from the National Inpatient Sample. Chest 2019;155:749–57. https://doi.org/10.1016/j.chest.2018.11.026; PMID: 30543806.

Kotronias RA, Teitelbaum M, Webb JG, et al. Early versus standard discharge after transcatheter aortic valve replacement: a systematic review and meta-analysis. JACC Cardiovasc Interv 2018;11:1759–71. https://doi.org/10.1016/j. jcin.2018.04.042; PMID: 30190065.

Hein-Rothweiler R, Jochheim D, Rizas K, et al. Aortic annulus to left coronary distance as a predictor for persistent left bundle branch block after TAVI. Catheter Cardiovasc Interv 2017;89:E162–8. https://doi.org/10.1002/ccd.26503; PMID: 27038099.

Houthuizen P, Van Garsse LA, Poels TT, et al. Left bundlebranch block induced by transcatheter aortic valve implantation increases risk of death. Circulation 2012;126:720– 8. https://doi.org/10.1161/CIRCULATIONAHA.112.101055; PMID: 22791865.

Aktug Ö, Dohmen G, Brehmer K, et al. Incidence and predictors of left bundle branch block after transcatheter aortic valve implantation. Int J Cardiol 2012;160:26–30. https:// doi.org/10.1016/j.ijcard.2011.03.004; PMID: 21458085.

Urena M, Webb JG, Cheema A, et al. Impact of new-onset persistent left bundle branch block on late clinical outcomes in patients undergoing transcatheter aortic valve implantation with a balloon-expandable valve. JACC Cardiovasc Interv 2014;7:128–36. https://doi.org/10.1016/j.jcin.2013.08.015; PMID: 24440024.

Katsanos S, van Rosendael P, Kamperidis V, et al. Insights into new-onset rhythm conduction disorders detected by multidetector row computed tomography after transcatheter aortic valve implantation. Am J Cardiol 2014;114:1556–61. https://doi. org/10.1016/j.amjcard.2014.08.020; PMID: 25245414.

Rodriguez-Olivares R, van Gils L, El Faquir N, et al. Importance of the left ventricular outflow tract in the need for pacemaker implantation after transcatheter aortic valve replacement. Int J Cardiol 2016;216:9–15. https://doi.org/10.1016/j. ijcard.2016.04.023; PMID: 27135150.

Jilaihawi H, Zhao Z, Du R, et al. Minimizing permanent pacemaker following repositionable self-expanding transcatheter aortic valve replacement. JACC Cardiovasc Interv 2019;12:1796–807. https://doi.org/10.1016/j.jcin.2019.05.056; PMID: 31473236.

Kiani S, Kamioka N, Black GB, et al. Development of a risk score to predict new pacemaker implantation after transcatheter aortic valve replacement. JACC Cardiovasc Interv 2019;12:2133–42. https://doi.org/10.1016/j.jcin.2019.07.015; PMID: 31699374.

Tang GHL, Zaid S, Michev I, et al. ‘Cusp-overlap’ view simplifies fluoroscopy-guided implantation of self-expanding valve in transcatheter aortic valve replacement. JACC Cardiovasc Interv 2018;11:1663–5. https://doi.org/10.1016/j.jcin.2018.03.018; PMID: 30139479.

Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013;368:1585–93. https://doi.org/10.1056/NEJMoa1210356; PMID: 23614585.

Meguro K, Lellouche N, Teiger E. Cardiac resynchronization therapy improved heart failure after left bundle branch block during transcatheter aortic valve implantation. J Invasive Cardiol 2012;24:132–3. PMID: 22388308.

Osmancik P, Stros P, Herman D, et al. Cardiac resynchronization therapy implantation following transcatheter aortic valve implantation. Europace 2011;13:290– 1. https://doi.org/10.1093/europace/euq336; PMID: 20852291.

Meduri CU, Kereiakes DJ, Rajagopal V, et al. Pacemaker implantation and dependency after transcatheter aortic valve replacement in the REPRISE III trial. J Am Heart Assoc 2019;8:e012594. https://doi.org/10.1161/JAHA.119.012594; PMID: 31640455.

Shikama T, Miura M, Shirai S, et al. Leadless pacemaker implantation following transcatheter aortic valve implantation using SAPIEN 3. Korean Circ J 2018;48:534–5. https://doi. org/10.4070/kcj.2018.0024; PMID: 29856150.

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Corrigendum

Corrigendum to: Management of Tricuspid Regurgitation: The Role of Transcatheter Therapies Maurizio Taramasso, Christelle Calen, Andrea Guidotti, Shingo Kuwata, Hector Rodriguez Cetina Biefer, Fabian Nietlispach, Michel Zuber and Francesco Maisano Heart Valve Clinic, University Hospital of Zurich, University of Zurich, Zurich, Switzerland

Citation: Interventional Cardiology Review 2020;15:e12. DOI: https://doi.org/10.15420/icr.2020.22 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 noncommercial purposes, provided the original work is cited correctly.

In the article by Taramasso et al. entitled Management of Tricuspid Regurgitation: The Role of Transcatheter Therapies (Interventional Cardiology Review 2017;12(1):51–5. https://doi.org/10.15420/ icr.2017:3:2), the following correction should be made.

The authors’ conflicts of interest were omitted at the time of publication.

They should read as follows: Maurizio Taramasso is a consultant for Abbott Vascular, Boston Scientific and 4tech; received personal fees from Edwards Lifesciences, Mitraltech, CoreMedic and Swissvortex; and is a shareholder of 4Tech.

Michel Zuber is a consultant for Abbott and Edwards Lifesciences.

Francesco Maisano discloses grant and/or research support from Abbott, Medtronic, Edwards Lifesciences, Biotronik, Boston Scientific, NVT and Terumo; consulting fees and honoraria from Abbott, Medtronic, Edwards Lifesciences, Swissvortex, Perifect, Xeltis, Transseptal Solutions, Cardiovalve (Mitraltech) and Magenta; royalty income/IP rights from Edwards Lifesciences; and is a shareholder of Cardiogard, Magenta, SwissVortex, Transseptalsolutions, Occlufit, 4Tech and Perifect.

All other authors have no conflicts of interest to declare.

Fabian Nietlispach serves a consultant for Edwards Lifesciences, Abbott, Medtronic and St Jude Medical.

© RADCLIFFE CARDIOLOGY 2020

The authors apologise for this error.

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Coronary

Cardioprotection for Acute MI in Light of the CONDI2/ERIC-PPCI Trial: New Targets Needed Joel P Giblett1 and Heerajnarain Bulluck2 1. Department of Cardiology, Liverpool Heart and Chest Hospital, Liverpool, UK; 2. Department of Cardiology, Norfolk and Norwich University Hospital, Norwich, UK

Abstract Protection against ischaemia–reperfusion injury after revascularisation in acute myocardial infarction remains an enigma. Many targets have been identified, but after the failure of the recent Effect of Remote Ischaemic Conditioning on Clinical Outcomes in ST-elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention (CONDI2/ERIC-PPCI) trial to show translation to clinical benefit, there is still no pharmacological or mechanical strategy that has translated to clinical practice. This article addresses the results of the CONDI2/ ERIC-PPCI trial in the context of previous studies of ischaemic conditioning, and then considers the prospects for other potential targets of cardioprotection. Finally, the authors examine the pitfalls and challenges in trial design for future investigation of cardioprotective strategies.

In particular, this article highlights the need for careful endpoint and patient selection, as well as the need to pay attention to the biology of cardioprotection during the study.

Keywords Cardioprotection, remote ischaemic conditioning, trial design, MI, glucagon-like peptide 1, ischaemia–reperfusion injury, cyclosporine A Disclosure: The authors have no conflicts of interest to declare.

Received: 23 January 2020 Accepted: 28 May 2020 Citation: Interventional Cardiology Review 2020;15:e13. DOI: https://doi.org/10.15420/icr.2020.01 Correspondence: Joel Giblett, Department of Cardiology, Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool L14 3PE, UK. E: joel.giblett@doctors.org.uk 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 noncommercial purposes, provided the original work is cited correctly.

The translation to clinical practice of agents or techniques that protect against the effect of ischaemia–reperfusion (IR) injury remains one of the most challenging areas of research in the field of cardiovascular medicine.1–4 This is particularly the case when IR injury follows revascularisation for acute MI (AMI). The publication of the combined Effect of Remote Ischaemic Conditioning on Clinical Outcomes in ST Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention (CONDI2/ERIC-PPCI) trial, which showed that remote ischaemic conditioning (RIC) did not reduce infarct size or improve cardiovascular outcomes, was a blow to the most promising cardioprotective target in the last few decades.5 This short article will set the scene for this trial, review the results and conclusions of the study, and then consider why the field of cardioprotection has suffered so many disappointing failures.

The Need for Cardioprotection Ischaemic heart disease remains the leading non-infective cause of morbidity and mortality in the world. Despite the advances in primary percutaneous coronary intervention (PPCI) during AMI, studies have suggested that up to 50% of the final infarcted territory is viable at the point of reperfusion.6,7 This suggests that continuing injury after, and attributable to, reperfusion occurs in the ischaemic myocardium. A therapy that consistently reduces the infarct size in this setting would have the potential to improve survival and reduce

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morbidity associated with AMI. IR injury is associated with recurrent ischaemia in the setting of no-reflow syndrome and coronary microvascular injury, heart failure secondary to impaired ventricular function, and an increased scar burden, which is associated with increased arrhythmia. Although timely reperfusion can limit these consequences, many patients are several hours into their AMI at the time of presentation. Mechanisms of myocardial IR injury are addressed in detail in other reviews.8,9

Ischaemic Conditioning The history of the field of cardioprotection stretches back more than 30 years, with extensive literature that is well reviewed elsewhere.10,11 In summary, ischaemic preconditioning was first demonstrated by Murry et al. when they discovered that a period of transient occlusion, followed reperfusion, of a canine coronary artery reduced infarct size when the same vessel was later subjected to a more prolonged period of ischaemia and reperfusion.12 This effect occurred even when the brief period of IR occurred in a different vascular bed, such as a different coronary artery, or a remote bed, such as a limb.13 This became known as remote ischaemic preconditioning. It was shown to reduce biomarker release and improve long-term outcomes when performed during elective percutaneous coronary intervention.14 Remote ischaemic preconditioning has a number of characteristics that need to be exploited for it to be effective. It is an all or nothing effect,

© RADCLIFFE CARDIOLOGY 2020

Cardioprotection for Acute MI

A number of small to medium-sized trials have attempted to confirm that RIC trials have shown benefits on surrogate markers for clinical outcome, such as infarct size and the myocardial salvage index.24–31 Others have confirmed benefits in clinical endpoints, such as major adverse cardiovascular and cerebrovascular events or mortality.32–34 More details regarding these randomised trials of ischaemic conditioning are shown in Table 1. Despite the abundance of smallscale studies demonstrating improvement, the practice of RIC did not translate into a change in clinical practice within interventional cardiology. Ischaemic conditioning in other contexts had been beset by a failure to translate into benefit in the largest-scale trials. For example, the large Remote Ischaemic Preconditioning for Heart Surgery (RIPHeart) and Effect of Remote Preconditioning on Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Graft Surgery (ERRICA) trials of ischemic conditioning prior to and during elective cardiac surgery with cardiopulmonary bypass did not show any evidence of improved outcomes.35,36 After these studies, a number of editorials suggested that the failures of translation in these studies were at least partially related to the effect of the anaesthetic agent, propofol, on the intracellular pathways of cardioprotection, as shown by Kottenberg et al., together with trial protocols that failed to address the populations most likely to benefit from RIC.37–39 Failure to address the biology of cardioprotection has been behind the difficulty in translating cardioprotective interventions into clinical practice for a long time (Figure 1).1,40–42

The CONDI2/ERIC-PPCI Trial The CONDI2/ERIC-PPCI trial was a combination of two trials with harmonised protocols to carry out single-blind RIC during ST-elevation MI (STEMI). The trial randomised 5,401 patients at 33 centres to receive either ischaemic conditioning using an automated remote ischaemic conditioning device, or a sham procedure. Some centres offered standard care rather than the sham. The primary endpoint was cardiovascular death or hospitalisation for heart failure at 12 months.

Secondary endpoints included major adverse cardiovascular and cerebrovascular events, and infarct size measured using the area under the curve for high-sensitivity troponin T.

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Onset

Time

Before PPCI centre Mild hypothermia RIC Oral antiplatelets

At PPCI centre RIC GLP-1 RA Cangrelor Beta blockade

After reperfusion Post-conditioning

Window closed

Ischaemia Reperfusion

Reperfusion with PPCI

Since remote ischaemic preconditioning was difficult to deliver prior to AMI in the clinical setting due to its unpredictable nature, other studies have considered whether postconditioning after the event, or delivering the conditioning stimulus during ischaemia, prior to reperfusion is of benefit. Zhao et al. demonstrated that a postconditioning stimulus, administered in the moments after reperfusion, was effective in reducing infarct size for patients receiving PPCI for AMI.21 This observation suggested that conditioning may be an adjunct to PPCI, limiting the impact of IR injury. While this study used a staggered reperfusion technique, others have demonstrated that RIC could protect the myocardium.22,23

Figure 1: The Window of Cardioprotection

Presentation

likely reflecting a steep dose–response curve, with a trigger threshold required to achieve protection.15 Both the number of cycles and their duration have been shown to be important in achieving protection.16 In trials where an adequate ‘dose’, usually a number of cycles of ischaemia and reperfusion, has not been achieved, there has been no cardioprotection. Furthermore, the protection is short-lived, with a window of only a few hours during which time the myocardium is protected. A second window of protection caused by transcriptional changes in the nucleus has also been investigated.17–20

After the window is closed, cardioprotection is unlikely to be effective

The opportunities for cardioprotection around ischaemia and reperfusion are shown. The time in which effective therapy can be delivered after reperfusion with percutaneous coronary intervention is brief. After this time the window in which patients will benefit is closed.

GLP-1 = glucagon-like peptide-1; PPCI = primary percutaneous coronary intervention; RA = receptor agonist; RIC = remote ischaemic conditioning. Source: Giblett et al. 2014.42 Adapted with permission from Elsevier.

The trial found that there were no clinically meaningful differences between the RIC group and the control group. The primary outcome occurred in 8.6% of the control group and 9.4% of the RIC group (treatment effect 1.10, 95% CI [0.91–1.32]; p=0.32) with no significant difference in biomarker-assessed infarct size. The cardiac MRI substudy is still awaited, but regardless of its findings it is unlikely to provide evidence that RIC offers substantial clinical benefit. Other editorial and opinion pieces have concluded that the low overall mortality was the reason for the failure of the study.43 Certainly, the study was appropriately powered for the expected event rate, but one possibility is that the patients were simply not unwell enough to see a significant benefit.

These findings are at odds with those of the previously published investigations discussed above. However, this study was adequately powered to provide a definitive answer, and evaluation of the previous literature now needs to be placed in the context of this study. Other studies were substantially smaller, with low numbers of events, potentially leading to type 1 error. Furthermore, publication bias may have favoured those RIC studies with positive results. The disappointing results of this trial have left researchers in the field looking for alternative targets that can be used to mitigate the impact of IR injury.

Alternative Targets for Cardioprotection A number of potential pharmacological targets have presented themselves as alternatives to RIC. These include agents that interact with the cascade of biochemical and cellular changes that lead to cell death. A comprehensive review of all targets that have been investigated is beyond the scope of this review, but many of these have failed to translate to clinical practice, because trials have ignored the biology of cardioprotection and benefit in vitro, or small animal studies have not been replicated in human trials. Table 2 offers some of the reasons for the failure of clinical trials.

Adenosine Binding of the adenosine receptor prior to ischaemia has been shown to provide cardioprotection and reduce infarct size. However, whether this benefit occurs if adenosine is administered after the onset of ischaemia is less clear. While some clinical studies have shown a reduction in infarct size and improvement in clinical outcome with adenosine, others have been neutral.44–47 These trials have been characterised by variability in dose, timing and route of

Coronary Table 1: The Flaws of Cardioprotective Trials Flaw

Explanation

Timing

• Must be administered during ischaemia or first moments of reperfusion to be effective • Intervention administered after cardioprotective window is closed will not reduce infarct size • For some interventions, however biologically attractive, timing may be impossible to practically achieve in the setting of AMI

Dose

• If the intervention does not achieve the required dose in the ischaemic tissue, it will not be effective • Careful decisions regarding route and timing of administration are required to ensure biological effects can be exploited • Animal and small-scale human dose finding studies will aid the design of larger scale trials

Patient selection

• Patients with both too little ischaemia and too long an ischaemic time are less likely to benefit from cardioprotective interventions • Heterogenous groups included in trials (older people and people with diabetes) may have different thresholds of resistance to cardioprotection • Optimising patient recruitment by including more high-risk patients may increase the chance of demonstrating benefit, as the cost of reduced applicability of the study to current practice

Animal studies

• Interventions with inconsistent effects in animal models need careful consideration before application to large-scale human trials • Attention to biology demonstrated in these studies, including evidence in larger animal models with physiology more closely related to humans, will improve trial design

Concurrent medication

• Exclusion of patients on medications likely to reduce the effectiveness of the intervention (such as propofol in CABG RIC trials) may increase the chance of demonstrating benefit

Endpoints

• Inconsistent use of endpoints between trials make comparison more challenging • Biomarker endpoints may be consistently reduced with cardioprotective interventions, but these may be of little clinical consequence • Care must be taken when infarct size is corrected for area at risk, particularly when estimation of area at risk can be affected by the intervention itself

AMI = acute MI; CABG = coronary artery bypass graft; RIC = remote ischaemic conditioning.

administration. A recent meta-analysis suggests there may be a benefit for intracoronary adenosine in reducing the incidence of heart failure after AMI.48

Glucagon-like Peptide-1 Glucagon-like peptide-1 (GLP-1) is an incretin hormone used as a target in the treatment of type 2 diabetes. GLP-1 receptors may provide cardioprotection through activation of intracellular pathways, such as the reperfusion injury survival kinase and survivor activating factor enhancement pathways.49,50 While these pathways share components with the pathways of ischaemic conditioning, they are not identical.51 GLP-1 receptor agonists have been shown to reduce the frequency of major adverse cardiovascular and cerebrovascular events in high-risk patients with diabetes in some larger cardiovascular outcome studies, improve myocardial function after non-lethal IR injury, as well as reducing infarct size and improving left ventricular function after PPCI in small proof of concept trials.52–57

reduced infarct size when administered before reperfusion, whereas in the Early Beta-blocker Administration Before Reperfusion in Patients with ST-elevation Myocardial Infarction (EARLY-BAMI) trial, a smaller dose given to a less selected population had no effect on infarct size.60,61 Earlier administration to metoprolol was associated with reduced infarct size in a post hoc analysis of METOCARD-CNIC.61 Furthermore, ivabradine, which acts at the sinoatrial node to reduce heart rate, reduced infarct size in a porcine model of IR injury, but when given to humans up to 1 hour after PPCI, no benefit was seen.62,63 This was likely too late to prevent IR injury.

Dose-finding and timing studies are not routinely undertaken in humans in the field of cardioprotection, often leaving more questions than answers in the search for protection. The interpretation of these larger studies has been confounded by the absence of appropriate early studies establishing these characteristics.

Cyclosporine However, not all trials have shown such benefit. GLP-1 agonists did not reduce the frequency of major adverse cardiovascular and cerebrovascular events following administration to diabetes patients after AMI, nor did they reduce periprocedural MI or cardiac troponin release during elective percutaneous coronary intervention.58,59 This conflicting evidence suggests the need for a larger and more definitive trial to establish benefit

Beta-blockers and Ivabradine Early administration of beta-blockers has been considered an attractive cardioprotective strategy, since cardiologists are familiar with administering these agents in this patient group, making translation to clinical practice easier if effective. However, there are discrepancies between trials of the beta-blocker metoprolol during STEMI. In the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) study, a large dose of IV metoprolol

Cyclosporine A prevents opening the mitochondrial permeability transition pore, which is part of the final pathway of cell death in reperfusion injury.64 Early trials showed apparent benefit in small numbers of patients treated with cyclosporine.65,66 Disappointingly, however, the much larger Cyclosporine to Improve Clinical Outcome in ST-elevation Myocardial Infarction Patients (CIRCUS) trial failed to show any benefit in terms of infarct size or clinical outcomes in patients with STEMI.67 This failure has been attributed to a number of different factors, including an increased length of ischemic time, a difference in the formulation of cyclosporine A and increased use of newer antiplatelet agents.9 Nonetheless, cyclosporine A has fallen at the same stage of translation as RIC. The definitive randomised control trial was neutral in outcome. Other mitochondrial permeability transition pore inhibitors have had mixed or neutral results in small proof of concept trials or animal studies.68 The mitochondrial permeability transition pore may remain a target for cardioprotection with the right agent.

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Cardioprotection for Acute MI Table 2: Randomised Trials of Ischaemic Conditioning in Primary Percutaneous Coronary Intervention Study

n

Endpoints

Results

Comments

Botker et al. 201024

333

Myocardial salvage index (MPI)

Mean salvage index 0.69 (RIC) versus 0.57 (control), p=0.03

RIC

118

25

Infarct size (CMR)

17% reduction in infarct size as %LV with PostC

PostC

Sorrenson et al. 201026 76

Infarct size (CMR)

No difference in infarct size for overall group, post hoc analysis suggests benefit in patients with large area at risk

PostC

Freixa et al. 201227

79

Myocardial salvage index (CMR)

Lower myocardial salvage index in PostC group (18.9 ± 27.4 versus 30.9 ± 20.5%, p=0.038). No significant difference in infarct size or LV ejection fraction

PostC

Zhao et al. 201228

62

LV ejection fraction (Echo)

No difference between PostC and control at 1 week. Improved LV ejection fraction at 6-month follow-up in PostC group

PostC

Thuny et al. 201229

50

Infarct size (CMR)

Reduced infarct size after PostC (13 ± 7 g/m2 versus 21 ± 14 g/m2; p=0.01). Note PostC also reduced myocardial oedema on CMR, suggesting this may not be reliable for area-at-risk calculation

PostC. Note: PostC also reduced myocardial oedema on CMR, suggesting this may not be reliable for area-at-risk calculation

Hahn et al. 201330 (POST)

700

ST segment resolution at 30 minutes

No difference between PostC and control in ST segment resolution at 30 minutes or MACE

PostC

Sloth et al. 201432

251

MACE

Reduced MACE events with HR 0.49 (95% CI [0.27–0.89]); p=0.018

All-cause mortality also improved in per protocol analysis

White et al. 201531

83

Infarct size (CMR)

Reduction in infarct size by 27% (p<0.01)

RIC. Also reduced myocardial oedema, and myocardial salvage index

Gaspar et al. 201833 (RIC STEMI)

448

Cardiovascular death or heart failure hospitalisation at long-term follow-up

Reduction in clinical events of composite endpoint at follow up (HR 0.35, 95% CI [0.15–0.78])

RIC

MACE

Combined RIC and PostC reduced events compared to control and PostC alone

1:1:1 randomisation to control, PostC alone, or PostC and RIC

No difference between RIC and control (HR 1.10, 95% CI [0.91–1.32], p=0.32)

RIC

Lonborg et al. 2010

Stiermaier et al. 201934 696 Hausenloy et al. 20195 (CONDI2/ERIC-PPCI)

5,401 Cardiovascular death or heart failure hospitalisation at 12 months

CMR = cardiac magnetic resonance; LV = left ventricle; MACE = major adverse cardiovascular events; MPI = myocardial perfusion imaging; PostC = postconditioning; RIC = remote ischaemic conditioning; STEMI = ST-elevation MI.

P2Y12 inhibitors Yang et al. first demonstrated a direct cardioprotective effect with the P2Y12 receptor antagonist cangrelor prior to reperfusion, and showed a 30% reduction in MI size in rabbits.69 Crucially, cangrelor was only effective at limiting MI size if it was administered prior to reperfusion.

Cangrelor-mediated cardioprotection (but not platelet inhibition) was abrogated by pharmacological inhibitors of phosphoinositide 3-kinase and mitogen-activated protein kinase kinase 1/2, both known mediators of cardioprotection, suggesting the protective effect of cangrelor was independent of antiplatelet effects.

The cardioprotective effects of P2Y12 inhibitors have also been shown using pretreatment with oral ticagrelor in rats, and cangrelor in primates.70,71 Furthermore, pretreatment with ticagrelor was also shown to reduce MI size in a porcine MI model.72 The Platelet Inhibition to Target Reperfusion Injury (PITRI) trial is currently ongoing, and is evaluating whether cangrelor administered prior to reperfusion would reduce reperfusion injury, as assessed by CMR in 210 patients (NCT03102723).73

Supersaturated Oxygen Therapy Delivery of supersaturated oxygen with a partial pressure of 750– 1,000 mmHg immediately after reperfusion has been shown to reduce anterior myocardial infarct size in the Acute Myocardial Infarction with Hyperoxemic Therapy II (AMIHOT-II) trial.74 Furthermore, the IC-HOT study demonstrated that it was feasible for supersaturated oxygen to be delivered directly to the left main stem during STEMI.75 While the

INTERVENTIONAL CARDIOLOGY REVIEW

TherOx system has been approved by the Food and Drug Administration for treatment of AMI, randomised trials have only been conducted in relatively small numbers of patients. Similar results have been seen for other cardioprotective interventions, which have proven to be ineffective in larger or less well selected trials. It is worth noting that in AMIHOT-II, only 317 patients out of 2,517 screened with STEMI were enrolled, and most of these failures were due to failure to meet inclusion criteria. It is uncertain how generalisable this data is to the unselected STEMI population. Larger trials in this area are required.

How Can We Do Better with Future Targets for Cardioprotection?

Translation in this field has proved beyond challenging. Despite an enormous investment of time, money and resources in the search for an adjunct to coronary revascularisation to prevent IR injury, no candidate therapy has become a part of the armamentarium of the interventional cardiologist. It is more than 30 years since the discovery of ischaemia preconditioning, but we still wait. Criticisms of decisions taken in trials are not new and have been repeated many times.

Nonetheless, it is worth rehearsing some of the challenges of study design, which may provide better direction for future research.

Failure to pay attention to the biology of IR injury, cardioprotection and the specific cardioprotective agents under investigation is a key factor in many studies. No agent will be effective at reducing infarct size if it is delivered too late, or in too small a dose to be effective.

Coronary Small-scale human trials can provide much information in this regard, and ideally dose and timing studies should be undertaken with appropriately powered surrogates for benefit, before proceeding to larger human studies. Careful selection of patients in both small and large studies is also key to success. Inclusion of patients who will not benefit from the intervention will reduce the power of the study to show benefit. This could include patients with both too little ischaemia or too long an ischaemic time. Enriching the cohort with patients likely to benefit, such as those with anterior infarcts or with moderate ischaemic times, will increase the power of the study to show benefit, although this may come at the cost of generalisability in the real world of clinical practice.

Post hoc analysis of the Botker et al. study suggests that RIC was effective in patients with a delayed transfer to a PPCI centre while not benefiting those who received more rapid reperfusion.24,76 Furthermore, inclusion of older patients, or patients with diabetes, may require adjustment of the dosing regimens to increase the likelihood of benefit.

The selection of a single target has been a consistent theme in trials of cardioprotection. It is possible that an effective reduction in infarct size depends upon accessing multiple pathways of cardioprotection simultaneously.77 There may be additive and synergistic effects between interrelated pathways, or it may be that in a heterogenous population presenting with AMI, different pathways will provide more or less effective cardioprotection for a given individual, depending upon comorbidities and other patient factors. A large number of animal models have been successfully tested, but there have been relatively few human trials of this approach reported. Combination Therapy in Myocardial Infarction (COMBAT-MI) is an example of a clinical trial combining RIC with exenatide infusion to evaluate whether combination therapy is more effective (NCT02404376).

Endpoint selection is a key factor in the success of translational studies.9 Assessment of infarct size using biomarker endpoints, such as cardiac troponin, are very sensitive, but unless high thresholds are used, small changes in these may be of limited clinical relevance, particularly in the context of periprocedural MI.78 Cardiomyocyte-specific creatine kinase has been shown to be the most robust biomarker for quantification of

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infarct size, but in clinical practice it has largely been replaced with cardiac troponin, which limits its availability for multicentre clinical trials.79 Cardiac MRI is an excellent method to quantify infarct size and assess cardioprotective strategies used during AMI.80,81 The more sensitive myocardial salvage index can be used to increase the power of the study, but remains controversial, as T2-weighted imaging is used to delineate the oedema-based area at risk.82 The myocardial oedema may be impacted by both the timing and nature of the intervention, and the timing of the MRI.29,31 New late gadolinium after AMI is a more robust tool to investigate the impact of cardioprotection in phase II studies.83 Assessment of the microcirculation may also prove to be important. Some retrospective evidence suggests that therapies improving microcirculatory function after MI may improve clinical outcome independently of the infarct size.84 This requires further investigation, and these endpoints investigated prospectively.

Clinical endpoints are important, but should reflect the biology of cardioprotection. Hard endpoints, such as cardiovascular mortality, are important. Endpoints, such as heart failure admission or the need for escalation in heart failure medication, are important, as this is the syndrome most likely to be impacted by therapies that reduce infarct size. They need to be carefully defined, as these are softer clinical endpoints that are vulnerable to a number of biases. Endpoints commonly used in trials of percutaneous coronary intervention strategies and stents, such as the need for repeat revascularisation, reduce the power of these studies to show benefit, as they are unlikely to be affected by the cardioprotective intervention.

Conclusion The CONDI2/ERIC-PPCI study was a well-run clinical trial of a potentially valuable therapy. Its neutral result leaves behind serious questions for the field of cardioprotection; the next avenue that should be pursued in a large-scale trial is not altogether clear. The development of collaborative groups, such as the European Society of Cardiology Working Group on Cellular Biology of the Heart and the EUCARDIOPROTECTION COST Action, to push the field forward is welcome, and is likely to produce more fruitful translation to clinical practice.

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Coronary

ISCHEMIA Trial and the Significance of MI Eduardo A Arias,1,2 Félix Damas-de los Santos1,2 and Heriberto Ontiveros-Mercado1 1. Department of Interventional Cardiology, National Institute of Cardiology, Mexico City, Mexico; 2. The American British Cowdray Medical Center, Mexico City, Mexico

Abstract During the past decade, the treatment of choice for chronic coronary syndromes (CCS) has been a contentious issue. Whether revascularisation, either percutaneous or surgical, or optimal medical therapy, offers better prognosis in terms of mortality, MI, and symptom relief, has yet to be confirmed. The long-awaited and recently published International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial randomised more than 5,000 patients into a revascularisation plus optimal medical therapy group and an optimal medical therapy alone group. The authors analyse the trial, with particular emphasis on the incidence of MI. They propose a patient-centred approach to incorporate the results of the ISCHEMIA trial into daily practice and determine the best treatment strategy for patients with CCS.

Keywords Chronic coronary syndromes, angina, ISCHEMIA trial, invasive strategy, optimal medical therapy, percutaneous coronary intervention, MI Disclosure: The authors have no conflicts of interest to declare.

Received: 7 May 2020 Accepted: 9 September 2020 Citation: Interventional Cardiology Review 2020;15:e14. DOI: https://doi.org/10.15420/icr.2020.15 Correspondence: Eduardo A Arias, National Institute of Cardiology, Juan Badiano No 1, Col. Sección XVI, Tlalpan, ZC, Mexico City 14080, Mexico.

E: dreduardoarias@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 noncommercial purposes, provided the original work is cited correctly.

For more than a decade, studies have sought to address the best treatment strategy for patients with chronic coronary syndromes (CCS), with many suggesting an invasive approach through revascularisation (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]), and others suggesting a conservative strategy, such as optimal medical therapy (OMT), for this heterogeneous group of patients.

Two important trials, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial and the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, were completed before the routine use of drug-eluting stents (DES) and enhanced adjunctive pharmacotherapy.1,2 The COURAGE trial demonstrated that the addition of PCI to OMT did not reduce the longterm rates of death and non-fatal MI, and the BARI 2D indicated less angina and subsequent coronary revascularisation. A meta-analysis in 2012 involving 7,229 patients did not demonstrate any reduction in death or MI with PCI versus OMT for patients with CCS.3 It is important to mention that, in that meta-analysis, up to one-third of patients in the OMT group required unplanned revascularisation at some point. With the subsequent development and introduction of novel stent technology (i.e. second-generation DES, thinner struts, bioresorbable polymers) and contemporary medical therapy, the need for randomised clinical trials became important.

The recently published International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial was a multicentre randomised trial that commenced in 2012.4 In total, 5,179 patients with moderate to severe ischaemia were assigned to an

© RADCLIFFE CARDIOLOGY 2020

initial invasive strategy (either PCI or CABG) plus either OMT or a conservative approach, based on OMT alone, with a median follow-up of 3.2 years. The main objective of the ISCHEMIA trial was to determine the effect of adding cardiac catheterisation and revascularisation to OMT in patients with CCS and moderate to severe ischaemia. Ischaemia had to be demonstrated using stress imaging or exercise-stress testing without imaging. High-risk patients were excluded, including those with recent acute coronary syndromes, an estimated glomerular filtration rate <30 ml/min/1.73 m2, an unprotected left main artery stenosis >50% by coronary computed tomographic angiography (CCTA), left ventricular ejection fraction <35%, New York Heart Association class III or IV and unacceptable/persistent angina despite OMT. The primary outcomes were a composite of death from cardiovascular (CV) causes, MI, hospitalisation for unstable angina, heart failure and resuscitated cardiac arrest. Secondary outcomes were a composite of death from CV causes, MI and angina-related quality of life.

The results of the study showed that an initial invasive strategy did not significantly reduce the rates of the primary or key secondary composite outcomes among patients with CCS and moderate to severe ischaemia upon stress testing. These results are in accordance with previous evidence, and although it would be easy to generalise these assumptions and continue to reduce the volume of PCIs performed in CCS patients, the incidence of MI in this landmark clinical trial needs to be discussed.5 MI in both groups demonstrated a particular behaviour. Patients in the invasive strategy group had a higher rate of non-significant CV events (CV death/MI) during the first year of follow-up due to an increased

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Coronary incidence of procedural MI. However, patients in the conservative strategy group had a higher rate of non-significant late CV events due to an increased incidence of non-procedural MI. Although the incidence of procedural MI was higher when the secondary MI definition was used, the opposing trend in MI was the same regardless of the definition.

We know from previous studies that procedural MI are associated with an increased risk of morbidity and mortality during the first year after revascularisation, and this clearly explains the higher incidence of early events in the invasive strategy group.6–8 As there is a lack of information relating to specific invasive percutaneous and surgical procedures, such as anatomical complexity, risk stratification, procedural success rate, stent restenosis/thrombosis, the incidence of chronic total occlusion, number of grafts, cardiopulmonary bypass time and complications, among many others (most of which are known procedural MI risk factors), it is futile to try to interpret the relevance of early procedural MI within the invasive strategy group.9 Instead, we focus on late CV events driven by differences in non-procedural MI between both treatment strategy groups.

After the second year, the conservative strategy group had a higher, sustained increase in the incidence of non-procedural MI compared with the invasive strategy group. Interestingly, this did not translate into increased mortality. One-fifth of these patients underwent revascularisation at some point during follow-up; 30% due to a confirmed primary event and 69% due to a suspected primary event, refractory angina, non-adherence or other event. Although differences in both early and late events lacked statistical significance, there was a clear separation in the time-to-event curves of non-procedural MI towards the end of the clinical follow-up period. This finding should compel researchers to undertake a longer monitoring period to establish if there are further differences in non-procedural MI rates, as a preliminary analysis of the ISCHEMIA trial data showed that nonprocedural MI resulted in a higher risk of subsequent death when compared to procedural MI. Furthermore, a recent meta-analysis of more than 14,000 patients (including ISCHEMIA patients) showed a significant decrease in late non-procedural MI with revascularisation at the expense of an increase in early procedural MI, indicating the benefits of revascularisation in CCS.10 There are some factors that we think could have influenced the incidence of late events in the invasive group. First, almost half of the randomised patients had angiographic or tomographic evidence of three-vessel disease. We know from previous studies that, in multivessel disease, single-photon emission computed tomography underestimates the true extent of coronary artery disease.11 Therefore, this poses the question of how many patients with mild/moderate ischaemia had the degree of their defect underestimated, and subsequently had a misled revascularisation. These non-obstructive lesions with mild/moderate ischaemia that were not revascularised could in part be responsible for late CV events.

Second, as part of the study protocol, vessels with stenotic lesions between 50% and 79%, with no ischaemia observed on stress imaging in the distribution of the stenosis, were required to have fractional flow reserve (FFR)/instantaneous wave-free ratio (iFR) performed to proceed with PCI. Despite this, the reported use of FFR/iFR was roughly 20%.

PCIs for these types of lesions and the use of intravascular physiology were left to the operator’s discretion. As such, we question whether a stricter application of FFR/iFR could have led to a decrease in the rates

of urgent revascularisation, as previously reported.12 Also, intracoronary physiology could have been very useful in patients with severe diffuse ischaemia without significant coronary stenosis.

Third, we question whether vulnerable non-obstructive plaques could be responsible for late non-procedural MI in the invasive strategy group. Recent evidence has shown that near-infrared spectroscopy ultrasound imaging can evaluate vulnerable plaques and identify segments and lesions at risk of future coronary events.13 To date, there has been no robust data that stenting non-obstructive vulnerable plaques leads to better clinical outcomes, although it has been reported that stenting significant vulnerable plaques does.

The results presented in this remarkable landmark trial provide us with valuable information and lessons that can be incorporated into daily practice (Table 1).

From a methodological point of view, there are some considerations that may be of great interest and warrant further investigation. First, the primary outcome definition was modified throughout the study as a protocol-defined procedure due to slow recruitment and lower-thanexpected aggregated event rates. The reduction in sample size then resulted in a decrease of power.

Second, the follow-up, as stated by the authors, was modest, with a 3.2-year median follow-up period. In terms of MI, there was a continuous and sustained, although non-significant, separation of the curves after the third year, with a greater number of non-procedural MIs in the conservative group. As previously discussed, a longer follow-up period is mandatory and will help to clarify whether the lack of differences in the primary outcomes between the groups is maintained over time.

Third, it is important to point out that, even though a secondary MI definition was added at some point during the study, this did not impact the results. Procedural MIs were more prevalent in the invasive group, and non-procedural MIs were more prevalent in the conservative group, regardless of the definition used.

Fourth, the majority of randomised patients were either asymptomatic or mildly symptomatic, so we must be cautious and avoid extrapolating these results to a more symptomatic/higher-risk group of patients.

Fifth, from an anatomical point of view, in the setting of moderate to severe ischaemia, the proportion between one–two vessel disease and three-vessel disease was about equal, which is remarkable. Anatomical complexity, employing the SYNTAX score, was not reported.

Sixth, PCI and CABG were treated as equivalent methods of revascularisation in the invasive group. Future analyses by the authors will clarify whether there is a difference in mortality and MI between these two revascularisation modalities in the setting of CCS. As per protocol, patients with a low SYNTAX score were deemed suitable for PCI, whereas patients with a high SYNTAX score were treated with CABG. Patients with an intermediate SYNTAX score could have either based on the centre of practice. Given that almost 75% of patients in the invasive group were treated by PCI, we can imply that the majority had low/intermediate anatomical complexity. This supports the concept of an ISCHEMIA type of patient being of low/intermediate risk, mildly symptomatic with moderate to severe ischaemia and with low/ intermediate anatomical complexity.

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ISCHEMIA Trial and MI Table 1: Proposed Approach to Incorporate ISCHEMIA Trial Results into Everyday Clinical Practice 1. Angina severity

Determine the clinical profile and risk of CCS patients. Always proceed with a patient-focused approach, rather than an imaging- or lesion-focused approach. Patients should be at least moderately symptomatic before requesting a stress imaging or exercise test.14 If symptoms are associated with an increased risk, then closer monitoring should be ensured.

2. CCTA

Relevant as an initial imaging modality to rule out LM stenosis in patients with mild symptoms, but with severe ischaemia.

3. Classic ISCHEMIA patient (low risk, mildly symptomatic with moderate to severe ischaemia on stress imaging)

It is reasonable to start OMT and follow-up, bearing in mind that there is a 20% chance of revascularisation at any point due to symptom progression, non-adherence or MI. Early PCI/CABG could also be offered, as there were no significant differences in terms of CV death and MI between both groups. Although early procedural MI incidence at 1 year was 5.3%, its long-term clinical significance is unknown.

4. Highly symptomatic ISCHEMIA patient

Revascularisation (PCI or CABG) showed a clear benefit in symptom reduction and quality of life when compared to OMT in the ISCHEMIA trial.15

5. High-risk patients (not included in the ISCHEMIA trial)

Significant LM stenosis, complex three-vessel disease, NYHA class III/IV ejection fraction <35% with a viable myocardium, unacceptable angina despite medical treatment: revascularisation (PCI or CABG) to improve survival and symptoms, as per current guidelines.16

6. FFR and intracoronary imaging

In patients with severe ischaemia and three-vessel disease, invasive physiological assessment should be mandatory to determine which vessels/lesions should be treated for complete revascularisation. Adding intravascular imaging (IVUS/optical coherence tomography) to assess plaque vulnerability should also be encouraged.

CABG = coronary artery bypass grafting; CCS = chronic coronary syndromes; CCTA = coronary computed tomographic angiography; FFR = fractional flow reserve; IVUS = intravascular ultrasound; LM = left main; NYHA = New York Heart Association; OMT = optimal medical therapy; PCI = percutaneous coronary intervention.

Finally, in the statistical analysis, the proportional hazards assumption underlying the Cox model was not met for the primary outcomes (patients in the invasive group had an increased risk of having a procedural MI, whereas patients in the conservative group did not).

Given this proportional hazards assumption violation, secondary outcomes were reported as cumulative event-rate estimates with CIs, which underpowers the conclusions and makes them difficult to interpret.

Conclusion The available data from randomised trials, including the ISCHEMIA trial, provide enough evidence to implement an initial OMT strategy in mildly symptomatic, low-risk patients, regardless of the degree of ischaemia on stress or exercise imaging. Around 20%–30% of these patients will require either a PCI or CABG due to angina progression/ unresponsiveness to medical therapy, non-adherence or development of an acute coronary syndrome. The invasive strategy showed a nonsignificant lower incidence of late non-procedural MI at the expense of

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Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease.

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Dagenais GR, Lu J, Faxon DP, et al. Effects of optimal medical treatment with or without coronary revascularization on angina and subsequent revascularizations in patients with type 2 diabetes mellitus and stable ischemic heart disease.

Circulation 2011;123:1492–500. https://doi.org/10.1161/ CIRCULATIONAHA.110.978247; PMID: 21444887.

Stergiopoulos K, Brown DL. Initial coronary stent implantation with medical therapy vs medical therapy alone for stable coronary artery disease: meta-analysis of randomized controlled trials. Arch Intern Med 2012;172:312–9. https://doi.org /0.1001/archinternmed.2011.1484; PMID: 22371919.

Maron DJ, Hochman HR, Reynolds S, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395–407. https://doi.org/10.1056/NEJMoa1915922; PMID: 32227755.

Bangalore S, Gupta N, Généreux P, et al. Trend in percutaneous coronary intervention volume following the COURAGE and BARI-2D trials: Insight from over 8.1 million percutaneous coronary interventions. Int J Cardiol 2015;183:6–10. https://doi. org/10.1016/j.ijcard.2015.01.053; PMID: 25662046.

Zeitouni M, Silvain J, Guedeney P, et al. Periprocedural

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early procedural-MI, so follow-up for ISCHEMIA trial patients should continue, because there could be greater differences in the rate of nonprocedural MI over time. These results should not be extrapolated to a more symptomatic, higher-risk population, as this specific niche of patients was not included in the study.

Decision-making processes in these heterogeneous stable coronary disease patients should continue to be individualised, taking into account risk factors, symptoms, medical therapy adherence, procedural risks and the patient’s preference. We recommend a patient-centred approach, rather than an imaging or lesion-centred approach, to determine the best treatment strategy.

It is important that trials that include patients with frequent angina and proven severe ischaemia with the routine use of coronary physiological assessment and coronary imaging are conducted as soon as possible.

This will undoubtedly help to clarify most of the ambiguities in the current results.

myocardial infarction and injury in elective coronary stenting.

Eur Heart J 2018;39:1100–9. https://doi.org/10.1093/eurheartj/ ehx799; PMID: 29365133.

7. Cho MS, Ahn JM, Lee CH, et al. Differential rates and clinical significance of periprocedural myocardial infarction after stenting or bypass surgery for multivessel disease according to various definitions. JACC Cardiovasc Interv 2017;10:1498–507. https://doi.org/10.1016/j.jcin.2017.05.051; PMID: 28797425.

8. Madhavan MV, Redfors B, Ali ZA, et al. Long-term outcomes after revascularization for stable ischemic heart disease: an individual patient-level pooled analysis of 19 randomized coronary stent trials. Circ Cardiovasc Interv 2020;13:e008565. https://doi.org/10.1161/CIRCINTERVENTIONS.119.008565; PMID: 32279561.

9. Ikeno F, Brooks MM, Nakagawa K, et al. SYNTAX score and long-term outcomes: the BARI-2D trial. J Am Coll Cardiol 2017;69:395–403. https://doi.org/10.1016/j.jacc.2016.10.067; PMID: 28126156.

10. Bangalore S, Maron D, Stone G, et al. Routine revascularization versus initial medical therapy for stable ischemic heart disease: a systematic review and meta-analysis of randomized trials. Circulation 2020;142:841–57. https://doi.org/10.1161/ CIRCULATIONAHA.120.048194; PMID: 32794407.

11. Dewey M, Siebes M, Kalchelrieß M, et al. Clinical quantitative cardiac imaging for the assessment of myocardial ischaemia.

Nat Rev Cardiol 2020;17:427–50. https://doi.org/10.1038/ s41569-020-0341-8; PMID: 32094693.

12. De Bruyne B, Piljs NH, Kalesan B, et al. Fractional flow reserveguided PCI versus medical therapy in stable coronary disease.

N Engl J Med 2012;367:991–1001. https://doi.org/10.1056/ NEJMoa1205361; PMID: 22924638.

13. Waksman R, Di Mario C, Torguson R, et al. Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging: a prospective cohort study. Lancet 2019;394:1629–37. https://doi.org/10.1016/S0140-6736(19)31794-5; PMID: 31570255.

14. Mancini GBJ, Boden WE. Diagnostic implications in the aftermath of the ISCHEMIA trial. Am J Cardiol 2020;125:1438– 40. https://doi.org/10.1016/j.amjcard.2020.01.039; PMID: 32145898.

15. Spertus JA, Jones PG, Maron DJ, et al. Health status outcomes with invasive or conservative care in coronary disease. N Engl J Med 2020;382:1408–19. https://doi.org/10.1056/ NEJMoa1916370; PMID: 32227753.

16. Knuuti J, Wijns W, Saraste A, et al. ESC guidelines for the diagnosis and management of chronic coronary syndromes.

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Structural

Patent Foramen Ovale Closure: State of the Art Joel P Giblett,1 Lynne K Williams,2 Stephen Kyranis,2 Leonard M Shapiro2 and Patrick A Calvert2 1. Liverpool Centre for Cardiovascular Science, Liverpool Heart and Chest Hospital, Liverpool, UK; 2. Department of Cardiology, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK

Abstract Patent foramen ovale (PFO) is a common abnormality affecting between 20% and 34% of the adult population. For most people, it is a benign finding; however, in some people, the PFO can open widely to enable paradoxical embolus to transit from the venous to arterial circulation, which is associated with stroke and systemic embolisation. Percutaneous closure of the PFO in patients with cryptogenic stroke has been undertaken for a number of years, and a number of purpose-specific septal occluders have been marketed. Recent randomised control trials have demonstrated that closure of PFO in patients with cryptogenic stroke is associated with reduced rates of recurrent stroke. After a brief overview of the anatomy of a PFO, this article considers the evidence for PFO closure in cryptogenic stroke. The article also addresses other potential indications for closure, including systemic arterial embolisation, decompression sickness, platypnoea–orthodeoxia syndrome and migraine with aura. The article lays out the pre-procedural investigations and preparation for the procedure. Finally, the article gives an overview of the procedure itself, including discussion of closure devices.

Keywords Stroke, patent foramen ovale, patent foramen ovale closure, migraine, platypnoea–orthodeoxia syndrome, decompression illness, cryptogenic stroke Disclosure: The authors have no conflicts of interest to declare.

Received: 24 November 2019 Accepted: 22 September 2020 Citation: Interventional Cardiology Review 2020;15:e15.

DOI: https://doi.org/10.15420/icr.2019.27 Correspondence: Patrick Calvert, Department of Cardiology, Royal Papworth Hospital NHS Foundation Trust, Papworth Road, Cambridge Biomedical Campus, Cambridge CB2 0AY, UK. E: patrick.calvert1@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 noncommercial purposes, provided the original work is cited correctly.

Patent foramen ovale (PFO) is common and occurs in 20–34% of the population.1 In most infants, the foramen ovale closes soon after birth, with a reduction in pulmonary vascular resistance raising the left atrial pressure above that of the right atrium during the first few breaths, closing the septum. In a significant proportion of individuals, the primum and secundum atrial septa do not fuse, and the foramen ovale remains incompletely closed. There is a residual, but transitory, communication between the right and left atria, particularly likely to open during actions that cause sudden rises and falls in intrathoracic pressure, such as sneezing, coughing or straining. The pressure changes that transiently open a PFO can often be produced by asking patients with a PFO to perform and then release a Valsalva manoeuvre.

In most adults, a PFO will appear only as a chance finding during cardiac investigation, or more likely remain undetected. Some PFOs may open widely, providing a conduit for thrombus, air or vasoactive peptides to travel from the venous to arterial circulation – causing a paradoxical embolus. This transfer is associated with several clinical phenomena, including cryptogenic stroke, systemic embolus, migraine with aura and decompression sickness in divers. Percutaneous PFO closure provides a practical and elegant solution to the problem of PFO in carefully selected individuals. This review evaluates the evidence for PFO closure, discusses which patients should be considered for this treatment and reviews how the procedure should be undertaken.

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The Anatomy of a Patent Foramen Ovale As the heart develops in the foetus, the primum and secundum septa grow and overlap. At birth, the PFO should close. In patients with a PFO, the atrial septal growth is normal; however, the communication between the right and left atria (PFO) fails to close postpartum (Figure 1). This phenomenon is distinct from a hole in either septum, which would constitute an atrial septal defect (ASD) – a separate entity with different functional consequences and different indications for closure. Table 1 compares PFO and ASD. Despite their differences, both PFOs and ASDs may permit the transit of a paradoxical embolism. The overlapping of the primum and secundum atrial septa in a PFO forms a flap valve that usually only opens when the right atrial pressure exceeds the left atrial pressure. PFOs are functionally closed most of the time, as right atrial pressure is usually less than the left atrial pressure. This pressure gradient can be reversed by manoeuvres that change the intrathoracic pressure (e.g. sneezing, coughing or straining to defecate), allowing the PFO to open, and blood, thrombus or any other substance to pass across from the right to left atrium.

Indications for Patent Foramen Ovale Closure Cryptogenic Stroke Often, despite extensive investigation, a clear cause cannot be found for stroke. Causes that can be identified include AF, atherosclerotic

© RADCLIFFE CARDIOLOGY 2020

Patent Foramen Ovale Closure Figure 1: Echocardiographic Assessment of a Patent Foramen Ovale

A and B: A transthoracic echo bubble study. A: An apical four chamber view. Agitated saline after IV injection is seen to fill the right ventricular cavity (white arrow). B: Bubbles are seen in the left atrium (LA) and ventricle within three cardiac cycles (blue arrow). C: A 2D transoesophageal echo image (90°) of a patent foramen ovale (PFO; orange arrow) with shunting evident on the colour flow Doppler. D: The same PFO is seen in 3D, viewed from the left atrium. The points of attachment of the septum primum tissue are shown by the white asterisks. The PFO opening into the left atrium is seen between these two points. The septum secundum tissue is behind, and this overlap of tissue extends to the roof of the fossa ovalis, demarcated by the white dotted line.

The PFO tunnel therefore extends from the top of the fossa ovalis to the PFO opening. LA = left atrium; MV = mitral valve; RA = right atrium.

disease, carotid dissection and intracerebral pathology, such as haemorrhage or space-occupying lesions.2,3 The cause of stroke remains unknown in up to 40% of patients with a stroke diagnosis.

These are designated as cryptogenic stroke. In the presence of a PFO, the presumed cause of stroke is paradoxical embolus. As the likely cause is known, the term ‘cryptogenic’ is a misclassification, but remains in use throughout the literature. An alternative term is embolic stroke of undetermined source, which was first used in 2014.

This still misclassifies stroke from paradoxical embolism, where the cause is known.4–6 Zahn first described paradoxical embolus in 1881.7 Translocation of venous thrombus to the arterial circulation under the haemodynamic

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conditions in which a PFO is open leads to embolic stroke. Transit of thrombus occurs after a rapid rise and fall in right atrial pressure through the aforementioned mechanisms. The PFO channel briefly provides a communication between the atria. This mechanism is supported by case studies showing thrombus across a PFO.8–10 There is also an association between cryptogenic stroke and venous thrombosis in patients with a PFO.11 The earliest randomised trials of PFO closure (Evaluation of the STARFlex Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale [CLOSURE I] and Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder With Medical

Structural Table 1: Comparison of Patent Foramen Ovale and Atrial Septal Defects Patent Foramen Ovale Atrial Septal Defect Anatomy

Fusion of primum and secundum atrial septa does not occur as an infant leading to flap valve opening

Congenital failure of overlap of the atrial septa leads to a hole in atrial septum)

Shunt

Right to left shunt occurs when right atrial pressure exceeds left atrial pressure (usually transient after rapid rise and fall in thoracic pressure)

Continuous left-to-right (usually) shunting

Epidemiology

20–34% of adult population1

1.6/1,000 live births48

Consequences

In most cases there is no clinical consequence and the defect remains undetected May permit paradoxical embolus

Continuous left-to-right shunt may cause volume loading of right heart, which may reduce long-term survival if not corrected May increase pulmonary artery pressure, reduce exercise tolerance and promote arrhythmia Can also allow paradoxical embolus (indication for closure)

Treatment in Patients With Cryptogenic Embolism [PC Trial]) did not demonstrate the superiority of closure compared with medical therapy.12,13 However, the studies were confounded by limited power, high crossover between groups, failure to randomise those patients whose strokes were likely to have been caused by PFO and inconsistent use of anticoagulants in the medical therapy group.14 In addition, the STARFlex occluder used in CLOSURE I has been abandoned in Europe due to concerns around residual defects and left-sided thrombus formation.15 Some have concluded that numerical equipoise in these trials were enough to recommend a one-off mechanical vaccination paradoxical embolus rather than lifelong anticoagulation.16,17 However, PFO closure was given a Class III recommendation in the 2014 American Heart Association/American Stroke Association guidelines based on the results of these trials.

Nonetheless, further randomised trials learned lessons from earlier neutral studies and have demonstrated that PFO closure is superior to medical therapy for the prevention of recurrent stroke. Early results from the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial were neutral for PFO closure but extended follow up of patients demonstrated a reduction in ischaemic stroke compared to medical therapy (HR 0.55; 95% CI [0.31–0.999]; p=0.046; number needed to treat [NNT] 45).18,19 The Gore Septal Occluder Device for PFO Closure in Stroke Patients (REDUCE) clinical study demonstrated that PFO closure produced significant improvement in the clinical ischaemic stroke rate (1.4 versus 5.5%; p=0.002; NNT=25) compared with antiplatelet therapy alone.20 The Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk PFO (DEFENSE PFO) study showed that PFO closure reduced a composite endpoint of stroke, vascular death and thrombolysis in MI major bleeding at 2 years compared with medical therapy (0 versus 12.9%; p=0.013; NNT=8).21 Finally, in the PFO Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE) trial, no patient receiving PFO closure experienced

an ischaemic stroke compared with 14 in the antiplatelet group (HR 0.03; 95% CI [0–0.26]; p<0.001; NNT=17).22 Meta-analyses of these trials confirm that PFO closure reduces the risk of ischaemic stroke in patients with a PFO and cryptogenic stroke.23-25 Absolute risk reduction is low (1.0 stroke per 100 patient-years), but this needs to be weighed against the prolonged period that younger patients are likely to be at risk. Patients with atrial septal aneurysm or large shunts may obtain greater benefit. In these trials, and in subsequent meta-analyses, AF occurred more frequently in patients who underwent PFO closure than those receiving medical therapy alone. However, this finding did not seem to counteract the overall stroke reduction in this population. Randomised trials of PFO closure for the prevention of recurrent ischaemic stroke are shown in Table 2.

Observational data suggest that post-closure AF may be transient, with a lower stroke risk than AF with other aetiology.26 No trial or observational study has demonstrated a reduction in mortality with PFO closure, and indeed meta-analysis of multiple trials has not found a significant effect either.27–29 There may be a benefit, but it will remain difficult to prove without large randomised trials with very long followup periods.

Patients enrolled in PFO closure trials were young, with few studies enrolling patients age >60 years. Older patients may have an increased absolute risk of paradoxical embolus, but untangling this from other causes of stroke that also increase over time is challenging. Patients needed to have symptoms consistent with stroke and confirmation of ischaemia or infarction on cross-sectional brain imaging. Transoesophageal echocardiographic confirmation of the presence of a PFO was also required. Studies excluded patients with an alternative attributable cause for their stroke, and required enrolment no longer than 6–9 months after the index stroke.

One of the major alternative explanations for embolic stroke is AF, and this was excluded in all patients. Studies have demonstrated that over the medium to long term, PFO closure is cost-effective in both the US and UK healthcare systems.30–32 Furthermore, longer-term observational studies have shown very low stroke rates (<1%), even up to 12 years after PFO closure.33 The strict criteria of these studies are important and should be respected in clinical practice. There is little or no evidence for treatment of PFO outside these criteria, and there is no symptomatic benefit to closure in patients with cryptogenic stroke. Patients who meet trial criteria for closure should be considered for this treatment in preference to medical therapy. Patient selection is best decided in a multidisciplinary team meeting including neurology/stroke physicians, and implanting and imaging cardiologists.

Systemic Embolisation Paradoxical emboli are likely to present with ischaemic stroke, as the brain is exquisitely sensitive to ischaemia and also receives a large proportion of cardiac output. However, systemic embolisation to the limbs, gut and down the coronary arteries have been described.10,34–36 No randomised trial evidence exists to show that closure of PFO in the case of otherwise unexplained systemic embolisation is protective.

However, closure would seem to be a reasonable strategy in select cases. For example, closure of PFO would be indicated in a young patient presenting with acute MI of embolic source, with otherwise

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Patent Foramen Ovale Closure Table 2: Randomised Trials Comparing Patent Foramen Ovale Closure with Medical Therapy Study

Year

Device

n

Endpoints

Results

Comments

CLOSURE 112

2012

STARFlex Septal Closure System

909

Composite of death (0–30 days), neurological death (≥31 days), stroke or TIA at 2-year follow-up

Non-significant reduction in primary endpoint (HR 0.78; 95% CI [0.45–1.35] p=0.37)

Left atrial thrombus formation in closure group Inadequate closure at 2 years

PC Trial13

2013

Amplatzer PFO Occluder

414

Composite of death, stroke, TIA or peripheral embolism at 4,5 years

Non-significant reduction in primary endpoint (HR 0.63; 95% CI [0.24–1.62]; p=0.34)

Underpowered trial High volume of crossover to PFO closure during follow-up

RESPECT18,19

2013 Long-term data published in 2017

Amplatzer PFO Occluder

980

Composite of early death, stroke or TIA

Non-significant reduction in primary endpoint at median follow-up 2.1 years (HR 0.49; 95% CI [0.22–1.11]; p=0.08) Long-term follow-up (median 5.9 years) showed significant reduction with closure (HR 0.55; 95% CI [0.31–0.99]; p=0.046)

As treated analysis shows a benefit in favour of closure even at the early timepoint.

CLOSE22

2017

11 approved devices (Amplatzer PFO Occluder >50%)

663

Fatal or non-fatal stroke

Significant reduction in stroke with occlusion compared with antiplatelet therapy only (HR 0.03, 95% CI [ 0-0.26]; p<0.001)

1:1:1 randomisation PFO closure versus antiplatelets versus anti-coagulation

Gore REDUCE20

2017

Helex Septal Occluder or Cardioform Septal Occluder

664

Co-primary endpoints of clinical stroke and incidence of new brain infarction

Significant reduction in clinical stroke at median follow-up 3.2 years (HR 0.23; 95% CI [0.09–0.62]; p=0.002) Significant reduction in new brain infarction (RR 0.51; 95% CI [0.29–0.91]; p=0.04)

2:1 randomisation to PFO closure

DEFENSE PFO21

2018

Amplatzer PFO Occluder

120

Stroke, vascular death or Major bleeding at 2-year follow-up

Significant reduction in primary endpoint with PFO closure. No events in PFO closure arm versus 12.9% 2-year event rate in medication only arm (p=0.013)

PFO = patent foramen ovale; TIA = transient ischaemic attack.

unremarkable coronary arteries and an absence of risk factors for atherosclerosis or atrial fibrillation. The indications are similar to those for cryptogenic stroke. Importantly, care must be taken to exclude alternative causes, and this may require intravascular imaging, such as optical coherence tomography, to exclude plaque rupture in the coronary artery. Cardiac MRI is also recommended to confirm a pattern consistent with MI.

Decompression Illness Divers and high-altitude pilots, who rapidly transition from high- to lowpressure environments, may suffer from decompression illness.

Sudden changes in pressure causes nitrogen bubbles to form within tissues and accumulate in the venous circulation. These bubbles are filtered from the bloodstream through pulmonary capillary diffusion, but if a return to low pressure (or ascent from depth for divers) is too rapid, then this pulmonary filtration process can be overwhelmed. Gas bubbles can enter the systemic arterial circulation.37 Bubbles continue to enlarge, causing tissue trauma and even vessel occlusion. There is a wide range of symptoms, from mild muscle and joint pain, dizziness, fatigue, headache, rash and paraesthesia, to severe breathing difficulties, confusion, motor incoordination and paralysis. A right-toleft shunt, such as a PFO, allows nitrogen bubbles to bypass the

INTERVENTIONAL CARDIOLOGY REVIEW

pulmonary filter, increasing the risk that usually safe ascents will cause systemic embolisation.

Diving profiles are usually designed to limit the time at depth, and slowly ascend towards the surface, minimising the risk of decompression illness. Occurence of decompression illines, despite use of safe dive profiles, implies an increased risk of right-to-left shunt. Investigation for atrial septal defect or PFO should be considered.38,39 A longitudinal, non-randomised follow-up study showed that PFO closure reduced both symptomatic neurological events and total brain lesions among recreational divers with PFO and decompression illness, compared with those who continued to dive without closure.40 A recent prospective registry evaluated 489 recreational divers for PFO using transcranial Doppler. This demonstrated that large PFO was a major independent risk factor for unprovoked decompression illness (HR 92; 95% CI [12.5-689]; p<0.001).41 A recent study noted that in a cohort of 59 divers with decompression illness and PFO closure, four continued to have decompression illness over the 10-year follow-up period. This was shown to be due to residual shunting, despite reported successful closure.42 Where a professional diver wishes to continue diving, PFO closure could be recommended. Alternatively, discontinuation

Structural of diving or curtailing provocative dive profiles should be considered. If diving is recreational, then the risk–benefit analysis for continued diving with a PFO closure is less clear, and certainly procedural risk should be carefully weighed against the benefits of continuing to dive.

Platypnoea–Orthodeoxia Syndrome Platypnoea–orthodeoxia syndrome is a rare condition characterised by dyspnoea and positional desaturation in individuals with a PFO. In certain body positions, the geometry of the atrial septum is altered, allowing a continuous stream of deoxygenated blood from the inferior vena cava to flow across the PFO. Deoxygenation is typically seen when the patient is seated, but oxygen saturations normalise when the patient lies flat.43 The distortion of the atrial septal geometry can be caused by thoracic and cardiothoracic surgery, such as pneumonectomy, aortic dilatation and aortic surgery, or may not have an identifiable cause.

Regurgitant jets from the tricuspid valve can also be directed across the PFO. Underlying cavity pressures do not affect platypnoea– orthodeoxia syndrome, and it responds well to PFO closure so long as pulmonary artery pressures are not markedly elevated. This is not usually the case. A 54-patient case series demonstrated that percutaneous closure was safe and effective for platypnoea– orthodeoxia syndrome.44

Migraine with Aura Migraine is common in young people. It is associated with aura in approximately one-third of cases.45,46 Migraine with aura has been associated with right-to-left shunts, such as PFO.47,48 Large shunts are particularly associated with migraine with aura.49 Transfer of a vasoactive substance, usually filtered by the pulmonary circulation into the systemic circulation, is the proposed mechanism for the relationship between migraine and PFO.47 A number of non-randomised studies reported improvement in patient symptoms after closure.50 In the Migraine Intervention With STARFlex Technology (MIST) trial, patients with refractory migraine with aura were randomised to either percutaneous PFO closure or a sham procedure. There was no difference in cessation of headache or reduction in headache-free days. However, the trial population had a relatively low frequency of migraine, and a high frequency of residual shunts after closure – this trial used the same prosthesis as the negative CLOSURE 1 stroke trial with similar issues. These confounders may have negatively influenced the trial result.51 More recently, the Percutaneous Closure of PFO in Migraine with Aura (PRIMA) and Prospective Randomised Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the Amplatzer PFO Occluder Compared With Medical Management (PREMIUM) trials have reported their results.52,53 Both studies were negative for their primary endpoints, although there were some reductions in headache. These effects were small and occurred at the expense of procedural complications. The evidence for PFO closure is not strong enough to offer a routine recommendation for PFO closure in migraine with aura.

The Patent Foramen Ovale Closure Procedure Pre-procedure Investigations As cryptogenic stroke is the most common indication for closure, an emphasis should be placed on investigation looking for alternative

causes of stroke. Cross-sectional brain imaging should be undertaken to confirm the diagnosis of an embolic stroke. Lacunar strokes are unlikely to be embolic in nature.

AF is the most common source of thrombus, with studies suggesting that 13% of patients with AF have cardiac thrombus.54 In 90% of patients with non-valvular AF, the thrombus was located in the left atrial appendage.54 The presence of AF in the context of a stroke is an indication for anticoagulation, and closure of a PFO is not indicated.

No study has shown that closure of a PFO confers additional benefit.

ECG monitoring is mandatory to exclude AF, and the duration depends upon the patient’s risk factors. We recommend in young patients (<50 years) with no risk factors, using a minimum of 72-hour ambulatory surface electrocardiographic recording, and in those aged >50 years, using 6 months of implantable loop recording. Implantable loop recording has the advantage of extended rhythm surveillance; however, it is prone to false positives and false negatives.55–57 Conclusive evidence for the best strategy to diagnose AF is lacking. The high burden of supraventricular ectopics on ambulatory ECG or enlarged atrial size increases the likelihood of AF, and may indicate that an implantable loop recording is required in a younger patient.

Carotid imaging should exclude significant carotid plaque disease.

Screening for thrombophilia should be considered, but its complex nature with inconsistent results means repeated investigations are often required. Thrombophilia often predisposes to venous rather than arterial thrombosis. Interpretation of complex results can be difficult, and should be undertaken in conjunction with haematologists who have a special interest in thrombosis.

The first-line investigation to exclude intracardiac thrombus is transthoracic echocardiography. A number of conditions, apart from AF, are associated with cardiac thrombus, which could embolise to cause stroke. These include MI, left ventricular aneurysm, atrial myxoma, noncompaction cardiomyopathy, left ventricular failure and mitral stenosis.

Prior to closure of PFO, these should all have been excluded as the potential source of the stroke.

A key investigation while working up patients with cryptogenic stroke is bubble contrast echocardiography. A PFO needs to produce a rightto-left shunt to cause a stroke. Bubble contrast studies are initially performed with transthoracic echocardiography, with no sedation necessary. Agitated saline is injected via a peripheral venous cannula (ideally placed in the lower body, but the left antecubital fossa is usually a more realistic option), while the patient releases a Valsalva manoeuvre or sniff. In the presence of a cardiac shunt, bubbles should appear in the left side of the heart within three to four cardiac cycles of arrival in the right atrium. Later appearance of bubbles may reflect a pulmonary shunt. The study should be performed by an experienced operator. The procedure may require multiple repeats to confirm the diagnosis.

Figure 1 shows a bubble study with transmission of bubbles from rightto-left. Transcranial Doppler is a non-invasive alternative to a contrast echocardiogram. It is a reliable method of assessing for the presence of a right-to-left shunt, although it does not delineate the anatomy of the PFO.58,59 A positive transthoracic bubble study or transcranial Doppler study after a cryptogenic stroke indicates the need for detailed transoesophageal echocardiography (TOE). A further bubble study can

INTERVENTIONAL CARDIOLOGY REVIEW

Patent Foramen Ovale Closure Figure 2: The Patent Foramen Ovale Closure Procedure

A wire crossing a patent foramen ovale into the left upper pulmonary vein with a Judkins Right 4 catheter (white arrow) is shown (A). The delivery sheath (blue arrow) is advanced through the patent foramen ovale over the stiff wire (B), and the device â&#x20AC;&#x201C; a Gore Cardioform septal occluder â&#x20AC;&#x201C; is deployed (C,D) with the left atrial disc (green arrow) deployed first and then apposed to the atrial septum. The right atrial disc (black arrow) is then deployed, but the device is not released until the operator is happy with the position both fluoroscopically and with echocardiography.

A released device is shown (E; yellow arrow) using 3D transoesophageal echocardiography (F; purple arrow) viewed from the left atrium.

be undertaken using TOE if required. This allows the structural heart team to accurately determine the anatomy of the PFO. Assessment of a PFO is shown in Figure 1. A TOE also allows the exclusion of alternative shunts, such as ventricular septal defects, anomalous pulmonary venous drainage or sinus venosus defects. A detailed guide to TOE assessment of PFO is outside the scope of this review, and is well reviewed elsewhere.60 Multiple specialties (including stroke physicians or neurologists, cardiac imaging specialists, radiologists and interventional cardiologists) are involved in diagnosis and treatment decisions for cryptogenic stroke with PFO. Investigation should be considered in a multidisciplinary setting, with a holistic approach to the management of the patient.

The Closure Procedure Closure is performed as a day case procedure in many centres. The procedure can be undertaken in a standard catheter laboratory using fluoroscopic guidance and physiological monitoring. Patients undergoing this procedure will have a reduced long-term risk of stroke, but obtain no immediate symptomatic benefit from this procedure.

Therefore, all possible steps to reduce complications should be taken.

In the opinion of the authors, the procedure should be, as far as possible, complication-free, because even a small complication rate is likely to neutralise the benefit over optimal medical therapy. Ultrasound-

INTERVENTIONAL CARDIOLOGY REVIEW

guided femoral venous access, echocardiographic guidance, adequate anticoagulation and special care to reduce the risk of air embolus are all important to ensure this goal.

Periprocedural guidance with TOE or intracardiac echocardiography is mandatory, in the opinion of the authors, to consistently achieve the best result.61,62 Furthermore, it is considered mandatory within commissioning guidelines in the UK, and recommended in the Society for Cardiovascular Angiography and Interventions 2019 consensus statement.63,64 Although the procedure can be undertaken by very experienced operators with fluoroscopy alone, echocardiographic guidance allows evaluation of interatrial septal anatomy, direct visualisation of the device position, and the relationship with aortic and mitral valves before device release. General anaesthesia is generally required to facilitate TOE, which may increase the cost and length of the procedure.

The procedure is undertaken from the femoral vein with ultrasound guidance for the puncture. Adequate anticoagulation (unfractionated heparin 80â&#x20AC;&#x201C;100 IU/kg) should be administered. A 6-Fr multipurpose diagnostic catheter and a 0.035" J-tipped guidewire is used to cross the PFO and is passed into a pulmonary vein (usually the left upper pulmonary vein). This can then be exchanged for a stiff wire to assist delivery of balloons.

Structural Figure 3: Devices Approved for Patent Foramen Ovale Closure

A: Ceraflex PFO Occluder. B: Gore Cardioform Septal Occluder. C: Figulla Flex II Occluder. D: Amplatzer PFO Occluder. E: Ultrasept PFO Closure Device. These devices are approved for patent foramen ovale closure, with the Amplatzer and Gore devices most widely deployed.

Sizing of the PFO can be undertaken both before and after crossing with the wire, which may result in the PFO tunnel widening and shortening.

Three-dimensional imaging software can be used to determine the maximum left and right atrial opening and minimum tunnel length.

Balloon sizing of the PFO is usually not required, but can be performed using quantitative angiographic tools, and confirmed with TOE or intracardiac echocardiography. A left anterior oblique cranial fluoroscopic projection may assist with this, as the septum is seen in profile. Compliant balloons with marked graduations are used, but balloon sizing can still shorten and widen the PFO. Shortening may be desirable if there is a particularly long PFO tunnel, but this can increase the size of the hole, necessitating a larger device. Factors that predispose to a larger device include PFO tunnel length, the presence of atrial septal aneurysm and male sex.65 Precise sizing will depend upon the choice of device used.

PFO closure. In our practice, aspirin and clopidogrel are usually given for 6 months, but evidence for this is limited and practice varied markedly between trials. Earlier discontinuation of dual antiplatelet therapy was associated with an increased frequency of minor cerebrovascular events in a study level meta-analysis of PFO closure trials. 66 Long-term observation studies have suggested this is a safe practice.33

Once sizing is completed, an appropriate device (with delivery sheath) can be passed into the left atrium through the PFO. The left atrial disc is deployed, followed by the right disc. Ensuring that the delivery sheath remains de-aired and flushed throughout the procedure minimises the risk of air or thrombotic embolism. After the device is deployed, confirmation of the adequate position with echocardiography and fluoroscopy should be performed prior to device release. If the device is malpositioned after release, a large gooseneck snare can be used to recover the device. The steps involved in a PFO closure procedure are shown in Figure 2.

Follow-up is important, but uncertainty remains about the appropriate timeframe. As most devices endothelialise over a period of approximately 6 months, then a repeat bubble study could be considered at that stage.

Timing is of particular relevance where the PFO has been closed for occupational reasons, such as professional diving.

Evidence for antiplatelet therapy after device deployment remains incomplete. Device thrombosis remains a feared complication of

Some operators preload patients with antiplatelets, but again, the evidence for this is uncertain. Single antiplatelet therapy, usually clopidogrel 75 mg daily, is continued indefinitely, as the device may take up to 5 years to endothelialise. The European Association for Percutaneous Cardiovascular Interventions consensus statement recommends this approach at present.66

Closure Devices A large number of devices with varying shape and size have been marketed. Many have received CE mark status in the EU. In the US, fewer devices have been approved by the Food and Drug Administration, due to the need for randomised evidence prior to approval.

INTERVENTIONAL CARDIOLOGY REVIEW

Patent Foramen Ovale Closure Most devices are of double-disc design, connected by a short waist. The Gore Septal Occluder (WL Gore and Associates) and the Amplatzer PFO Occluder (Abbott Vascular) are two of the more commonly used devices and are shown in Figure 3. The Gore Septal Occluder is constructed from five nitinol wires covered with expanded polytetrafluoroethylene.67 Early clinical experience has shown that it is a versatile device with easy deployment, high procedural success and low complication rates.68,69 The Amplatzer PFO Occluder is also a nitinol-based device. This device has been used most commonly in randomised clinical trials. The evidence base for its use is therefore very strong.21,22 There are numerous other commercially available devices, including the Occlutech PFO occluder (Occlutech International) and Ultrasept (Cardia), plus suture-based technologies, such as NobleStitch (HeartStitch).

Future Directions There are a number of outstanding research questions regarding PFO closure that need to be answered. First, the optimal antiplatelet or anticoagulation regimen balancing the risk of recurrent stroke or embolism against the risk of bleeding needs to be established. Current guidance is based on consensus statements and the strategies adopted in the clinical trials mentioned earlier. Meta-analyses have not shown any clear additional benefit for anticoagulation when PFO is not closed after stroke.70 Further studies evaluating the benefit of anticoagulation and optimal duration of dual antiplatelet therapy would be welcome.

Simplification of the procedure with the use of non-invasive echocardiography may be attractive, but is not recommended in consensus statements.64 A clinical trial to establish the safety and efficacy of a fluoroscopic approach with transthoracic echocardiography support is currently underway (NCT03828825).

needed, but will be challenging to recruit, given the relatively small numbers of patients in this group.

A recent observational study of patients undergoing surgery found a significantly higher incidence of ischemic stroke over a 1-year period in those with PFO.73 This risk was mitigated for those receiving dual antiplatelet therapy or anticoagulation, or those who had undergone PFO closure. These observational data are hypothesis generating, but suggest that there may be a population that could be identified to benefit from upfront closure, but further well-designed clinical trials would be required to justify this against the procedural risk.

Furthermore, there are limited data to support differences in treatment by subgroup. A meta-analysis of trials reporting outcome by sex (RESPECT, REDUCE, CLOSURE 1) suggested that there was a significant reduction in men, and a non-significant numeral reduction in stroke for women. The majority of patients treated in these studies were men.

Further work is required to identify whether there are meaningful differences in these groups. Similarly, differences between ethnic groups could also be examined.

Finally, expansion to other indications, particularly for migraine relief requires a better quality of evidence. The planned GORE CARDIOFORM Septal Occluder Migraine Clinical Study (RELIEF study) is a sham randomised controlled trial of PFO closure for migraine relief with recruitment due to start in 2020. A sham procedure is important to tease out the strong placebo effect associated with migraine studies (NCT04100135).

Conclusion Identification of a high risk of PFO-associated stroke prior to the first stroke remains the golden ticket. Some have published studies with scoring systems to identify high-risk PFO, but these have not identified patients prior to cryptogenic stroke, when the PFO is usually silent.71 Patients with inherited thrombophilia found to have PFO may be candidates for prophylactic PFO closure. Observational studies have suggested that those in this group who have a PFO closure have a reduced incidence of stroke or transient ischaemic attack.72 Randomised trials to assess whether this group would benefit are

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In this review, the main indications for PFO closure have been discussed (cryptogenic stroke, paradoxical systemic embolisation, platypnoea– orthodeoxia syndrome and decompression illness), together with the strengthening evidence for closure. The skills required for this procedure need to be learnt with the assistance of experienced interventional cardiologists who can proctor and advise those starting out with PFO closure. Attention to detail in the indication for the procedure, and minimising the risks to the patient during the closure are key to an effective PFO closure service.

successful management by multidisciplinary team approach.

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Wilmshurst PT, Byrne JC, Webb-Peploe MM. Relation between interatrial shunts and decompression sickness in divers. Lancet 1989;2:1302–6. https://doi.org/10.1016/S0140-6736(89)919119; PMID: 2574256.

Torti SR, Billinger M, Schwerzmann M, et al. Risk of decompression illness among 230 divers in relation to the presence and size of patent foramen ovale. Eur Hear J 2004;25:1014–20. https://doi.org/10.1016/j.ehj.2004.04.028; PMID: 15191771.

Billinger M, Zbinden R, Mordasini R, et al. Patent foramen ovale closure in recreational divers: effect on decompression

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illness and ischaemic brain lesions during long-term follow-up.

Heart 2011;97:1932–7. https://doi.org/10.1136/ heartjnl-2011-300436; PMID: 21917666.

Honěk J, Šrámek M, Šefc L, et al. High-grade patent foramen ovale is a risk factor of unprovoked decompression sickness in recreational divers. J Cardiol 2019;74:519–23. https://doi. org/10.1016/j.jjcc.2019.04.014; PMID: 31255461.

Vanden Eede M, Van Berendoncks A, De Wolfe D, et al.

Percutaneous closure of patent foramen ovale for the secondary prevention of decompression illness in sports divers: mind the gap. Undersea Hyperb Med 2019;46:625–32.

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Godart F, Rey C, Prat A, et al. Atrial right-to-left shunting causing severe hypoxaemia despite normal right-sided pressures. Report of 11 consecutive cases corrected by percutaneous closure. Eur Hear J 2000;21:483–9. https://doi. org/10.1053/euhj.1999.1944; PMID: 10681489.

Shah AH, Osten M, Leventhal A, et al. Percutaneous intervention to treat platypnea-orthodeoxia syndrome: the Toronto experience. JACC Cardiovasc Interv 2016;9:1928–38. https://doi.org/10.1016/j.jcin.2016.07.003; PMID: 27659570.

Burch RC, Loder S, Loder E, et al The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies.

Headache 2015;55:21–34. https://doi.org/10.1111/head.12482; PMID: 25600719.

Lipton RB, Liberman JN, Kolodner KB, et al. Migraine headache disability and health-related quality-of-life: a population-based case-control study from England. Cephalalgia 2003;23:441–50. https://doi.org/10.1046/j.1468-2982.2003.00546.x; PMID: 12807523.

Finocchi C, Del Sette M. Migraine with aura and patent foramen ovale: myth or reality? Neurol Sci 2015;36(Suppl 1):61– 6. https://doi.org/10.1007/s10072-015-2163-8; PMID: 26017514.

Schwerzmann M, Nedeltchev K, Lagger F, et al. Prevalence and size of directly detected patent foramen ovale in migraine with aura. Neurology 2005;65:1415–8. https://doi. org/10.1212/01.wnl.0000179800.73706.20; PMID: 16148260.

Anzola GP, Morandi E, Casilli F, et al. Different degrees of rightto-left shunting predict migraine and stroke: data from 420 patients. Neurology 2006;66:765–7. https://doi.org/10.1212/01. wnl.0000201271.75157.5a; PMID: 16534123.

Butera G, Biondi-Zoccai GG, Carminati M, et al. Systematic review and meta-analysis of currently available clinical evidence on migraine and patent foramen ovale percutaneous closure: much ado about nothing? Catheter Cardiovasc Interv 2010;75:494–504. https://doi.org/10.1002/ccd.22232; PMID: 20088014.

Dowson A., Mullen MJ., Peatfield R., et al. Migraine Intervention with STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation 2008;117:1397–404. https://doi. org/10.1161/CIRCULATIONAHA.107.727271; PMID: 18316488.

Mattle HP, Evers S, Hildick-Smith D, et al. Percutaneous closure of patent foramen ovale in migraine with aura, a randomized controlled trial. Eur Hear J 2016;37:2029–36. https://doi. org/10.1093/eurheartj/ehw027; PMID: 26908949.

Tobis JM, Charles A, Silberstein SD, et al. Percutaneous closure of patent foramen ovale in patients with migraine: the PREMIUM trial. J Am Coll Cardiol 2017;70:2766–74. https://doi. org/10.1016/j.jacc.2017.09.1105; PMID: 29191325.

Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9. https://doi.org/10.1016/00034975(95)00887-X; PMID: 8572814.

Cotter PE, Martin PJ, Ring L, et al. Incidence of atrial fibrillation detected by implantable loop recorders in unexplained stroke.

Neurology 2013;80:1546–50. https://doi.org/10.1212/ WNL.0b013e31828f1828; PMID: 23535493.

Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478–86. https://doi.org/10.1056/NEJMoa1313600; PMID: 24963567.

Podd SJ, Sugihara C, Furniss SS, et al. Are implantable cardiac monitors the “gold standard” for atrial fibrillation detection? A prospective randomized trial comparing atrial fibrillation monitoring using implantable cardiac monitors and DDDRP permanent pacemakers in post atrial fibrillation ablation patients. Europace 2016;18:1000–5. https://doi.org/10.1093/

europace/euv367; PMID: 26585596.

58. Nemec JJ, Marwick TH, Lorig RJ, et al. Comparison of transcranial Doppler ultrasound and transesophageal contrast echocardiography in the detection of interatrial right-to-left shunts. Am J Cardiol 1991;68:1498–502. https://doi. org/10.1016/0002-9149(91)90285-S; PMID: 1746433.

59. Mojadidi MK, Roberts SC, Winoker JS, et al. Accuracy of transcranial Doppler for the diagnosis of intracardiac right-toleft shunt: a bivariate meta-analysis of prospective studies.

JACC Cardiovasc Imaging 2014;7:236–50. https://doi. org/10.1016/j.jcmg.2013.12.011; PMID: 24560213.

60. Rana BS, Thomas MR, Calvert PA, et al. Echocardiographic evaluation of patent foramen ovale prior to device closure.

JACC Cardiovasc Imaging 2010;3:749–60. https://doi. org/10.1016/j.jcmg.2010.01.007; PMID: 20633854.

61. Yared K, Baggish AL, Solis J, et al. Echocardiographic assessment of percutaneous patent foramen ovale and atrial septal defect closure complications. Circ Cardiovasc Imaging 2009;2:141–9. https://doi.org/10.1161/ CIRCIMAGING.108.832436; PMID: 19808580.

62. Bechis MZ, Rubenson DS, Price MJ. Imaging assessment of the interatrial septum for transcatheter atrial septal defect and patent foramen ovale closure. Interv Cardiol Clin 2017;6:505–24. https://doi.org/10.1016/j.iccl.2017.05.004; PMID: 28886842.

63. NHS England. Clinical Commissioning Policy: Percutaneous patent foramen ovale closure for the prevention of recurrent cerebral embolic stroke in adults (around the age 60 years and under). NHS England: 2019. https://www.england.nhs.uk/commissioning/wp-content/ uploads/sites/12/2019/07/Clinical-Commissioning-Policy_ Percutaneous-patent-foraman-ovale-closure-for-the-preventionof-recurrent-cerebr.pdf (accessed 21 October 2020).

64. 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.

65. Venturini JM, Retzer EM, Estrada JR, et al. A practical scoring system to select optimally sized devices for percutaneous patent foramen ovale closure. J Struct Hear Dis 2016;2:217–23. https://doi.org/10.12945/j.jshd.2016.009.15; PMID: 29104878.

66. 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.

67. Sondergaard L, Loh PH, Franzen O, et al. The first clinical experience with the new GORE® septal occluder (GSO).

EuroIntervention 2013;9:959–63. https://doi.org/10.4244/ EIJV9I8A160; PMID: 23764807.

68. MacDonald ST, Daniels MJ, Ormerod OJ. Initial use of the new GORE® septal occluder in patent foramen ovale closure: implantation and preliminary results. Catheter Cardiovasc Interv 2013;81:660–5. https://doi.org/10.1002/ccd.24405; PMID: 23436483.

69. Hardt SE, Eicken A, Berger F, et al. Closure of patent foramen ovale defects using GORE® CARDIOFORM septal occluder: results from a prospective European multicenter study.

Catheter Cardiovasc Interv 2017;90:824–9. https://doi. org/10.1002/ccd.26993; PMID: 28296023.

70. Romoli M, Giannandrea D, Eusebi P, et al. Aspirin or anticoagulation after cryptogenic stroke with patent foramen ovale: systematic review and meta-analysis of randomized controlled trials. Neurol Sci 2020:1–6. https://doi.org/10.1007/ s10072-020-04388-4; PMID: 32306140.

71. Nakayama R, Takaya Y, Akagi T, et al. Identification of high-risk patent foramen ovale associated with cryptogenic stroke: development of a scoring system. J Am Soc Echocardiogr 2019;32:811–6. https://doi.org/10.1016/j.echo.2019.03.021; PMID: 31130417.

72. Buber Y, Orion D, Borik S, et al. Percutaneous closure of patent foramen ovale is associated with lower incidence cryptogenic strokes among patients with inherited thrombophialias treated with anticoagulant or antiaggregant therapy. J Am Coll Cardiol 2017;69(Suppl):962. https://doi. org/10.1016/S0735-1097(17)34351-6.

73. Friedrich S, Ng PY, Platzbecker K, et al. Patent foramen ovale and long-term risk of ischaemic stroke after surgery. Eur Heart J 2019;40:914–24. https://doi.org/10.1093/eurheartj/ehy402; PMID: 30020431.

INTERVENTIONAL CARDIOLOGY REVIEW

COVID-19

Management of Acute Coronary Syndromes During the Coronavirus Disease 2019 Pandemic: Deviations from Guidelines and Pragmatic Considerations for Patients and Healthcare Workers Henry Seligman,1,2 Sayan Sen,1,2 Sukhjinder Nijjer,1,2 Rasha Al-Lamee,1,2 Piers Clifford,1 Amarjit Sethi,1 Nearchos Hadjiloizou,1 Raffi Kaprielian,1 Punit Ramrakha,1 Michael Bellamy,1 Masood A Khan,1 Jaspal Kooner,1,2 Rodney A Foale,1 Ghada Mikhail,1 Christopher S Baker,1 Jamil Mayet,1,2 Iqbal Malik,1 Ramzi Khamis,1,2 Darrel Francis1,2 and Ricardo Petraco1,2 1. Imperial College Healthcare NHS Trust, London, UK; 2. National Heart and Lung Institute, Imperial College London, UK

Abstract Coronavirus disease 2019 (COVID-19) is forcing cardiology departments to rapidly adapt existing clinical guidelines to a new reality and this is especially the case for acute coronary syndrome pathways. In this focused review, the authors discuss how COVID-19 is affecting acute cardiology care and propose pragmatic guideline modifications for the diagnosis and management of acute coronary syndrome patients, particularly around the appropriateness of invasive strategies as well as length of hospital stay. The authors also discuss the use of personal protective equipment for healthcare workers in cardiology. Based on shared global experiences and growing peer-reviewed literature, it is possible to put in place modified acute coronary syndrome treatment pathways to offer safe pragmatic decisions to patients and staff.

Keywords COVID-19, acute coronary syndrome, safety, angioplasty, thrombolysis Disclosure: HS has received research funding from Amgen. SS has received speaking fees from AstraZeneca, Pfizer and Philips Volcano, and an educational grant from Medtronic. SN has received speaking fees from Philips Volcano. RAL has received speaking fees from Philips Volcano. RP has acted as a consultant for Philips. All other authors have no conflicts of interest to declare.

Acknowledgement: The authors are grateful for the infrastructural support from the National Institute of Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London.

Received: 18 June 2020 Accepted: 22 September 2020 Citation: Interventional Cardiology Review 2020;15:e16. DOI: https://doi.org/10.15420/icr.2020.21 Correspondence: Ricardo Petraco, The Hammersmith Hospital, B-Block South, 2nd Floor, Du Cane Rd, London W12 0NN, UK. E: r.petraco@imperial.ac.uk 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 noncommercial purposes, provided the original work is cited correctly.

International guidelines provide clinicians with evidence-based recommendations on how to manage patients presenting with acute coronary syndromes (ACS). Guidance includes the appropriateness and optimal timing for percutaneous interventions as well as the ideal length of hospital stay.1–5 However, the current global pandemic of coronavirus disease 2019 (COVID-19), has posed an unprecedented challenge to acute and intensive care units (ICU), and forced many previously accepted clinical guidelines to be revisited and adapted across all medical and surgical specialties.6 In these circumstances, cardiology services and clinical pathways equally had to be rapidly modified and implemented. 6,7 In this focused review, we discuss how COVID-19 has affected acute cardiology services, with particular focus on ACS. We propose pragmatic deviations from guidelines based on our local experience, as well as on those shared by other countries. 8–10 Finally, we suggest strategies for the use of personal protective equipment (PPE) for staff when dealing with ACS patients. Whenever possible, we aim to provide support to proposed changes based on peer-reviewed literature.

© RADCLIFFE CARDIOLOGY 2020

Effects of the COVID-19 Pandemic on Acute Cardiology Care Global pandemics, such as COVID-19, can affect cardiology services at many levels, with some effects being particularly relevant to the care of ACS patients.

Firstly, there has been a need for a drastic adaptation of inpatient care and redistribution of beds, with many wards transformed into dedicated COVID-19 units. This shift has impacted inpatient cardiology capacity, led to cancellation and delays of elective work and affected the normally acceptable length of hospital stay for acute cardiology patients. Secondly, as ICUs have become largely dedicated to severely ill COVID-19 patients, there remains limited capacity for the recovery of cardiothoracic surgery patients or acute cardiology patients (e.g. cardiogenic shock following MI).

Another challenge is that patients with COVID-19 can present with ECG changes and a clinical syndrome of myopericarditis that mimics ACS, potentially increasing the number of false-positive ACS calls.11–13 Troponin elevation is observed in 18–23% of hospitalised COVID-19

Access at: www.ICRjournal.com

COVID-19 patients, even in the absence of chest pain, with fulminant myocarditis being reported as directly responsible for up to 7% of COVID-19-related deaths.14–16 As per data available on 9 April 2020, close to 20,000 COVID-19 patients were hospitalised in the UK, which would create approximately 4,000 new ‘false diagnoses’ of ACS.17 Thus, while the incidence of true ACS cases has fallen since the beginning of the pandemic – possibly due to patients’ reluctance to attend hospital – cases of late-presenting MI and its complications have been described.18–20 Finally, healthcare workers working in cardiology face a higher than average risk of contamination, particularly those involved in potential aerosol-generating procedures (AGPs).21 This risk is especially high during ambulance transportation and echocardiography (because of close patient interaction) and urgent percutaneous interventions.7,22,23,24

Proposed Adaptations of Acute Coronary Syndrome Pathways For ease of display we present the ACS pathways being used at our centre (Imperial College NHS Healthcare Trust, London, UK) as schematic flowcharts. Figure 1 displays the adapted pathway for the treatment of patients presenting with ST-elevation MI (STEMI) and high-risk ACS and Figure 2 shows the modified pathway for nonSTEMI (NSTEMI) and ACS. We briefly discuss the reasoning behind the most important deviations from guidelines, providing peer-reviewed evidence whenever possible. Our ACS pathways have been subjected to regional debates at the pan-London Heart Attack Centre Group and open public discussions at the Imperial College COVID-19 webinar, as well as on social media platforms and societal web content.25–27 Figure 3 summarises and displays our suggested protocol for the use of PPE by the cardiology team and catheter laboratory staff.

STEMI and High-risk Acute Coronary Syndrome Our modified pathway to treat patients presenting with a STEMI or high-risk ACS is presented in Figure 1. The most relevant points for discussion are described in the following sections.

Reperfusion Strategies in Critically Ill Patients Due to their high mortality and risk of transportation (for patients and staff), severely ill COVID-19 patients in ICU (patients requiring invasive organ support) who develop a STEMI or high-risk ACS should not be considered immediate candidates for emergency percutaneous revascularisation. Fibrinolysis could be considered on an individual basis following discussion with a senior colleague. If feasible, a rapid electronic multidisciplinary team meeting should occur between the clinicians involved, including intensivist, interventional cardiologist and general cardiologist, so that therapy can be administered in a timely fashion.

Triage of Patients Arriving From Ambulance Services Up to the point of this paper being drafted, there is no approved pointof-care test for COVID-19 infection. Therefore, we suggest that patients presenting via ambulance with suspected STEMI should be assessed outside the arriving centre. In the UK, Heart Attack Centres such as our own are often based in separate units without general emergency care and so triage accordingly. If the case is clearly not cardiac based upon clinical grounds and ECG, patients should be diverted to the appropriate emergency department. This will avoid unnecessary viral exposure of

hospital staff and ambulance crew caused by taking patients out of the ambulance. In centres with both emergency medicine and STEMI care, the decision is made between departments rather than between centres.

Identification of True STEMI Versus Myocarditis COVID-19 can present as a STEMI-mimic myocarditis picture.13 Although this will result in emergency angiograms showing nonoccluded coronaries, we judge that the only way of accurately reaching this diagnosis is via exclusion of STEMI. Therefore, the consideration of myocarditis as a differential diagnosis should not delay efforts to offer percutaneous reperfusion in possible COVID-19 patients presenting with chest pain and regional ST elevation on ECG. Radial angiography is recommended to reduce the risk of femoral bleeding complications.

Consideration of Lysis for COVID-19 Patients Primary percutaneous coronary intervention (PPCI) should remain the preferred choice of revascularisation for STEMI during the COVID-19 pandemic. However, confirmed or highly suspicious COVID-19 patients (red box category on Figure 1) should be considered for fibrinolysis with staged PCI, particularly if the following clinical and/or logistical circumstances are present: the patient is not in a cardiac centre and transportation is likely to increase door-to-balloon time by more than 60–90 minutes; STEMI is not anterior and not involving a large myocardial territory on ECG; bleeding risk is low; patient is hypoxic and a potential high risk for generating aerosols during high-flow oxygen therapies, intubation or cardiopulmonary resuscitation; and there are no contraindications for thrombolysis.

The rationale for considering lysis therapy in such circumstances is the following: the survival benefit of PPCI over lysis is important but small – in the region of 2% absolute risk reduction in non-COVID-19 patients.28,29 Therefore it is likely that such benefit may be smaller or even abolished when an underlying pathology of high mortality, such as COVID-19 is present leading to inevitable delays in PCI reperfusion, caused by the inevitable delays in patient transportation and the extra time needed for protecting catheter laboratory staff members.30 In addition, transportation (from a general hospital to a cardiac centre) of highly infective COVID-19 patients, particularly those requiring high flow oxygen therapy, imposes a very high risk of contamination to healthcare workers, including ambulance crew and catheter laboratory staff.31–33 Finally, it is possible that offering PCI after COVID-19 infection has settled (fever, hypoxia, inflammation, etc) would reduce the risk of stent thrombosis. However, we believe it is important that pathways that include fibrinolysis are put in place in advance.

Firstly, decisions must be individualised and made by more than one senior physician, with the reasoning for offering lysis over PPCI being clearly documented in the patients’ medical records. Secondly, there should be a clear upfront revascularisation plan as to what to do if lysis is effective and – more importantly – if it is not and rescue PCI is needed. Finally, fibrinolysis protocols (agents, doses, contraindications, etc) should be reviewed and staff should be retrained, particularly if the centre does not use such reperfusion strategy routinely. In our pathway we present two possible drugs for lysis therapy (bottom of Figure 1).

INTERVENTIONAL CARDIOLOGY REVIEW

COVID-19 ACS Pathway Figure 1: Suggested Pathway for the Management of ST-elevation MI and High-risk Acute Coronary Syndrome Patients

Proposed STEMI and High-risk ACS Pathway During COVID-19 Crisis 2020

Yes

Review case while still in ambulance. Is it likely cardiac?

Severely ill in ICU? No

Not for PCI Consider fibrinolysis

Divert to A&E

Arrivals from ambulance

Inpatients with known COVID-19

Clearly not cardiac

Yes

Assess COVID-19 probability Confirmed or high probability* of COVID-19 infection *Fever, cough, sepsis, myalgia or recent contact with COVID-19 Clinical assessment ± echo with full PPE

Moderate probability* of COVID-19 infection *Respiratory distress, but no sepsis or fever Clinical assessment ± echo with full PPE

PPCI in COVID-19 lab ✔ Full PPE for all lab team ✔ Surgical mask on patient

Low probability* of COVID-19 infection *Nothing to suspect COVID-19 Clinical assessment ± echo with basic PPE

PPCI in COVID-19 lab

PPCI in clean lab

✔ Full PPE for all lab team ✔ Surgical mask on patient

✔ Full PPE for all lab team ✔ Surgical mask on patient

Consider fibrinolysis if ✔ Non-anterior STEMI ✔ Low bleeding risk ✔ Patient >60 minutes away from PCI centre ✔ High risk of becoming AGP ✔ Discuss with one other senior colleague

No

>50% resolution of ST in 60–90 minutes?

Yes Consider CT chest after PCI

Consider CT chest after PCI To COVID-19 room/ward for recovery and subsequent IP management

To COVID-19 room/ward for recovery if confirmed or high suspected COVID

If good LV, non-anterior STEMI, no VT or recurrent pain: discharge with early outpatient angiography (3–6 weeks) or inpatient angiography in COVID-19 lab when patient less infective

If coronaries unobstructed in the context of suspected COVID-19 and STEMI, COVID-19 myopericarditis highly likely

Recovery in clean ward Aim for discharge within 48 hours if no PCI or PCI in low-risk patient (good LV, no arrhythmias and no other acute issues)

Aim for discharge within 48 hours if no PCI or PCI in low-risk patient (good LV, no arrhythmias and no other acute issues)

If poor LV, anterior STEMI, VT or recurrent pain: inpatient angiography in COVID-19 lab when less infective

Transport of COVID-19 positive patients with full PPE

Fibrinolysis SOP First line: Tenecteplase

Alternative: Alteplase

Add 10 ml of water for injection to ONE vial of tenecteplase 50 mg. Administration: single IV bolus over 10 seconds. In patients over 75 years of age reduce dose by 50% to reduce risk of intracranial bleeding.

Body weight <60 kg

Tenecteplase dose

Volume of solution

30 mg (6,000 units)

6 ml

60–69 kg

35 mg (7,000 units)

7 ml

70–79 kg

40 mg (8,000 units)

8 ml

80–89 kg

45 mg (9,000 units)

9 ml

90+ kg

50 mg (10,000 units)

10 ml

Add 50 ml of water for injection into to each 50 mg vial of alteplase to give a 1 mg/ml solution using the transfer connector provided. Two vials are required for each patient. Dose as per table. Max total dose 100 mg.

For patients >65 kg

Volume of solution

15 mg as an IV bolus over 3–5 minutes, then

15 ml

50 mg as an IV infusion over 30 minutes, then

50 ml

35 mg as an IV infusion over 60 minutes

35 ml

For patients <65 kg

Volume of solution

15 mg as an IV bolus over 3–5 minutes, then

15 ml

0.75 mg/kg IV infusion over 30 minutes, then

0.75 ml/kg

0.5 mg/kg IV infusion over 60 minutes

0.5 ml/kg

For both drugs, IV heparin to be given as per Trust infusion guidelines for 24–48 hours. Clopidogrel to be used instead of ticagrelor as second antiplatelet.

A&E = accident and emergency; ACS = acute coronary syndrome; AGP = aerosol-generating procedures; COVID-19 = coronavirus disease 2019; ICU = intensive care unit; LV = left ventricle; PCI = percutaneous coronary intervention; PPCI = primary PCI; PPE = personal protective equipment; SOP = standard operating procedure; STEMI = ST-elevation MI; VT = ventricular tachycardia.

INTERVENTIONAL CARDIOLOGY REVIEW

COVID-19 Figure 2: Suggested Clinical Pathway for the Management of Non-STEMI and Acute Coronary Syndrome Patients

Proposed NSTEMI – ACS Pathway During COVID-19 Crisis 2020 Patients in hospital with ? ACS High-risk ACS? Ongoing chest pain with deep ST depression, arrhythmias or hypotension

Yes

Refer to STEMI/high-risk Patients in hospitalACS with pathway ?ACS

No Yes

Severely ill COVID-19 patient in ICU? No Is the predominant clinical presentation infection/pneumonia but troponin is elevated?

Yes

No It appears to be a genuine presentation of ACS Based on pain, ECG changes and troponin

• Not immediate candidate for PCI • Discuss merits of ACS drug treatment • Reassess if patient recovers from infection and there is persistent evidence of ischaemia

• Test for COVID-19 • No need for immediate transfer to HAC • No need for immediate cardiology input or echocardiography if sole abnormality is raised troponin levels • Consider ACS drug treatment depending on risk factors • Reassess the need for cardiology input if patient recovers from infection and has on-going cardiac issues

COVID-19 status Confirmed COVID-19

✔ ✔

✔

Start ACS treatment Transfer to COVID-19 area of HAC once not perceived to be highly contagious (no high fever, cough, etc) V-scan with full PPE only if required

✔ ✔ ✔

✔

Benefit from IP angiography based on risk stratification?

No

COVID-19 negative or not at all suspected

Suspected COVID-19 waiting list

Confirm COVID-19 diagnosis with swab and/or CT chest Start ACS treatment Transfer to COVID-19 area of HAC once not perceived to be highly contagious (no high fever, cough, etc) V-scan with full PPE only if required

✔ ✔ ✔

Depending on COVID-19 status at time of angiography Positive or still unknown

Negative

Yes

Start ACS treatment Transfer to clean area of HAC as usual V-scan with basic PPE only if required

?PCI in clean lab ✔ ✔ ✔

Full PPE for all lab team if high-risk of becoming AGP Basic PPE otherwise (switch to full PPE if CPR needed) Surgical mask on patient

?PCI in COVID-19 lab ✔ ✔

Full PPE for all lab team Surgical mask on patient

To COVID-19 room/ward

Recovery in clean ward

Aim for discharge within 24 hours if no PCI or PCI in low-risk patient (normal LV, no arrhythmias and no other acute issues)

Aim for discharge within 24 hours if no PCI or PCI in low-risk patient (normal LV, no arrhythmias and no other acute issues)

Transport of COVID-19 positive patients with full PPE

AGP = aerosol-generating procedures; PPE = personal protective equipment. A&E = accident and emergency department; ACS = acute coronary syndrome; AGP = aerosol generating procedures; COVID-19 = coronavirus disease 2019; CPR cardiopulmonary resuscitation; HAC = heart attack centre; ICU = intensive care unit; IP = inpatient; LV = left ventricle; NSTEMI = non-ST-elevation MI; PCI = percutaneous coronary intervention; PPE = personal protective equipment; STEMI = ST-elevation MI.

INTERVENTIONAL CARDIOLOGY REVIEW

COVID-19 ACS Pathway Routine Use of CT before Primary Percutaneous Coronary Intervention While this has been suggested in some algorithms, our internal pathway does not involve routine use of chest CT to confirm the diagnosis of COVID-19 before PPCI. At a pre-PPCI stage, CT would not change immediate management for patients or staff (who will be offered full PPE in all STEMI cases, as per below PPE section) and it would delay reperfusion time significantly.34 We believe that CT should be considered after PPCI for further stratification and inpatient management if clinicians believe it would support diagnosis of COVID-19 or would alter management.35

Early Discharge of Low-risk Patients Following STEMI revascularisation of patients during the COVID-19 pandemic, early discharge will likely reduce the risk of contamination between patients and to healthcare workers.36 Therefore, low-risk patients (those with normal left ventricular [LV] function, no haemodynamic compromise and no evidence of malignant arrhythmias) should be offered discharge within 48 hours of presentation. Such an early discharge approach has already been documented to be safe in non-COVID-19 cohorts.2,37 More formal risk scores such as the Zwolle risk score could be used to help decision-making.38–39

Personal Protective Equipment for Staff and Subsequent Management For STEMI and high-risk ACS patients, we propose to offer the catheter laboratory staff full PPE in all cases, regardless of their COVID-19 status (see Figure 3 and PPE section below). Protection with full PPE should also apply to any close clinical and echocardiographic assessment prior to transfer to the catheter laboratory. Subsequent inpatient management and ward allocation will still be determined by their COVID-19 status or probability of disease; those patients with confirmed or highly suspected COVID-19 should be transferred to appropriate COVID-19 wards.

On-call Rota Adaptations and Multidisciplinary Team Discussions During the pandemic, it is reasonable to adopt a buddy system for rotas, with one consultant on-call and a second on stand-by in case the first one falls ill. In addition, social distancing measures have affected routine implementation of face-to-face discussions among physicians.

Therefore, adoption of virtual multidisciplinary teams and data compliant group messaging allows for rapid decision-making deliberations during the pandemic. All discussions should be clearly documented in patients’ medical records.

targeted ACS treatment or invasive angiography. Equally, although assessment of LV function in these patients might be of prognostic value in high-risk patients, routine inpatient echocardiography studies for all cases should be avoided as it would increase the risk of transmission to staff without affecting clinical management.40 There are ongoing studies assessing the role of antiplatelets and anticoagulation on COVID-19.41,42

Management of True Acute Coronary Syndrome Cases If the clinical picture is typical of ACS, management should remain as standard as possible for stable patients, regardless of COVID-19 status.1–5 This includes prompt initiation of pharmacological therapy and transfer to a cardiac unit with catheter laboratory facilities.

We propose that patients should be offered invasive angiography before discharge, particularly those with raised cardiac biomarkers, high-risk ECG features or regional ventricular abnormalities on echocardiography. While an early conservative discharge on medical therapy alone would reduce hospital stay, the risk of reinfarction is considerable.43 Furthermore, because a significant proportion of patients will be unwilling to seek hospital attention again because of fears of acquiring COVID-19, we judge that early medical discharge would pose an unacceptably high mortality risk during the pandemic.44–47 Finally, most cardiology units have reduced elective work, therefore there should be capacity for early angiography to all suitable patients. The timing for invasive angiography should be guided by the patient’s COVID-19 status and infectiveness. Those with acute viral symptoms, high fever, cough and sepsis are most likely highly contagious. Therefore delaying angiography until such markers are settled should be safer for staff and should also in theory reduce the risk of immediate procedural complications, such as stent thrombosis.48 In confirmed or suspected COVID-19 patients, we believe bedside echocardiography should be offered judiciously for those patients with a clear clinical indication, such as clinical heart failure or suspected valvular disease.22 Also, to minimise exposure for the operator, we agree with current society guidelines that echocardiographic studies should be focused and covered by full PPE.22,31 Finally, it is expected that short turnaround point-of-care COVID-19 testing will be available soon to help decision making. The timing of testing is important and we aimed for testing at the time of first clinical contact but no later than exit from the catheter laboratory.

Early Discharge

Non-STEMI and Acute Coronary Syndrome The NSTEMI–ACS pathway is presented in Figure 2. The points in the following sections should be highlighted.

Identification of False-positive Acute Coronary Syndrome Cases COVID-19 infection in hospitalised patients is associated with elevation in cardiac troponin in a significant proportion of cases – up to 23% of cases in a Chinese cohort.15 The precise pathophysiological mechanisms behind this myocardial injury has not yet been established, hence optimal management remains unknown. Therefore, the management of raised troponin in COVID-19 patients should be individualised and guided by their clinical presentation: if the syndrome is infective and typical of COVID-19, there is no need for specific cardiology input,

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Following invasive angiography, the aim should be for an early discharge of all uncomplicated ACS patients, ideally within 24 hours of the procedure. This strategy has been previously demonstrated to be safe and would decrease the risk of infection transmission in hospital.37,49

Personal Protective Equipment and Strategies for Staff WHO and Public Health England have issued guidelines on the use of PPE for healthcare workers.50–51 Hospitals and cardiology units have had to adapt them to their local acute and catheter laboratory circumstances, taking into account equipment availability and costs.52 In our view, it is prudent to assume that all ACS cases have a high probability of becoming AGPs (possibly requiring high flow oxygen

COVID-19 Figure 3: Suggested Use of Personal Protective Equipment by Cardiology Staff During the COVID-19 Pandemic

FULL PPE

BASIC PPE

Full surgical hood

Sterile gloves x 2

Standard surgical cap

Sterile gloves x 1

Face shield ± goggles

Blue + yellow gown

Goggles/visors/glasses

Sterile gown x 1

N95 mask

Tall wellie boots

Surgical or N95 masks

Standard low shoes

Check training video at: https://www.youtube.com/watch?v=aP_7NBaPq5E This figure displays the recommended PPE to be used in the COVID lab or clean lab for high-risk cases (left panel) and in the clean lab for lower-risk cases (right panel). This guidance should be adapted to local circumstances, equipment availability and costs. PPE = personal protective equipment.

therapy, airway intubation or cardiopulmonary resuscitation), posing a high risk of exposure to staff. Also, emerging evidence supports the idea that many other benign physiological phenomena such as coughing and talking loudly can potentially generate droplets and aerosols.53 Finally, experience from other centres and in our own have taught us that a significant proportion of acute patients coming in via ambulance who are not known to have COVID-19, develop symptoms while in hospital and a diagnosis of the infection will be made at a later stage.54

• •

• Therefore, we judge that during the peak of the pandemic, and if financially and logistically viable, the following PPE strategies should be adopted for ACS cases regardless of the patient’s COVID-19 status (Figure 3): • Patients should wear a surgical mask during the entire hospital stay, providing it will not affect clinical care.55 Patients who require

•

oxygen should have controlled doses administered via nasal cannula under the mask. Those requiring higher flows should be considered as an AGP. Close (<2 m) contact with patients should be restricted to the minimum necessary during ward rounds.

It is reasonable to offer full PPE to all ambulance crew, catheter laboratory staff and echocardiography operators, as well as to acute workers with close clinical contact with the patient (Figure 3, left panel).

For all other healthcare workers involved with direct patient care, a minimum of basic PPE should be provided (Figure 3, right panel).

Thought should be given to the ventilation of catheter laboratory and ward areas as a way of promoting aerosol elimination.21,31,49

If departments face an issue of availability of PPE, it would be reasonable to offer basic PPE (Figure 3) to all staff when treating patients with very low probability of COVID-19 infection (green box on Figures 1 and 2).

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COVID-19 ACS Pathway Importantly, this should be switched to full PPE in the event of AGP during PCI or hospital stay. For instance, patients suffering cardiac arrest would require staff in basic PPE to don full PPE before coming to provide support.

Limitations Where possible, we have used high quality peer-reviewed data to guide these recommendations. However, at the time of writing, there was an urgent need to respond to an unprecedented medical emergency, which did not allow time for much data of this kind to emerge.

Accordingly, we were required to make use of the pool of data available through direct communication, social media and preprints. We have

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Bangalore S, Sharma A, Slotwiner A, et al. ST-segment elevation in patients with covid-19 – a case series. N Engl J Med 2020;382:2478–80. https://doi.org/10.1056/NEJMc2009020; PMID: 32302081.

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maintained these in our references to remain true to the challenges of that period.

Conclusion The COVID-19 pandemic has forced cardiology departments to review previously established guidelines, particularly those affecting the care of ACS patients. However, based on shared global experiences and growing peer-reviewed literature, it is possible to put in place ACS treatment pathways that offer evidence-based decisions to patients and staff. While pathway modifications could be implemented more rapidly in the future, only further COVID-19 studies will guide us as to whether further modifications are needed.

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De Filippo O, D’Ascenzo F, Angelini F, et al. Reduced rate of hospital admissions for ACS during Covid-19 outbreak in northern Italy. N Engl J Med 2020;383:88–9. https://doi. org/10.1056/NEJMc2009166; PMID: 32343497.

Garcia S, Albaghdadi MS, Meraj PM, et al. Reduction in ST-segment elevation cardiac catheterization laboratory activations in the United States during COVID-19 pandemic.

J Am Coll Cardiol 2020;75:2871–2. https://doi.org/10.1016/j. jacc.2020.04.011; PMID: 32283124.

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Armstrong PW, Gershlick AH, Goldstein P, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N

Engl J Med 2013;368:1379–87. https://doi.org/10.1056/ NEJMoa1301092; PMID: 23473396.

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32. Boehronger B, O’Meara P, Wingrove G, Nudell N. An emergency amendment to the national scope of practice for paramedics in the setting of a global pandemic. J Rural Health 2020. https:// doi.org/10.1111/jrh.12441; PMID: 32277773; epub ahead of press.

33. Buick JE, Cheskes S, Feldman M, et al. COVID-19: what paramedics need to know! CJEM 2020;22:426–30. https://doi. org/10.1017/cem.2020.367; PMID: 32290887.

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45. Mitchell J. NHS urges public to get care when they need it.

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47. Kwok CS, Gale CP, Kinnaird T, et al. Impact of COVID-19 on

COVID-19 percutaneous coronary intervention for ST-elevation myocardial infarction. Heart 2020. https://doi.org/10.1136/ heartjnl-2020-317650; PMID: 32868280; epub ahead of press.

48. Ahmed I, Nelson WB, Biring TS, et al. Acute coronary thrombosis in a patient with septic shock without any evidence of disseminated intravascular coagulation. BMJ Case Rep 2009;2009:bcr05.2009.1887. https://doi.org/10.1136/ bcr.05.2009.1887; PMID: 21857877.

49. Guo ZD, Wang ZY, Zhang SF, et al. Aerosol and surface distribution of severe acute respiratory syndrome coronavirus 2 in hospital wards, Wuhan, China, 2020. Emerging Infect Dis 2020;26:1583–91. https://doi.org/10.3201/eid2607.200885; PMID: 32275497.

50. WHO. Rational use of personal protective equipment (PPE) for coronavirus disease (COVID-19). Geneva: WHO, 19 March 2020. https://apps.who.int/iris/bitstream/handle/10665/331498/ WHO-2019-nCoV-IPCPPE_use-2020.2-eng.pdf (accessed 29 September 2020).

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52. Curzen N, Ray S, Slade A. Interpretation of Public Health England (PHE) PPE guidelines in cardiology-specific scenarios.

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53. Broom D. This Japanese experiment shows how easily coronavirus can spread – and what you can do about it. World Economic Forum 14 April 2020. https://www.weforum.org/ agenda/2020/04/coronavirus-microdroplets-talking-breathingspread-covid-19 (accessed 29 September 2020).

54. Sutton D, Fuchs K, D’Alton M, et al. Universal screening for SARS-CoV-2 in women admitted for delivery. N Engl J Med 2020;382:2163–4. https://doi.org/10.1056/NEJMc2009316; PMID: 32283004.

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Corrigendum

Corrigendum to: Intraventricular Conduction Disturbances After Transcatheter Aortic Valve Implantation Shu-I Lin,1 Mizuki Miura,2 Ana Paula Tagliari,2 Ying-Hsiang Lee,1 Shinichi Shirai,3 Rishi Puri,4 Francesco Maisano2 and Maurizio Taramasso2 1. Cardiovascular Center, MacKay Memorial Hospital, Taipei, Taiwan; 2. Department of Cardiac Surgery, University Hospital Zurich, Zurich, Switzerland; 3. Department of Cardiology, Kokura Memorial Hospital, Fukuoka, Japan; 4. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, US

Citation: Interventional Cardiology Review 2020;15:e17. DOI: https://doi.org/10.15420/icr.2020.33 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 noncommercial purposes, provided the original work is cited correctly.

In the article by Lin et al. entitled Intraventricular Conduction Disturbances After Transcatheter Aortic Valve Implantation (Interventional Cardiology Review 2020;15:e11. https://doi. org/10.15420/icr.2020.07), the following correction should be made.

Š RADCLIFFE CARDIOLOGY 2020

Author Ying-Hsian Lee should be spelled Ying-Hsiang Lee The authors and Interventional Cardiology Review apologise for this error.

Access at: www.ICRjournal.com

Coronary

Iterative Improvement and Marginal Gains in Coronary Revascularisation: Is Robot-assisted Percutaneous Coronary Intervention the New Hope?

Kalpa De Silva,1 Aung Myat,2 Julian Strange1 and Giora Weisz3 1. Bristol Heart Institute, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK; 2. Frimley Park Hospital, Frimley Health NHS Foundation Trust, Camberley, UK; 3. Columbia University Medical Center, New York, NY, US

Abstract Percutaneous coronary intervention (PCI) has undergone a rapid and adaptive evolution since its introduction into clinical practice more than 40 years ago. It is the most common mode of coronary revascularisation in use, with the scope, breadth and constellation of disease being treated increasing markedly over time. This has principally been driven by improvements in technology, engineering and training in the field, which has facilitated more complex PCI procedures to be undertaken safely. Robot-assisted PCI represents the next paradigm shift in contemporary PCI practice. It has the ability to enhance procedural accuracy for the patient while improving radiation safety and ergonomics for the operator. This state-of-the-art review outlines the current position and future potential of robot-assisted PCI.

Keywords Robotic percutaneous coronary intervention, radiation protection, precision percutaneous coronary intervention Disclosure: GW has served on the advisory board of Corindus. All other authors have no conflicts of interest to declare.

Received: 21 August 2020 Accepted: 26 October 2020 Citation: Interventional Cardiology Review 2020;15:e18. DOI: https://doi.org/10.15420/icr.2020.24 Correspondence: Kalpa De Silva, The Bristol Heart Institute, University Hospitals Bristol NHS Foundation Trust, Bristol Royal Infirmary, Bristol BS2 8HW, UK. E: kalpa.desilva@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 noncommercial purposes, provided the original work is cited correctly.

Percutaneous coronary intervention (PCI) has evolved since its inception more than 40 years ago. There have been major advances in technology, with adaptations made across all facets of the procedure, from stent engineering to adjunctive physiology and intracoronary imaging. Despite this progress, the mainstay for all PCI procedures remains fluoroscopic X-ray imaging guidance, with manual manipulation of guidewires, balloons, stents and other devices. This has meant there has been little change in the occupational hazards for operators and catheterisation laboratory staff. Furthermore, although the anatomical complexity of percutaneous revascularisation has increased, there remains an innate degree of variability seen with human operative methods.

Medical robots are gaining widespread use in surgery because of high precision, speed, reproducibility, greater access to areas under operation and machine endurance, all features that are prone to the variability of human error.1–3 The use of robotic systems has expanded to incorporate the field of PCI. Despite accumulating evidence that supports the feasibility and safety of robot-assisted PCI (R-PCI), these procedures are only performed in a limited number of centres worldwide.4 Although the interventional cardiology community has a heightened awareness of the many potential hazards of working in the catheterisation laboratory, adoption of R-PCI has been slow, with concerns around learning curves, costs and adaptability in contemporary practice.5 This review outlines and summarises the current position, limitations and future potential of R-PCI.

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What is Robotic Percutaneous Coronary Intervention?

An R-PCI system enables control of coronary guidewires and intracoronary devices, such as balloons and stents, during PCI from a protected control cockpit. The CorPath 200 (Corindus Vascular Robotics) was the first incarnation of an R-PCI system and was used in the initial feasibility trials. This system has been further improved upon, with the CorPath GRX (Corindus Vascular Robotics) being the current iteration.

The CorPath GRX system is composed of two subunits: a bedside unit and the remote physician workspace (Figure 1). The bedside unit consists of the articulated arm, the robotic drive and a single-use cassette in which devices, including wires, balloons and stents, are loaded (by a member of the catheterisation laboratory team who remains within proximity of the patient). The remote workspace consists of an interventional cockpit, which is surrounded by a radiation shield and houses the control console, angiographic and haemodynamic monitors and the X-ray foot pedal.

During the procedure, the interventional cardiologist can sit comfortably within the shielded environment, almost completely eliminating radiation exposure, without needing to wear lead aprons. The operator may choose to have the cockpit ‘sterilised’, and thereby remain in a sterile gown throughout the procedure, or to perform the PCI without a sterile gown. The remote workspace can also be taken to the control room to completely eliminate radiation exposure. The latter facilitates removal of the operator’s lead garments during PCI. The system allows

© RADCLIFFE CARDIOLOGY 2020

Robot-assisted PCI the operator to control and manipulate guidewires, balloon and stents using a set of joysticks and touch screens while fluoroscopy provides image guidance.6 Axial and rotational motion are achieved by a mechanical transmission module. The balloon or stent can be guided both in a continuous motion using the joystick and in discrete, highly sensitive small steps using the touch screen. Axial motion is achieved by the motored roller pair. If the device meets resistance and the motored rollers slide, the motion-sensing rollers report malfunction and the system halts.7

Figure 1: The CorPath GRX System

Potential Advantage for the Patient Increased Procedural Accuracy The main aim of using robotic systems in interventional cardiology is to provide increased procedural precision and improve efficiency in clinical care. Although the advent of various intracoronary imaging techniques (e.g. intravascular ultrasound [IVUS] and optical coherence tomography [OCT]) has undoubtedly increased the accuracy and precision of PCI procedures, the adoption of these techniques, in routine PCI procedures remains relatively low. The 2019 British Cardiovascular Intervention Society audit data indicate that only 13.2% of all PCI procedures (n=100,294) used either IVUS or OCT.8 There are numerous reasons for this, including fiscal ramifications surrounding reimbursement, the perception of increased procedural times and a reduction in catheter laboratory efficiency when these technologies are used routinely. Therefore, angiography-guided PCI continues to be the mainstay in contemporary PCI practice.

Following a PCI procedure, a major modifiable risk factor for further target vessel revascularisation is accurate stent selection during the index procedure, which is primarily influenced by operator experience and procedural technique. In a US multicentre observational registry that included >1,500 patients, incomplete coverage of the entire length of the coronary lesion was observed in 46.5% of cases, with incomplete lesion coverage (longitudinal geographic miss [LGM]) being associated with higher rates of target vessel revascularisation at 1 year, independent of clinical or anatomical risk factors.9 Furthermore, in a recent analysis of the accuracy of visual angiographic lesion assessment by interventional cardiologists, lesion length was underestimated by 51% and overestimated by 19%, highlighting the variance with the current angiography-guided reference standard.10 The use of visual angiographic assessment has specific limitations, particularly in stent length selection, where 2D angiographic imaging, most notably in curved and tortuous vessels, leads to foreshortening, which affects accurate measurement of length. When using R-PCI, a special measurement feature can be used, measuring the real length unrelated to the angiographic view and possible foreshortening. This is achieved by using the actual intravascular device and taking into account the distal and proximal edges of the artery segment: the balloon markers are advanced to the distal and proximal edges of the lesion of interest. The distal edge is marked as ‘0’ on the touch screen display. By withdrawing the marker to the proximal edge of the lesion, the distance travelled by the marker can be measured to provide lesion length. The R-PCI system can make submillimetre measurements, improving accuracy compared with the visual estimates currently used.

In a retrospective, propensity-matched cohort analysis, Bezerra et al. demonstrated that the incidence of LGM was greater in those treated with conventional PCI compared with R-PCI (43.1% versus 2.2%, respectively; p<0.0001).11 Subsequent data on stent length selection and

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the consequent health economics of more accurate device selection suggest that the use of R-PCI reduces variability in device selection, with a reduction in the use of extra stents by approximately 8%, and therefore reductions in both procedural cost and the risk of LGM.12

Potential Advantages for the Operator Reduced Radiation Exposure Although there is the potential of increased precision when using robotic assistance during PCI, the key advantage lies in the reduction of radiation exposure and orthopaedic risk to the operator and potentially other catheter laboratory personnel.13 Conventional PCI is performed while standing beside the patient, in close proximity to the ionising radiation source, which necessitates the use of heavy lead aprons for protection. Numerous occupational hazards, including orthopaedic complications related to the use of lead aprons and radiation-related complications, such as cataracts and, more seriously, malignancies, have been identified.14–17 Interventional cardiologists are reported to have the highest radiation exposure among health professionals, with an exposure per person per year that is 2- to 10fold higher than that of diagnostic radiologists. The calculated cumulative dose after 30 years of working is in the range 50–200 mSv, with a projected professional lifetime attributable excess cancer risk in the order of 1 in 100.18 Although it is difficult to prove occupational radiation exposure to increased cancer risk, there is evidence that mandates caution. The Brain Radiation Exposure and Attenuation During Invasive Cardiology Procedures (BRAIN) study confirmed that radiation exposure to the cranium is higher on the left side during interventional cardiology procedures. 19 The potential that this has a causal link to the development of brain tumours was alluded to in a study of physicians diagnosed with brain tumours, 85% of which were left sided in origin, with the majority of physicians diagnosed being interventional cardiologists.20 Furthermore, the clinically appropriate increase in the adoption of procedures undertaken via a radial artery approach means that interventional cardiologists are exposed to small but significantly higher doses of ionising radiation.21 More broadly, Venneri et al. reported that the cumulative exposure dose among catheter laboratory personnel over time was associated with an

Coronary increased risk of malignancy.16 Although a number of safety precautions, including collimation, the use of dose reduction software and operator education, all significantly limit radiation exposure, the long-term adverse risk of exposure cannot be completely ameliorated.14,17 However, the advent and use of robots to assist with PCI have resulted in a marked reduction in operator radiation exposure. The Percutaneous Robotically Enhanced Coronary Intervention (PRECISE) study was the first demonstration of the safety and feasibility of R-PCI in a nonrandomised multicentre registry of 164 patients undergoing R-PCI.4 Importantly, radiation exposure for the primary operator was 95.2% lower than the levels found at the traditional table position.4 This reduction in radiation is in concert with the procedure being performed with the operator seated and without any lead apron, which also mitigates some of the orthopaedic hazards facing PCI operators.

complex R-PCI were compared to a manual PCI (M-PCI) control group.23 In that study, 315 patients (mean ± SD age 67.7 ± 11.8 years; 78% men) underwent 334 PCI procedures (108 R-PCIs: 157 lesions, 78.3% type B2/C; 226 M-PCIs: 336 lesions, 68.8% type B2/C). The technical success with R-PCI was 91.7%, with a 11.1% rate of manual assistance and a 7.4% rate of manual conversion and no difference in clinical success compared with M-PCI (99.1% versus 99.1%, respectively; p=1.00).

However, procedure time was longer in the R-PCI than the M-PCI group (mean ± SD 44:30 ± 26:04 versus 36:34 ± 23:03 min; p=0.002), despite a similar fluoroscopy time (mean ± SD 18.2 ± 10.4 versus 19.2 ± 11.4 min, respectively; p=0.39).23 Although this was insightful in showing the potential of R-PCI in the treatment of more challenging lesion subsets, there were notable exclusions that were ineligible for R-PCI, including patients who required atherectomy, a planned two-stent strategy for bifurcation lesions and chronic total occlusions that required a hybrid approach (Table 1).

Improved Ergonomics One of the major advances with the advent of robotic technology is the potential of more ergonomic working in the catheter laboratory.

PCI complexity has steadily increased with other technological advances, leading to interventional cardiologists spending increasing periods of time in lead aprons, which has a significant impact on the musculoskeletal system. A survey of interventional operators highlighted that 50% of respondents reported at least one occupational orthopaedic injury; these were commonly cervical and lumbar injuries, and were strongly correlated with both case load and advancing operator age.22 Not needing the heavy lead personal protective equipment and the ability to remotely control the procedure while in a seated position mean that R-PCI has the potential to minimise the risk of the long-term sequelae of current PCI working. However, the current systems do not allow for complete automation. The traditional manual method is still needed to obtain arterial access, perform diagnostic coronary angiography and intubate the guiding catheter. Once the guiding catheter is engaged, operators can remove the lead aprons and position themselves in the interventional cockpit.

Evidence Base Supporting Robotic-Assisted Percutaneous Coronary Intervention The pivotal assessment of R-PCI safety was seen in the PRECISE study, which included 164 patients with at least 50% diameter stenosis in vessels ranging from 2.5 to 4.0 mm in diameter that could be covered with a single stent.4 Key exclusion criteria were the presence of a previous stent within 5 mm of the planned stent deployment, planned atherectomy, intraluminal thrombus, severe tortuosity or calcification proximal to the lesion, ostial location, bifurcation lesion and unprotected left main lesions. Of the 164 patients, 112 (68.3%) had type A or B1 lesions, whereas the remainder had type B2 (18.9%) or type C (12.8%) lesions. Procedural success (without conversion to a conventional manual procedure) was achieved in 98.8% (n=162/164). There were no deaths, strokes, Q wave MIs or target lesion revascularisation after 30 days of follow-up.4 Although the findings of the PRECISE study confirmed both procedural safety and improved operator ergonomics and radiation safety, there are considerable concerns about the ability of R-PCI to perform revascularisation in more complex lesions and patient subsets. In the single-centre Complex Robotically Assisted Percutaneous Coronary Intervention (CORA-PCI) Study, consecutive patients undergoing

The current robotic system is limited to rapid exchange (monorail) devices only, meaning that rotational or orbital atherectomy, which require the use of specialised wires and an over-the-wire technique, are not possible. However, recently, case descriptions of the safe use of laser atherectomy, which can be performed using routine guidewires, as an alternative lesion modification device have been published.24 Furthermore, there have been descriptions of the use of R-PCI in multivessel coronary disease, saphenous venous graft disease, left main stem disease and in the setting of ST-elevation myocardial infarction.25,26 This suggests that a combination of developing operator technical expertise and continued iteration of the engineering of the robotic system could allow the envelope of R-PCI to expand further.

Current Limitations The adoption of R-PCI has been slow for a number of reasons. Most importantly, there is a lack of robust clinical data, with no randomised clinical trials with the currently available systems. Most of the available data are based on small or medium-sized clinical registries of highly selected patients with relatively simple coronary lesions. There is a need for clinical evidence from large-scale randomised clinical trials showing improved radiation safety for the operators and non-inferior angiographic and clinical results across a broad spectrum of patient and lesion subsets.

The healthcare funding infrastructures and resource utilisation across many countries and systems mean that there is concern about the costs of installing and operating R-PCI systems. Increasingly many hospitals have multiple catheter laboratories, where there are numerous procedures being performed simultaneously. The current robotic systems can only be installed in a single room within the catheterisation laboratory environment. This will limit more widespread, systematic use, unless numerous systems are purchased, which clearly has considerable fiscal implications. In addition to clinical data about the utility of R-PCI, further data are required through well-designed health economic studies as to whether R-PCI systems confer an advantage if adopted on a more generic scale for healthcare systems.

Moreover, with regard to resource utilisation, it is important to point out that R-PCI can be associated, particularly in the early phase of the learning curve, with prolonged procedural time compared with conventional manual PCI. This is seemingly overcome rapidly after a period of consistent use, but the nature of the initial phase of use needs to be considered when adopting the technology.

INTERVENTIONAL CARDIOLOGY REVIEW

Robot-assisted PCI Table 1: Robotic-assisted Percutaneous Coronary Intervention Trial Data Granada et al. 20116

Weisz et al. 20134

Mahmud et al. 201723

Madder et al. 201728

Study design

Prospective, single-arm, Prospective, single-arm, single-centre, non-randomised multicentre, non-randomised study study

Prospective, single-arm, single-centre, comparative study

Prospective, single-arm, single-centre, non-randomised study

Study size (n)

8

108

20

164

Number of lesions

8

164

157

22

Technical success (%)

97.9

98.8

91.7

86.4

Type B2/C lesions, n (%)

0

52 (32)

122 (78)

11 (50)

Lesion length (mm), mean ± SD

11.4 ± 6.1

12.2 ± 4.8

22.2 ± 10.6

–

In-hospital MACE

0

4 (4.2)

6 (5.6)

0

Operator radiation reduction (%)

97

95.2

–

–

MACE = major adverse cardiac events.

Technically, the initial CorPath 200 system had several limitations, which included the lack of haptic mechanical feedback, the inability to manipulate guiding catheters during complex cases and the inability to use over-the-wire equipment (e.g. microcatheters, rotational atherectomy) or to control more than one wire and balloon or stent. The subsequent version, the CorPath GRX, overcame some of these limitations. Importantly, the CorPath GRX allows for guide catheter control and manipulation. This is important for active guide support during intracoronary intervention, including challenging coronary anatomy.

Although much of the data obtained shows excellent technical success rates with R-PCI, albeit in narrow, highly selected groups, many interventional cardiologists feel that the lack of tactile sensation remains a limiting factor. The inability to detect variance in tactile feedback when using wires that have different mechanical properties (e.g. polymer coated, hydrophilic, varying lubricity) is important in complex cases, where the interaction between the wire, lesion and operator is key in understanding lesion morphology and subsequent technical success. Further development and advancement of haptics within the robotic system will allow for a more natural interaction between the wire and operator. Furthermore, the current iteration of the robotic system does not allow the remote use of intracoronary imaging. This limits the PCI to angiographic guidance only. However, as the system is improved upon and advanced, this may change to allow adjunctive imaging to be added to the portfolio of devices that could be used during R-PCI. The issue of R-PCI being limited to less complex lesion subsets is due, in part, to the fact that current robotic systems do not support overthe-wire coronary interventions. Therefore, adjunctive tools and techniques, such as rotational and orbital atherectomy for calcium modification, the use of microcatheters and aspiration devices, cannot be used with R-PCI. In addition, the current systems do not support planned coronary bifurcation stenting with a two-stent approach. With advanced coronary interventions becoming more common, this limitation means that a major portion of the procedure needs to be performed manually.

Finally, R-PCI does not completely ameliorate scattered radiation risk.

Although the interventional operator sits within a shielded environment protected from ionising radiation, other members of the team, technicians and fellows, are still required to stay within the radiation field during the procedure to inflate the balloon and stents, and therefore may be less motivated to adopt this new technology. Furthermore, robot-assisted

INTERVENTIONAL CARDIOLOGY REVIEW

systems do not currently offer the operator a means to decrease radiation exposure during diagnostic procedures.

Future Developments The current robotic systems are in the relatively early stages of development compared with established modes of working and techniques in PCI practice, which have been developed and been iterated upon over the past 40 years. However, the robotic systems are continuously improving. Their scope for more accurate intervention and improved ergonomic working is evident already.

Further technological advancements will further improve R-PCI and allow it to be adopted across a wider group of patients and lesion subsets.

A key potential advancement that robotic assistance could bring is in the field of ‘telerobotics’. This could allow robot-assisted PCI systems to treat patients who are in geographically distant locations. This could be invaluable for patients who otherwise could not be transported in time to a PCI-capable hospital, potentially reducing door-to-balloon times in those that are in remote locations.

Contemporary communication systems have allowed for the use of telerobotics in the surgical arena, which is now in routine use.

A Canadian telerobotic surgical service was developed between a teaching hospital and rural hospital for the provision of a variety of advanced laparoscopic surgeries in their community patients.27 This early description of a telerobotic service showed the feasibility and safety of such a service with increasingly complex laparoscopic surgical operations, with no intraoperative complications or conversion to open operations.

The REMOTE-PCI study demonstrated the potential feasibility of such an approach.28 In that small study (n=20), the interventional cockpit of the robotic system was removed from the catheter laboratory with the patient in situ and placed behind the closed doors of an isolated room, with no direct visual or auditory contact with the patient or catheterisation laboratory team. Communication between the operators and the laboratory personnel occurred via telecommunication devices providing real-time audio and video connectivity, with a technical success rate of 86%.

To achieve robotic PCI with a remote operator location, additional data, including video displays similar to those used for telemedicine, would be needed to allow the operator to observe the patient and

Coronary the procedure room environment. In addition, added controls would be needed on the console, such as camera controls, table and C-arm controls, dye injectors and, ideally, a microphone with headset so that the operator could communicate directly with those in the procedure room in real time. Although this off-site approach is promising, there will still be a need for a local experienced operator who would be able to address procedural complications. Patel et al. recently described the first ‘off-site’ robotassisted PCI in a cohort of five patients, all of whom underwent successful, uncomplicated PCI procedures for Type A coronary lesions.29 This confirmed the feasibility of the concept in the presence of appropriate local cardiac catheterisation facilities and clinical support with reliable network connectivity.29 Finally, there is an increasing need for neurointervention in the treatment of cerebrovascular accidents, with a lack of sufficiently skilled operators to treat this critically unmet patient subset. This could be bridged by the use of PCI operators’ technical skillsets and telerobotics to provide remote care in populations in many parts of the world that have limited access to prompt neurointerventional treatments.

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Srivastava S, Barrera R, Quismundo S. One hundred sixty-four consecutive beating heart totally endoscopic coronary artery bypass cases without intraoperative conversion. Ann Thorac Surg 2012;94:1463–8. https://doi.org/10.1016/j. athoracsur.2012.05.028; PMID: 22771485.

Mihaljevic T, Jarrett CM, Gillinov AM, et al. Robotic repair of posterior mitral valve prolapse versus conventional approaches: potential realized. J Thorac Cardiovasc Surg 2011;141:72–80.e1–4. https://doi.org/10.1016/j. jtcvs.2010.09.008; PMID: 21093881.

Weisz G, Metzger DC, Caputo RP, et al. Safety and feasibility of robotic percutaneous coronary intervention: PRECISE (Percutaneous Robotically-Enhanced Coronary Intervention) study. Am J Coll Cardiol 2013;61:1596–600. https://doi. org/10.1016/j.jacc.2012.12.045; PMID: 23500318.

Smilowitz NR, Balter S, Weisz G. Occupational hazards of interventional cardiology. Cardiovasc Revasc Med 2013;14:223– 8. https://doi.org/10.1016/j.carrev.2013.05.002; PMID: 23759715.

Granada JF, Delgado JA, Uribe MP, et al. First-in-human evaluation of a novel robotic-assisted coronary angioplasty system. JACC Cardiovasc Interv 2011;4:460–5. https://doi. org/10.1016/j.jcin.2010.12.007; PMID: 21511227.

Beyar R, Gruberg L, Deleanu D, et al. Remote-control percutaneous coronary interventions: concept, validation, and first-in-humans pilot clinical trial. Am J Coll Cardiol 2006;47:296– 300. https://doi.org/10.1016/j.jacc.2005.09.024; PMID: 16412850.

Ludman P. BCIS Audit data 2019. British Cardiovascular Intervention Society 2020. http://www.bcis.org.uk/wp-content/ uploads/2020/03/BCIS-Audit-2018-19-data-ALL-24-01-2020bfor-web.pdf (accessed 3 December 2020).

Costa MA, Angiolillo DJ, Tannenbaum M, et al. Impact of stent deployment procedural factors on long-term effectiveness and safety of sirolimus-eluting stents (final results of the multicenter prospective STLLR trial). Am J Cardiol 2008;101:1704–11. https://doi.org/10.1016/j. amjcard.2008.02.053; PMID: 18549844.

Campbell PT, Mahmud E, Marshall JJ. Interoperator and intraoperator (in)accuracy of stent selection based on visual estimation. Catheter Cardiovasc Interv 2015;86:1177–83. https:// doi.org/10.1002/ccd.25780; PMID: 25510826.

Conclusion R-PCI is an emerging technology with significant potential for iterating upon current PCI methods. R-PCI is safe and feasible in a variety of lesion subsets, with clinical efficacy comparable to the conventional approach, possibly with increased procedural accuracy. In addition, R-PCI appears to provide operators protection from both radiation exposure and orthopaedic injuries.

The potential utility of telerobotic PCI systems to reduce costs and foster wider access to specialist coronary care by allowing interventional cardiologists to perform off-site procedures in remote locations would represent a major advancement in cardiac care. However, to reach their full potential, the next versions of robotic systems must address the limitations of the current generation of devices, which include a lack of compatibility with over-the-wire devices and the inability to manipulate multiple devices simultaneously to allow for more complex PCI cases to be completed without manual conversion. R-PCI represents a technique with great promise, and although improvements need to be made, greater adoption of the technique may perpetuate further improvements in technology and network-based care.

11. Bezerra HG, Mehanna E, Vetrovec GW, et al. Longitudinal geographic miss (LGM) in robotic assisted versus manual percutaneous coronary interventions. J Interv Cardiol 2015;28:449–55. https://doi.org/10.1111/joic.12231; PMID: 26489972.

12. Campbell PT, Kruse KR, Kroll CR, et al. The impact of precise robotic lesion length measurement on stent length selection: ramifications for stent savings. Cardiovasc Revasc Med 2015;16:348–50. https://doi.org/10.1016/j.carrev.2015.06.005; PMID: 26235977.

13. Moore B, vanSonnenberg E, Casola G, Novelline RA. The relationship between back pain and lead apron use in radiologists. AJR Am J Roentgenol 1992;158:191–3. https://doi. org/10.2214/ajr.158.1.1530763; PMID: 1530763.

14. Wassef AW, Hiebert B, Ravandi A et al. Radiation dose reduction in the cardiac catheterization laboratory utilizing a novel protocol. JACC Cardiovasc Interv 2014;7:550–7. https://doi. org/10.1016/j.jcin.2013.11.022; PMID: 24746655.

15. Vano E, Kleiman NJ, Duran A, et al. Radiation cataract risk in interventional cardiology personnel. Radiat Res 2010;174:490–5. https://doi.org/10.1667/RR2207.1; PMID: 20726724.

16. Venneri L, Rossi F, Botto N et al. Cancer risk from professional exposure in staff working in cardiac catheterization laboratory: insights from the National Research Council’s Biological Effects of Ionizing Radiation VII Report. Am Heart J 2009;157:118–24. https://doi.org/10.1016/j.ahj.2008.08.009; PMID: 19081407.

17. Rehani MM. Training of interventional cardiologists in radiation protection – the IAEA’s initiatives. Int J Cardiol 2007;114:256–60. https://doi.org/10.1016/j.ijcard.2005.11.061; PMID: 16624432.

18. Andreassi MG, Piccaluga E, Guagliumi G, et al. Occupational health risks in cardiac catheterization laboratory workers. Circ Cardiovasc Interv 2016;9:e003273. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.003273; PMID: 27072525.

19. Reeves RR, Ang L, Bahadorani J, et al. Invasive cardiologists are exposed to greater left sided cranial radiation: the BRAIN study (Brain Radiation Exposure and Attenuation During Invasive Cardiology Procedures). JACC Cardiovasc Interv 2015;8:1197–206. https://doi.org/10.1016/j.jcin.2015.03.027; PMID: 26292583.

20. Plourde G, Pancholy SB, Nolan J, et al. Radiation exposure in relation to the arterial access site used for diagnostic coronary angiography and percutaneous coronary intervention: a systematic review and meta-analysis. Lancet 2015;386:2192–203. https://doi.org/10.1016/S0140-

6736(15)00305-0; PMID: 26411986.

21. Caputo S, Maran A, Mannino D et al. Safety and effectiveness of insulin detemir in combination with oral antidiabetic agents in an outpatient specialist setting: results of the Italian SOLVE observational study. Minerva Endocrinol 2015;40:249–58.

22. Klein LW, Tra Y, Garratt KN et al. Occupational health hazards of interventional cardiologists in the current decade: results of the 2014 SCAI membership survey. Catheter Cardiovasc Interv 2015;86:913–24. https://doi.org/10.1002/ccd.25927; PMID: 25810341.

23. Mahmud E, Naghi J, Ang L et al. Demonstration of the safety and feasibility of robotically assisted percutaneous coronary intervention in complex coronary lesions: results of the CORA-PCI study (Complex Robotically Assisted Percutaneous Coronary Intervention). JACC Cardiovasc Interv 2017;10:1320–7. https://doi.org/10.1016/j.jcin.2017.03.050; PMID: 28683937.

24. Almasoud A, Walters D, Mahmud E. Robotically performed excimer laser coronary atherectomy: proof of feasibility.

Catheter Cardiovasc Interv 2018;92:713–16. https://doi. org/10.1002/ccd.27589; PMID: 29521479.

25. Kapur V, Smilowitz NR, Weisz G. Complex robotic-enhanced percutaneous coronary intervention. Catheter Cardiovasc Interv 2014;83:915–21. https://doi.org/10.1002/ccd.25271; PMID: 24167108.

26. Mahmud E, Dominguez A, Bahadorani J. First-in-human robotic percutaneous coronary intervention for unprotected left main stenosis. Catheter Cardiovasc Interv 2016;88:565–70. https://doi. org/10.1002/ccd.26550; PMID: 27189238.

27. Anvari M, McKinley C, Stein H. Establishment of the world’s first telerobotic remote surgical service: for provision of advanced laparoscopic surgery in a rural community. Ann Surg 2005;241:460–4. https://doi.org/10.1097/01. sla.0000154456.69815.ee; PMID: 15729068.

28. Madder RD, VanOosterhout SM, Jacoby ME et al. Percutaneous coronary intervention using a combination of robotics and telecommunications by an operator in a separate physical location from the patient: an early exploration into the feasibility of telestenting (the REMOTE-PCI study).

EuroIntervention 2017;12:1569–76. https://doi.org/10.4244/EIJD-16-00363; PMID: 28105993.

29. Patel TM, Shah SC, Pancholy SB. Long distance tele-roboticassisted percutaneous coronary intervention: a report of firstin-human experience. EClinicalMedicine 2019;14:53–8. https:// doi.org/10.1016/j.eclinm.2019.07.017; PMID: 31709402.

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