ICR3 2022 - Volume 17 by Radcliffe Cardiology

Volume 17 • 2022

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Volume 17 • 2022

www.ICRjourna l.com Editor-in-Chief Peter O’Kane

Royal Bournemouth Hospital, Bournemouth, UK

Deputy Editors

Coronary

M Chadi Alraies

Detroit Medical Center and Wayne State University, Detroit, MI Development

Angela Hoye

Structural

Giuseppe Sangiorgi

University Tor Vergata; Cardiac Cath Lab, San Gaudenzio Hospital, Italy Development

Castle Hill Hospital, Hull, UK

Andrew SP Sharp

University Hospital of Wales, Cardiff, Wales, UK

Development

Nicolas M Van Mieghem

Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands

Statistical Editor Jufen Zhang

Anglia Ruskin University Medical School, Cambridge, UK

Editorial Board Mirvat Alasnag

Carlo Di Mario

King Fahd Armed Forces Hospital, Jeddah, Saudi Arabia

Careggi University Hospital, Florence, Italy

Fernando Alfonso

Mauro Echavarría-Pinto

Hospital Universitario de La Princesa, Madrid, Spain

Giuseppe Andò

Azienda Ospedaliera Universitaria Policlinico Gaetano Martino, Messina University, Messina, Italy

Andrew Archbold

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

Eduardo Arias

National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico

Antonious Attallah

Ascension St John Hospital, Detroit, MI, US

Rodrigo Bagur

London Health Sciences Centre, London, Ontario, Canada

Marco Barbanti

Ferrarotto Hospital, Catania, Italy

Jonathan Byrne

King’s College Hospital, London, UK

Antonio Colombo

EMO Centro Cuore Columbus, Milan, Italy

Pierluigi Costanzo

Royal Papworth Hospital, Cambridge, UK

Nick Curzen

University Hospital Southampton NHS Trust, and British Cardiovascular Intervention Society, Southampton, UK

Hospital General ISSSTE Querétaro, Querétaro, Mexico

Eric Eeckhout

Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Gemma Figtree

Royal North Shore Hospital, University of Sydney, Sydney, Australia

Tom Ford

University of Newcastle Central Coast Clinical School, Gosford, NSW, Australia

Sameer Gafoor

Won Keun Kim

Kerckhoff Heart Center, Bad Nauheim, Germany

Tim Kinnaird

University Hospital of Wales, Cardiff, Wales, UK

Ajay J Kirtane

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

Azeem Latib

Montefiore Medical Center, New York, NY, US

Didier Locca

Lausanne University Hospital, Lausanne, Switzerland

Mamas A Mamas

Swedish Heart and Vascular Institute, Seattle, WA, US

University of Keele, Keele, Staffordshire, UK

Philippe Garot

St Thomas’ Hospital, London, UK

Institut Cardiovasculaire Paris-Sud and European Cardiovascular Research Centre (CERC), Paris, France

Mario Iannaccone

San Giovanni Bosco Hospital, ASL Città di Torino, Turin, Italy

Raban Jeger

Stadtspital Zürich, Zurich, Switzerland

Kathleen E Kearney

University of Washington Heart Institute, Seattle, WA, US

Simon Kennon

Barts Heart Centre, St Bartholomew’s Hospital, London, UK

Jaffar M Khan

National Heart, Lung, and Blood Institute, Washington, DC, US

Hannah McConkey Roxana Mehran

Mount Sinai Hospital, New York, NY, US

Thomas Modine

CHRU de Lille, Lille, France

Darren Mylotte

Galway University Hospitals, Galway, Ireland

Sandeep Nathan

University of Chicago Medicine, Section of Cardiology, Chicago, IL, US

Elmir Omerovic

Sahlgrenska University Hospital, Gothenburg, Sweden

Crochan J O’Sullivan Triemli Hospital, Zurich, Switzerland

Liesbeth Rosseel

Algemeen Stedelijk Ziekenhuis, Aalst, Belgium

Fadi J Sawaya

American University of Beirut Medical Center, Beirut, Lebanon

Alexander Sedaghat

University of Bonn, Bonn, Germany

Lars Søndergaard

Rigshospitalet – Copenhagen University Hospital, Copenhagen, Denmark

James Spratt

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

Gregg W Stone

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

Corrado Tamburino

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

Luca Testa

Department of Cardiology, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy

Verena Veulemans

University Hospital Düsseldorf, Düsseldorf, Germany

Renu Virmani

CVPath Institute, Gaithersburg, MD, US

Nina C Wunderlich

Cardiovascular Center Darmstadt, Darmstadt, Germany

Volume 17 • 2022

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Official journal of

Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology, British Cardiovascular Intervention Society and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology, British Cardiovascular Intervention Society and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology or British Cardiovascular Intervention Society. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2022 All rights reserved • ISSN: 1756-1477 • eISSN: 1756-1485

Volume 17 • 2022

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Aims and Scope

• Interventional Cardiology: Reviews, Research Resources (ICR3) is an

international, English language, peer-reviewed, open access journal that publishes articles continuously on www.ICRjournal.com. • ICR3 aims to assist time-pressured physicians to stay abreast of key advances and opinion in interventional cardiology practice. • ICR3 comprises balanced and comprehensive articles written by leading authorities, addressing pertinent developments in the field. • ICR3 provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

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Contents Futility in Transcatheter Aortic Valve Implantation: A Search for Clarity

Kush P Patel, Thomas Treibel, Paul Scully, Michael Fertleman, Samuel Searle, Daniel Davis, James C Moon and Michael J Mullen https://doi.org/10.15420/icr.2021.15

Best Practice in Intravascular Lithotripsy Benjamin Honton and Jacques Monsegu https://doi.org/10.15420/icr.2021.14

Trends in Transcatheter Aortic Valve Implantation in Australia Rhys Gray and Kiran Sarathy https://doi.org/10.15420/icr.2021.27

Evaluating the Impact of COVID-19 on a Regional Primary Percutaneous Coronary Intervention Service During the First Wave of COVID-19 Adeogo Akinwale Olusan and Peadar Devlin https://doi.org/10.15420/icr.2021.22

A Review of the Impella Devices

Rami Zein, Chirdeep Patel, Adrian Mercado-Alamo, Theodore Schreiber and Amir Kaki https://doi.org/10.15420/icr.2021.11

REVIEW

Structural

Futility in Transcatheter Aortic Valve Implantation: A Search for Clarity Kush P Patel ,1,2 Thomas A Treibel ,1,2 Paul R Scully,1,2 Michael Fertleman ,3 Samuel Searle,4 Daniel Davis ,4 James C Moon 1,2 and Michael J Mullen1,2 1. Institute of Cardiovascular Sciences, University College London, London, UK; 2. Barts Heart Centre, St Bartholomew’s Hospital, London, UK; 3. Cutrale Perioperative and Ageing Group, Department of Bioengineering, Imperial College London, London, UK; 4. MRC Unit for Lifelong Health and Ageing, University College London, London, UK

Abstract

Although transcatheter aortic valve implantation (TAVI) has revolutionised the landscape of treatment for aortic stenosis, there exists a cohort of patients where TAVI is deemed futile. Among the pivotal high-risk trials, one-third to half of patients either died or received no symptomatic benefit from the procedure at 1 year. Futility of TAVI results in the unnecessary exposure of risk for patients and inefficient resource utilisation for healthcare services. Several cardiac and extra-cardiac conditions and frailty increase the risk of mortality despite TAVI. Among the survivors, these comorbidities can inhibit improvements in symptoms and quality of life. However, certain conditions are reversible with TAVI (e.g. functional mitral regurgitation), attenuating the risk and improving outcomes. Quantification of disease severity, identification of reversible factors and a systematic evaluation of frailty can substantially improve risk stratification and outcomes. This review examines the contribution of pre-existing comorbidities towards futility in TAVI and suggests a systematic approach to guide patient evaluation.

Keywords

Transcatheter aortic valve implantation, aortic stenosis, futility, risk stratification, resource utilisation, frailty, multimorbidity Disclosure: KPP and PRS are supported by a clinical research training fellowship from the British Heart Foundation. KPP has received a project grant from Edwards Lifesciences. TAT is supported by a BHF Intermediate Research Fellowship (FS/19/35/34374). JCM is directly and indirectly supported by the UCLH NIHR Biomedical Research Centre and Biomedical Research Unit at UCLH and Barts, respectively. MM has received grants and personal fees from Edwards Lifesciences, and personal fees from Abbott Vascular. Received: 25 May 2021 Accepted: 5 October 2021 Citation: Interventional Cardiology 2022;17:e01. DOI: https://doi.org/10.15420/icr.2021.15 Correspondence: Michael J Mullen, Barts Heart Centre, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK. E: mmullen@nhs.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve implantation (TAVI) has improved outcomes for many patients with aortic stenosis (AS), including high-risk and inoperable patients. However, some patients either have a high mortality despite TAVI or receive no symptomatic/functional benefit from the procedure. In the CoreValve US Pivotal Extreme and High Risk trials, TAVI was futile at 1 year in 50.8% of patients; 30.2% had died; quality of life (QoL) did not improve in 19.6%, and declined in 1.0%.1 Similarly, the PARTNER high-risk trial, showed that TAVI was futile in 40% of patients.2 Although technological, operator and pathway improvements have reduced mortality and complications since its inception, TAVI remains expensive, invasive and carries risk.3 TAVI studies have primarily focused on identifying predictors of mortality and major adverse cardiovascular events; however, many elderly TAVI patients value different treatment goals, such as independence and QoL. Current guidelines define futility as a lack of survival or improvement in QoL/symptoms at 1 year post-TAVI and do not recommend intervention for AS if TAVI is deemed futile.4 Although predicting outcomes and making management decisions can be challenging, it is becoming increasingly important as the utility of TAVI expands. This review aims to provide clarity on the topic by discussing the decisions regarding futility, evaluating the impact of comorbidities

on both mortality and functional outcomes, and importantly, which comorbidities can improve following TAVI. Although not exhaustive, the comorbidities discussed here represent those that are relevant and most influential in a high-risk/inoperable population with severe symptomatic AS. Asymptomatic patients are not discussed in this review, but may benefit from TAVI, largely from reducing the risk of mortality from AS and associated comorbidities.

Methods

PubMed was searched for articles relating to TAVI in high-risk and prohibitive-risk patients with severe symptomatic AS between 2010 and 2020. The following free-text terms were used to identify relevant references: predictors of outcomes, mortality, functional outcomes, symptomatic changes and futility. Articles were screened for their relevance to the topic and excluded if they were not relevant, were duplicates or not in English. Additional references were identified by searching reference lists of included articles and guidelines. Comorbidities were then selected based on their relative impact on futility, consistency in the literature, and both their relevance and prevalence in the high-risk/surgically inoperable TAVI population. This was discussed and decided upon by all authors. The quality of each reference was checked by two authors (KPP and MJM). All authors were involved in providing expert opinion to interpret the data and formulate recommendations.

Futility in TAVI This review article discusses comorbidities associated with futility in TAVI and those that can improve with TAVI. It then focuses on patient evaluation, challenges in grading the severity of AS and symptom assessment. Finally, it brings together all these elements into validated risk stratification tools, discussing their merits and limitations, before describing the pivotal role played by the multidisciplinary team.

Cardiac Conditions Affecting TAVI Outcomes AF

Although AF is a marker of increased morbidity, it has been shown to independently predict mortality at 1 year (HR compared with sinus rhythm 1.88–2.36), but not at 30 days.5–7 Mortality is often related to heart failure; however, renal failure, thromboembolic disease and mitral regurgitation are all associated with AF, and are likely to contribute to mortality.8,9 The risk increases with higher heart rate and CHA2DS2 VASc scores, supporting the importance of rate-control and comorbidities in determining futility.5,6 Stroke post-TAVI is an important determinant of functionality and quality of life. Pre-TAVI AF has not been shown to increase the risk of stroke, whereas new AF post-TAVI does.7 This is likely to be due to differences in antithrombotic treatment.10

Left Ventricular Function and Structure

Left ventricular systolic dysfunction independently increases mortality from heart failure and sudden cardiac death post-TAVI, with worse function conferring a higher risk.11 However, low transvalvular flow (measured as indexed stroke volume ≤35 ml/m2) may be a better prognostic marker than left ventricular ejection fraction (LVEF). This is supported by poorer outcomes in patients with paradoxical low-flow, low-gradient (LFLG) aortic stenosis (AS; where LVEF is normal) and a study where low flow remained an independent predictor of mortality (HR 1.29; 95% CI [1.03–1.62]), but LVEF and mean gradient did not.12 Thus, the effect of low forward flow might be more important than the mechanism causing it. It should be noted that despite poor outcomes compared with normal-flow, highgradient patients, those with LFLG have a lower mortality with TAVI than with conservative treatment (HR 0.36; 95% CI [0.24–0.55]; p<0.001).13 This is the case for both classical LFLG AS (HR 0.43; 95% CI [0.19–0.98]; p=0.04) and paradoxical LFLG AS (HR 0.38; 95% CI [0.16–0.87]; p=0.02).14 Among survivors, functional outcomes at 1 year post-TAVI with low flow are comparable to normal flow patients.12 Left ventricular systolic dysfunction can also be reversible in AS patients, with improvements seen in up to two-thirds of patients as early as 48 hours post-TAVI and continued up to over 1 year post-TAVI. Determinants of improvement in left ventricular systolic dysfunction are high transvalvular gradient at baseline and the absence of a permanent pacemaker.15 Even among patients with preserved LVEF, further refinement of risk is beneficial. Strain imaging is a more sensitive marker of LV systolic function than LVEF. Studies have demonstrated among patients with preserved LVEF, longitudinal strain can predict mortality over and above traditional risk factors (for every 1% increase in longitudinal strain HR 1.05–1.42; p<0.0001).16,17 A marked impact on mortality was observed in patients with longitudinal strain <−12.1% compared with better strain values (10% had died at 1 year).17 Cardiac fibrosis, which can either be reversible interstitial fibrosis or irreversible replacement fibrosis, develops as part of the remodelling process in AS, and in the case of replacement fibrosis, can be associated with previous MI. Replacement fibrosis, particularly in the mid-wall, identified using late gadolinium enhancement on cardiac MRI,

independently predicts mortality (HR 5.35; 95% CI [1.16–24.56]).18 It also precludes favourable reverse remodelling post-TAVI, but does not affect changes in LVEF.19 Extracellular volume measured using cardiac MRI, is a surrogate marker for diffuse fibrosis. Bearing in mind the constituents of extracellular space, one study demonstrated it independently predicts mortality after aortic valve replacement at a median of 3.8 years (HR per percentage increase in extracellular volume percentage: 1.10; 95% CI [1.02–1.19]). The study demonstrated 52.7 deaths per 1,000 patient years with an extracellular volume percentage >29.1%.20 Transthyretin amyloidosis (ATTR) has been identified as a common comorbidity in TAVI patients (13–16%).21,22 TAVI has been shown to improve outcomes among patients with coexisting AS and ATTR compared with medical therapy (p=0.03). Compared with patients with only AS, patients with AS and ATTR had a similar mortality (23% versus 21%; p=0.71) and procedural complications were similar (p=0.77).21 Prospective studies are required to ascertain functional outcomes and reverse remodelling in patients with coexisting AS and ATTR. Left ventricular function, mitral regurgitation (MR), pulmonary hypertension (PH) and right ventricular dysfunction (RVD) are inextricably linked, such that each pathology influences the others. Therefore, teasing out the contribution of individual diseases to outcomes is challenging, creating controversy among studies.

Mitral Regurgitation, Pulmonary Hypertension and Right Ventricular Dysfunction

MR independently increases mortality at both 30 days (effect size −0.18; 95% [CI 0.31, −0.04]) and 1 year (effect size −0.22, 95% CI [−0.36, −0.08]).23 Despite this, TAVI in patients with ≥moderate MR remains better than medical therapy for improving mortality at 1 year (HR 0.38; 95% CI [0.019–0.75]).24 TAVI can also reduce MR; patients with functional MR, and the absence of severe pulmonary hypertension, AF and coronary artery disease increased the likelihood of such an improvement.25,26 Between 51% and 58% of patients with moderate/severe functional MR at baseline experience at least one or more grade improvement in MR at 1 year.26–28 Another observational study demonstrated moderate/severe MR improved in 79% of patients with functional aetiology compared with 50% of those with primary aetiology (p=0.025).25 Interestingly, among patients where ≥MR persists post-TAVI, left ventricular reverse remodelling, improvement in symptoms and New York Heat Association functional class do not seem to be adversely affected.29 This suggests that the risk of futility with TAVI increases with primary MR and the presence of associated comorbidities. With advances in transcatheter techniques, patients in whom TAVI does not reduce MR, transcatheter mitral valve repair/replacement can be an option; with initial studies demonstrating high procedural success, an acceptable safety profile and an improvement in symptoms.30,31 However, as we have learned from the COAPT and MITRA-FR studies, patient selection is key to achieving benefit.32 MR pre- or post-TAVI increases left atrial volume and pressure that eventually can result in PH. A meta-analysis of TAVI patients demonstrated that PH (defined as pulmonary artery systolic pressure >60 mmHg) increased the risk of all-cause mortality both at 30 days (OR 1.48; 95% CI [1.17–1.88]) and at 1 year (OR 1.39; 95% CI [1.24–1.57]), along with acute kidney injury at 30 days and stroke at 1 year.33 Pre-capillary and combined PH, and increasing severity of PH confer a higher risk of mortality.34,35 Persistence of PH, regardless of its aetiology, seems to be more important than baseline PH in predicting outcomes. Approximately half of patients

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Futility in TAVI with PH have immediate improvement in pulmonary artery systolic pressure post-TAVI, which is sustained up to a year.36 This improvement is more likely with a LVEF >40%, functional MR, mild diastolic dysfunction and in the absence of moderate to severe TR and AF.36,37 By comparison, PH caused by chronic lung disease or associated with pulmonary vascular remodelling is less likely to improve with TAVI.34 Functional class improves regardless of baseline PH, again suggesting that if AS is the dominant pathology, patients are likely to benefit from TAVI.38 Therefore, among patients with PH, the risk of futility increases with the severity of PH, associated comorbidities and non-AS related aetiology of PH. RVD is often the consequence of transmitted pressure from the AS-loaded left ventricle, but co-existing pulmonary disease and other causes of precapillary PH do contribute. RVD (defined as tricuspid annular plane systolic excursion <1.7 cm) is prognostically important (HR at 12 and 43 months for all-cause mortality 2.94; 95% CI [2.02–4.27] and 2.14; 95% CI [1.31–3.51]; p<0.001, respectively).39,40 Over half of patients with baseline RVD demonstrate RV functional recovery within days post-TAVI, which is likely to be due to the reduction in LV afterload. Among patients in whom RVD did not recover, mortality (particularly early mortality) is up to eightfold higher. AF and a lower LVEF reduce the chances of recovery.39 Further work is required to determine the extent of symptomatic benefit that patients with RVD derive.

Extra-cardiac Conditions Affecting TAVI Outcomes Anaemia

Anaemia is associated with a poorer prognosis in a severity-dependant manner and affects mortality at 1 year (haemoglobin <10 g/dl, HR 2.78; 95% CI [1.60–4.82]; haemoglobin <13 g/dl for men and <12 g/dl for women, HR 2.10; 95% C: [1.06–4.18]) rather than at 30 days, and increases rates of hospitalisation due to heart failure.41–44 However, TAVI can also lead to the resolution of pre-existing anaemia; particularly that caused by ASinduced intravascular haemolysis and Von Willebrand factor cleavage.45 Post-TAVI anaemia rather than baseline anaemia is predictive of a poor symptomatic response to TAVI, indicating that non-AS-related causes of anaemia (such as renal failure) that persist post-TAVI are likely to affect outcomes, including symptom improvement.46 Targeting a treatable cause of anaemia in AS patients; for example with iron therapy, needs to be evaluated in prospective studies.

Chronic Lung Disease

Both chronic obstructive pulmonary disease (COPD) and restrictive lung disease increase the risk of mortality, in the short and long term (HR for 1-year all-cause mortality for COPD 1.09–1.46, 95% CI [1.02–1.79]; HR for restrictive lung disease 2.25, 95% CI [1.35–3.75]).47,48 Poor exercise tolerance measured using a 6-minute walk test (6MWT), oxygen dependency and the use of non-invasive ventilation are recognised predictors of TAVI futility.48,49 These factors all indicate a higher severity of lung disease. Consequently, patients with CLD stand to gain less of an improvement in New York Heat Association status with TAVI, although up to 80% of them can experience some improvement.49,50 The rate of futility among TAVI patients with CLD can be as high as 57% at 1 year. In addition to the predictors of futility mentioned above, lower diffusing capacity of the lung for carbon monoxide has been identified as a pulmonary-specific predictor of futility.50

Chronic Kidney Disease

CKD is a predictor of both 30-day and 1-year mortality in a severitydependent manner (every 10-ml/min/1.73 m2 reduction in baseline

estimated glomerular filtration rate increases mortality by 4.4%).51 Patients on dialysis have an approximately twofold increase in mortality compared with non-dialysis patients.52 It also increases the risk of bleeding and stroke among higher-risk patients.53 Despite this increased risk, TAVI is a better option than medical treatment, with lower mortality rates (at a mean of 1.9 years, HR of mortality with medical management compared with TAVI 3.95; 95% CI [2.59–6.02]) and potential stabilisation of renal function.54 CKD has been identified as an independent predictor of lack of improvement in functional status, in a severity-dependent manner, mainly due to associated comorbidities, such as anaemia and sarcopenia.46

Malignancy

This heterogenous group of pathologies with varying prognosis based on type, extent and treatment is common in the elderly – one study revealed a 5.4% prevalence of active cancer and 13.8% of a prior history of cancer among TAVI patients.55 The majority of cancers are prognostically important, and among TAVI patients have been shown to account for 7% of deaths at 30 days, and between 2 and 8.6% of deaths at 1 year.3,56,57 There is heterogeneity in the literature regarding outcomes in patients with cancer. At 1 year post-TAVI, mortality was higher (37.4 versus 20.8%; p<0.001) and improvement in functional class was lower among patients with active cancer compared with those without cancer.55 Another study demonstrated that active cancer does not affect TAVI procedural success and complications, and that at a median on 272 days, mortality was similar between the cancer and non-cancer group (p=0.42). However, the presence of metastatic cancer was an independent predictor of mortality (HR 4.73, 95% CI [1.12-29.0]; p=0.035).58 However, selection bias and confounding factors, such as anaemia and sarcopenia, which tend to coexist with cancer, were not accounted for in both studies. Incidental masses among elderly patients can be found in one in five patients who undergo pre-TAVI CT, with solitary lung nodules being the most common finding. As an entity, incidental masses do not affect outcomes, and the majority are benign. However, among patients with a prior history of cancer where it is more likely to represent malignancy, incidental masses are associated with increased 1-year mortality (OR 4.02; 95% CI [1.5–10.7]; p=0.006).59 Incidental masses may result in further investigations for a patient, providing an opportunity for commencing treatment if appropriate. For patients in this complex disease group, a tailored approach for each individual is required; with consideration of whether TAVI can facilitate further oncological treatments, such as surgery, and an evaluation by a multidisciplinary team involving an oncologist.

Frailty and Related Conditions Affecting TAVI Outcomes

Frailty is a state of decreased functional and physiological reserve, and is often caused by the accumulation of health deficits. Understanding frailty helps predict outcomes, stratify risk, and identify patient-specific targets and outcomes. It can also identify patients who may benefit from frailtyspecific interventions. Trials assessing the effectiveness of interventions on frailty among TAVI patients are still awaited; however, these interventions have proved to be beneficial in other populations (NCT03107897 and NCT0352245). Physical, nutritional, and cognitive interventions can improve frailty scores and status at 12 months.60 Intensive exercise leads to greater improvements in disability and physical functioning compared with light exercise.61 Nutritional supplementation in older patients demonstrated an improvement in quality of life and physical functioning.62 The assessment of frailty has generated enormous interest within the TAVI community, with the development of several scoring systems.

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Futility in TAVI Cognitive Impairment

Figure 1: Decision-making Algorithm for Determining Benefit Versus Futility of Transcatheter Aortic Valve Implantation

Cognitive impairment is under-recognised and a significant contributor to frailty.71 Patients with cognitive impairment at baseline (Mini Mental State Examination score <27) have more than a threefold increased risk of functional decline or mortality at 1-year post-TAVI.72 Another study showed that for every point gained on the Mini-Mental Test score, the OR of a poor outcome was 0.94 (95% CI [0.90–0.97]; p=0.001).71

Patient’s symptoms and expectations

Are symptoms caused by aortic stenosis?

Unlikely

Manage other causative comorbidities

Unlikely

Conservative management

Likely

★ Can TAVI relieve these

symptoms and/or improve quality of life? Likely

Asymptomatic AS and patient’s expectations

★ Short- and mid-term mortality risk +

+ Can TAVI reverse any

comorbidities and reduce the mortality risk?

STS score >15

Conservative management

STS score <15 TAVI is likely to be beneficial

TAVI is likely to be futile

This algorithm should be employed as part of a shared decision-making process that involves the patient. Among asymptomatic patients, the goal of transcatheter aortic valve implantation is largely to reduce mortality risk associated with aortic stenosis and any associated comorbidities. Consequently, the upper section is less relevant. To determine the risk of futility, the relevant sections marked ★ and + should be used in conjunction with Figure 2 and Figure 3, respectively. Dichotomising choices and predicting outcomes can be challenging, but based on the data presented above, a reasonable decision can be established. AS = aortic stenosis; STS = Society of Thoracic Surgeons; TAVI = transcatheter aortic valve implantation.

Consequently, the reported prevalence of frailty varies between 6% and 90%.63,64 Determining which score to use, balancing a comprehensive frailty assessment with a busy clinical workload and determining what to do once frailty has been recognised are challenging. Below, we provide a summary of the main domains of frailty with validated thresholds for futility. Regardless of how frailty is assessed, it is associated with a poor prognosis. Two meta-analyses demonstrated that frailty is an independent predictor of mortality at ≤30 days (HR 2.35; 95% CI [1.78–3.09]), >30 day (HR 1.63; 95% CI [1.34–1.97]) and at 1 year (HR 2.16, 95% CI [1.57–3.00]).65,66 Frailty also predicts functional decline post-TAVI (OR 1.82; 95% CI [1.14–2.91]).67

Physical Capacity

Mobility is a significant contributor to frailty and is often used to approximate its presence. Patients with AS and low physical capacity, determined by either a 6MWT and Timed Up and Go test have a poorer prognosis than those with higher capacities.49,68 A 6MWT <170 m was identified as the optimum cut-off to predict futility at 6 months among patients with COPD undergoing TAVI (area under the receiver operating characteristic curve 0.67).49 One study showed that for every 10 m walked during a 6MWT, the risk of a poor outcome reduced by 3%.69 Patients with Timed Up and Go test times between 10 and 20 seconds have a greater than fivefold increase in mortality at 1 year, compared with patients with a Timed Up and Go test time <10 seconds.68 However, defining specific cut-off points to determine futility using any of these continuous variables is clinically useful, but will misclassify some patients and, therefore, should be used judiciously. Additionally, if a patient’s mobility is limited by AS, those with lower values stand to gain the most functional benefit from TAVI.70 The key to determining futility is to identify physical limitations caused by non-AS related pathologies, which will not improve with TAVI.

Sarcopenia and Nutrition

Sarcopenia is a state of low muscle mass, strength and function, and is present in one-third of elderly patients.73 Psoas muscle area and volume act as surrogate markers of sarcopenia, and are calculated using preTAVI CT scans. Sarcopenia (psoas muscle area: men <20.3 cm2 and women <11.8 cm2) has been shown to predict mortality and worsening disability at 1 year.74,75 Up to 42% of patients undergoing TAVI are either at risk of malnourishment or are malnourished. These patients have more comorbidities and a lower BMI.76 Lower BMI (<18.5 kg/m2) at baseline is associated with increased mortality at 1 year rather than at 30 days, whereas, paradoxically, obese and overweight patients tend to have a survival advantage at 1 year.77 Functional outcomes among malnourished TAVI patients are unknown.

Outcomes in Specific Populations Acute Decompensated Aortic Stenosis

Acute decompensated AS (ADAS) is defined by debilitating symptoms related to AS (syncope, angina with minimal exertion or at rest and/or dyspnoea at rest). The condition frequently warrants hospitalisation and urgent valve replacement. Although TAVI has been performed safely in these patients, outcomes are worse than patients without decompensation; at 1 year post-TAVI, mortality is between 15.3 and 29.1%.78–80 Traditional markers of futility described above predict mortality in ADAS: AF, oxygen-dependent lung disease, low body surface area (a marker of sarcopenia/malnutrition), previous cardiac surgery and poor renal function.80 However, there is a large degree of overlap in baseline characteristics between ADAS and non-ADAS patients, making it challenging to differentiate and, therefore, predict futility. Among patients presenting with acute decompensation is a subgroup with cardiogenic shock. Data on TAVI within this subgroup are limited to small case series. Device success is reportedly high (94%), However, Valve Academic Research Consortium-2-defined early safety endpoints were reached in 35% of patients, with 30-day mortality of 12–24%.81,82 At 1 year, mortality was reported at 26% and related to non-cardiovascular causes in the majority of patients. However, among survivors, TAVI did improve symptoms; 91% were New York Heat Association class I or class II.81 For patients with ADAS, non-randomised data suggest that TAVI is a better therapeutic option than balloon aortic valvuloplasty.80,82

Patient Evaluation

By following a systematic approach, as suggested in Figure 1, using available evidence where present and clinical judgment where absent, a reasonable management decision can be made. Once the severity of AS is established, the next step involves symptom assessment to establish causality and explore a patient’s expectations. The third step involves evaluation of a patient’s comorbidities, their impact on mortality, symptoms, and quality of life with and without TAVI. Figure 2 identifies specific cut-offs for factors within four key domains that are associated with futility in TAVI. Many factors affect outcomes in a severity-dependent manner, therefore, while specific cut-offs are clinically useful, some patients will be misclassified and, therefore, should be used judiciously.

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Futility in TAVI Figure 2: Factors Associated With an Increased Risk of Futility in Transcatheter Aortic Valve Implantation Severe symptomatic aortic stenosis

Factors associated with an increased risk of futility in TAVI

Cardiac conditions

Extra-cardiac conditions

Left ventricle • Stroke volume indexed ≤35 ml/m2 • Longitudinal strain <−12.1% • Extracellular volume >29.1% • Presence of late gadolinium enhancement

Pulmonary diseases • 6MWD <170 m in COPD • Oxygen dependency • Non-invasive ventilation

Associated cardiac pathology • Primary MR • PASP >60mmHg • TAPSE < 1.7cm

Chronic kidney disease Estimated glomerular filtration rate <60 ml/min/1.73 m2

Anaemia Haemoglobin: men <13 g/dl, women <12 g/dl

Metastatic cancer

Frailty

Physical capacity • TUG <10 s • 6MWD <200 m

Presentation

Cognition MMSE <27

Sarcopenia and nutrition • Psoas muscle area: men <20.3 cm2, women <11.8 cm2 • BMI <18.5 kg/m2

• Acute decompensated aortic stenosis • Cardiogenic shock

Assess impact on quality of life, short-term and mid-term mortality

This figure summarises the four key domains and their most common comorbidities that need to be evaluated in the high-/prohibitive-risk, patient. Additionally, for each comorbidity, specific cut-offs have been identified, above or below which futility in transcatheter aortic valve implantation increases. These cut-offs, while clinically useful, should be used judiciously, as most comorbidities demonstrate a severity-dependent impact on outcomes and the cut-offs will misclassify some patients. 6MWT = 6-minute walk test; COPD = chronic obstructive pulmonary disease; MMSE = Mini-Mental State Examination; MR = mitral regurgitation; PASP = pulmonary artery systolic pressure; TAPSE = tricuspid annular plane systolic excursion; TAVI = transcatheter aortic valve implantation; TUG = Timed Up and Go test.

The final step that lends support to the decision-making process is whether TAVI can reverse existing comorbidities to improve outcomes. Figure 3 identifies comorbidities that tend to improve with TAVI. However, improvement in each is dependent on several other factors discussed above. Shared decision-making within a multidisciplinary team and with the patient is a pivotal part of this entire process.

Evaluation of Aortic Stenosis

Defining the severity of AS is important to justify the risk–benefit balance associated with TAVI; the higher the severity of AS, the greater the benefit of TAVI. Severe AS is straightforward to define when echocardiographic markers are concordant (peak velocity ≥4m/s, mean gradient ≥40 mmHg and aortic valve area ≤1 cm2). However, these markers can often be discordant if transvalvular flow is reduced (≤35 ml/m2). A detailed review of diagnostic challenges and solutions for low-gradient AS can be found elsewhere.83,84 However, two investigations are worth mentioning here. To differentiate between severe AS and pseudo-severe AS, low-dose dobutamine stress

Figure 3: Comorbidities That Can Improve With Transcatheter Aortic Valve Implantation Comorbidities that can be reversed by TAVI Cardiac comorbidities • LV systolic dysfunction • Diffuse fibrosis • Secondary MR • Pulmonary hypertension not associated with lung disease • RV dysfunction Non-cardiac comorbidities • Anaemia caused by shear-induced haemolysis • Physical capacity limited by AS These comorbidities are caused by aortic stenosis and, therefore, can improve with transcatheter aortic valve implantation. However, improvement is dependent on multiple factors. AS = aortic stenosis; LV = left ventricular; MR = mitral regurgitation; RV = right ventricular; TAVI = transcatheter aortic valve implantation.

echocardiography can be helpful. By iatrogenically increasing the flow to >35 ml/m2, valve haemodynamics can be recalculated at normal flow. If, however, flow cannot be increased sufficiently, the projected aortic valve

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Futility in TAVI Figure 4: Screening for Frailty Frailty screening Cognitive impairment: Mini-Cog test <5

Mobility: 6MWT <300 m, TUG >10 s

Blood biomarkers: hypoalbuminaemia,* anaemia†

Nutrition status: Low BMI <18.5 kg/m2, recent weight loss‡

Disability Rockwood CFS >4, Katz index <6

If a patient fulfils one or more criteria

Comprehensive frailty assessment If a patient meets any of these frailty criteria, a comprehensive frailty assessment is recommended. Each assessment has examples of assessments that are simple, quick to perform and routinely used among transcatheter aortic valve implantation patients. *Defined as serum albumin <3.5 g/dl; †defined as haemoglobin in men <13 g/dl and in women <12 g/dl; ‡defined as >5% loss in weight over the past 6–12 months. 6MWT = 6-minute walk test; CFS = clinical frailty score; TUG = Timed Up and Go test.

area can be calculated, as described by Blais et al.85 Dobutamine stress echocardiography can also provide a measure of contractile reserve (increase in stroke volume by 20%). While the presence of contractile reserve is prognostically important in patients undergoing surgical aortic valve replacement, it does not influence outcomes among TAVI patients.86,87 Furthermore, the aortic valve calcium score using CT can be beneficial to identify severe AS with established sex-specific cut-offs.88 Among elderly, high-risk patients, this is a useful tool; however, in younger patients with bicuspid AS, valve calcification plays less of a role in the pathobiology of AS, and the CT valve calcium score may underestimate the severity of AS.89

Symptom Evaluation

Identifying a patient’s symptoms and assessing the contribution made by AS is key. Multimorbidity makes attributing symptoms to a particular disease challenging; for example, distinguishing dyspnoea from severe AS versus COPD. If dyspnoea worsens with a simultaneous increase in AS severity and little change in lung function, it is likely that AS is the driving cause. Appreciating a patient’s expectations and whether these can be met with TAVI is important. Using the example above, even with successful TAVI, COPD cannot be cured, and a degree of dyspnoea is likely to remain. It is important that the patient understands this. Patients who have the least to gain from TAVI in terms of symptom benefit and improvements in QoL are those with mild or no symptoms, alternative causes contributing to their symptoms and phenotypic changes (e.g. certain features of frailty) that cannot be reversed with TAVI.

Risk Assessment for High-risk Patients Scoring Systems

Several frailty parameters and risk scores can be inaccurate, exclude important facets of frailty or require extensive assessments, discouraging their use in the clinical arena.72,90,91 Therefore, we propose a simple screening tool to identify frail patients (Figure 4) who would benefit from a more thorough assessment, preferably by a geriatrician.60,62 The cutoffs chosen for each domain have demonstrated prognostic or diagnostic importance.68,92–99 Included in this screening tool are several factors discussed above. In addition, assessing disability and independence using validated tools, such as the Rockwood Clinical Frailty Score and the Katz index, although semi-quantitative tools, can provide quick and important prognostic data for TAVI patients.66,99,100 Interventions to improve frailty and their impact on outcomes are ongoing, limiting the role of comprehensive frailty assessment to risk stratification rather than therapeutic interventions (NCT03107897 and NCT0352245).101,102

Although risk stratification using TAVI-specific tools provides a similar or better estimation of mortality compared with traditional surgical risk scores, further refinement is required.103,104 Table 1 summarises the predictors used in several TAVI-specific risk scores and their corresponding C-statistics. The Society of Thoracic Surgeons (STS)/ American College of Cardiology Transcatheter Valve Therapy TAVI score demonstrated an area under the receiver operating characteristic curve of 0.64 in determining 30-day mortality with better discrimination of mortality compared with STS-Predicted Risk of Mortality score for highrisk patients.105 Compared with surgical risk scores (Euroscore 2 and STS), the French Aortic National CoreValve and Edwards 2 (FRANCE 2) score had a lower, albeit non-significant C-statistic (0.67 versus 0.53; p=0.26).106 However, most scores do not predict functional or symptomatic improvements, which for many patients are equally if not more important. Newer tools are taking into consideration both functional/symptomatic outcomes and mortality. One model, predicting the composite of a poor QoL, decrease in QoL and mortality at 1 year, demonstrated moderate discriminatory ability (C-statistic 0.66). Using this model, among patients in a validation cohort judged to be at very high risk (>70% risk of the composite endpoint), 73% met the composite endpoint – demonstrating good predictive ability among this subpopulation.71 The Essential Frailty Toolset has been shown to be one of the strongest predictors of mortality at 30 days (OR 3.29; 95% CI [1.73–6.26]) and 1 year (OR 3.72; 95% CI [2.54–5.45]), as well as worsening disability at 1 year (OR 2.13; 95% CI [1.57–2.87]), compared with other scoring systems.90 The addition of the Essential Frailty Toolset to STS-PROM shows promise with a C-statistic of 0.83. If classified as severely frail using the Essential Frailty Toolset (5/5), patients had a 80% risk of mortality or disability at 1 year.90,107 The combination of these two scoring systems could prove to be a reliable tool to determine futility, and requires prospective studies to validate it. Decisions based on any scoring system need to be made around a patientcentred approach. Patients at very high-risk (STS >15%) do not have a survival benefit compared with conservative treatment.108 These newer risk stratification tools need to be validated in different populations, and will need to constantly evolve as TAVI evolves and novel predictors of futility are identified. Future studies are required to address whether frailty can be improved by treating particular factors, such as malnutrition, and whether this can improve TAVI outcomes.

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Futility in TAVI Table 1: Transcatheter Aortic Valve Implantation-specific Risk Scores from the Original Developmental and Validation Studies TAVI Risk Score

Endpoint

Predictive Factors

C-statistics

FRANCE 2110

30-day or in-hospital mortality

Age ≥90 years, BMI <18.5 and <30 kg/m2, New York Heart Association class IV, pulmonary hypertension, critical haemodynamic state, ≥2 pulmonary oedemas during the past year, respiratory insufficiency, dialysis and transapical or other (transaortic and transcarotid) approaches

Development cohort: 0.67 Validation cohort: 0.59

STS/TVT111

In-hospital mortality

Age, estimated glomerular filtration rate, haemodialysis, New York Heart Association functional class IV, severe chronic lung disease, nonfemoral access site and procedural acuity categories

Development cohort: 0.67 Validation cohort: 0.66

PARTNER69

6-month mortality, KCCQ score <45 or ≥10-point decrease in KCCQ-OS score

Sex, diabetes, major arrhythmia, serum creatinine, mean arterial pressure, BMI, oxygen dependant lung disease, mean aortic valve gradient, Mini-Mental State Examination, 6-minute walk test

Development cohort: 0.66 Validation cohort: 0.64

CoreValve112

1-year mortality

Home oxygen use, albumin levels <3.3 g/dl, falls in the past 6 months, STS-PROM score >7% and severe (≥5) Charlson comorbidity score

Development cohort: 0.83 Validation cohort: 0.79

GAVS II113 (Both surgical and transcatheter aortic valve replacements were included)

In-hospital mortality

Sex, age, BMI, New York Heart Association functional class IV, Canadian cardiovascular score 3/4, cardiogenic shock <48 h ago, cardiopulmonary resuscitation within 48 h, absence of pulmonary hypertension, sinus rhythm, American Society of Anaesthesiologists physical status, coronary artery disease, LVEF <30%, peripheral vascular disease, infective endocarditis/ septic condition, diabetes, haemodialysis, mechanical circulatory support, redo surgery

Validation cohort: 0.74

UK TAVI114

30-day mortality

Age, sex, critical preoperative status, BMI, extracardiac arteriopathy, estimated glomerular filtration rate, nontransfemoral TAVI, pulmonary hypertension, prior balloon aortic valvuloplasty, pulmonary disease, sinus rhythm, non-elective procedure, Katz index, poor mobility

Development cohort: 0.70 Validation cohort: 0.66

KCCQ-OS = Kansas City Cardiomyopathy Questionnaire Overall Summary; LVEF = left ventricular ejection fraction; TAVI = transcatheter aortic valve implantation.

Role of the Multidisciplinary Team

The multidisciplinary team has become the cornerstone for making complex management recommendations and is advocated by international guidelines.91,109 It is particularly helpful, where equipoise exists regarding the benefit/futility of TAVI. In the multimorbid, frail patient, a geriatrician is invaluable to guide this process. If TAVI is not recommended by the multidisciplinary team, it is important to sensitively convey this to the patient and their relatives. A discussion should be had regarding the patient’s thoughts, concerns and expectations, and the rationale for the recommendation. This discussion can then form the basis of the final decision. If a clinical decision has been made to avoid TAVI because of probable futility, palliative care should be involved to alleviate symptoms, personalise care, provide psychological support and ensure good lines of communication for the patient.

Conclusion

The more comorbidities a patient has, the lower the chances of an improvement in physical and psychological quality of life, and the higher the mortality rate. Additionally, the severity of these comorbidities is important, with higher severity pertaining a higher risk of futility. Futility should be considered, especially in patients whose health is affected primarily by comorbidities other than AS. It is important to consider certain comorbidities that can reverse post-TAVI (e.g. functional MR), despite conferring excess risk. Quantifying the contribution of specific comorbidities to a patient’s symptoms can facilitate better prediction of symptomatic improvement and allow patient expectations from TAVI to be

managed. Therefore, both patients and clinicians need to be clear about the potential improvements that TAVI can provide. Although our understanding of comorbidities and their impact on TAVI outcomes has improved, there is still a need to refine our prediction tools, and better understand the impact of TAVI on QoL and function, such that this rapidly growing technology is targeted towards those patients who are likely to gain the most benefit and avoided amongst those where it will be futile.

Clinical Perspective

• Futility in transcatheter aortic valve implantation (TAVI) is

• • • •

common and should be avoided. Up to half of high-risk patients undergoing TAVI do not gain any improvement in quality of life (QoL), symptoms or survival at 1 year. The number and severity of comorbidities increase the risk of futility. However, certain comorbidities can be reversed with TAVI, thus improving outcomes; for example, functional mitral regurgitation and anaemia caused by intravascular haemolysis. Screening and a comprehensive assessment of comorbidities and frailty can lead to better risk prediction and reduce futility. Further research is required to identify predictors of a lack of improvement in QoL and function.

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REVIEW

Coronary

Best Practice in Intravascular Lithotripsy Benjamin Honton

and Jacques Monsegu2

1. Department of Interventional Cardiology, Clinique Pasteur, Toulouse, France; 2. Department of Interventional Cardiology, Institut Cardio-Vasculaire, Groupe Hospitalier Mutualiste, Grenoble, France

Abstract

Intravascular lithotripsy (IVL) is a novel approach to lesion preparation of severely calcified plaques in coronary and peripheral vessels. Lithotripsy is delivered by vaporising fluid to create an expanding bubble that generates sonic pressure waves that interact with arterial calcification. Available data indicate that IVL leads to increased vessel compliance before stent implantation with high efficacy and an excellent safety profile. Since it gained the CE mark in 2017, and with improved operator experience, the use of IVL has expanded into more complex clinical situations. This review focuses on the best practice for IVL use in the cath lab, based on 3 years of experience with the technology and the latest scientific data from the Disrupt CAD clinical trials.

Keywords

Intravascular lithotripsy, coronary calcified lesion, best practice, plaque modification, Disrupt CAD Disclosure: BH receives speaker fees from Shockwave. JM has no conflicts of interest to declare. Acknowledgment: Editorial support was provided by Pelle Stolt, Basel, Switzerland. Received: 14 May 2021 Accepted: 23 September 2021 Citation: Interventional Cardiology 2022;17:e02. DOI: https://doi.org/10.15420/icr.2021.14 Correspondence: Benjamin Honton, Clinique Pasteur, 45 avenue de Lombez, BP 27617, 31076 Toulouse, France. E: bhonton@clinique-pasteur.com Support: The publication of this article was supported by Shockwave Medical Inc. Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The prevalence of calcified coronary lesions encountered in daily percutaneous coronary intervention (PCI) is set to increase with the growing prevalence of predisposing factors such as hypertension, ageing and diabetes.1 Calcified lesions lead to sub-optimal PCI outcomes by limiting the crossing of lesions, altering drug elution kinetics and interfering with optimal stent expansion, and they are also associated with poorer clinical prognosis.1–6 Common technologies to treat calcified plaque, such as rotational or orbital atherectomy, are associated with increased periprocedural complications without clear clinical evidence of efficacy.7 There is thus an unmet need for effective and safe methods to prepare calcified lesions and improve PCI outcomes.

Intravascular Lithotripsy: Technical and Scientific Overview

Intravascular lithotripsy (IVL) is a new vessel preparation technique for calcified coronary artery lesions that creates multiplane micro/macro fractures in the calcified plaque before stenting or allowing for an improved stent expansion.8 The C2 Shockwave Medical Coronary IVL system (Shockwave Medical) consists of three components: a generator; a connector cable and a sterile catheter incorporating the lithotripsy emitters enclosed in a semi-compliant balloon (Figure 1). IVL emitters produce electric sparks that create vapour bubbles in the surrounding fluid medium in the integrated balloon. IVL produces low levels of electric energy, leading to the formation and rapid expansion of vapour bubbles, resulting in acoustic pressure waves that radiate circumferentially and transmurally in an unfocused manner. These acoustic pressure waves interact with high-density tissues such as calcium without affecting soft

tissue. This interaction disrupts the calcium by creating micro-macro fractures, and increases vessel compliance.8 The catheter, available in 2.5–4.0 mm diameters, is programmed to deliver 10 pulses in sequence at a frequency of 1 pulse/second for a maximum of 80 pulses per catheter. The low pressure inflation avoids the barotraumatic vessel wall injuries related to high pressure inflation.8,9 The role of the fluid-filled integrated balloon is to facilitate efficient transmission of shockwave energy to vascular tissue by several mechanisms: creation of the spark which requires ions, adequate interface with similar acoustic impedances, avoiding thermal injury, and shielding the emitters from direct contact with the arterial wall.8 Compared with atherectomy, the IVL acoustic burst penetrates deeper into the arterial wall to generate multiplane longitudinal fractures without affecting healthy tissue. The coronary IVL system has received both the CE Mark and FDA approval. IVL has been studied in the Disrupt CAD clinical trials, including the pivotal Disrupt CAD III study. The most recent data confirms that IVL is a safe procedure with a high success rate – primary safety and effectiveness endpoints were achieved in 92.7% and 92.4% in the pooled analysis of all Disrupt clinical trials. At 30 days, the rates of target lesion failure, cardiac death and stent thrombosis were 7.2%, 0.5% and 0.8%, respectively.10 However, patients in such trials are highly selected and are not representative of daily clinical practice. The aim of this review is to focus on best IVL practice based on the authors’ 3 years of experience and the latest scientific data from Disrupt CAD.

Best Practice in Intravascular Lithotripsy Figure 1: Intravascular Lithotripsy Shockwave System

Power status Power on/off Remaining pulse content Battery capacity

Balloon size Therapy status Therapy on/off Therapy connector

Connector door Charger connector (behind door)

The system is composed of a generator – a connector and the C2 catheter. The generator has two buttons: the upper button switches on the generator and the lower button allows the delivering of the therapy by the generator. Note that for security reasons, you cannot plug the generator to the general electric alimentation through the charge connector when the connector is plugged to the therapy connector. The connector is related to the catheter through a magnetic plug and supports the therapy button. Reproduced with permission from Shockwave Medical.

Intravascular Lithotripsy Catheter Preparation

As the acoustic shockwaves are propagated through fluid and are impaired by air, the first step is to wash out the air in the catheter using a standard technique. This stage is essential to ensure optimal transmission of the sonic wave into intimal and medial layers. We recommend filling a syringe with 5 cc of 50/50 saline/contrast medium and connecting the syringe to the inflation port on the catheter hub. Pull vacuum at least three times to allow the fluid to replace the air in the catheter. Disconnect the syringe and connect the inflator device with 10 cc of 50/50 saline/contrast medium to the inflation port, ensuring no air is introduced into the system. Supplementary Material Figure 1 shows a step-by-step guide to therapy delivery.

Intravascular Lithotripsy Target Lesion Selection: Concentric or Eccentric Calcification?

As the IVL emitters generate a circumferential acoustic wave, arterial circumferential calcification is the most suitable target for IVL. Moreover, part of the acoustic wave is transferred across the calcified plaque and reflected, interacting with the opposite side of the lesion in a process known as spallation, which increases the procedure’s efficiency.11 Circumferential calcification modification increases vessel compliance and allows for full symmetrical stent expansion. For these reasons, circumferential calcification was an inclusion criterion in the Disrupt CAD trials, defined by the presence of fluoroscopic radio-opacities without cardiac motion involving both sides of the arterial wall, or by the presence of ≥270 degrees of calcium on at least one cross-section on intravascular imaging.12–14 Other criteria were a diameter stenosis ≥70%, native coronary artery lesion length ≤40 mm and heavy calcification, defined as calcification within the lesion on both sides of the vessel assessed during angiography.14 There is evidence that IVL may also be appropriate for eccentric lesions as suggested by a post-hoc analysis in a pooled patient population with eccentric calcified lesions (identified by an independent core lab) in Disrupt CAD I and II.15 Eccentric lesions were defined as a stenotic lesion that had one of its luminal edges in the outer one-quarter of the apparently normal vessel lumen whereas concentric lesion has the same criteria but involving both luminal edges.

We found a high procedural success rates, defined as a residual stenosis of <50% after stenting without intra-hospital major adverse cardiovascular events (MACE) of 93.6% and 93.2% in eccentric and concentric lesions, respectively. There was no difference in vascular complications and clinical outcomes according to the definitions of coronary artery disease (CAD). No difference in mean target delivery pulses between the two groups have been noted for reaching procedural success. However, over 3 years of IVL use in clinical practice, several users have suggested that more pulses may be required to modify calcium in eccentric lesions due to the emitter being at a greater distance from the plaque and the lack of wave reflection compared with concentric lesions. From our experience, we recommend using a 1.1 non-compliant (NC) balloon post IVL therapy to determine the effectiveness of the IVL procedure and to assess the need for an additional IVL catheter.

Intravascular Lithotripsy Therapy Application

The catheter diameter should be selected at a 1:1 ratio relative to the target-vessel diameter and inflated at a sub-nominal pressure (4 atm). Proper apposition of the catheter to the arterial wall is necessary for an adequate fluid/tissue interface to optimise acoustic energy transfer. As noted above, there are several mechanisms responsible for the disruption; in addition to spallation squeezing, cavitation and plaque fatigue that all play a role, as detailed in a recent review.11 The estimated peak pressure of the wave is 50 atm. Notably, the wave and not the balloon generates the disruptive force. This has several advantages – it allows low-pressure balloon inflation which reduces the risk of barotrauma, vascular dissection and perforation and post-dilation after IVL for residual stenosis before stenting (defined in Disrupt CAD III as a residual stenosis >50%) is often unnecessary. In the Disrupt CAD III study, post-dilation was used in only 20.7% of cases.14 In clinical practice, most operators recommend performing an NC balloon after dilation only if there is an incomplete expansion of IVL catheters of more than 30%. It remains unclear how many pulses need to be delivered to ensure good lesion preparation. One catheter can deliver a maximum of 80 pulses. On average, two IVL catheters were used in the Disrupt CAD I and 1.2 were employed in Disrupt CAD II and III. In the Disrupt pooled analysis,

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Best Practice in Intravascular Lithotripsy Figure 2: Decision Algorithm for Treatment of Calcified Coronary Vessels Coronary angiography Moderate/severe calcification

Mild calcification

Uncrossable lesion

IVUS*/OCT assessment: Calcium arc 180–270° (2 points) Calcium arc >270° (3 points) Calcium length >5 mm (1 or 2* points) Thickness >0.5 mm (1 point)†

Balloon predilatation No

Yes

Stent implantation and optimisation with IVUS/OCT

Suboptimal balloon expansion

*In case of IVUS assessment, for calcium length >5 mm + calcium arc >270°, add an extra point to the score †Calcium thickness is assessed only by OCT ‡RA or OA is preferred in localised protruding nodules

1–2 points

3–5 points

High- or very-highpressure NC balloons

Lithotripsy

Suboptimal result

Does not cross

RA or OA‡

Suboptimal balloon expansion

Optimal balloon expansion

Lithotripsy

Stent and OCT/IVUS optimisation IVUS = intravascular ultrasound; NC = non-compliant; OA = orbital atherectomy; OCT = optical coherence tomography; RA = rotational atherectomy. Source: Sorini Dini et al. 2019.19 Reproduced with permission from Radcliffe Cardiology.

the mean number of pulses were 74.7 ± 42.7 and 1.3 ± 0.6 catheter was used.10 According to protocol in Disrupt CAD I, II and III, we assume that a minimum of 20 pulses delivered to the target lesion should be the lowest threshold required for pulse delivery if there is no residual footprint on the balloon.

Figure 3: Typical Multiplane and Longitudinal Optical Coherence Tomography Fractures with Immediate Lumen Gain Increased After Stent Delivery Pre-procedure

Post-IVL

Post-stent

Lumen area: 1.69 mm2

Lumen area: 4.58 mm2

Lumen area: 9.51 mm2 Stent area: 8.01 mm2

Use of Endovascular Imaging

Endovascular imaging may be useful for pre- and post-procedural evaluations.

Pre-procedural Evaluation

Coronary angiography often underestimates calcium.16 In our experience, optical coherence tomography (OCT) is the preferred imaging modality due to its high spatial resolution and ability to measure calcification thickness. Intravascular ultrasound imaging (IVUS) is a valid alternative. In an in vivo sensitivity assessment of 440 lesions, OCT detected calcium in 76.8% and IVUS in 82.7% of lesions, whereas angiography identified calcium in only 40.2% of lesions.17 Several studies have suggested a pre-defined algorithm for analysing plaque characteristics and guiding the selection of PCI strategies and plaque preparation using OCT or IVUS (Figure 2).18,19 We consider IVL the therapy of choice in highly calcified lesions defined as having a severe calcium arc (>270°) or calcium thickness >0.5 mm. Moreover, an interesting finding from the DISRUPT CAD I OCT sub-study is that more extensive calcium modifications, defined by incidence of calcium fracture, calcium fracture per lesion and quadrants of calcium

IVL = intravascular lithotripsy.

fracture, were achieved in lesions in the highest calcification tertile, suggesting that the higher the degree of calcification, the greater the IVL efficacy.20

Post-therapeutic Evaluation

Multiplane and longitudinal fractures are typically observed on OCT after IVL therapy (Figure 3). In a sub-study core lab OCT analysis in DISRUPT CAD III, these fractures resulted in increased vessel compliance with a luminal gain of 1.41 mm2 and 4.35 mm2 at the site of the minimal lumen area after IVL and stent delivery, a mean post-procedural minimal stent area of 6.66 mm2 and full stent expansion defined as mean stent expansion at the maximal calcium site.14 The percentage of lesions with calcium fractures and the maximum calcium fracture depth were similar

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Best Practice in Intravascular Lithotripsy Figure 4: Calcic Microfractures Induced by Intravascular Lithotripsy in Micro CT and Histology Cadaveric superficial femoral artery (micro CT)

Pre-IVL

Histologic and micro CT after intravascular lithotripsy (super femoral artery)

Post-IVL

Histology (A,B)

Micro CT (C,D)

Left panel: Representative micro CT images before and after intravascular lithotripsy (IVL) treatment. Abluminal view of the left distal femoral artery demonstrating predominantly medial calcification. (A) Before (A) and after (B) IVL. Circumferential, transverse, and longitudinal calcium fractures were observed following IVL treatment. Right panel: Histological and micro CT imaging after IVL treatment. Cross-sectional histological Exakt ground section (A) matched with the micro CT cross-sectional image (C). Both sections show cross-shaped cracks highlighted by red boxed areas, which are shown at high-power magnification (B,D). Source: Kereiakes et al. 2021.8 Adapted with permission from Elsevier.

Figure 5: Intravascular Lithotripsy in Severe Calcified Unprotected Left Main Lesion A

A: Severe calcified unprotected LM lesion (Medina 1-1-0); B: After application of 40 pulses – 4 × 12 mm C2 catheter; C: After stent implantation, T-provisional strategy 4 × 22 mm and 5 mm proximal optimisation technique.

in post-IVL and post-stent acquisition; however, the maximum fracture width increased after stent expansion (from 0.55 ± 0.45 mm after IVL to 1.32 ± 1.04 mm after stent implantation). Another notable finding was that fracture incidence occurred in 67.7% of patients but without differences in angiographic, OCT or clinical outcomes.14 This suggests that the absence of calcium fracture on OCT is not a sign of failed therapy as the fracture can be ‘out of plane’ and acoustic waves induce calcification microfractures beyond the resolution of OCT technology, as shown on micro-CT and histology in Figure 4.8

Limitation of Endovascular Imaging

Access to intravascular imaging can be limited in different countries and can be because of cost. Moreover, crossability of the probes (IVUS or OCT) through complex calcified lesions can be challenging. Careful analysis of the baseline angiogram before contrast injection is crucial to classify the lesion according to the classification used by Mintz et al. and to predict PCI complexity and IVL success.21

Specific Clinical Situations Left Main Lesions

The feasibility and safety of IVL in calcified left main (LM) lesions are supported by a retrospective analysis of 31 lesions treated by IVL. In this study, the target minimal stent area was achieved in 97.3% of stented segments with no in-hospital MACE.22 Similarly, good results were provided in a prospective analysis of a registry cohort of 23 patients, in which the primary endpoint (successful stent delivery and expansion with attainment of <30% in-stent residual stenosis of the target lesion in the presence of thrombolysis in MI flow grade 3) was achieved in all patients.23 In this study, the mean IVL catheter diameter used was 3.7 ± 0.3 mm, and a median of eight cycles and 80 pulses were applied (interquartile range: 47–80). In large LM lesions, a 4.0 mm IVL catheter may be used to fracture the calcium, followed by a 1:1 sized NC balloon to expand the fractures created by IVL and prepare for a larger stent (Figure 5).

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Best Practice in Intravascular Lithotripsy Among the concerns with IVL for LM lesions is the need for prolonged vessel occlusion to deliver the required energy, which could lead to severe ischaemia. Salazar et al. distributed the energy by providing pulses individually or in small groups with shorter balloon inflations to minimise this risk. With this strategy, only 2 of 23 patients experienced severe arterial hypotension during inflation.23

Nodular Calcium Lesions

In these lesions, more pulses may be required to modify eccentric calcium as the emitter is further away from the calcium root, and there is none of the wave reflection seen with concentric calcium. If all 80 pulses have been applied, an NC balloon can help determine the procedural efficacy and whether an additional IVL catheter is needed to ensure full balloon expansion.

Long and Multiple Lesions

Ideally, IVL treatment should be applied from distal to proximal lesions. However, in long lesions, the operator can start by advancing the catheter as distally as possible, delivering energy and continuing to advance the catheter. To ensure full therapeutic coverage in the vessel, a 2 mm overlap is advisable when delivering energy in consecutive treatment zones. In case of multiple lesions, we recommend the delivery of 20 pulses for each lesion and subsequently assessing the optimal points for remaining pulses. It needs to be kept in mind that multiple wires within the catheter enable transmission of the energy from the generator to the emitters, which may be damaged during rigorous manipulation.

Difficulty in Crossing the Lesion with IVL

If the electrodes embedded in the balloon are a prowess of technical miniaturisation, the catheter has a low profile, with a bench crossing profile of 0.042" ± 0.002. Every tip and trick used in advanced PCI, such as buddy wire, anchoring and guiding catheter extension, can be applied to overcome deliverability issues. The 6 Fr guiding catheter extensions are compatible with all the diameters of the C2 catheter.

Critical Lesions

In Disrupt CAD II, pre-dilation with a balloon catheter was allowed to ensure crossing of the IVL catheter. This was necessary in 41.7% of cases, using an average balloon size of 2.2 ± 0.6 mm.11 In case of failure to cross, a hybrid rotational atherectomy approach with additional intracoronary lithotripsy (rotatripsy) can be used (as previously described by JuradoRomàn et al.) to deliver IVL and modify both superficial and deep calcium, especially in large vessels.24 From a technical perspective, it is essential to have sufficient space in the balloon to allow the formation of vapour bubbles to optimise sonic output. However, as the combination of atherectomy and IVL increased the cost of the procedure, this hybrid approach should be reserved in case of failure of one device (IVL or atherectomy bail out) and not as a front-line technique. The analysis of the pre-PCI angiogram is crucial to decide which are the best tools according to local resources and operator experience.

IVL and Stent Underexpansion

Stent underexpansion is a dramatic situation in coronary intervention leading to in-stent restenosis and/or stent thrombosis.25 Although there are numerous clinical cases in the literature reporting the efficacy of IVL in the treatment of restenosis related to underexpanded coronary stent,

there are no robust data to support this off-label indication for IVL.26 A study with a smaller cohort by Aksoy and al. suggests that using IVL in an in-stent restenosis (ISR) cohort has a procedural success lower than for de novo lesions.27 Moreover, there are still pending questions regarding the necessity for using an antiproliferative drug after IVL or potential mechanical consequences of the acoustic burst on metallic scaffolding. However, stent underexpansion related to inadequate plaque preparation is a dramatic situation in which IVL could be a game-changer. More clinical data from daily practice and large-scale registry are needed.

Shocktopics and Electrophysiological Disorders

IVL generates mechanical pulses, which may cause atrial or ventricular capture in patients with bradycardia. In patients with implantable pacemakers and defibrillators, the asynchronous capture may interact with the sensing capabilities. It is essential to understand that no electrical current leaves the IVL catheter. Instead, a small amount of mechanical energy is transferred to the vessel wall when sonic pressure waves are created that have been shown to create a stretch-activated response in the myocardium. In the event of clinically significant haemodynamic effects, you may have to temporarily interrupt the IVL therapy. Wilson et al. first described IVL-induced ventricular capture, called ‘shocktopics’. In this retrospective analysis, 77.8% of patients underwent IVL-induced ventricular capture with no resulting adverse clinical events.28 The occurrence and significance of shocktopics have been evaluated in Disrupt CAD III.14 IVL-induced capture was noted during IVL in 41.1% of cases. Decreased systolic blood pressure during the IVL procedure was more frequent in patients with IVL-induced capture than those without (40.5% versus 24.5%, p=0.0007). However, the magnitude of the drop in systolic blood pressure was similar between the two groups (p=0.07). IVL-induced capture did not result in sustained ventricular arrhythmias during or immediately after the IVL procedure in any patient and was not associated with adverse events. Multivariable Cox regression analysis identified that a heart rate of ≤60 BPM, male sex, and the total number of IVL pulses delivered were independent predictors of IVL-induced capture.14 However, one case of VF has been related to off-label use of IVL for instent restenosis in a right dominant coronary artery (RCA).29 The authors described a ventricular arrhythmia by IVL ventricular ectopy on a T wave. It is reasonable to think that this is the consequence of multiple parameters, including favourable electrophysiological susceptibility, pre-existing ventricular ectopy and ischaemia on dominant RCA being more prone to ventricular arrhythmia. However, it also provides a warning and highlights the need to be aware of such exceptional but potential side-effects.

IVL Versus Other Calcium Modification Technologies

Calcified plaque preparation is crucial for PCI success. Induced-calcium modifications are significantly different from pre-existing technology (NC balloon, high-pressure balloon, modified balloon and atherectomy device) with subsequent advantages. As described above, the efficiency is powered by acoustic burst and not balloon inflation, whereas in NC balloons or modified balloons avoids vessel wall barotraumatic injury and decreases the risk of arterial dissection. IVL does not suffer from wire bias as does atherectomy (and subsequent eccentric plaque guttering) and there is a decreased risk of vascular bed overload related to debris embolisation. IVL technology also affects the deeper calcium, whereas debulking technologies are limited to the superficial calcium, which may negatively affect vessel compliance. Last, in contrast to procedures such as atherectomy, the technology can be easily adopted, not least since

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Best Practice in Intravascular Lithotripsy it requires no specific training as the device is delivered similarly to standard catheter-based PCI.30

Conclusion

As a novel technology, published data on IVL includes highly selected clinical situations and patients, but are reinforced by operator experience in daily clinical practice. This growing experience and new trials would fill the gaps remaining in the current scientific literature for situations not encountered in the Disrupt studies. It would be interesting to have a comparator to IVL for plaque preparation, such as a modified balloon or atherectomy. In addition, the registry databases with real-world data 1.

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will continue to grow and provide valuable information, particularly on the safety of IVL. With increasing uptake, we can expect further methodological advances and information from the application of IVL to more complex clinical situations. IVL is a promising therapy for complex calcified lesions with a short learning curve and a favourable safety profile. However, knowledge of the technical characteristics of the catheter and appropriate considerations in terms of preparation, use and specific conditions for IVL will improve daily results and outcomes in patients presenting with complex calcified coronary disease.

patient-level pooled analysis of the Disrupt CAD studies. JACC Cardiovasc Interv 2021;14:1337–48. https://doi. org/10.1016/j.jcin.2021.04.015; PMID: 33939604. Karimi Galougahi K, Patel S, Shlofmitz RA, et al. Calcific plaque modification by acoustic shock waves: intravascular lithotripsy in coronary interventions. Circ Cardiovasc Interv 2021;14:e009354. https://doi.org/10.1161/ CIRCINTERVENTIONS.120.009354; PMID: 32907343. Brinton TJ, Ali ZA, Hill JM, et al. Feasibility of Shockwave coronary intravascular lithotripsy for the treatment of calcified coronary stenoses. Circulation 2019;139:834–6. https://doi.org/10.1161/CIRCULATIONAHA.118.036531; PMID: 30715944. Ali ZA, Nef H, Escaned J, et al. Safety and effectiveness of coronary intravascular lithotripsy for treatment of severely calcified coronary stenoses: the Disrupt CAD II study. Circ Cardiovasc Interv 2019;12:e008434. https://doi.org/10.1161/ CIRCINTERVENTIONS.119.008434; PMID: 31553205. Hill JM, Kereiakes DJ, Shlofmitz RA, et al. Intravascular lithotripsy for treatment of severely calcified coronary artery disease. J Am Coll Cardiol 2020;76:2635–46. https://doi. org/10.1016/j.jacc.2020.09.603; PMID: 33069849. Blachutzik F, Honton B, Escaned J, et al. Safety and effectiveness of coronary intravascular lithotripsy in eccentric calcified coronary lesions: a patient-level pooled analysis from the Disrupt CAD I and CAD II studies. Clin Res Cardiol 2021;110:228–36. https://doi.org/10.1007/s00392020-01737-3; PMID: 32948882. Wang X, Matsumura M, Mintz GS, et al. In vivo calcium detection by comparing optical coherence tomography, intravascular ultrasound, and angiography. JACC Cardiovasc Imaging 2017;10:869–79. https://doi.org/10.1016/j. jcmg.2017.05.014; PMID: 28797408. Mintz GS. Intravascular imaging of coronary calcification and its clinical implications. JACC Cardiovasc Imaging 2015;8:461– 71. https://doi.org/10.1016/j.jcmg.2015.02.003; PMID: 25882575. Shimamura K, Guagliumi G. Optical coherence tomography for online guidance of complex coronary interventions. Circ J 2016;80:2063–72. https://doi.org/10.1253/circj.CJ-16-0846; PMID: 27616595. Sorini Dini C, Nardi G, Ristalli F, et al. Contemporary approach to heavily calcified coronary lesions. Interv Cardiol 2019;14:154–63. https://doi.org/10.15420/icr.2019.19.R1; PMID: 31867062. Ali ZA, Brinton TJ, Hill JM, et al. Optical coherence tomography characterization of coronary lithoplasty for treatment of calcified lesions: first description. JACC

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Cardiovasc Imaging 2017;10:897–906. https://doi.org/10.1016/j. jcmg.2017.05.012; PMID: 28797412. Mintz GS, Popma JJ, Pichard AD, et al. Patterns of calcification in coronary artery disease. A statistical analysis of intravascular ultrasound and coronary angiography in 1,155 lesions. Circulation 1995;91:1959–65. https://doi. org/10.1161/01.CIR.91.7.1959; PMID: 7895353. Cosgrove CS, Wilson SJ, Bogle R, et al. Intravascular lithotripsy for lesion preparation in patients with calcific distal left main disease. EuroIntervention 2020;16:76–9. https://doi.org/10.4244/EIJ-D-19-01052; PMID: 32224480. Salazar CH, Gonzalo N, Aksoy A, et al. Feasibility, safety, and efficacy of intravascular lithotripsy in severely calcified left main coronary stenosis. JACC Cardiovasc Interv 2020;13:1727–9. https://doi.org/10.1016/j.jcin.2020.04.022; PMID: 32703602. Jurado-Román A, Gonzálvez A, Galeote G, et al. RotaTripsy: combination of rotational atherectomy and intravascular lithotripsy for the treatment of severely calcified lesions. JACC Cardiovasc Interv 2019;12:e127–9. https://doi. org/10.1016/j.jcin.2019.03.036; PMID: 31326422. Souteyrand G, Amabile N, Mangin L, et al. Mechanisms of stent thrombosis analysed by optical coherence tomography: insights from the national PESTO French registry. Eur Heart J 2016;37:1208–16. https://doi.org/10.1093/ eurheartj/ehv711; PMID: 26757787. Tovar Forero MN, Wilschut J, van Mieghem NM, Daemen J. Coronary lithoplasty: a novel treatment for stent underexpansion. Eur Heart J 2019;40:221. https://doi. org/10.1093/eurheartj/ehy593; PMID: 30289452. Aksoy A, Salazar C, Becher MU, et al. Intravascular lithotripsy in calcified coronary lesions: a prospective, observational, multicenter registry. Circ Cardiovasc Interv 2019;12:e008154. https://doi.org/10.1161/ CIRCINTERVENTIONS.119.008154; PMID: 31707803. Wilson SJ, Spratt JC, Hill J, et al. Incidence of ‘shocktopics’ and asynchronous cardiac pacing in patients undergoing coronary intravascular lithotripsy. EuroIntervention 2020;15:1429–35. https://doi.org/10.4244/EIJ-D-19-00484; PMID: 31130523. McGarvey M, Kumar S, Violaris A, et al. Ventricular fibrillation induced by a lithotripsy-pulse on T during coronary intravascular Shockwave lithotripsy. Eur Heart J Case Rep 2020;4:1–3. https://doi.org/10.1093/ehjcr/ytaa416; PMID: 33629000. Kimball BP, Bui S, Cohen EA, et al. Early experience with directional coronary atherectomy: documentation of the learning curve. Can J Cardiol 1993;9:177–85. PMID: 8490789.

REVIEW

Structural

Trends in Transcatheter Aortic Valve Implantation in Australia Rhys Gray

1,2,3

and Kiran Sarathy

1,2,3

1. Department of Cardiology, Prince of Wales Hospital, Sydney, Australia; 2. Prince of Wales Clinical School, University of New South Wales Medicine, Sydney, Australia; 3. Eastern Heart Clinic, Sydney, Australia

Abstract

Aortic valve stenosis is the most common valvular lesion in Australia, with a rising prevalence in line with the ageing population. Recent trials have demonstrated the efficacy of transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement in consecutively lower surgical risk patient cohorts. Despite this, the current indication for TAVI in Australia is for the treatment of severe symptomatic aortic stenosis in patients who are of prohibitive or high surgical risk and ultimately deemed suitable by a heart team. This article summarises the trends in TAVI in Australia over the last 5 years in terms of funding, accreditation and service delivery, as well as advances in technique, technology, patient selection and local outcomes.

Keywords

Aortic stenosis, transcatheter aortic valve implantation, surgical aortic valve replacement, Australia, review. Disclosure: The authors have no conflicts of interest to declare. Received: 20 September 2021 Accepted: 5 December 2021 Citation: Interventional Cardiology 2022;17:e03. DOI: https://doi.org/10.15420/icr.2021.27 Correspondence: Kiran Sarathy, Prince of Wales Hospital, Barker St, Randwick, Sydney, NSW 2031, Australia. E: kiran.sarathy@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Aortic valve stenosis is the most common valvular lesion in Australia, with a rising prevalence in line with the ageing population.1 The number of Australian and New Zealanders aged >65 years will increase by 25% between 2020 and 2027.2,3 The most robust recent modelling has estimated a 4.4% annual incidence of severe aortic stenosis in this population.4 Aortic stenosis is characterised by progressive thickening, fibrosis and calcification of the aortic valve leaflets leading to restriction and valve obstruction.5 Clinical manifestations of severe aortic stenosis include angina, dyspnoea, syncope and heart failure.1 If left untreated, symptomatic severe aortic stenosis has an extremely poor prognosis, with a 30–50% mortality at 12 months.1 Traditionally, treatment has entailed surgical aortic valve replacement (SAVR), but many patients deemed excessively high risk for an open surgical procedure are left untreated. Transcatheter aortic valve implantation (TAVI) has generated a worldwide paradigm shift in the treatment of severe symptomatic aortic stenosis. TAVI initially emerged as a novel alternative treatment modality to SAVR in patients with multiple comorbidities at high risk of surgical complications, originally reserved for carefully selected inoperable patients with very high surgical risk.6 Subsequently, data have emerged on the safety and efficacy of TAVI in sequentially lower risk cohorts.6–9 Despite the PARTNER trials continuously demonstrating the efficacy of TAVI versus SAVR in consecutively lower risk cohorts, the current publicly funded universal healthcare insurance scheme in Australia – known as Medicare – requires a patient to have severe symptomatic aortic stenosis and an unacceptably high surgical risk, as assessed by a TAVI case conference including a cardiothoracic surgeon, interventional cardiologist and non-procedural physician.6–10 However, there are current applications by Medtronic, Edwards Lifesciences and Abbott Vascular to the Australian Medical Services Advisory Committee to approve public funding for their respective valves in intermediate- and low-risk patients.

The Funding Model, Accreditation and Heart Teams

TAVI was first performed in Australia in 2008 as part of early clinical trials, but growth of this therapy has been slow compared with other developed nations because of high prosthesis costs and delays in Medicare funding for the procedure.11 Until recently, funding for TAVI has required individual hospital or health service arrangements – often directly with industry or via clinical trials – to be able to offer the service. The introduction of a Medicare benefits schedule item number in November 2017 has made TAVI rebateable and thus more accessible to patients and providers across the Australian healthcare system. Specifically, the indication chosen was, and remains, individuals who have severe symptomatic aortic stenosis and are of prohibitive or high surgical risk and ultimately deemed suitable for TAVI by a heart team.10 This has resulted in rapid growth of the number of TAVI sites, operators and procedures being undertaken in Australia, with the number of implanting sites growing from seven in 2008 to 45 in 2020, with 91 proceduralists now accredited as TAVI operators.11,12 Approximately 50 TAVIs were performed in Australia in 2008, with the number having grown to more than 1,000 by 2018 with a yearly growth of 30–40%.11 Between April 2018 and May 2020, 4,098 TAVI procedures were performed in Australia.12 Despite the recent acceleration in TAVI numbers, the uptake of TAVI in Australia has been relatively slow compared to that of the northern hemisphere, and SAVR continues to be the dominant form of aortic valve intervention, with only 6–10% of all aortic valve procedures being performed using a transcatheter approach between 2013 and 2015.13 TAVI continues to be restricted by limited public funding that caps the number of procedures able to be offered at each centre per year. The penetration

Trends in TAVI Practice in Australia of TAVI in Australia has increased from 48 cases per million in 2016, to 81 cases per million in 2018, and 119 cases per million in 2019.12 In comparison, current TAVI procedural rates for symptomatic severe AS have reached over 200 per million in many European countries, while in the US the number of TAVI procedures exceeded the number of all SAVR procedures in 2019, according to the latest transcatheter valve therapy registry data.14 In view of this increase, the Cardiac Society of Australia and New Zealand and the Australia and New Zealand Society of Cardiac and Thoracic Surgeons have provided guidance on training requirements for centres contemplating TAVI programmes. To ensure ongoing high standards of care, a national TAVI accreditation committee was set up, which requires hospitals and implanting cardiologists to go through a rigorous accreditation process to perform TAVI and monitors procedural volumes and audits patient outcomes. Institutions and individuals are expected to achieve outcomes that are consistently within two standard deviations from the average outcomes of peer institutions in the TAVI registry and are required to have a 90% submission rate of complete data, including 1-year follow-up, to the National TAVI registry.12 Current accreditation of TAVI operators in Australia requires performance of 30 TAVIs (as primary or secondary operator) and 10 initial proctored cases.15 Recent data demonstrate that patient outcomes relate to TAVI volume in the early site experience, although the learning curve effect dissipates after 200 cases.16 This supports the importance of heart teams and proceduralists having appropriate levels of experience. The current emphasis on the indication being patients at prohibitive or high risk for surgical AVR and the requirement for a heart team discussion are central tenets of the Australian TAVI experience. The mandated requirement for heart team discussion is now the cornerstone of TAVI clinical practice in Australia and is entirely consistent with recommendations in Europe, North America and the UK.14 It is anticipated that the role of the heart team will become particularly important with expansion of indications to lower risk groups. Heart team discussion is thought to minimise bias in patient selection, prevent indication creep and ultimately ensure optimal patient outcomes.1 The goal is for Australian patients to have access to heart team assessment in a safe and timely manner and not be denied access to aortic valve intervention on the basis of geographical or funding restrictions.

Valve Types and Procedural Techniques

Over the last 10 years in Australia, rapid progression has occurred in the dynamic field of TAVI, resulting in changes in patient cohorts and procedural techniques, as well as updated iterations of the transcatheter heart valves themselves. Specifically, the first-generation Edwards Lifesciences and Medtronic transcatheter heart valves that were implanted in 2008 under special access schemes have been replaced by the latest generation SAPIEN 3 Ultra and Evolut Pro and joined on the Australian market by the availability of Portico (St. Jude Medical) and Lotus (Boston Scientific). There has been a reduction in delivery sheath size from 21 Fr to 14 Fr, the provision of sealing cuffs, improvements in deliverability, the ability to reposition and retrieve, a move to a minimalist approach under local anaesthesia and a less aggressive approach to percutaneous coronary intervention pre-TAVI and revascularisation only for significant angina and critical, proximal disease.17,18 In addition, safety has been facilitated by developments in imaging and its analysis, particularly using CT scanning. This has led to more accurate determination of device sizing, which may improve device apposition and reduce the risk of annular rupture or coronary occlusion. Pre-procedure

CT scanning can also accurately evaluate the luminal size, tortuosity and calcification of the iliofemoral arteries and reduce vascular and bleeding complication related to femoral access.19 Additional factors that will need to be considered in future younger patient cohorts include the extent of concomitant coronary disease and potential need for future revascularisation, the presence of an associated aortopathy in patients with congenitally bicuspid aortic valves, the long-term consequences of pacemaker implantation and options for re-do or surgical AVR in the event of prosthetic valve degeneration.12 Delivery sheaths, vascular access techniques, implant depth and patient selection criteria have all undergone massive shifts over the last 10 years in Australia leading to improved safety and outcomes of the procedure. TAVI is now performed with conscious sedation, without the need for intra-procedural transoesophageal ultrasound, reducing the number of staff needed and the requirement for post-procedure intensive care, making TAVI a more cost effective, time efficient and less labour-intensive procedure for the Australian healthcare system (Figure 1).

Local Outcomes

A multicentre prospective cohort study of 540 patients across eight Australian hospitals and two New Zealand hospitals between 2008 and 2013 described the early Australian experience with the Medtronic CoreValve system for patients with symptomatic severe aortic stenosis.20 This study included initial use of the CoreValve system for all investigators. They found a mean patient age of 84 years and mean Society of Thoracic Surgeons (STS) score of 5.7%. At 2 years, all-cause mortality was 21.2%, cardiovascular mortality 15.2%, and stroke 10.1%. The rate of permanent pacemaker implantation was 28.4% at 30 days and 29.4% at 2 years. Allcause mortality was found to be similar to that in the UK TAVI registry.21 However, major vascular complications, bleeding and permanent pacemaker (PPM) rates were higher than other CoreValve studies. This was possibly explained by this study cohort including the learning curve of all investigators, and the addition of the AccuTrak Delivery System and more consistent use of CT for valve sizing to later enrolments towards the end of the study period. In 2018, the Australasian cardiac outcomes registry (ACOR) TAVI registry was commenced encompassing 39 TAVI sites across Australia, with the goal of quality control and monitoring of procedural and clinical outcomes of patients undergoing aortic valve replacement via a transcatheter approach. Currently 43 sites across Australia are included in the ACOR registry (25 private hospitals and 18 public hospitals). Early registry data were published in 2019, demonstrating that 865 procedures had been undertaken since commencement of the registry, with the majority (81%) being performed in the private sector.22 The mean patient age was 83 years, mean STS score 5.87% and average length of stay 4 days. Mortality, adverse event rates and patient reported outcome measures were comparable to other international registries.22 A recently published multi-centre Australian cohort of 601 patients who underwent TAVI for severe symptomatic aortic stenosis between 2008 and 2018 found a trend to lower risk patients undergoing TAVI.23 They found mean patient age was 84, with 47% deemed low risk (STS <4%) and 40% intermediate risk (STS 4–7.9%) with only 12% deemed high risk according to STS score. Again, this cohort reported adverse events and outcome measures comparable to other international registries and – importantly – showed no difference in pacemaker insertion rates between groups, which represents a significant on-going hurdle for TAVI in low-risk populations.

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Trends in TAVI Practice in Australia

TAVI cases per million population in Australia

Figure 1: Historical Timeline of Transcatheter Aortic Valve Implantation Trends and Practice in Australia8

2016 CoreValve Evolut-R valve listed on ARTG 2015 Portico valve listed on ARTG

2018 ACOR TAVI registry commenced: 39 TAVI sites across Australia

119 per million

81 per million 2017 SAPIEN 3 valve listed on ARTG

2019 CoreValve Evolut Pro valve listed on ARTG

48 per million

First TAVI in Australia

2008

2011 PARTNER 1 TAVI versus SAVR in high-risk patients

2016

2016 PARTNER 2 TAVI versus SAVR in intermediaterisk patients

2017 Introduction of MBS item number fo TAVI

2018

2019

2019 PARTNER 3 TAVI versus SAVR in low-risk patients

2021

2020 91 proceduralists accredited as TAVI operators across 45 sites

ACOR = Australasian Cardiac Outcomes registry; ARTG =Australian Register of Therapeutic Goods; MBS = Medicare benefits schedule; SAVR = surgical aortic valve replacement; TAVI = transcatheter aortic valve implantation.

Most recently, the SOLACE-AU trial was published in 2020, which was a multicentre, prospective clinical trial on 199 consecutively enrolled intermediate risk Australian patients who underwent TAVI with the SAPIEN XT (Edwards Lifesciences) transcatheter heart valve.24 Mean patient age was 85.5 years with a mean STS score of 5.9%, and results compared favourably with the outcomes of the PARTNER IIA trial.8 At 2 years, allcause mortality and cardiovascular mortality were 16.8% and 8.8%, respectively. Stroke, major vascular complications and the new PPM rate at 30 days were 3.5%, 6% and 8%, respectively.24 Recent excellent outcomes have also been achieved in the private system in Australia, illustrated by a recently published single centre cohort of 300 consecutive patients undergoing TAVI between 2015 and 2018.25 Median age was 85 years with a mean STS score of 4.0%. Peri procedural complication rates were low with a major vascular complication rate of 3.0%, new PPM rate of 9% and no life-threatening or disabling bleeding. At 1 year, mortality was 4.2%, stroke 2.1%, MI 0.3% and PPM rate 11.4%.25 As discussed above, the current funding model in Australia presents unique challenges to service delivery, but excellent outcomes have been demonstrated via both public and private hospitals in the country.

Access to Care and Service Delivery

The land mass of Australia is 32 times the size of the UK, yet the population of the UK is almost three times that of Australia.2 This results in a geographically dispersed population, which provides difficulties in providing a TAVI service to regional and rural Australians. Australians

living in regional and remote areas have inferior health outcomes compared with their urban counterparts.26 Australian regional and rural health services have limited access to invasive therapies, such as for acute coronary syndromes and patients require lengthy transfers to tertiary referral centres, which might delay definitive treatment.27,28 Despite this, equitable outcomes have been achieved in rural patients undergoing TAVI in Australia. A single-centre study of 142 patients consisting of 54% from regional Australia and 13% from outer regional Australia found no differences in procedural success and 30-day or 12-month mortality rates between regional and urban patients.29 Importantly, these were regional patients who had to travel to a tertiary referral hospital to undergo their procedure. More recently, a TAVI programme was developed at a geographically isolated tertiary hospital in Townsville in regional Australia. A total of 19 patients underwent TAVI over a 12-month period with zero major vascular complications, stroke, PPM insertion or mortality, and a 10% incidence of moderate paravalvular leak at 30 days.30 This small, single-centre study outlined the safe and effective implementation of a TAVI programme in a regional tertiary hospital in Australia.30 These outcomes may support other regional centres in the introduction of a TAVI service. However this needs to be balanced with recommendations that TAVI should take place in major tertiary centres with on-site cardiac surgery, interventional radiology and intensive treatment units to

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Trends in TAVI Practice in Australia appropriately manage complications as well as extensive operator and site experience, which has been shown to be an important predictor of patient outcomes.14,16

Conclusion

TAVI outcomes have significantly improved over time in Australia with operator experience, improved patient selection and new device technology including second-generation valves and delivery systems. The focus within Australian heart teams and health systems has shifted from 1.

5. 6.

10.

11.

12.

Adams HSL, Ashokkumar S, Newcomb A, et al. Contemporary review of severe aortic stenosis. Intern Med J 2019;49:297–305. https://doi.org/10.1111/imj.14071; PMID: 30091235. Australian Bureau of Statistics. Population Projections, Australia, 2017–2066. 2018. https://www.abs.gov.au/ statistics/people/population/population-projections-australia/ latest-release (accessed 11 January 2022). Statistics New Zealand. National population projections, by age and sex, 2020(base)-2073. http://nzdotstat.stats.govt. nz/wbos/Index.aspx?DataSetCode=TABLECODE7542&_ ga=2.37673888.1874216751.1603887453113855905.1603887453# (accessed 20 January 2022). Durko AP, Osnabrugge RL, Van Mieghem NM, et al. Annual number of candidates for transcatheter aortic valve implantation per country: current estimates and future projections. Eur Heart J 2018;39:2635–42. https://doi. org/10.1093/eurheartj/ehy107; PMID: 29546396. Sverdlov AL, Ngo DT, Chapman MJ, et al. Pathogenesis of aortic stenosis: not just a matter of wear and tear. Am J Cardiovasc Dis 2011;1:185–99; PMID: 22254198. Leon MB, Smith CR, Mack M, et al. Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. https:// doi.org/10.1056/NEJMoa1008232; PMID: 20961243. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. https://doi.org/10.1056/ NEJMoa1103510; PMID: 21639811. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med. 2016;374:1609–20. https://doi. org/10.1056/NEJMoa1514616; PMID: 27040324. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aorticvalve replacement with a balloon-expandable valve in lowrisk patients. N Engl J Med 2019;380:1695–705. https://doi. org/10.1056/NEJMoa1814052; PMID: 30883058. Australian Government department of Health, MBS listing for transcatheter aortic valve implantation. http://www. mbsonline.gov.au/internet/mbsonline/publishing.nsf/Content/ Factsheet-TAVI (accessed 20 January 2022). Nelson AJ, Montarello NJ, Cosgrove CS, et al. Transcatheter aortic valve implantation: a new standard of care. Med J Aust 2018;209:136–41. https://doi.org/10.5694/mja17.01255; PMID: 30071816. Bennetts J, Sinhal A, Walters D, et al. 2021 CSANZ and

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how to technically perform TAVI to how we select individuals most likely to benefit from the intervention. With applications pending to perform TAVI in lower risk patient cohorts and restricted public funding for the procedure, deciding who is appropriate for intervention will continue to be a challenge for structural heart teams now and into the future. Further intra-procedural and device-related improvements should continue to drive transcatheter technology into the future and ultimately see TAVI become the gold standard for most patients with severe aortic stenosis in Australia and abroad.

ANZSCTS Position Statement on the operator and institutional requirements for a transcatheter aortic valve implantation (TAVI) program in Australia. Heart Lung Circ 2021;30:1811–8. https://doi.org/10.1016/j.hlc.2021.07.017; PMID: 34483050. Si S, Hillis SG, Sanfilippo FM, et al. Surgical aortic valve replacement in Australia, 2002–2015: temporal changes in clinical practice, patient profiles and outcomes. ANZ J Surg 2019;89:1061–7. https://doi.org/10.1111/ans.15370; PMID: 31414527. MacCarthy P, Smith D, Muir D, et al. Extended statement by the British Cardiovascular Intervention Society President regarding transcatheter aortic valve implantation. Interv Cardiol 2021;16:e03. https://doi.org/10.15420/icr.2021.02; PMID: 33897829. Adams H, Roberts-Thomson R, Patterson T, et al. The lowrisk TAVI trials for severe aortic stenosis: future implications for Australian and New Zealand heart teams. Heart Lung Circ 2020;29:657–61. https://doi.org/10.1016/j.hlc.2020.01.006; PMID: 32115372. Russo MJ, McCabe JM, Thourani VH, et al. Case volume and outcomes after TAVR with balloon-expandable prostheses: insights from TVT registry. J Am Coll Cardiol 2019;73:427–440. https://doi.org/10.1016/j.jacc.2018.11.031; PMID: 30704575. Aroney C. TAVI or not TAVI – in low risk patients? That is the question. Heart Lung Circ 2017;26:749–52. https://doi. org/10.1016/j.hlc.2017.02.002; PMID: 28343947. Kotronias RA, Kwok CS, George S, et al. Transcatheter aortic valve implantation with or without percutaneous coronary artery revascularization strategy: a systematic review and meta-analysis. J Am Heart Assoc 2017;6:e005960. https://doi. org/10.1161/JAHA.117.005960; PMID: 28655733. Reinthaler M, Aggarwal SK, De Palma R, et al. Predictors of clinical outcome in transfemoral TAVI: circumferential iliofemoral calcifications and manufacturer-derived recommendations. Anatol J Cardiol 2015;15:297–305. https:// doi.org/10.5152/akd.2014.5311; PMID: 25413227. Meredith IT, Walton A, Walters DL, et al. Mid-term outcomes in patients following transcatheter aortic valve implantation in the CoreValve Australia and New Zealand Study. Heart Lung Circ 2015;24:281–90. https://doi.org/10.1016/j. hlc.2014.09.023; PMID: 25456213. Moat NW, Ludman P, de Belder MA, et al. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation)

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registry. J Am Coll Cardiol 2011;58:2130–8. https://doi. org/10.1016/j.jacc.2011.08.050; PMID:22019110. Sinhal A, Hooper T, Bennetts J, et al. Transcatheter aortic valve implantation in Australia: insights from the ACOR TAVI registry. Heart Lung Circ 2019;28(Suppl 4):433. https://doi. org/10.1016/j.hlc.2019.06.702. Quine EJ, Duffy SJ, Stehli J, et al. Comparison of early outcomes in patients at estimated low, intermediate and high risk undergoing transcatheter aortic valve implantation: a multicentre Australian experience. Heart Lung Circ 2020;29:1174–9. https://doi.org/10.1016/j.hlc.2019.12.001; PMID: 31980394. Yong G, Walton T, Ng M. et al. Performance and safety of transfemoral TAVI with SAPIEN XT in Australian patients with severe aortic stenosis at intermediate surgical risk: SOLACEAU Trial. Heart Lung Circ 2020;29:1839–46. https://doi. org/10.1016/j.hlc.2020.04.010; PMID: 32712017. Chacko Y, Poon KK, Keegan W, et al. Outcomes of the first 300 cases of transcatheter aortic valve implantation at a high-volume Australian private hospital. Heart Lung Circ 2020;29:1534–41. https://doi.org/10.1016/j.hlc.2020.03.010; PMID: 32305328. Australian Institute of Health and Welfare. Heart, stroke and vascular disease – Australian facts. https://www.aihw.gov. au/reports/heart-stroke-vascular-disease/cardiovascularhealth-compendium/data (accessed 11 January 2022). Allenby A, Kinsman L, Tham R, et al. The quality of cardiovascular disease prevention in rural primary care. Aust J Rural Health 2016;24:92–8. https://doi.org/10.1111/ajr.12224; PMID: 26255899. Tuttle CS, Carrington MJ, Stewart S, Brown A. Overcoming the tyranny of distance: an analysis of outreach visits to optimise secondary prevention of cardiovascular disease in high-risk individuals living in Central Australia. Aust J Rural Health 2016;24:99–105. https://doi.org/10.1111/ajr.12222; PMID: 27087389. Paleri S, Tham JL, Jin D, et al. Transcatheter aortic valve implantation for severe aortic stenosis in the Australian regional population. Aust J Rural Health 2019;27:229–36. https://doi.org/10.1111/ajr.12508; PMID: 31074928. Kirk F, Eng L, Yadav S. Decentralisation of transcatheter aortic valve implantation – a review of outcomes and experiences in developing a service in remote Australia. Authorea 22 June 2021. https://doi.org/10.22541/ au.162436851.15778725/v1; preprint.

ORIGINAL RESEARCH

Coronary

Evaluating the Impact of COVID-19 on a Regional Primary Percutaneous Coronary Intervention Service During the First Wave of COVID-19 Adeogo Akinwale Olusan

and Peadar Devlin

Department of Cardiology, Royal Victoria Hospital, Belfast, Northern Ireland, UK

Abstract

Background: Primary percutaneous coronary intervention (pPCI) is the preferred reperfusion strategy in ST-segment elevation MI (STEMI). This study evaluates the impact of COVID-19 on the authors’ pPCI service. Methods: A retrospective study of referrals to the Belfast pPCI service between 23 March and 9 June 2020 – the period of the first full lockdown in the UK – was performed. All ECGs were reviewed alongside patient history. A pPCI turndown was deemed inappropriate if the review demonstrated that the criteria to qualify for pPCI had been met. The number of pPCIs was compared with 2019. Results: The unit had 388 referrals in 78 days, from which 134 patients were accepted for pPCI and 235 referrals were turned down. Of these, nine (4%) were deemed inappropriate. No referrals were turned down because of COVID-19. Of the nine inappropriate cases, six had pPCI following re-referral, two had routine PCI and one had takotsubo syndrome. From the accepted cohort, 85% had pPCI. In the appropriate turndown cohort, there was a final cardiovascular diagnosis in 53% (n=127) of patients, 1-year mortality was 16% (n=38), 55% (n=21) of which were due to a cardiovascular death. There was a 29% reduction in the number of pPCIs performed compared with 2019. Conclusion: During the first wave of COVID-19 there was a significant reduction in the number of pPCIs performed at the Department of Cardiology at Royal Victoria Hospital in Belfast. This was not due to an increase in referrals being inappropriately turned down. The majority of the cohort who had their referral turned down had a final cardiovascular diagnosis unrelated to STEMI; 1-year mortality in this group was significant.

Keywords

Primary percutaneous coronary intervention, reperfusion strategy, COVID-19, acute coronary syndrome, cardiovascular diseases, turned down referrals, 1-year mortality. Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: AAO acknowledges the support and input of PD in ensuring that this project was successful. Both authors are grateful to the cardiology service coordinator at the Belfast Royal Victoria Hospital. The abstract of this article was presented as a poster at the Irish Cardiac Society annual meeting in October 2021 and this was published in a supplement in Heart, October 2021. Data Availability: The data that support this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions. Declaration of Helsinki: This research work adheres to the tenets within the declaration of Helsinki. Informed Consent: All patients provided consent for data follow-up and publication as part of the National Institute of Cardiovascular Outcomes Research (NICOR)/British Cardiovascular Intervention Society (BCIS) data, which is covered by section 251 of the NHS Act 2006. Authors’ Contributions: Conceptualisation: AAO; formal analysis: AAO; investigation: AAO, PD; methodology: AAO, PD; project administration: AAO; resources: AAO, PD; writing – original: AAO; writing – review and editing: AAO, PD. Received: 24 June 2021 Accepted: 14 December 2021 Citation: Interventional Cardiology 2022;17:e04. DOI: https://doi.org/10.15420/icr.2021.22 Correspondence: Adeogo Akinwale Olusan, Department of Cardiology, Royal Victoria Hospital, Belfast BT12 6BA, UK. E:aakinwale@yahoo.co.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.

Cardiovascular diseases (CVD) are the world’s number one cause of death with an estimated 17.9 million deaths per year, representing about 31% of deaths globally. CVDs manifest in various forms including ischaemic heart disease (IHD; either as acute coronary syndrome or chronic coronary syndrome), cerebrovascular disease and peripheral vascular disease. The lesser forms of CVD include heart failure, heart rhythm disturbance (arrhythmias), valvular heart disease, congenital heart disease, cardiomyopathies, aortic aneurysms and venous thromboembolism, with 85% of deaths from CVD worldwide caused by acute coronary syndrome and cerebrovascular disease.1,2 Although IHD is the single most common cause of death globally and its frequency continues to increase, the overall mortality trend in Europe has been steadily decreasing in the past three decades, with the largest declines in the Netherlands and the UK.3

Acute coronary syndrome includes ST-segment elevation MI (STEMI), nonSTEMI (NSTEMI) and unstable angina. The relative incidence of NSTEMIs has increased slightly and that of the STEMIs decreased significantly in the US, with long-term mortality in these patients reducing.4,5 Primary percutaneous coronary intervention (pPCI) is the preferred reperfusion strategy for patients with STEMI. STEMI diagnosis and treatment begins from the point of first medical contact and strategies to reduce delays and maximise the efficiency of the pPCI using regional reperfusion strategies have been recommended by various guidelines.6.8 The Belfast pPCI service became operational in April 2007. It offers a 24 hours a day, 7 days a week and 365 days a year service to the catchment areas of Ulster, Downe, Lagan Valley, Antrim, Daisy Hill, Craigavon,

Evaluating the Impact of COVID-19 on a Regional pPCI Service Figure 1: Northern Ireland Flowchart for Suspected ST-segment Elevation MI and Primary Percutaneous Coronary Intervention Activation

Figure 2: Details of All Primary Percutaneous Coronary Intervention Referrals Received Between 23 March and 9 June 2020 Referral to pPCI service in lockdown (23 March–9 June 2020) (n=388)

Suspected STEMI or acute posterior MI less than 12 hours from onset of maximum pain

ST-segment elevation: 1 mm or more in at least 2 contiguous limb leads Or 2 mm or more in at least 2 contiguous chest leads Or ST depression suggestive of acute posterior MI: horizontal or downsloping ST depression of at least 2 mm in leads V1–V3

Belfast Email ECG to pPCI coordinator then Call primary PCI coordinator

Diagnostic uncertainty Discuss with local cardiology on-call team

Altnagelvin Email ECG to pPCI lead nurse then Contact CCU

Accepted for primary PCI: Give aspirin 300 mg Give ticagrelor 180 mg unless contraindicated* DO NOT GIVE enoxaparin or any further GTN Get IV access, avoiding right cephalic vein close to radial artery – minimum 20 G (pink) DO NOT perform ABGs unless there is a clear reason Place on continuous cardiac monitor Arrange immediate transfer to cath lab or CCU as instructed

Not accepted for primary PCI: Discuss with local cardiology on-call team

*Contraindications to ticagrelor • Previous intracranial haemorrhage • Known severe hepatic impairment • Known hypersensitivity to ticagrelor If uncertain, load instead with clopidogrel 600 mg

ABGs = arterial blood gases; CCU = coronary care unit; GTN = glyceryl trinitrate; pPCI = primary percutaneous coronary intervention; STEMI = ST-segment elevation MI.

Ballycastle and Ballymoney in the UK.9 The service involves nurse-led ECG interpretation undertaken after these have been transmitted electronically to a dedicated email address in conjunction with a pre-alert call to a dedicated telephone line from the Northern Ireland Ambulance Service (NIAS). With the outbreak of COVID-19 and its subsequent declaration as a public health emergency by the WHO on 30 January 2020, the effect of COVID-19 on healthcare systems around the world cannot be overemphasised.10 As of 27 February 2020, there were confirmed cases within and outside China.11 As the number of cases continued to rise exponentially globally, there were 6,650 cases in the UK when it entered a full national lockdown on 23 March 2020.12 A study from London has shown there was a reduction in admission of patients with STEMIs and that the pPCI pathways can be maintained during the pandemic.13 Similarly, a survey of 3,101 responders from 141 countries and six continents indicated that there was >40% reduction in STEMI admissions during the pandemic and this is also in agreement with the National Institute for Cardiovascular Outcomes Research (NICOR) COVID-19 report.14,15 Historically, about 60% of patients referred to the Belfast pPCI service are appropriately turned down as shown in previous studies.16,17 In light of this,

Referrals without ECGs removed (n=15)

Duplicated referrals removed (n=4)

Total referrals within this period (n=369)

Accepted for pPCI (n=134; 36%)

Underwent pPCI (n=114; 85%)

No intervention done (n=20; 15%)

Not accepted for pPCI/turned down (n=235; 64%)

Appropriately turned down (n=226; 96%)

Inappropriately turned down (n=9; 4%)

pPCI = primary percutaneous coronary intervention. Source: Olusan et al. 2021.23 Reproduced with permission from BMJ Publishing Group and British Cardiovascular Society.

we evaluated the impact of COVID-19 on our pPCI service during the first wave of the pandemic in the UK from 23 March to 9 June 2020. The aim was to find out if there had been a reduction in the number of pPCIs performed and whether there had been any changes to the referrals to the pPCI service which meant patients had been inappropriately turned down.

Methods

When a patient is referred to the Belfast pPCI service, their ECGs are triaged by the pPCI coordinator who logs the details of referrals and the ECG in a standardised locally agreed Proforma document and a Microsoft Access database. Criteria for acceptance for pPCI are chest pain of <12 hours onset and either ST-segment elevation (1 mm or more in at least two contiguous limb leads; 2 mm or more in at least two contiguous chest leads) or ST segment depression suggestive of acute posterior MI (horizontal or downsloping ST segment depression of at least 2 mm in leads V1–V3). Patients meeting these criteria are immediately transferred to the catheter laboratory (Figure 1). However, patients who are not accepted into this pathway by not meeting the above criteria are advised to be reassessed by the local cardiology team. Furthermore, patients without clear-cut diagnosis of STEMI on ECG, including those with left bundle branch block morphology or paced rhythm, are discussed with either the on-call cardiology registrar or interventional cardiologist before a decision is taken to either accept the referral or turn it down. This was a retrospective observational study of all referrals to the Belfast pPCI service during the first wave of COVID-19. All ECGs were reviewed with corresponding referral history logged on the database and call log sheets. Supplementary clinical data was collected using the Northern Ireland Electronic Care Record (NIECR) to assess admission location, cardiovascular risk factors (diabetes, hypertension, dyslipidaemia, smoking, high BMI and chronic kidney disease), prior ischaemic heart disease, high sensitivity troponin-T levels, final diagnoses, COVID-19 swab

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Evaluating the Impact of COVID-19 on a Regional pPCI Service Table 1: Baseline Characteristics and Source of Patient Referrals from the Turned-down Cohort Characteristics

n=235, n (%)

Age (years); median (IQR)

69 (24–94)

Male sex

172 (73)

Referral source: • Northern Ireland Ambulance Service • Emergency department • Inpatient

146 (62) 68 (29) 21 (9)

Was the referral appropriately rejected? • No • Yes

9 (4) 226 (96)

Was pPCI done? • No • Yes

224 (95) 11 (5)

Were patients re-referred for PCI? • No • Yes

182 (77) 53 (23)

Number of patients who had intervention: • PCI • CABG

35 (15) 2 (1)

Diabetes

70 (30)

Hypertension

133 (57)

Dyslipidaemia

184 (78)

Smoking history: • Never smoked • Current smoker • Ex-smoker • Unknown

73 (31) 48 (20) 86 (37) 28 (12)

Chronic kidney disease

68 (29)

Prior ischaemic heart disease

100 (43)

Body mass index (mean, SD)

24.05 ± 12.02 kg/m²

Troponin T (median, IQR)

35 (0, 10,000) ng/l

Clinical COVID-19 diagnosis

16 (7)

COVID-19 swab positive

4 (2)

Mortality Days before death; median (IQR)

38 (16) 10 (0–157)

CABG = coronary artery bypass graft; pPCI = primary percutaneous coronary intervention. Source: Olusan et al. 2021.23 Reproduced with permission from BMJ Publishing Group and British Cardiovascular Society.

results and mortality. A turndown was deemed inappropriate if the retrospective review of history and ECG demonstrated that the pPCI entry criteria had been met. The number of pPCIs performed was compared with the same period in 2019. Statistical analyses were performed using Stata/IC 15.1. Continuous variables were expressed as mean alongside standard deviation (SD), median alongside interquartile range (IQR) for parametric and nonparametric variables, respectively. Similarly, categorical variables were expressed as proportion (%) and χ2 or Fisher’s exact tests were used to test for statistical significance. A p-value ≤0.05 showed statistical significance.

Results

During the 78-day period, a total of 388 patients were referred to the Belfast pPCI service – an equivalent of five referrals per day. Of these, 19 were excluded from analysis owing to duplicated (n=4) and incomplete

Figure 3: Proportion of Patients who were Re-referred for Primary Percutaneous Coronary Intervention Within the Inappropriately Turned-down Cohort

11% (n=1) pPCI following inappropriate turndown Routine pPCI due to missed STEMI

22% (n=2) 67% (n=6)

Takotsubo syndrome (nonobstructive coronary arteries)

pPCI = primary percutaneous coronary intervention; STEMI = ST-segment elevation MI.

(n=15) referrals (i.e. without ECGs). Of the 369 patients included in the study, 235 (64%) were turned down for pPCI and 134 patients (36%) were accepted for pPCI. In the accepted cohort, 114 patients (85%) had pPCI to a culprit coronary artery and 20 patients (15%) had no intervention performed. The reasons for no intervention included: takotsubo syndrome (n=3); coronary spasm (n=1); pericarditis (n=4); chronic total occlusion (CTO) (n=3); non-obstructed coronary artery (n=8); and stroke (n=1). In the turndown cohort, nine patients (4%) were inappropriately turned down for pPCI which was 2.4% of all referrals (Figure 2). The median age of patients from the turndown cohort was 69 years with an IQR 24–94 years and 73% were men. The vast majority of turned down referrals (n=146; 62%) were received from NIAS (Table 1) and 46% (n=109) of the patients who were turned down were admitted to cardiology wards (Figure 3). Of the nine patients who were inappropriately turned down, six subsequently had a pPCI performed to culprit vessels following re-referral from the local district general hospital. These include pPCI to the left circumflex artery (LCx) for a lateral STEMI (n=1); pPCI to the vein graft to obtuse marginal artery for a posterior STEMI (n=1); pPCIs to the left anterior descending artery (LAD) for an anterior STEMI and an initially missed anterior STEMI (n=2); pPCI to the left main coronary artery (LMCA), LAD and LCx for an anterior STEMI (n=1); and pPCI to the right coronary artery (RCA) for an Inferior STEMI (n=1). Two patients from the inappropriately turned down cohort had missed STEMI, each of whom had a routine PCI to LAD for anteroseptal STEMI and routine PCI to LMCA and LCx for posterior STEMI on day 9 and day 4, respectively, after intial referal. The remaining patient from the inappropriately turned down cohort was diagnosed with takotsubo syndrome after coronary angiography demonstrated non-obstructive coronary arteries (Figure 3). Furthermore, there were four cases of NSTEMIs with subsequently evolving ECG changes and ongoing ischaemia that required pPCI (two RCA, one LCx and one vein graft to the obtuse marginal artery). One patient who was initially appropriately turned down subsequently developed anterior STEMI and required pPCI to LAD. Further analysis of the appropriately turned down cohort demonstrated that three patients had ST-segment elevation on lead aVR associated with inferolateral ST-segment depression. These were appropriately turned down because they did not meet the pPCI pathway activation criteria. Two

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Evaluating the Impact of COVID-19 on a Regional pPCI Service Figure 4: Comparison of Primary Percutaneous Coronary Interventions in 2019 and 2020

Table 2: Final Diagnosis of Patients and the Proportion of Patients Who Died During Study Period from the Turned-down Cohort

Comparison between the numbers of pPCI performed

Final Diagnosis

Number (%)

Mortality (%)

STEMI

12 (5)

2 (5)

Late STEMI

8 (3)

5 (13)

NSTEMI

41 (17)

4 (11)

Unstable angina

3 (1)

Spontaneous coronary artery dissection

1 (0.5)

Angina

13 (6)

Takotsubo syndrome

6 (3)

2 (5)

Pericarditis

3 (1)

Myocarditis

1 (0.5)

Congestive cardiac failure

10 (4)

3 (8)

Arrhythmia

29 (12)

5 (13)

Non-cardiac chest pain

25 (11)

pPCI = primary percutaneous coronary intervention. Source: Olusan et al. 2021. Reproduced with permission from BMJ Publishing Group and British Cardiovascular Society.

Miscellaneous

67 (29)

12 (32)

COVID-19

16 (7)

5 (13)

of the three patients had cardiovascular mortality (aged 85 and 94 years) and the third patient (aged 65) had a coronary artery bypass graft (CABG).

Total

235

70 60 50

44 37

2019 2020

January 61 57

February 60 59

March 62 44 2019

April 57 37

May 63 49

2020 23

The impact of COVID-19 on referrals to our pPCI service during the first wave of the pandemic was then assessed to see if there were any referrals turned down due to COVID-19. There were 16 patients with clinically suspected COVID-19, four of whom were swab positive for COVID-19 infection. No patient was turned down because of COVID-19. In 2020, there was a 29% reduction (130 versus 180) in the number of pPCIs performed in the 3 months from March to May in comparison with the previous year (Figure 4). In the appropriately turned down cohort, the final diagnosis was cardiovascular in 127 patients (53%), non-cardiac chest pain in 25 patients (11%) and miscellaneous in 67 patients (29%), while COVID-19 was diagnosed in 16 patients (7%; Table 2). The miscellaneous diagnoses included gastritis, acute kidney injury, myositis, hepatosplenic abscess, transient ischaemic attack, gastroenteritis, infective exacerbation of chronic obstructive lung disease, vestibular neuritis, subarachnoid haemorrhage, diabetic ketoacidosis, pneumonia, seizure, septic shock, upper gastrointestinal bleeding, overdose, colitis, pancreatitis, anaemia, liver tumour, prostate cancer, metastatic colon cancer, alcohol intoxication and renal lithiasis. The admission ward of patients within the turndown cohort was examined and about 46% of patients were admitted to a cardiology ward (Figure 5). The 1-year mortality rate of the 235 turned-down patients was 16% (n=38) of which about 55% (n=21) was due to a cardiovascular cause – STEMIs (n=2), late STEMIs (n=5), NSTEMIs (n=4), takotsubo syndrome (n=2), congestive cardiac failure (n=3) and ventricular arrhythmias (n=5); 13% (n=5) were due to COVID-19 and 32% (n=12) were due to the miscellaneous causes listed above (Tables 1 and 2). There were no deaths recorded within the inappropriately turned down patients. We assessed the effect of inappropriately turned down referrals on mortality, but there was no statistically significant association (p=0.51, Fisher’s exact). The association between sex and mortality was also assessed using the Fisher exact test, and this demonstrated a significant association between

NSTEMI = non-ST-segment elevation MI; STEMI = ST-segment elevation MI. Source: Olusan et al. 2021.23 Reproduced with permission from BMJ Publishing Group and British Cardiovascular Society.

female sex and mortality (female 14/45 [31.1%]) versus men 24/145 [16.6%], p=0.042). There was no difference noted between the sexes in relation to clinical COVID-19 diagnosis (p=0.16). The association between clinical COVID/swab-positive COVID-19 and cardiovascular risk factors, such as diabetes, hypertension, dyslipidaemia, smoking, chronic kidney disease and past history of ischaemic heart disease, was examined, but the only statistically significant association was found between diabetes and clinical COVID-19 diagnosis (χ2 test, p=0.03). There was a statistically significant association between diabetes and mortality (χ2 test, p=0.05).

Discussion

This study provides contemporary data of the impact of COVID-19 on the pPCI service during the first wave of the pandemic in the Belfast region. A higher proportion of referrals did not meet the criteria for pPCI from which 4% were inappropriately turned down. Of those, 89% had pPCI to the culprit vessel. A number of these patients had clinical reasons for being declined initially: resolution of ST-segment elevation; three-vessel coronary disease including known CTO-LAD (patient was awaiting CABG). The proportion of turned-down referrals is similar to published data from previous studies within the UK.16–18 About half of those who were appropriately turned down had a final cardiovascular diagnosis. A higher proportion of referrals were received from paramedics (NIAS) and this is similar to what is expected within the general population. A culture of paramedics’ upskilling in the early detection of STEMI on ECG and subsequent referral to the pPCI pathway has been developed over the years, in line with stipulated guidelines.6–9 Of those patients excluded from this study, 15 were due to non-transmission of ECGs at the time of referral, which could be improved upon. COVID-19 significantly reduced the number of pPCIs performed during the first wave of the epidemic at the Belfast trust and this is in agreement with

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Evaluating the Impact of COVID-19 on a Regional pPCI Service Figure 5: Admission Location of Patients Turned Down Following Primary Percutaneous Coronary Intervention Referral Admission ward 2% (n=4)

Cardiology ward Intensive care unit

22% (n=51) 46% (n=109)

Other medical wards Not admitted/unknown

28% (n=66)

Surgical ward

2% (n=5)

findings in other studies; nevertheless, no referrals were inappropriately turned down because of COVID-19 at our regional centre.13–14,19 ST-segment elevation in at least two contiguous leads has been a universal criteria for STEMI diagnosis as stipulated by recommended guidelines which is reflected in the Belfast pPCI activation pathway (Figure 1). 6–8 There was a 67% (n=2) mortality in patients presenting with ST-segment elevation in lead aVR and 33% (n=1) had CABG. It is well recognised that ST-segment elevation in aVR denotes significant left main coronary artery disease or occlusion.20–22 Although these patients do not meet criteria for pPCI they can be referred for emergency PCI after initial cardiology assessment in the referring hospital. The study’s strengths included examining first referrals to the Belfast pPCI service not just from paramedics but also those from emergency department and inpatient wards which gives an overview of all referrals to the service. Although there were concerns that COVID-19 transmission could have affected the decision-making of the pPCI coordinators, there were no cases turned down because of COVID-19. The use of electronically transmitted ECG helped ensure that all transmitted ECGs could be retrospectively analysed to ascertain whether the referrals were appropriate. The availability of a national electronic healthcare database, NIECR, helped ensure the tracking of most patients to ascertain their final diagnoses and mortality. There are some limitations to this study. As with all observational studies, we cannot fully eliminate the risk of bias; however, we ensured that all 1.

WHO. Fact sheet on non-communicable diseases. 2021. https://www.who.int/news-room/fact-sheets/detail/ noncommunicable-diseases (accessed 21 January 2022). 2. Jennings CS, Graham I, Gielen S. The ESC Handbook of Preventive Cardiology: Putting Prevention into Practice. 1st ed. Oxford, UK: Oxford University Press, 2016; 3–15. https://doi. org/10.1093/med/9780199674039.001.0001. 3. Hartley A, Marshall DC, Salciccioli JD, et al. Trends in mortality from ischemic heart disease and cerebrovascular disease in Europe: 1980 to 2009. Circulation 2016;133:1916– 26. https://doi.org/10.1161/CIRCULATIONAHA.115.018931; PMID: 27006480. 4. Sugiyama T, Hasegawa K, Kobayashi Y, et al. Differential time trends of outcomes and costs of care for acute myocardial infarction hospitalizations by ST elevation and type of intervention in the United States, 2001–2011. J Am Heart Assoc 2015;4:e001445. https://doi.org/10.1161/ JAHA.114.001445; PMID: 25801759.

electronically transmitted ECGs assessed in this study were reviewed by four different cardiology specialist registrars individually, which helped eliminate bias to some extent. A few of the patients had missing data, e.g. nine of the patients had no available health and social care number, which meant we were unable to track this subset of the cohort, but this was not significant enough to invalidate this study. This study was unable to ascertain a statistically significant association between COVID-19 and known comorbidities for COVID-19 except for diabetes, which may be because the few patients in the study with COVID-19 were among this cohort. Learning points gained during the first wave of COVID-19 which have influenced our service during subsequent waves include: ensuring patients seek help early and feel safe to be admitted to hospital to avoid late presentation and increased mortality; turned-down patients with alternative diagnoses to STEMI (such as NSTEMIs, takotsubo syndrome, congestive cardiac failure and ventricular arrhythmias) should be assessed by a specialist team and treated appropriately to reduce mortality in these cohorts.

Conclusion

During the first wave of COVID-19 there was a significant reduction in the number of pPCIs performed. This was not due to an increase in referrals being inappropriately turned down and no patient was turned down because of COVID-19. Of the patients whose referrals were turned down, the majority (53%) had a final cardiovascular diagnosis unrelated to STEMI and 1-year mortality in this group was significant. Measures to ensure patients seek help early and feel safe in a hospital environment in addition to specialist team review of turned-down patients will help mitigate mortality.

Clinical Perspective

• COVID-19 significantly reduced the number of pPCIs performed

during the first wave, although there were no patients turned down for pPCI due to COVID-19. • Measures to reduce 1-year mortality include ensuring that patients seek help early to avoid late presentation and those with alternative diagnoses obtain specialist help and follow-up. • It is well recognised that ST-segment elevation in aVR denotes significant left main coronary artery disease or occlusion. Although these patients do not meet criteria for pPCI they can be referred for emergency PCI after initial cardiology assessment in the referring hospital.

5. McManus DD, Gore J, Yarzebski J, et al. Recent trends in the incidence, treatment, and outcomes of patients with STEMI and NSTEMI. Am J Med 2011;124:40–7. https://doi. org/10.1016/j.amjmed.2010.07.023; PMID: 21187184. 6. Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–77. https://doi.org/10.1093/eurheartj/ehx393; PMID: 28886621. 7. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78–140. https://doi.org/10.1016/j.jacc.2012.11.019; PMID: 23256914. 8. National Institute for Health and Care Excellence. Acute

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Coronary Syndromes. London; NICE, 2020. https://www.nice. org.uk/guidance/ng185 (accessed 18 January 2022). Herity N, Corrigan D, McNeill A. Transformation of heart attack care: a primary percutaneous coronary intervention service for Northern Ireland. Ulster Med J 2019;88:36–40. PMID: 30675077. WHO. Timeline: WHO’s COVID-19 Response. 2021. https:// www.who.int/emergencies/diseases/novel-coronavirus-2019/ interactive-timeline (accessed 18 January 2022). WHO. Coronavirus disease 2019 (COVID-19) Situation Report – 38. 2020. https://www.who.int/docs/default-source/ coronaviruse/situation-reports/20200227-sitrep-38-covid-19. pdf?sfvrsn=9f98940c_6 (accessed 18 January 2022). Hainey F. Number of confirmed cases of coronavirus in UK increases by nearly 1,000 with 54 more deaths. Manchester Evening News 23 March 2020. https://www. manchestereveningnews.co.uk/news/uk-news/coronavirustests-latest-figures-uk-17966865 (accessed 18 January

Evaluating the Impact of COVID-19 on a Regional pPCI Service 2022). 13. Little CD, Kotecha T, Candilio L et al. COVID-19 pandemic and STEMI: pathway activation and outcomes from the panLondon heart attack group. Open Heart 2020;7:e001432. https://doi.org/10.1136/openhrt-2020-001432; PMID: 33106441. 14. Pessoa-Amorim G, Camm CF, Gajendragadkar P, et al. Admission of patients with STEMI since the outbreak of the COVID-12 pandemic: a survey by the European Society of Cardiology. Eur Heart J 2020;6:210–6. https://doi. org/10.1093/ehjqcco/qcaa046; PMID: 32467968. 15. National Institute for Cardiovascular Outcomes Research. NICOR COVID-19 Report. 2021. https://www.nicor.org.uk/ covid-19-and-nicor/nicor-covid-19-report (accessed 18 January 2022). 16. Linden K, Tweedie J, McCarrick L, et al. Appropriateness and outcomes of patients turned down by a primary

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percutaneous coronary intervention service. Heart 2015;101(Suppl 5):A3–4. https://doi.org/10.1136/ heartjnl-2015-308621.6. Linden K, Herity N, McGeough M. Evaluation of the diagnostic accuracy of nurse-leg ECG interpretation for a large primary percutaneous intervention service. Heart 2019;105 (Suppl 6):A138–9. https://doi.org/10.1136/heartjnl2019-BCS.163. Rossington JA, Cole SF, Zaidy Y, et al. Pre-alert calls for primary PCI: a single-centre experience. British Journal of Cardiology 2015;22:157. https://doi.org/10.5837/bjc.2015.035. Nan J, Zhang T, Tian Y et al. Impact of the 2019 novel coronavirus disease pandemic on the performance of a cardiovascular department in a non-epidemic centre in Beijing, China. Front Cardiovasc Med 2021;8:630816. https:// doi.org/10.3389/fcvm.2021.630816; PMID: 33681305. Williamson K, Mattu A, Plautz CU, et al. Electrocardiographic

applications of lead aVR. Am J Emerg Med 2006;24:864–74. https://doi.org/10.1016/j.ajem.2006.05.013; PMID: 17098112. 21. Nough H, Jorat MV, Varasteravan HR, et al. The value of ST-segment elevation in lead aVR for predicting left main coronary artery lesion in patients suspected of acute coronary syndrome. Rom J Intern Med 2012;50:159–64. PMID: 23326960. 22. Chenniappan M, Sankar RU, Saravanan K, Karthikeyan. Lead aVR – the neglected lead. J Assoc Physicians India 2013;61:650–4. PMID: 24772703. 23. Olusan A, Devlin P, Johnston P. Evaluating the impact of COVID-19 on regional primary percutaneous coronary intervention service during the first wave of COVID-19. Heart 2021;107(Suppl 2):A38–9. https://doi.org/10.1136/heartjnl2021-ICS.45.

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REVIEW

Coronary

A Review of the Impella Devices Rami Zein , Chirdeep Patel, Adrian Mercado-Alamo , Theodore Schreiber and Amir Kaki Interventional Cardiology Department, Ascension St John Hospital and Medical Center, Detroit, MI, US

Abstract

The use of mechanical circulatory support (MCS) to provide acute haemodynamic support for cardiogenic shock or to support high-risk percutaneous coronary intervention (HRPCI) has grown over the past decade. There is currently no consensus on best practice regarding its use in these two distinct indications. Impella heart pumps (Abiomed) are intravascular microaxial blood pumps that provide temporary MCS during HRPCI or in the treatment of cardiogenic shock. The authors outline technical specifications of the individual Impella heart pumps and their accompanying technology, the Automated Impella Controller and SmartAssist, their indications for use and patient selection, implantation techniques, device weaning and escalation, closure strategies, anticoagulation regimens, complications, future directions and upcoming trials.

Keywords

Impella, mechanical circulatory support, cardiogenic shock, high-risk percutaneous coronary intervention Disclosure: TS is a consultant for Abiomed. AK receives speaker honoraria, consultant fees and research funding from Abiomed, Abbott, CSI and Terumo. All other authors have no conflicts of interest to declare. Acknowledgements: JetPub Scientific Communications, supported by Abiomed, assisted in the preparation of this manuscript, in accordance with Good Publication Practice (GPP3) guidelines. Jennifer Even Melton provided editorial assistance. Karey Dutcheshen provided assistance with the weaning protocol. Received: 8 March 2021 Accepted: 1 December 2021 Citation: Interventional Cardiology 2022;17:e05. DOI: https://doi.org/10.15420/icr.2021.11 Correspondence: Rami Zein, VEP, 2nd floor Cath Lab, 22101 Moross Rd, Detroit, MI, 48236, US. E: rami.zein@ascension.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Mechanical circulatory support (MCS) device use for cardiogenic shock (CS) and high-risk percutaneous coronary intervention (HRPCI) has grown over the past decade. However there are ongoing problems, including the standardisation of guidelines for patient selection, protocols for use, weaning and addressing complications.1,2 Among patients undergoing percutaneous coronary intervention (PCI) for acute MI complicated by CS (AMICS), data from a recent cross-sectional study show that 42.7% received an mechanical circulatory support (MCS) device; during the study period of 2015–2017, the use of intravascular microaxial left ventricular assist devices (LVADs) increased substantially while intra-aortic balloon pump (IABP) use decreased significantly.3 In a Premier database analysis, Amin et al. identified that Impella use among percutaneous coronary intervention (PCI) patients requiring MCS rose from approximately 1% in 2008 to 31.9% to 2016, encompassing 9.9% of all PCI procedures performed for MCS.4 The authors did not observe a trend of increasing use of Impella in critically ill patients. This being the case, the overall trend in growing use likely reflects greater utilisation in the context of HRPCI. Since the introduction of Impella, IABP use has been found to either decline slightly or stay constant. When results from the IABP-SHOCK II trial did not demonstrate a benefit of IABP use on 30-day or 1-year mortality, the use of IABP in cardiogenic shock was downgraded to a class III B recommendation in European guidelines.5 Similarly, in the US, IABP use has been downgraded to a class IIb B recommendation. In addition, a 2005–2014 analysis of the Nationwide Inpatient Sample database found a significant decrease in the use of IABP in patients with acute MI

complicated by cardiogenic shock, while the use of both Impella devices and extracorporeal membrane oxygenation (ECMO) increased significantly over this decade.2 The analysis found that patients receiving any MCS were significantly more likely to be younger and to undergo revascularisation; patients receiving MCS also had significantly lower inhospital mortality than those not receiving MCS.2

Impella Pumps

The Impella device (Abiomed) is an intravascular microaxial blood pump that provides temporary MCS to patients, thereby reducing the workload of the heart and improving systemic circulation. Impella devices are used during HRPCI or for treatment of cardiogenic shock following acute MI or cardiac surgery, in the context of cardiomyopathy and in severe myocarditis.6,7 The left-sided Impella devices are microaxial pumps positioned across the aortic valve into the left ventricle (LV) that provide continuous antegrade blood flow from the LV into the ascending aorta, which reduces the workload of the LV and increases cardiac output (Figure 1). The result is improved systemic perfusion and increased coronary flow accompanied by a reduction in myocardial oxygen demand.6,7 A right-sided device delivers blood from the inlet area of the inferior vena cava into the pulmonary artery. The characteristics of each Impella device are detailed in Table 1.

Automated Impella Controller with SmartAssist Technology

The Automated Impella Controller (AIC) is the primary user control interface for all Impella heart pumps. This technology is accompanied by

The Impella Devices: A Review Figure 1: Impella Position

3.5 cm

5.5 cm

Correct positioning of the Impella CP, Impella 2.5 and Impella 5.0 across the aortic valve and into the left ventricle. The radiopaque marker should be positioned across the aortic valve annulus, allowing an approximate distance of 3.5 cm from the aortic valve annulus to mid-inlet for the Impella CP, 2.5 and 5.0 devices (left). The device extends a further 5.5 cm from mid-inlet to the tip of the pigtail catheter. On transthoracic echocardiography (TTE), two echogenic double lines of the cannula indicate either end of the Impella inlet. Reverberation artefacts on TTE posterior to the cannula may also assist in identification of the inlet. Correct placement of the Impella 5.5 catheter is 5.5 cm from the aortic valve annulus to mid-inlet of the inflow cage. This is deeper due to the lack of pigtail on the Impella 5.5 catheter. Ao = aorta; LV = left ventricule; MV = mitral valve; RV = right ventricle.

the Impella Connect, a cloud-based platform that allows for secure, remote viewing and collaborative patient management. The Impella CP and 5.5 are provided with SmartAssist technology, which enables a realtime display of informative pump metrics and device placement on the AIC (Figure 2). Left-sided Impella devices with SmartAssist technology are equipped with optical sensors that sense the pressure at the outlet of the device (this is the aortic pressure when the devices are in the correct position) and provide the AIC with exact device positioning. In addition, the microaxial motor senses the pressure difference between the inlet and outlet of the Impella device (when placed in the proper position, this reflects the pressure difference between the aorta and left ventricle) to assist in managing and positioning the device. Left-sided SmartAssist technology provides the AIC with data on left ventricular pressure, end-diastolic pressure, continuous cardiac output and cardiac power output (CPO). CPO is a metric that is calculated with the following formula: (cardiac output × mean arterial pressure) / 451.8 These haemodynamic metrics aid device management and weaning. The Impella RP with SmartAssist provides the AIC with data on pulmonary artery pressures, central venous pressure and the pulmonary artery

pulsatility index (PAPi). PAPi is a metric that is calculated with the following formula: (systolic PAP – diastolic PAP) / right atrial pressure.

High-risk PCI Indication

PCI is considered to be high risk, based on a wide range of criteria involving patient characteristics, including age and comorbidities, lesion characteristics and clinical presentation.9 Patients deemed ineligible for surgery – referred to as surgical turndown patients – are at a higher risk of worse clinical outcomes.10,11 Without the option of surgery, these patients are more likely to undergo PCI. A thorough understanding of patient characteristics and clinical presentation must be considered before any intervention. Predictive risk scores, including SYNTAX and STS scores, have emerged as key tools in the stratification of surgical turndown patients to identify those who could benefit from PCI.12 The PROTECT II study was the first randomised controlled trial (RCT) comparing outcomes with different forms of MCS in patients undergoing HRPCI.13 There was no significant difference in the primary endpoint – 30day major adverse event rate – in patients treated with the Impella 2.5 or IABP in the PROTECT II trial, which resulted in early trial termination. However, patients supported with the Impella 2.5 showed better performance on a prespecified analysis of the primary endpoint at

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The Impella Devices: A Review

Table 1: Impella Device Technical Specifications Impella Device

2.5

5.0

5.5

HRPCI and CS

RHF or decompensation

Introducer diameter

13 Fr

14 Fr

23 Fr

Pump motor

12 Fr

14 Fr

21 Fr

19 Fr

22 Fr

Access

Percutaneous femoral or axillary

Femoral cutdown or axillary

Direct insertion into AA

Axillary cutdown or direct insertion into AA

Percutaneous femoral vein (to PA)

Maximum average flow (l/min)

2.5

3.7

5.0

5.3

5.5

4.4

Maximum duration of support

HRPCI: ≤6 hours CS: ≤4 days

14 days

SmartAssist?

Indication

All catheter diameters are 9 Fr, with the exception of the Impella RP (11 Fr). AA = ascending aorta; CS = cardiogenic shock; HRPCI = high-risk percutaneous coronary intervention; PA = pulmonary artery; RHF = right heart failure.

90 days, attaining significance in those treated per the protocol, resulting in Food and Drug Administration (FDA) approval for the Impella 2.5 pump in this setting.13 In addition, patients in the Impella arm received more vigorous atherectomy with more runs and longer durations. A PROTECT II subgroup analysis by Cohen et al. found that patients treated with atherectomy (either trial arm) were older, had significantly higher STS scores and more severe comorbidity burdens, with higher rates of 30-day and 90-day major adverse events, largely driven by higher periprocedural MI rates in patients receiving Impella and undergoing atherectomy.14 Conversely, people receiving an Impella and undergoing atherectomy showed significantly lower rates of repeat revascularisation within 90 days compared to IABP patients. To date, no robust randomised data exist to support the routine use of Impella pumps for HRPCI. However, the randomised PROTECT IV trial (NCT04763200) is enrolling patients and the CHIP-BCIS3 trial (NCT05003817) will soon be enrolling patients. Both trials are being conducted on non-emergent populations, with patients with cardiogenic shock or acute ST-elevation MI (STEMI) excluded. The PROTECT IV trial is enrolling patients with chronic coronary syndrome or non-ST-elevation MI (NSTEMI) with LVEF ≤40% or acute STEMI ≥24 hours with LVEF ≤30%, with complex PCI planned. CHIP-BCIS3 will enrol patients with a British Cardiovascular Intervention Society Jeopardy Score ≥8 and an LVEF ≤35%, with complex PCI planned. Both trials aim to provide a more definitive answer as to the value of prophylactic Impella support in the HRPCI setting. Guidelines by major societies regarding the use of MCS during HRPCI are lacking. There have been many previous attempts to objectively risk stratify patients undergoing HRPCI. The algorithm by Kearney et al. is a comprehensive attempt to objectively evaluate these patients.15

Patients at High Bleeding Risk

The decision to use MCS during PCI in patients at a high risk of bleeding must involve a careful assessment that weighs the overall benefits against the risks of thrombotic or ischaemic events, and the treatment plan must be crafted on an individual patient basis. Benefits include maintaining normal haemodynamics, enabling complete revascularisation, and reducing cardiac mechanical stress. Risks include major bleeding and vascular complications. A comprehensive literature

review evaluating the risk of major bleeding and vascular complications in Impella-supported HRPCI revealed a median rate of major bleeding complications of 5.2% and a median rate of major vascular complications of 2.6%.16 Such complications have been associated with a significant increase in mortality and duration of hospital stay.17

Cardiogenic Shock Indication

Mortality rates for patients with CS have historically ranged from 40% to 60% and have not improved despite advancements in therapies.18 Previous trials comparing Impella and IABP in AMICS patients have demonstrated better haemodynamic parameters including cardiac index, cardiac output and mean arterial pressure in Impella patients; however, acute mortality rates were found to be similar between the two devices.19–21 These trials were small and underpowered, highlighting the difficulty of patient recruitment in this context. In recent years, some institutions have adopted a shock-team approach, in which a designated team follows specific protocols to improve clinical outcomes. A large, quaternary care centre implemented such an approach, utilising early shock team activation, rapid MCS initiation, haemodynamic-guided management and strict protocol adherence.22 Results showed an increase in survival rate from 47% in 2016 to 57.9% in 2017 and 81.3% in 2018. There is no consensus over the optimal timing for initiating MCS support for patients with cardiogenic shock undergoing PCI. Some evidence suggests that Impella implantation prior to PCI results in improved survival secondary to effective LV unloading and increased systemic and coronary perfusion.23 An analysis of 154 consecutive AMICS patients treated at 38 US hospitals participating in the USpella registry found that early initiation of haemodynamic support before PCI was associated with more complete revascularisation and improved survival.24 The National Cardiogenic Shock Initiative (NCSI) reported a survival to discharge rate of 72%, using a shock protocol that emphasises initiation of Impella support prior to PCI and pulmonary artery catheterisation (PAC) for haemodynamic monitoring.25 NCSI findings also identified the predictive utility of lactate and CPO measurements post procedure to guide clinical decision-making.25,26 PAC has also been recommended for use with MCS in cardiogenic shock to help monitor effectiveness, optimise device settings, determine escalation requirements and assist decisionmaking on weaning.27

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The Impella Devices: A Review Figure 2: Automated Impella Controller

Right Ventricular Failure

The Impella RP is indicated for patients with right heart failure, which can arise secondary to acute MI, myocarditis, acute decompensated heart failure, acute pulmonary embolism and pulmonary hypertension, and following cardiotomy, transplantation and LVAD implantation. Although invasive, PAC is essential for continuous haemodynamic monitoring of pulmonary artery pressure and other metrics to ensure that adequate support is being administered to the patient.28 The Impella RP can be used in tandem with a left-sided Impella device. The use of two Impella devices concurrently has demonstrated decreased LV filling pressures and improved cardiac output for cardiogenic shock patients, although reported data on this use is limited and future studies are required.29 Quantifying right ventricular (RV) failure and identifying patients in need of an RV assist device is not always easy. Many noninvasive and invasive parameters have been used. One such invasive haemodynamic parameter is PAPi, which was first used in patients with RV failure after inferior MI, but has since been shown to be helpful in many scenarios including nonischaemic cardiogenic shock.30–32 Various PAPi cut-off values have been used to classify patients in need of RV support; the most commonly used cut-off value of PAPi ≤0.9 has been shown to have 100% sensitivity and 98% specificity for predicting in-hospital mortality and/or requirement for RV support.30

Impella Implantation Technique Femoral Access

The Impella 2.5 and Impella CP are inserted using 13 Fr and 14 Fr sheaths, respectively, via a retrograde femoral arterial approach. The catheter is inserted percutaneously through the femoral artery into the ascending aorta, across the aortic valve and into the left ventricle, guided by fluoroscopic or echocardiographic imaging. The femoral approach is the most common insertion route for Impella 2.5 and CP, but is not indicated for patients with severe peripheral arterial disease (PAD) or for those requiring longer-term support that necessitates lengthy immobilisation.33 The Impella 5.0, which requires a 23 Fr sheath, may be inserted via surgical cutdown of the femoral artery but is more commonly inserted via axillary cutdown.

The Automated Impella Controller (AIC) features a left ventricular (LV) waveform display (red graph) showing diastolic and systolic pressures and a motor current display (green graph), and also provides real-time Impella flow rates as well as other haemodynamic parameters. The top panel illustrates normal flow conditions in a patient implanted with the Impella CP. The middle panel illustrates one diastolic suction alarm scenario. This may be identified in the LV waveform display, which shows normal systolic pressures and negative diastolic pressures that recover by the end of diastole. Sharp negative deflections in the motor current during diastole also indicate a potential suction event. A diastolic suction alarm accompanied by these displays indicates low volume or possible right ventricular dysfunction. The lower panel illustrates a diastolic suction alarm due to incorrect Impella positioning, with the Impella positioned too shallowly at the aortic valve annulus, and not advanced far enough into the left ventricle. This is identified in the LV waveform display by negative diastolic pressures that do not recover by the end of diastole, and lower than expected peak systolic pressure as compared to the aortic placement signal.

Iliofemoral angiographic evaluation is warranted before any consideration of large-bore femoral access. For HRPCI patients, this evaluation should be performed during the index diagnostic coronary angiogram procedure. This allows for a discussion of MCS placement technique as part of the revascularisation strategy. The evaluation could be performed during the staged HRPCI procedure, but it is preferable to perform this before the PCI procedure to avoid surprises and to adequately assess the risks of PCI. In our experience, the best outcomes are achieved with thorough pre-procedure planning.

Axillary Access

When Impella 2.5 or Impella CP femoral access is precluded due to PAD, it may be feasible to use the axillary artery as an alternative access site.34,35 Axillary insertion is not as restrictive to ambulation as femoral artery insertion – an important factor for patients requiring longer-term support who would otherwise be immobilised. Impella 2.5 and CP can be placed by percutaneous peripheral insertion into the axillary artery, while the large sheaths of Impella 5.0 and Impella 5.5 necessitate surgical cutdown of the axillary artery.

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The Impella Devices: A Review Surgical and Transcaval Implantation

Because of the 23 Fr sheath required to insert Impella 5.0, 5.5 and LD, these devices must be placed by a surgical cutdown arteriotomy or via a transcaval approach by highly skilled operators with transcaval access experience. The Impella LD is exclusively surgically inserted into the ascending aorta through a 10 mm vascular graft and advanced across the valve into the left ventricle.33 The Impella 5.0 and 5.5 may be implanted via a transcaval approach for patients with prohibitive iliac artery anatomy or disease, or through axillary cutdown or direct insertion into the ascending aorta through either the supraclavicular fossa or the midclavicular intercostal space.36

Right Heart Access

The Impella RP is a 23 Fr pump on an 11 Fr catheter that is inserted percutaneously through the femoral vein into the pulmonary artery, guided by fluoroscopic imaging. The inflow portion of the catheter is placed in the inferior vena cava, and the nitinol cannula is advanced across the right atrium, tricuspid valve and pulmonary valve to position the outflow portion of the catheter in the main pulmonary artery.37

Left Ventricular Device Repositioning

Correct initial device placement can be confirmed by imaging with fluoroscopy, although bedside echocardiography after the patient has been moved from the cath lab should be mandatory. If repositioning is required, transthoracic echocardiography (TTE) can be used to visualise the device. Repositioning without visualisation, although generally not recommended except in emergencies, can be accomplished by retracting the cannula until the diastolic pressure normalises, or through using SmartAssist technology on the Impella CP or Impella 5.5 devices.38 If the TTE images are difficult to interpret, repositioning based on fluoroscopy or transoesophageal echocardiography may also be considered.

Single Access Technique

Jason Wollmuth first proposed the Single-access for Hi-risk PCI (SHiP) technique, where a PCI catheter up to 7 Fr is inserted through the valve of the 14 Fr Impella CP sheath parallel to the catheter.39 In a case series of 17 patients undergoing SHiP, Wollmuth et al. reported no bleeding events during the procedure or after the removal of the sheath, although in one patient iliac thrombus was noted with Impella catheter removal several days after PCI.39

Device Weaning and Escalation

As there are no universally accepted guidelines for weaning, strategies vary between individual patients and rely on haemodynamic parameters predictive of patient outcomes. The majority of patients receiving Impella support during HRPCI do not require an extended duration of support and undergo device removal at the end of the procedure. CPO has been shown to be the strongest predictor of mortality in patients receiving MCS for cardiogenic shock, and can be used to guide weaning.25 At our facility, the interventional cardiologist supervises the weaning process over the course of a few hours. Box 1 describes our weaning and escalation process for Impella support for cardiogenic shock. It should be noted that prolonged high or low levels of Impella support can be harmful. Low support levels for long periods of time can precipitate thrombosis. Higher levels of support can put the patient at risk of haemolytic events. The true incidence of haemolysis is not well reported and is likely to vary depending on factors such as Impella positioning and patient volume status in addition to the level of support.40

Box 1. Impella Weaning/Escalation Protocol at Ascension St John Hospital and Medical Center 1. Consider weaning from Impella support if cardiac power output >0.6 W and other haemodynamic parameters are adequate without the use of vasopressors and high-dose inotropes. 2. Reduce Impella performance level (P-level) every hour. 3. Measure mixed venous oxygen saturation (SvO2), lactic acid and urine output every hour to ensure that the patient continues to have adequate cardiac output. 4. With every change in P-level, calculate cardiac power output, pulmonary artery pulsatility index (PAPi), and systemic vascular resistance (SVR). 5. Continue weaning if the SvO2 remains >50%, cardiac power output is >0.6 watts, mean arterial pressure is >60 mmHg and lactic acid remains <3 mmol/l. If these values are not achieved, initiate positive inotropic therapies to expedite the weaning of the Impella device. 6. If the patient develops tachycardia, arrhythmia-related decreases in mean arterial pressure, decreased urine output, increasing lactic acidosis or worsening pulmonary artery pressures, consider increasing Impella support as necessary to stabilise the patient before reattempting weaning. 7. If CPO <0.6 W, consider escalation from Impella 2.5 or CP to Impella 5.0 or 5.5 depending on the patient’s characteristics. Support may be continued until native heart recovery or as a bridge to durable therapy, such as a long-term LVAD or transplantation (in the absence of multi-organ failure).

Patients with Impella support devices should be monitored closely for haemolysis. It is routine at our institution to check haemolysis lab findings (i.e. plasma-free haemoglobin, lactate dehydrogenase, haptoglobin and bilirubin) every 6–12 hours, with plasma-free haemoglobin identified as being highly sensitive and specific for haemolysis in patients treated with Impella in line with a recent analysis by Esposito et al.41 The frequency should be adjusted as necessary. Patients with significant haemolysis are at risk of kidney injury so early detection can be organ saving. These patients should be monitored more frequently whereas those without signs of significant haemolysis can have lab tests carried out less often. Haemolysis can be treated with confirmation of correct device positioning, administration of IV fluids and reduction in the level of Impella support; however, in many patients, expedited explantation is necessary. Initiation or titration of inotropes is necessary in many of these patients for successful reduction in support and device removal.42

Closure Strategies

Vascular closure devices (VCDs) have arisen as a potential tool for reducing complications associated with large-bore femoral artery closure, including uncontrolled bleeding, patient immobilisation, increased length of hospital stay and vascular complications. Of note is the MANTA VCD (Teleflex), a collagen-based VCD designed for large-bore femoral access closure, which received FDA approval in 2019. Outcomes with the MANTA and the double-pre-close closure technique were compared in patients undergoing transcatheter aortic valve replacement (TAVR) in the MASH RCT. Similar performance on the primary

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The Impella Devices: A Review endpoint of access-related vascular complications was reported; however, those receiving the MANTA had a significantly shorter time to haemostasis and significantly lower rate of modified VCD failure.43 Many clinicians find it useful to ‘pre-close’ large-bore access sites using two sequentially placed Perclose ProGlide devices (Abbott Vascular Devices) at the 10 o’clock and 2 o’clock positions before placing the Impella sheath. This pre-close technique has been found to be useful in achieving haemostasis in immediate as well as delayed closure cases.44 In patients at a high risk of bleeding, the dry closure technique with balloon tamponade is recommended to prevent excessive bleeding. This method involves the advancement and subsequent inflation of a balloon proximal to the access site, followed by slow balloon deflation until haemostasis is achieved. Perclose sutures are then used to close the access site.45

Anticoagulation Regimens

Systemic anticoagulation is required with Impella use to decrease the risk of thrombus formation along the length of the catheter or on the body of the Impella device. A purge solution containing heparin flows through the Impella catheter in the opposite direction of the patient’s blood to generate a pressure barrier that prevents blood from entering the motor, and to keep purge gap regions clear of debris. Strategies for IV-based anticoagulation must take into account purge flow rates with the Impella, pre-existing coagulopathy and heparin allergies. The viscosity and flow rate of the purge solution is determined by its dextrose concentration. When the concentration of dextrose is low, the purge flow rate will be faster due to the lower viscosity, resulting in greater delivery of heparin to the patient. Higher dextrose concentrations yield greater viscosity and a slower purge flow rate that delivers less heparin to the patient. The current recommendation for the initial purge solution is a heparin concentration of 25 U/ml in 5% dextrose. In some patients, the addition of titratable, supplemental IV heparin is required to provide optimal anticoagulation. In patients with heparin-induced thrombocytopenia, an anticoagulantfree purge solution is recommended with an alternative systemic anticoagulant. In a recent case series at the Cleveland Clinic, nine patients with suspected or proven heparin-induced thrombocytopenia received Impella CP support with low-concentration bivalirudin added to the purge in addition to systemic bivalirudin.46

Complications

Femoral insertion of the Impella 2.5 or Impella CP involves standard catheterisation procedures except for the requirement of a large-bore 13 or 14 Fr sheath, which can result in haematoma formation, uncontrolled bleeding and injury to the vasculature that may necessitate surgery. Haemostatic complications can arise from all forms of MCS because they involve the placement of a foreign object and shear forces on blood flowing through the device. Platelet aggregation, thrombosis, mechanical haemolysis and thrombocytopenia due to heparin use are potential complications that must be managed for each patient. A comprehensive literature review of Impella use during HRPCI demonstrated that, over time, rates of major bleeding complications have

varied considerably, while transfusion rates have decreased and vascular complication rates have remained consistently below 5%.16 Patient selection in view of bleeding risk as well as careful access vessel selection and approach are important to mitigate the risk of accessrelated bleeding and vascular complications. Vascular access techniques that include the use of fluoroscopy, ultrasound, micropuncture, angiography and vascular closure devices help optimise patient outcomes.47 Maintaining femoral skills (as radial access for PCI has come to predominate) is paramount. Novel emerging technologies and techniques such as the MANTA VCD and the single-access technique may have potential utility in alleviating the risks of large bore access. Haemolysis can occur with Impella devices so avoiding suction alarms, daily imaging and maintaining adequate fluid status are imperative to reduce its likelihood. Pulmonary artery diastolic pressures should be maintained between 15 mmHg and 20 mmHg to ensure adequate intravascular volume. Haemolysis is monitored via daily laboratory values including but not limited to LDH, plasma free haemoglobin and haptoglobin. All patients should be fitted with a Foley catheter to monitor urine output as a marker of adequate perfusion as well as haemolysis. It is important to note that daily echocardiograms should be done to ensure appropriate positioning of the Impella device; haemolysis may be an early indicator of poor Impella placement which may lead to decreased cardiac output and poor outcomes.

Future Directions

In December 2020, the FDA granted 510(k) clearance to the Impella XR Sheath, a low-profile sheath made of nitinol braids designed to be inserted at 10 Fr and to expand and recoil for simplified percutaneous insertion with the Impella 2.5.48 The reduction in size is intended to lower the incidence of vascular and bleeding complications related to largebore access. The Impella ECP heart pump, which is inserted and removed through a 9Fr sheath, has completed the first stage of its early feasibility study and was granted breakthrough device designation from the FDA in August 2021. The Impella ECP expands after insertion to provide peak flows greater than 3.5 l/min. For patients in cardiorespiratory failure, the main percutaneous extracorporeal life support system in use is venoarterial ECMO. The ECMO circuit provides temporary MCS along with gas exchange; however, venoarterial-ECMO circuits result in increased afterload, which is not sustainable for patients with LV contractile dysfunction. Abiomed’s Breethe OXY-1 System (an all-in-one cardiopulmonary bypass system that can be used in conjunction with the Impella, and allows patient ambulation) received 510(k) clearance in October 2020.49 The combination of ECMO with Impella, a therapy known as ECpella, provides venting for the left ventricle in order to continue forward flow from the left ventricle.50,51 Further investigation is warranted to elucidate the risk-benefit profile of the ECpella approach.

Upcoming Trials

Upcoming RCTs will provide much-needed evidence assessing outcomes with Impella use in PCI. STEMI DTU is a prospective, multicentre, two-arm trial expected to enrol

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The Impella Devices: A Review 668 patients undergoing treatment for STEMI and not in cardiogenic shock. Patients will be randomised 1:1 to either 30 minutes of unloading with Impella CP prior to reperfusion, or the standard care, which is immediate reperfusion. The pivotal trial follows the DTU STEMI pilot study, which showed no prohibitive safety signals to the unloading-beforereperfusion approach.52 The upcoming PROTECT IV RCT will randomise patients with LVEF ≤40% and chronic coronary syndrome or NSTEMI or LVEF ≤30% and STEMI >24 hours, who were selected for complex PCI after heart team discussion to HRPCI with Impella or standard care. The first patient was enrolled, at our institution, in April 2021. The trial aims to validate the best practices 1.

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Strom J, Zhao Y, Shen C, et al. Hospital variation in the utilization of short-term non-durable mechanical circulatory support in myocardial infarction complicated by cardiogenic shock. Cric Cardiovasc Interv 2019;12:e007270. https://doi. org/10.1161/CIRCINTERVENTIONS.118.007270; PMID: 30608880. Shah M, Patnaik S, Patel B, et al. Trends in mechanical circulatory support use and hospital mortality among patients with acute myocardial infarction and non-infarction related cardiogenic shock in the United States. Clin Res Cardiol 2018;107:287–303. https://doi.org/10.1007/s00392017-1182-2; PMID: 29134345. Dhruva SS, Ross JS, Mortazavi BJ, et al. Use of mechanical circulatory support devices among patients with acute myocardial infarction complicated by cardiogenic shock. JAMA Netw Open 2021;4:e2037748.https://doi.org/10.1001/ jamanetworkopen.2020.37748; PMID: 33616664. Amin AP, Spertus JA, Curtis JP, et al. The evolving landscape of Impella use in the United States among patients undergoing percutaneous coronary intervention with mechanical circulatory support. Circulation 2020;141:273–84. https://doi.org/10.1161/CIRCULATIONAHA.119.044007; PMID: 31735078. Thiele H, Zeymer U, Thelemann N, et al. Intraaortic balloon pump in cardiogenic shock complicating acute myocardial infarction: long-term 6-year outcome of the randomized IABP-SHOCK II trial. Circulation 2019;139:395–403. https:// doi.org/10.1161/CIRCULATIONAHA.118.038201; PMID: 30586721. Henriques JP, Remmelink M, Baan J Jr, et al. Safety and feasibility of elective high-risk percutaneous coronary intervention procedures with left ventricular support of the Impella Recover LP 2.5. Am J Cardiol 2006;97:990–2. https://doi.org/10.1016/j.amjcard.2005.10.037; PMID: 16563902. Burzotta F, Russo G, Previ L, et al. Impella: pumps overview and access site management. Minerva Cardioangiol 2018;66(5):606–11. https://doi.org/10.23736/S00264725.18.04703-5; PMID: 29687700. Fincke R, Hochman JS, Lowe AM, et al. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 2004;44:340–8.https://doi.org/10.1016/j. jacc.2004.03.060; PMID: 15261929. Myat A, Patel N, Tehrani S, et al. Percutaneous circulatory assist devices for high-risk coronary intervention. JACC Cardiovasc Interv 2015;8:229–44. https://doi.org/10.1016/j. jcin.2014.07.030; PMID: 25700745. Head SJ, Holmes DR Jr, Mack MJ, et al. Risk profile and 3-year outcomes from the SYNTAX percutaneous coronary intervention and coronary artery bypass grafting nested registries. JACC Cardiovasc Interv 2012;5:618–25. https://doi. org/10.1016/j.jcin.2012.02.013; PMID: 22721656. Sukul D, Seth M, Dixon SR, et al. Clinical outcomes of percutaneous coronary intervention in patients turned down for surgical revascularization. Catheter Cardiovasc Interv 2017;90:94–101. https://doi.org/10.1002/ccd.26781; PMID: 27651035. Serruys PW, Farooq V, Vranckx P, et al. A global risk approach to identify patients with left main or 3-vessel disease who could safely and efficaciously be treated with percutaneous coronary intervention: the SYNTAX trial at 3 years. JACC Cardiovasc Interv 2012;5:606–17. https://doi. org/10.1016/j.jcin.2012.03.016; PMID: 22721655 O’Neill WW, Kleiman NS, Moses J, et al. A prospective, randomized clinical trial of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary intervention: the PROTECT II study. Circulation 2012;126:1717–27. https://

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learned for Impella-supported HRPCI since the completion of the PROTECT II trial more than a decade ago.

Conclusion

The use of the Impella devices for cardiogenic shock and HRPCI has increased since their inception. The ideal access site, including implantation and closure techniques, requires endovascular expertise and nursing experience is needed to ensure successful patient outcomes. Patients on pump require constant haemodynamic and haematological monitoring to ensure adequate response to therapy and early detection in bleeding complications. Furthermore, new research is on the horizon to help us better understand how these devices can advance patient care.

doi.org/10.1161/CIRCULATIONAHA.112.098194; PMID: 22935569. Cohen MG, Ghatak A, Kleiman NS, et al. Optimizing rotational atherectomy in high-risk percutaneous coronary interventions: insights from the PROTECT II study. Catheter Cardiovasc Interv 2014;83:1057–64. https://doi.org/10.1002/ ccd.25277; PMID: 24174321. Kearney KE, McCabe JM, Riley RF. Hemodynamic support for high-risk PCI. Cardiac Interventions Today 2019;13:44–8. https://citoday.com/articles/2019-jan-feb/hemodynamicsupport-for-high-risk-pci (accessed 11 January 2021) Vetrovec G, Kaki A, Dahle T. A review of bleeding risk with impella-supported high-risk percutaneous coronary intervention. Heart Int 2020;14:92–9. https://doi.org/10.17925/ HI.2020.14.2.92. Redfors B, Watson B, McAndrew T, et al. Mortality, length of stay, and cost implicationsof procedural bleeding after percutaneous interventions using large-bore catheters. JAMA Cardiol 2017;2:798–802. https://doi.org/10.1001/ jamacardio.2017.0265; PMID: 28315573. Shaefi S, O’Gara B, Kociol RD, et al. Effect of cardiogenic shock hospital volume on mortality in patients with cardiogenic shock. J Am Heart Assoc 2015;4:e001462. https:// doi.org/10.1161/JAHA.114.001462; PMID: 25559014. Mebazaa A, Combes A, van Diepen S, et al. Management of cardiogenic shock complicating myocardial infarction. Intensive Care Med 2018;44:760–73. https://doi.org/10.1007/ s00134-018-5214-9; PMID: 29767322. Ouweneel DM, Engstrom AE, Sjauw KD, et al. Experience from a randomized controlled trial with Impella 2.5 versus IABP in STEMI patients with cardiogenic pre-shock. Lessons learned from the IMPRESS in STEMI trial. Int J Cardiol 2016;202:894–6. https://doi.org/10.1016/j.ijcard.2015.10.063; PMID: 26476989. Seyfarth M, Sibbing D, Bauer I, et al. A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction. J Am Coll Cardiol 2008;52:1584–8. https://doi.org/10.1016/j.jacc.2008.05.065; PMID: 19007597. Tehrani B, Truesdell A, Singh R, et al. Implementation of a cardiogenic shock team and clinical outcomes (INOVASHOCK Registry): observational and retrospective study. JMIR Res Protoc 2018;7:e160. https://doi.org/10.2196/ resprot.9761; PMID: 29954728. Flaherty MP, Khan AR, O’Neill WW. Early initiation of Impella in acute myocardial infarction complicated by cardiogenic shock improves survival: a meta-analysis. JACC Cardiovasc Interv 2017;10:1805–6. https://doi.org/10.1016/j. jcin.2017.06.027; PMID: 28882288. O’Neill WW, Schreiber T, Wohns DH, et al. The current use of Impella 2.5 in acute myocardial infarction complicated by cardiogenic shock: results from the USpella registry. J Interv Cardiol 2014;27:1–11. https://doi.org/10.1111/joic.12080; PMID: 24329756. Basir MB, Kapur NK, Patel K, et al. Improved outcomes associated with the use of shock protocols: updates from the National Cardiogenic Shock Initiative. Catheter Cardiovasc Interv 2019;93:1173–83. https://doi.org/10.1002/ccd.28307; PMID: 31025538. O’Neill WW, Grines C, Schreiber T, et al. Analysis of outcomes for 15,259 US patients with acute myocardial infarction cardiogenic shock (AMICS) supported with the Impella device. Am Heart J 2018;202:33–8. https://doi. org/10.1016/j.ahj.2018.03.024; PMID: 29803984. Saxena A, Garan AR, Kapur NK, et al. Value of hemodynamic monitoring in patients with cardiogenic shock undergoing mechanical circulatory support. Circulation 2020;141:1184–97. https://doi.org/10.1161/CIRCULATIONAHA.119.043080;

PMID: 32250695. 28. Jozwiak M, Monnet X, Teboul JL. Less or more hemodynamic monitoring in critically ill patients. Curr Opin Crit Care 2018;24:309–15. https://doi.org/10.1097/ MCC.0000000000000516; PMID: 29889132. 29. Kuchibhotla S, Esposito ML, Breton C, et al. Acute biventricular mechanical circulatory support for cardiogenic shock. J Am Heart Assoc 2017;6:e006670. https://doi. org/10.1161/JAHA.117.006670; PMID: 29054842. 30. Lim HS, Gustafsson F. Pulmonary artery pulsatility index: physiological basis and clinical application. Eur J Heart Fail 2020;22:32–8. https://doi.org/10.1002/ejhf.1679; PMID: 31782244. 31. Kang G, Ha R, Banerjee D. Pulmonary artery pulsatility index predicts right ventricular failure after left ventricular assist device implantation. J Heart Lung Transplant 2016;35:67–73. https://doi.org/10.1016/j.healun.2015.06.009; PMID: 26212656. 32. Morine KJ, Kiernan MS, Pham DT, et al. Pulmonary artery pulsatility index is associated with right ventricular failure after left ventricular assist device surgery. J Card Fail 2016;22:110–6. https://doi.org/10.1016/j.cardfail.2015.10.019; PMID: 26564619. 33. Ziemba EA, John R. Mechanical circulatory support for bridge to decision: which device and when to decide. J Card Surg 2010;25:425–33. https://doi.org/10.1111/j.1540-8191. 2010.01038.x; PMID: 20412350. 34. Mathur M, Hira RS, Smith BM, et al. Fully percutaneous technique for transaxillary implantation of the Impella CP. JACC Cardiovasc Interv 2016;9:1196–8. https://doi.org/10.1016/j. jcin.2016.03.028; PMID: 27282605. 35. Tayal R, Barvalia M, Reana Z, et al. Totally percutaneous insertion and removal of impella device using axillary artery in the setting of advanced peripheral artery disease. J Invasive Cardiol 2016;28:374–80. PMID: 27430667. 36. Anderson M, Smith D, Kane P, et al. Impella 5.5 direct aortic implant and explant techniques. Ann Thorac Surg 2021;111: e373–5. https://doi.org/10.1016/j.athoracsur.2020.09.069; PMID: 33345787. 37. Cheung AW, White CW, Davis MK, Freed DH. Short-term mechanical circulatory support for recovery from acute right ventricular failure: clinical outcomes. J Heart Lung Transplant 2014;33:794–9. https://doi.org/10.1016/j.healun.2014.02.028; PMID: 24726682. 38. Myers TJ. Temporary ventricular assist devices in the intensive care unit as a bridge to decision. AACN Adv Crit Care 2012;23:55–68. https://doi.org/10.4037/ NCI.0b013e318240e369; PMID: 22290091. 39. Wollmuth J, Korngold E, Croce K, Pinto DS. The Singleaccess for Hi-risk PCI (SHiP) technique. Catheter Cardiovasc Interv 2020;96:114–6. https://doi.org/10.1002/ccd.28556; PMID: 31654483. 40. Roberts N, Chandrasekaran U, Das S, et al. Hemolysis associated with Impella heart pump positioning: in vitro hemolysis testing and computational fluid dynamics modeling. Int J Artif Organs 2020:391398820909843. https:// doi.org/10.1177/0391398820909843; PMID: 32126866. 41. Esposito ML, Morine KJ, Annamalai SK, et al. Increased plasma-free hemoglobin levels identify hemolysis in patients with cardiogenic shock and a trans valvular micro-axial flow pump. Artif Organs 2019;43:125–31. https://doi.org/10.1111/ aor.13319; PMID: 30216467. 42. Badiye AP, Hernandez GA, Novoa I, Chaparro SV. Incidence of hemolysis in patients with cardiogenic shock treated with impella percutaneous left ventricular assist device. ASAIO J 2016;62:11–4. https://doi.org/10.1097/ MAT.0000000000000290; PMID: 26418208. 43. van Wiechen MP, Tchetche D, Ooms JF, et al. Suture- or plug-based large-bore arteriotomy closure: a pilot

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The Impella Devices: A Review randomized controlled trial. JACC Cardiovasc Interv 2021;14:149–57. https://doi.org/10.1016/j.jcin.2020.09.052; PMID: 33358648. 44. Lata K, Kaki A, Grines C, et al. Pre-close technique of percutaneous closure for delayed hemostasis of large-bore femoral sheaths. J Interv Cardiol 2018;31:504–10. https://doi. org/10.1111/joic.12490; PMID: 29405431. 45. Kaki A, Blank N, Alraies MC, et al. Access and closure management of large bore femoral arterial access. J Interv Cardiol 2018;31:969–77. https://doi.org/10.1111/joic.12571; PMID: 30456854. 46. Hohlfelder B, Militello MA, Tong MZ, et al. Anticoagulation with temporary Impella device in patients with heparininduced thrombocytopenia: a case series. Int J Artif Organs 2021;44:367–70. https://doi.org/10.1177/0391398820964810;

PMID: 33050762. 47. Sandoval Y, Burke MN, Lobo AS, et al. Contemporary arterial access in the cardiac catheterization laboratory. JACC Cardiovasc Interv 2017;10:2233–41. https://doi.org/10.1016/j. jcin.2017.08.058; PMID: 29169493. 48. US Food and Drug Administration. Impella XR sheath set. 510(k) premarket notification. 12 December 2020. https:// www.accessdata.fda.gov/cdrh_docs/pdf20/K202330.pdf (accessed 11 January 2022) 49. BREETHE OXY-1 System. 2020. https://www.abiomed.com/ products-and-services/abiomed-breethe-oxy-1-system (accessed 11 January 2022). 50. Patel SM, Lipinski J, Al-Kindi SG, et al. Simultaneous venoarterial extracorporeal membrane oxygenation and percutaneous left ventricular decompression therapy with

impella is associated with improved outcomes in refractory cardiogenic shock. ASAIO J 2019;65:21–8. https://doi. org/10.1097/MAT.0000000000000767; PMID: 29489461. 51. Vallabhajosyula S, O’Horo J, Antharam P, et al. Venoarterial extracorporeal membrane oxygenation with concomitant impella versus venoarterial extracorporeal membrane oxygenation for cardiogenic shock. ASAIO J 2020;66:497– 503. https://doi.org/10.1097/MAT.0000000000001039; PMID: 31335363. 52. Kapur NK, Alkhouli MA, DeMartini TJ, et al. Unloading the left ventricle before reperfusion in patients with anterior ST-segment-elevation myocardial infarction. Circulation 2019;139:337–46. https://doi.org/10.1161/ CIRCULATIONAHA.118.038269; PMID: 30586728.

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REVIEW

Coronary

Use of Optical Coherence Tomography in MI with Non-obstructive Coronary Arteries Grigoris Karamasis , Iosif Xenogiannis , Charalampos Varlamos , Spyridon Deftereos and Dimitrios Alexopoulos Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

Abstract

MI with non-obstructive coronary arteries (MINOCA) comprises an important minority of cases of acute MI. Many different causes have been implicated in the pathogenetic mechanism of MINOCA. Optical coherence tomography (OCT) is an indispensable tool for recognising the underlying pathogenetic mechanism when epicardial pathology is suspected. OCT can reliably identify coronary lesions not apparent on conventional coronary angiography and discriminate the various phenotypes. Plaque rupture and plaque erosion are the most frequently found atherosclerotic causes of MINOCA. Furthermore, OCT can contribute to the identification of ischaemic non-atherosclerotic causes of MINOCA, such as spontaneous coronary artery dissection, coronary spasm and lone thrombus. Recognition of the exact cause will enable therapeutic management to be tailored accordingly. The combination of OCT with cardiac magnetic resonance can set a definite diagnosis in the vast majority of MINOCA patients.

Keywords

MI with non-obstructive coronary arteries, optical coherence tomography, plaque rupture, plaque erosion, calcified nodule, coronary spasm, spontaneous coronary artery dissection Disclosure: GK has received honoraria from Abbott Vascular. DA has received lecturing honoraria/advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Medtronic, Biotronik and Chiesi Hellas. All other authors have no conflicts of interest to declare. Received: 11 October 2021 Accepted: 20 January 2022 Citation: Interventional Cardiology 2022;17:e06. DOI: https://doi.org/10.15420/icr.2021.31 Correspondence: Grigoris Karamasis, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Rimini 1, Chaidari 124 62, Athens, Greece. E: grigoris.karamasis@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

MI with non-obstructive coronary arteries (MINOCA) is a common clinical entity, with a prevalence estimated at between 5% and 7% of MI cases, although it has been reported to be as high as 15%.1,2 Compared with patients who have MI with obstructive coronary artery disease (CAD), patients with MINOCA are more likely to be younger, female and nondiabetic, to have lower admission and peak troponin concentrations and to present with non-ST segment elevation MI (NSTEMI).1,3

important tool for the detection of culprit lesions and the assessment of ambiguous or inconclusive angiographic lesions.9

Patients with MINOCA have a better prognosis than patients with MI and obstructive CAD. However, MINOCA is not a benign condition and MINOCA patients have worse clinical outcomes than matched patients without CAD.1,3,4 Thus, current guidelines recommend that the treating physician should follow a diagnostic work-up seeking the underlying cause of MINOCA.5 Identification of the responsible pathophysiological mechanism is imperative because the various clinical disorders that are potentially the cause of MINOCA have different prognoses and therapies.

In the past, the term ‘MINOCA’ has been broadly used, occasionally leading to the misclassification of cases; however, recent European and American scientific documents provide a formal and updated definition of MINOCA.5,10 Accordingly, MINOCA is defined as the fulfilment of the following criteria: acute MI (AMI) as defined by the Fourth Universal Definition of Myocardial Infarction; non-obstructive coronary arteries on coronary angiography, defined as no lesions ≥50% in a major epicardial vessel; and no specific alternative diagnosis for the clinical presentation, such as non-cardiac conditions (i.e. sepsis, pulmonary embolism) or nonischaemic causes (i.e. myocarditis, takotsubo syndrome and other cardiomyopathies).5,10,11

Optical coherence tomography (OCT) is an intravascular imaging modality that, because of its high spatial resolution (10–20 μm), can visualise intraluminal and coronary vessel wall microstructures in detail.6 OCT has been shown to be superior to other imaging modalities in identifying, at a coronary level, MI pathologies such as plaque rupture, erosion and intracoronary thrombus.7,8 Therefore, OCT has been proposed as an

In this review, we describe the use of OCT in delineating causes of MINOCA, review the relevant literature and discuss the therapeutic implications of OCT.

Contemporary Definition and Causes of MINOCA

The above definition is clinically relevant because it differentiates true MINOCA from numerous conditions where a coronary angiogram was performed showing non-obstructive disease. However, MINOCA is still an

OCT in MINOCA Figure 1: Examples of MINOCA Caused by Plaque Rupture

A: A 58-year-old man with arterial hypertension and dyslipidaemia presented with acute onset chest pain. Initial ECG showed ST-segment elevation in leads II, III and aVF. Echocardiography showed inferior left ventricle wall hypokinesia. On arrival in the catheterisation laboratory, ST-segment elevation had been resolved. Coronary angiography revealed multiple <50% stenoses in the right coronary artery (RCA). Optical coherence tomography (OCT) was performed, illustrating a ruptured plaque. B: A 66-year-old man with dyslipidaemia and diabetes presented with chest pain lasting for 1 h. ECG showed transient ST-segment elevation in leads II, III and aVF. Emergency coronary angiography showed unobstructed coronaries. OCT revealed a ruptured plaque in the distal RCA.

umbrella term, rather than a definite diagnosis, under which multiple clinical disorders with diverse pathophysiological mechanisms fall. The most recent scientific statement by the American Heart Association discriminates specific aetiologies of MINOCA into ‘atherosclerotic’ and ‘non-atherosclerotic’ causes of myocardial necrosis.10 Plaque disruption is the ‘atherosclerotic’ cause, encompassing its pathoanatomical substrates of plaque rupture, plaque erosion and calcific nodule.12 Non-atherosclerotic causes include epicardial coronary vasospasm, spontaneous coronary artery dissection (SCAD), coronary embolism/thrombosis, microvascular dysfunction and supply–demand mismatch (type 2 MI).10

OCT Delineation of Specific Causes of MINOCA Atherosclerotic Causes

Plaque rupture is defined as a discontinuity of the fibrous cap of thin cap fibroatheroma with underlying lipid and a necrotic core, with or without core ‘washout’ or associated thrombus.6 Examples of plaque rupture in patients with MINOCA are shown in Figure 1. Plaque erosion is characterised by the presence of thrombi and an irregular luminal surface with no evidence of plaque rupture.6 Examples of plaque erosion in patients with MINOCA are shown in Figure 2. Calcified nodule is defined as one or more protruding, signal-poor and well-delineated regions (characteristics that imply the presence of calcium) frequently forming sharp, jutting angles.6 In contrast to plaque erosion, which is more prevalent in young, premenopausal women, calcified nodules are found in older, diabetic patients.10

Non-atherosclerotic Causes of MINOCA

Coronary artery spasm is a recognised cause of MINOCA.10 Angiographic resolution of coronary spasm by nitrates could provide the diagnosis, but often MINOCA patients undergo angiography remote from the acute phase. Provocative testing for coronary artery spasm is the test of choice

when vasomotor abnormalities are suspected.13 OCT can identify areas of intimal bumping (intimal projections into the lumen with thickening of the media), which have been found to correspond to areas of spasm.14 An example of a coronary spasm as a cause of MINOCA is shown in Figure 3. SCAD is a spontaneous separation of the coronary artery wall that is not iatrogenic, and not related to trauma or atherosclerosis.15 SCAD angiographic characteristics vary, and a standardised classification has been proposed.9 Type 1 SCAD represents the classical linear coronary defect with potential arterial wall stain. Type 2 SCAD is characterised by an abrupt reduction in vessel size and subsequent normalisation or with persistent size reduction to the distal vessel and is the most observed type. SCAD can also mimic atherosclerosis (Type 3) or simply present with abrupt vessel closure (Type 4). OCT can delineate the diagnosis when there is angiographic uncertainty (typically Types 3 and 4) because it produces characteristic images of SCAD.9 Nevertheless, it should only be used when deemed safe and necessary for diagnostic purposes because vessel manipulation and contrast injection could propagate the dissection plane.16 An example of SCAD as a cause of MINOCA is shown in Figure 4.

Existing Evidence of OCT Use in MINOCA

A small number of studies examined the usefulness of OCT in MINOCA patients (Table 1). The design of these studies varied widely with regard to the studied population, the description and classification of OCT findings and the diagnostic work-up followed. For example, the provocation test was used to exclude epicardial spasm as the cause of MINOCA before performing OCT in one study.17 In another study, OCT was encouraged in all three vessels regardless of the ECG, echocardiography and coronary angiography findings.18 Some studies used OCT with cardiac magnetic resonance (CMR) to evaluate the diagnostic yield of this combination, as well as the agreement of these two imaging modalities regarding the final diagnosis.17–19 Some of these studies are heavily limited by the small number of patients and their single-centre design.

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OCT in MINOCA Figure 2: Examples of MINOCA Caused by Plaque Erosion

A: 71-year-old woman presented with non-ST segment elevation myocardial infarction (biphasic T-wave inversion in anterior leads). An echocardiogram showed anterior hypokinesia. Coronary angiography showed <50% stenosis at the left anterior descending artery, but optical coherence tomography (OCT) revealed a mid-vessel plaque erosion (intimal irregularities with superimposed white thrombus). B: A 50-year-old man presented with chest pain and transient ST-segment elevation in inferior leads. Coronary angiography showed an atheromatic right coronary artery with no significant stenosis and an area of haziness in the proximal segment. OCT revealed plaque erosion: a red thrombus (a high-backscattering mass protruding into the artery lumen, with signal-free shadowing) and no evidence of fibrous cap rupture at the underlying atheromatic plaque.

Figure 3: Examples of MINOCA Caused by Coronary Spasm and Spontaneous Coronary Artery Dissection

A: A 48-year-old man presented with chest pain and transient ST-segment elevation in the inferior leads. The patient had a similar presentation a few years ago, when a coronary angiogram showed unobstructed coronaries and subsequent cardiac magnetic resonance showed late gadolinium enhancement in an area of the inferior wall. At that time, the patient was discharged with a diagnosis of MINOCA without further specification of the underlying cause. This time the patient developed chest pain and ST changes while on the catheterisation laboratory table. Coronary angiography showed a severe proximal right coronary artery lesion that was resolved with the administration of IC nitrates. A subsequent optical coherence tomography (OCT) image in the corresponding area is shown. Although, there is pathological intimal thickening, the image is not a typical example of OCT findings in coronary spasm because there is no obvious corresponding medial thickening. B: A 78-year-old hypertensive woman presented with recurrent episodes of chest pain at rest. ECG showed anterior T wave inversion, high-sensitivity troponin was increased and echocardiography showed anterior wall hypokinesis. Coronary angiography showed an unobstructed left anterior descending artery, but OCT revealed a SCAD with false lumen and intramural haematoma extending from the mid to proximal vessel.

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OCT in MINOCA Figure 4: Clinical Algorithm for the Use of Optical Coherence Tomography in MINOCA Coronary angiography for NSTEMI/STEMI

Unobstructed coronaries → MINOCA working diagnosis

Exclude alternative diagnosis (i.e. pulmonary embolism, takotsubo, myocarditis, cardiomyopathies, sepsis)

ECG changes +/– Regional WMA (echocardiography or left ventricle angiogram) +/– Angiography ambiguity

Yes

OCT to the corresponding coronary artery

Identification of epicardial pathology

No*

Perform CMR

Ischaemic (i.e. LGE)† versus nonischaemic (i.e. cardiomyopathies etc.)

Yes Treat accordingly

Treat accordingly

*Consider ACh provocation test if available. †In cases of regional ischaemic pattern detection, repeated invasive assessment with OCT of the ‘suspected’ culprit vessel could be considered. CMR = cardiac magnetic resonance; LAD = left anterior descending artery; LGE = late gadolinium enhancement; LV = left ventricle; NSTEMI = non-ST-segment elevation MI; RCA = right coronary artery; SCAD = spontaneous coronary artery dissection; STEMI = ST-segment elevation myocardial infraction; WMA = wall motion abnormalities.

In a retrospective single-centre study, Yamamoto et al. sought to evaluate the morphological characteristics of non-obstructive coronary lesions as assessed by OCT in a mixed population of acute coronary syndrome (ACS) and stable CAD patients.20 In this small ACS cohort (n=31), the incidence of any ‘high-risk OCT finding’ (i.e. plaque rupture, calcified nodule, intimal laceration or thrombus) was 25.8%, with thrombus being recognised in 12.9% of cases.20 Interestingly, the rate of ‘high-risk findings’ was similar in the stable CAD group (22.5%; p=0.70).20 Another small, single-centre study reported OCT findings in patients with ACS and non-significant coronary lesions on coronary angiography.21 In that study, an ‘unstable plaque’ was found in 78% of patients. Specifically, plaque erosion (41%) was the most common finding, followed by plaque rupture (30%) and calcified nodule with thrombus/plaque disruption (7%).21 Although all patients had angiographic coronary stenoses of <50%, percutaneous coronary intervention (PCI) was performed in 95% of those with an unstable plaque identified by OCT.21 The value of that study is questionable due to the very high rate of revascularisation in lesions causing mild stenosis, a practice that, as discussed below in the Therapeutic Implications section, is not generally recommended.9,10 Opolski et al. were the first investigators to follow a robust prospective methodology including the combination of OCT with CMR in the work-up of MINOCA patients. In their study, they included 38 patients with MI and coronary stenosis of ≤50%.19 Plaque rupture, plaque erosion and calcified

nodule were identified in 8 (21%), 4 (11%) and 2 (5%) patients respectively, with the total percentage of patients with an underlying atherosclerotic mechanism of MINOCA being 36% (one patient had both plaque rupture and calcified nodule).19 Interestingly, immediate interpretation of OCT led to a change in therapeutic plan in 16% of cases, including referral for PCI in five patients and/or modification of antithrombotic therapy for two patients.19 In a subgroup of 31 patients who underwent CMR, ischaemictype late gadolinium enhancement (LGE) was present in 7 (23%) and was more common in patients with than without plaque disruption (50% versus 13%, respectively; p=0.053) and coronary thrombus (67% versus 12%, respectively; p=0.014).19 In their study, Taruya et al. included 82 consecutive patients with ACS and non-obstructive CAD who underwent OCT and had clinical follow up for up to 2 years.22 High-risk lesions in the culprit artery were identified in approximately half the patients (51.2%), including ruptured plaque (15.9%), calcified nodule (11.0%), SCAD (8.5%), lone thrombus (8.5%) and plaque erosion (1.2%).22 Although none of the patients without high-risk lesions experienced major adverse cardiovascular events (MACE), four (10%) of the patients in the high-risk-lesion group had a recurrent ACS event with obstructive coronary artery stenosis. All the recurrent ACS events occurred at the segment where the high-risk lesion had been originally identified.22 Gerbaud et al. evaluated the diagnostic yield of OCT accompanied by CMR in a highly selected group of 40 MINOCA patients.17 The authors followed the contemporary MINOCA definition, and their cohort was carefully selected because they only included patients with a suspected diagnosis of epicardial cause based on the correlation between ECG changes and regional wall motion abnormalities (WMA) observed either on admission echocardiography or left ventricle angiogram. Furthermore, before final inclusion, the authors used provocation testing for coronary artery spasm in patients presenting with suspected vasospastic angina according to COVADIS (Coronary Vasomotion Disorders International Study) group recommendations.23 In the final study cohort, OCT identified a pathological substrate in 80% of cases.17 Plaque rupture (35%) and plaque erosion (30%) were the most commonly recognised potential MINOCA mechanisms, followed by lone thrombus (7.5%), SCAD (5%) and eruptive calcific nodule (2.5%). OCT findings changed medical management in 11 patients (27.5%). AMI was evident at CMR in 31 of 40 patients (77.5%). Twenty-three patients (57.5%) had a substrate and/or diagnosis supported by both techniques, with an evident relationship between the findings obtained by the two techniques. By coupling OCT with CMR, a substrate and/or diagnosis was found in 100% of cases.17 Reynolds et al. conducted the largest study to date in the field, including 145 women with MINOCA who per protocol would undergo multivessel (ideally three-vessel) OCT followed by CMR within 1 week.18 Eventually, OCT in all three major coronary arteries was performed in 59.3% of cases. A definite or possible culprit lesion was identified on OCT in 67 (46.2%) of patients, with the most common culprit lesions being intraplaque cavity (21.4%), layered plaque (13.1%), plaque rupture (5.5%) and thrombus without plaque rupture (3.1%; i.e. thrombus overlying an intact fibrous cap, or lone thrombus). Furthermore, three patients (2.1%) had intimal bumping suggesting coronary artery spasm and one (0.7%) had SCAD.18 Not surprisingly, there was no calcified nodule identified, a phenotype that is more common among older, male, diabetic patients. CMR, which was available in 116 of the 145 participants, was abnormal in 74.1% of cases with an ischaemic pattern of LGE, regional injury or non-ischaemic findings (i.e. myocarditis, takotsubo and other cardiomyopathies) in 32.8%, 20.7% and 20.7% of cases, respectively.18 After the combination of OCT and CMR,

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OCT in MINOCA Table 1: Studies Evaluating the Findings of Optical Coherence Tomography in MI with Non-obstructive Coronary Arteries Author

No. Study Patients Population

Recognition Plaque Plaque Calcified Lone Spasm SCAD Ischaemia/ Non-ischaemic of Unstable Rupture Erosion Nodule Thrombus MI in CMR Pathological Coronary Pattern Lesions

Yamamoto et al.20 31 patients ACS and stable 8 (25.8) with ACS* CAD with stenosis <50%

2 (6.5)

4 (12.9)

Mas-Lladó et al.21 27

MINOCA

21 (78)

8 (30)

11 (41)

2 (7)

Opolski et al.

MINOCA

15 (39)

8 (21)

4 (11)

2 (5)

7 (23)

8 (26)†

Taruya et al.

ACS patients with stenosis <50%

42 (51.2)

13 (15.9)

1 (1.2)

9 (11)

7 (8.5)

Gerbaud et al.17

MINOCA

32 (80)

14 (35)

12 (30)

1 (2.5)

3 (7.5)

NA‡

2 (5)

31 (77.5)

NA||

Reynolds et al.18

145

MINOCA

67 (46.2)

8 (6)

0 (0)

5 (4)

3 (2.1)

1 (0.7)

62 (53.5)

24 (20.7)

Unless indicated otherwise, data are presented as n (%). *Only findings for the 31 patients with ACS are described in the table. †One patient (3%) had both transmural and mid-wall late gadolinium enhancement (mixed pattern). ‡Provocation testing with methylergonovine (0.4 mg) was performed in patients with suspected coronary spasm before study enrolment. Epicardial coronary artery spasm with provocation testing was confirmed in 35 of 114 patients (31%). ||CMR was used for the diagnosis of non-ischaemic causes, such as myocarditis, before patient enrolment in the study. ACS = acute coronary syndrome; CAD = coronary artery disease; CMR = cardiac magnetic resonance; MINOCA = MI with non-obstructive coronary artery disease; NA = not applicable; SCAD = spontaneous coronary artery dissection.

a cause was identified in 84.5% of women, with an ischaemic cause/MI being confirmed in 63.8% of cases.18 Although Gerbaud et al. identified abnormal findings on OCT in 80% of patients, Reynolds et al. identified a culprit lesion by OCT in less than half of the patients (46%).17,18 This discrepancy is not surprising if the screening/ recruiting process of the two studies is considered. Gerbaud et al. followed the contemporary MINOCA definition and mandated ECG changes and correlated WMA for all included cases.10,17 In contrast, in the study of Reynolds et al., 35% of patients had a normal ECG and only 44.1% had WMA on echocardiography.18 The latter study was conducted exclusively in women; hence, the results cannot be extrapolated to men. In addition, the study was criticised because it included layered plaque among the unstable plaque phenotypes. The formation of such a plaque may take weeks to months and likely represents a sequela rather than a pathophysiological mechanism of ACS.24

Therapeutic Implications

Robust scientific data with respect to MINOCA therapeutic strategies are missing. In any case, the diverse population with multiple discrete underlying pathologies that is described under the umbrella term of MINOCA would make a one-size-fits-all strategy faulty and meaningless. This is probably the disadvantage of a large observational study derived by the SWEDEHART registry, which reported that dual antiplatelet therapy (DAPT) showed no benefit.25 Because multiple distinct pathologies could be involved in the clinical presentation of MINOCA, it seems intuitive that subsequent management should be based on the final established underlying cause. This is supported by the current European guidelines, which recommend the management of patients with an initial diagnosis of MINOCA and a final established underlying cause according to diseasespecific guidelines.5 In cases in which a final diagnosis is not reached, the guidelines state that secondary prevention for atherosclerotic disease may be applied.5 When OCT has demonstrated plaque disruption (rupture, erosion or calcific nodule) as the underlying cause, the administration of a P2Y12 receptor inhibitor in addition to aspirin seems logical based on studies of patients with MI that did not discriminate between obstructive and non-

obstructive CAD.26 The duration of DAPT should be individualised after taking into consideration the bleeding risk as well as the therapeutic management (medical versus invasive) of the patient with the by-default strategy being DAPT administration for 12 months followed by lifetime single antiplatelet therapy.27 Regarding the need for routine stent implantation, more research is needed because currently there is no consensus and management remains controversial. An expert consensus document of the European Association of Percutaneous Cardiovascular Interventions is in favour of PCI when intravascular imaging identifies a ruptured plaque in MINOCA patients.9 According to the same statement, stenting can be deferred in cases of plaque erosion when the lesion is non-obstructive and flow has been restored.9 In contrast, a scientific statement from the American Heart Association recommends against routine stenting in cases of plaque rupture and erosion with no residual significant stenosis without discriminating between the two mechanisms.10 A small randomised trial (EROSION study) on patients with ACS caused by plaque erosion that leads to ≤70% stenosis demonstrated that DAPT with aspirin and ticagrelor without stenting was associated with favourable outcomes at 1 year, with approximately 93% of patients remaining without MACE, supporting the concept of medical-only management in this group of patients.28 There are no studies or expert recommendations when the underlying lesion is an eruptive calcific nodule. What should be considered though is the fact that calcified nodules are related to stent underexpansion and higher rates of future target vessel revascularisation.29 Therefore, when PCI is deemed necessary, it should be accompanied by calcium modification techniques. When the cause of MINOCA is one of the non-atherosclerotic causes, management should be according to the underlying condition. For example, when vasospasm is identified as the underling pathophysiological mechanism, β-blockers should be halted/avoided and the patient should be started on calcium channel blockers, which are the agents of choice with short-acting nitrates being the second option.10,27 Regarding SCAD, there are no randomised controlled trials to guide management, and the use and duration of aspirin alone or DAPT in medically managed cases

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OCT in MINOCA remains controversial. A recent document by a panel of experts suggested DAPT for 2–4 months followed by low-dose aspirin as monotherapy for up to 12 months; aspirin alone or not antiplatelet therapy at all was proposed as a reasonable alternative for patients at high bleeding risk.15 The same document emphasised that patient counselling and shared decision making should be employed, especially among the younger, female population, which carries an advanced risk of bleeding (e.g. due to menorrhagia).15 Importantly, a recently published multicentre SCAD registry that investigated single and dual antiplatelet regimens on conservatively treated patients challenged the paradigm of DAPT in SCAD.30 That study showed that prolonged DAPT (97% of patients received DAPT for 12 months) was independently associated with a higher rate of adverse cardiovascular events at the 1-year follow-up.30 Regarding further intervention, spontaneous angiographic healing is the natural history of the disease in 95% of patients, highlighting that conservative therapy is preferred in stable patients without ongoing ischaemia, as in cases with MINOCA where, by definition, there is no significant angiographic coronary stenosis.31 In any case, it should be highlighted that intervention in SCAD cases carries elevated risks.32

Clinical Perspectives

Current scientific documents underline the significance of CMR in MINOCA. European guidelines for the management of ACS without persistent ST-segment elevation recommend the performance of CMR in all MINOCA patients without an obvious underlying cause (class I, level of evidence B).5 The guidelines do not give any specific recommendation for the utilisation of OCT, although the recent studies that support the use of CMR (e.g. Reynolds et al.) have shown the value of OCT too.17–19 CMR is an excellent modality to discriminate between ischaemic and non-ischaemic causes of MINOCA, as discussed previously. However, CMR cannot inform us regarding the underlying pathology of the ischaemic insult: for example, it cannot tell us whether the ischaemia was due to a ruptured plaque or coronary spasm. As shown previously, OCT can discriminate the various phenotypes of epicardial pathologies.9,14,16–22 Importantly, it can take place at the time of coronary angiography, guiding immediate management. Conversely, ‘blind’ three-vessel OCT is not practical and the diagnostic yield of such a strategy is low. It is characteristic that in the study of Reynolds et al., although threevessel OCT was recommended, it took place in 59.3% of cases, highlighting the practical limitations of such a strategy.18 In addition, it is 1.

Barr PR, Harrison W, Smyth D et al. Myocardial infarction without obstructive coronary artery disease is not a benign condition (ANZACS-QI 10). Heart Lung Circ 2018;27:165–74. https://doi.org/10.1016/j.hlc.2017.02.023; PMID: 28408093. Pasupathy S, Air T, Dreyer RP et al. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation 2015;131:861–70. https://doi.org/10.1161/ CIRCULATIONAHA.114.011201; PMID: 25587100. Safdar B, Spatz ES, Dreyer RP et al. Presentation, clinical profile, and prognosis of young patients with myocardial infarction with nonobstructive coronary arteries (MINOCA): results from the VIRGO Study. J Am Heart Assoc 2018;7:e009174. https://doi.org/10.1161/JAHA.118.009174; PMID: 29954744. Pizzi C, Xhyheri B, Costa GM et al. Nonobstructive versus obstructive coronary artery disease in acute coronary syndrome: a meta-analysis. J Am Heart Assoc 2016;5:e004185. https://doi.org/10.1161/JAHA.116.004185; PMID: 27986756. Collet J-P, Thiele H, Barbato et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021;42:1289–367. https://doi.org/10.1093/eurheartj/

likely that ‘blind’ three-vessel OCT, not guided by electrocardiographic and imaging findings, could lead to the erroneous recognition of a bystander lesion as the culprit because ‘unstable’ plaques have been also found in patients with stable CAD.20 Furthermore, as discussed previously, the rate of pathological findings is much lower when compared with OCT guided by ECG and echocardiography/left ventricle angiogram findings. Considering the above aspects, we propose a practical algorithm for OCT use in cases of MINOCA (Figure 4). In our algorithm, OCT vessel interrogation is guided by ECG changes and regional WMA, and is suggested in the corresponding coronary artery. A hazy non-obstructive coronary lesion in a MINOCA case is highly suspicious of a coronary pathology and should prompt further investigation by OCT. However, even when the vessel appears smooth in angiography, there still may be an underlying pathology (i.e. Figure 1B) and OCT should be considered in the artery corresponding to ECG changes and/or WMA. Finally, it needs to be acknowledged that even in coronary causes of MINOCA, OCT cannot always give a definite diagnosis. OCT could generate the suspicion for the presence of epicardial coronary spasm, but it is not the test of choice. Furthermore, OCT does not provide any information regarding coronary microvascular spasm, which plays a role in several MINOCA cases.13 In patients with suspected coronary vasomotor abnormalities, a provocation test with acetylcholine should be considered to assess the presence of epicardial or microvascular spasm33 (Figure 4). Provocation testing in MINOCA patients has been shown to be safe and able to identify high-risk patients.13 However, its use in clinical practice is currently limited and mainly restricted to specialised centers.34 Thrombus embolism not related to plaque disruption is another coronary cause of MINOCA where OCT is not diagnostic. A patient’s clinical history and characteristics could set the suspicion of embolism (e.g. prosthetic heart valves, apical thrombus, infective endocarditis or myxoma) and echocardiography could be useful in delineating the cause of MINOCA in such cases.33

Conclusion

OCT is an indispensable tool for the recognition of the underling pathogenetic mechanism of MINOCA when epicardial pathology is suspected because it can reliably identify pathologies not apparent on coronary angiography. OCT should be part of the diagnostic work-up for a patient with MINOCA when ECG changes and WMA on an echocardiogram or left ventricle angiogram indicate a localised epicardial coronary cause.

ehaa575; PMID: 32860058. 6. Tearney GJ, Regar E, Akasaka T et al. Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation. J Am Coll Cardiol 2012;59:1058–72. https://doi.org/10.1016/j. jacc.2011.09.079; PMID: 22421299. 7. Kubo T, Imanishi T, Takarada S et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007;50:933–9. https://doi.org/10.1016/j.jacc.2007.04.082; PMID: 17765119. 8. Jia H, Abtahian F, Aguirre AD et al. In vivo diagnosis of plaque erosion and calcified nodule in patients with acute coronary syndrome by intravascular optical coherence tomography. J Am Coll Cardiol 2013;62:1748–58. https://doi. org/10.1016/j.jacc.2013.05.071; PMID: 23810884. 9. Johnson TW, Räber L, di Mario C et al. Clinical use of intracoronary imaging. Part 2: acute coronary syndromes, ambiguous coronary angiography findings, and guiding interventional decision-making: an expert consensus document of the European Association of Percutaneous

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Cardiovascular Interventions. Eur Heart J 2019;40:2566–84. https://doi.org/10.1093/eurheartj/ehz332; PMID: 31112213. Tamis-Holland JE, Jneid H, Reynolds HR et al. Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association. Circulation 2019;139:e891–908. https://doi. org/10.1161/CIR.0000000000000670; PMID: 30913893. Thygesen K, Alpert JS, Jaffe AS et al. Fourth universal definition of myocardial infarction (2018). J Am Coll Cardiol 2018;72:2231–64. https://doi.org/10.1016/j.jacc.2018.08.1038; PMID: 30153967. Falk E, Nakano M, Bentzon JF et al. Update on acute coronary syndromes: the pathologists’ view. Eur Heart J 2013;34:719–28. https://doi.org/10.1093/eurheartj/ehs411; PMID: 23242196. Montone RA, Niccoli G, Fracassi F, et al. Patients with acute myocardial infarction and nonobstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests. Eur Heart J 2018;39:91–8. https://doi. org/10.1093/eurheartj/ehx667; PMID: 29228159. Tanaka A, Shimada K, Tearney GJ et al. Conformational change in coronary artery structure assessed by optical coherence tomography in patients with vasospastic angina.

OCT in MINOCA

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J Am Coll Cardiol 2011;58:1608–13. https://doi.org/10.1016/j. jacc.2011.06.046; PMID: 21958888. Hayes SN, Tweet MS, Adlam et al. Spontaneous coronary artery dissection: JACC state-of-the-art review. J Am Coll Cardiol 2020;76:961–84. https://doi.org/10.1016/j. jacc.2020.05.084; PMID: 32819471. Adlam D, Tweet MS, Gulati R et al. Spontaneous coronary artery dissection: pitfalls of angiographic diagnosis and an approach to ambiguous cases. JACC Cardiovasc Interv 2021;14:1743–56. https://doi.org/10.1016/j.jcin.2021.06.027; PMID: 34412792. Gerbaud E, Arabucki F, Nivet H et al. OCT and CMR for the diagnosis of patients presenting with MINOCA and suspected epicardial causes. JACC Cardiovasc Imaging 2020;13:2619–31. https://doi.org/10.1016/j.jcmg.2020.05.045; PMID: 32828786. Reynolds HR, Maehara A, Kwong RY et al. Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of myocardial infarction with nonobstructive coronary arteries in women. Circulation 2021;143:624–40. https://doi.org/10.1161/ CIRCULATIONAHA.120.052008; PMID: 33191769. Opolski MP, Spiewak M, Marczak M et al. Mechanisms of myocardial infarction in patients with nonobstructive coronary artery disease: results from the Optical Coherence Tomography Study. JACC Cardiovasc Imaging 2019;12:2210– 21. https://doi.org/10.1016/j.jcmg.2018.08.022; PMID: 30343070. Yamamoto MH, Maehara A, Song L et al. Optical coherence tomography assessment of morphological characteristics in suspected coronary artery disease, but angiographically nonobstructive lesions. Cardiovasc Revasc Med 2019;20:475– 9. https://doi.org/10.1016/j.carrev.2018.07.011; PMID: 30054255.

21. Mas-Lladó C, Maristany J, Gómez-Larab J et al. Value of the optical coherence tomography in the diagnosis of unstable patients with non-significant coronary stenosis. REC Interv Cardiol 2020;2:272–9. https://doi.org/10.24875/RECICE. M20000117. 22. Taruya A, Tanaka A, Nishiguchi T et al. Lesion characteristics and prognosis of acute coronary syndrome without angiographically significant coronary artery stenosis. Eur Heart J Cardiovasc Imaging 2020;21:202–9. https://doi. org/10.1093/ehjci/jez079; PMID: 31056642. 23. Beltrame JF, Crea F, Kaski JC, et al. International standardization of diagnostic criteria for vasospastic angina. Coronary Vasomotion Disorders International Study Group (COVADIS). Eur Heart J 2017;38:2565–8. https://doi. org/10.1093/eurheartj/ehv351 PMID: 26245334. 24. Bryniarski K, Gasior P, Legutko J et al. OCT findings in MINOCA. J Clin Med 2021;10:2759. https://doi.org/10.3390/ jcm10132759; PMID: 34201727. 25. Lindahl B, Baron T, Erlinge D et al. Medical therapy for secondary prevention and long-term outcome in patients with myocardial infarction with nonobstructive coronary artery disease. Circulation 2017;135:1481–9. https://doi. org/10.1161/CIRCULATIONAHA.116.026336; PMID: 28179398. 26. Chen ZM, Jiang LX, Chen YP et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1607– 21. https://doi.org/10.1016/S0140-6736(05)67660-X PMID: 16271642. 27. Scalone G, Niccoli G, Crea F. Editor’s choice – pathophysiology, diagnosis and management of MINOCA: an update. Eur Heart J Acute Cardiovasc Care 2019;8:54–62. https://doi.org/10.1177/2048872618782414; PMID: 29952633. 28. Jia H, Dai J, Hou J et al. Effective anti-thrombotic therapy without stenting: intravascular optical coherence

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tomography-based management in plaque erosion (the EROSION study). Eur Heart J 2017;38:792–800. https://doi. org/10.1093/eurheartj/ehw381; PMID: 27578806. Kobayashi N, Takano M, Tsurumi M et al. Features and outcomes of patients with calcified nodules at culprit lesions of acute coronary syndrome: an optical coherence tomography study. Cardiology 2018;139:90–100. https://doi. org/10.1159/000481931; PMID: 29301128. Cerrato E, Giacobbe F, Quadri G, et al. Antiplatelet therapy in patients with conservatively managed spontaneous coronary artery dissection from the multicentre DISCO registry. Eur Heart J 2021;42:3161–71. https://doi.org/10.1093/ eurheartj/ehab372; PMID: 34338759. Hassan S, Prakash R, Starovoytov A, Saw J. Natural history of spontaneous coronary artery dissection with spontaneous angiographic healing. JACC Cardiovasc Interv 2019;12:518–27. https://doi.org/10.1016/j.jcin.2018.12.011; PMID: 30826233. Kotecha D, Garcia-Guimaraes M, Premawardhana D, et al. Risks and benefits of percutaneous coronary intervention in spontaneous coronary artery dissection. Heart 2021;107:1398–406. https://doi.org/10.1136/ heartjnl-2020-318914; PMID: 34006503. Montone RA, Jang IK, Beltrame JF, et al. The evolving role of cardiac imaging in patients with myocardial infarction and non-obstructive coronary arteries. Prog Cardiovasc Dis 2021;68:78–87. https://doi.org/10.1016/j.pcad.2021.08.004; PMID: 34600948. Montone RA, Meucci MC, De Vita A, et al. Coronary provocative tests in the catheterization laboratory: pathophysiological bases, methodological considerations and clinical implications. Atherosclerosis 2021;318:14–21. https://doi.org/10.1016/j.atherosclerosis.2020.12.008; PMID: 33360263.

REVIEW

Position Statement

Can Interventional Cardiologists Help Deliver the UK Mechanical Thrombectomy Interventional Programme for Patients with Acute Ischaemic Stroke? A Discussion Paper from the British Cardiovascular Interventional Society Stroke Thrombectomy Focus Group Helen Routledge ,1 Andrew SP Sharp,2,3 Jan Kovac ,4 Mark Westwood,5 Thomas R Keeble ,6,7 Raj Bathula ,8 Hany Eteiba,9 Iris Q Grunwald 10,11 and Nick Curzen ;12,13 on behalf of the British Cardiovascular Interventional Society Stroke Thrombectomy Working Group 1. Worcestershire Acute Hospitals NHS Trust, Worcester, UK; 2. University Hospital of Wales, Cardiff, Wales, UK; 3. University of Exeter, Exeter, UK; 4. University Hospitals of Leicester NHS Trust, Leicester, UK; 5. Department of Cardiology, Barts Heart Centre, St Bartholomew’s Hospital, London, UK; 6. Essex Cardiothoracic Centre, Mid and South Essex NHS Foundation Trust, Basildon, Essex, UK; 7. Medical Technology Research Centre, Anglia Ruskin University, Chelmsford, Essex, UK; 8. London North West University Healthcare NHS Trust, London, UK; 9. West of Scotland Regional Heart and Lung Centre, Golden Jubilee National Hospital, Glasgow, Scotland, UK; 10. University of Dundee, Dundee, Scotland, UK; 11. Cardiovascular Center Frankfurt, Frankfurt, Germany; 12. Faculty of Medicine, University of Southampton, Southampton, UK; 13. Cardiothoracic Unit, University Hospital Southampton, Southampton, UK

Abstract

There is a willingness among UK interventional cardiologists to contribute to provision of a 24/7 mechanical thrombectomy (MT) service for all suitable stroke patients if given the appropriate training. This highly effective intervention remains unavailable to the majority of patients who might benefit, partly because there is a limited number of trained specialists. As demonstrated in other countries, interdisciplinary working can be the solution and an opportunity to achieve this is outlined in this article.

Keywords

Ischaemic stroke, mechanical thrombectomy, interventional cardiology Disclosure: ASPS and NC are on the Interventional Cardiology editorial board; this did not influence peer review. All other authors have no conflicts of interest to declare. Received: 18 November 2021 Accepted: 6 March 2022 Citation: Interventional Cardiology 2022;17:e07. DOI: https://doi.org/10.15420/icr.2021.35 Correspondence: Helen Routledge, Department of Cardiology, Worcestershire Royal Hospital, Worcester WR5 1DD, UK; E: h.routledge@nhs.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The Challenge

Only 2% of ischaemic stroke patients in the UK receive emergency interventional thrombectomy treatment.1 More than 7,000 eligible patients each year are unable to access a therapy that might prevent life-changing disability.

The Aim

To contribute to a national solution, allowing equitable access for all eligible patients to stroke thrombectomy treatment. The aim of our document is to describe the potential contribution that UK interventional cardiologists (ICs) could make to the current unmet need of providing a 24/7 mechanical thrombectomy (MT) service for all suitable stroke patients. This initiative is motivated by:

• An awareness of the clinical effectiveness of MT. • The difficulty in providing MT to as many patients as possible using existing trained specialist groups.

The Case for Interventional Cardiologists Performing Mechanical Thrombectomy in the UK

Between April 2019 and March 2020, Sentinel Stroke National Audit Programme (SSNAP) data reported 89,280 strokes in the UK, of which

77,735 were due to cerebral infarction. An estimated 10−12% of these strokes would in theory be candidates for emergency MT. Despite a wellestablished infrastructure of specialist stroke care centres, only 1.57% of these patients received this potentially life-changing treatment.1 Until 2014, reperfusion treatment for ischaemic stroke was primarily through IV thrombolysis, even though this is a relatively ineffective treatment for large vessel arterial occlusion. In terminal internal carotid artery thrombotic occlusions, successful recanalisation with thrombolysis occurs in as few as one in 10 cases.2 Better methods of reperfusion are therefore clearly desirable. In 2015, multiple randomised controlled trials began to show large benefits from reperfusion of cerebral circulation through the strategy of systemic thrombolysis followed by immediate MT. A meta-analysis of these trials showed a number needed to treat (NNT) of 2.6 to achieve a one-point improvement in the modified Rankin score (where 0 is no disability and 6 is dead).3 Treatment has further evolved over the last 6 years and a comprehensive review of the evidence was undertaken by the National Institute for Health and Care Excellence in 2019.4

Cardiologists and Stroke Thrombectomy Figure 1: Current Access to Existing Neuroscience Centres Time to MT unit (mins) 0 - 10 10 - 20 20 - 30 30 - 40 40 - 50 50 - 60 60 - 70 70 - 80 80 - 90 90 - 100 100 - 110 110 - 120 120 - 130 130 - 140 140 - 150

Patients should also be considered as potential candidates for MT based on their clinical presentation and CT angiography results. Unfortunately, while CT angiography could technically be undertaken in all hospitals, radiological expertise for reporting the results is not currently available on a 24/7 basis across the UK. However, if scans can be undertaken, the diagnostic skill set can be relatively easily acquired locally or alternatively be delivered through remote expert support, with or without the assistance of artificial intelligence (AI) software. A national optimal stroke imaging pathway has been developed based on best evidence, investment in both training and AI has been secured at a national level, and a digital lead appointed to ensure that all regions gain equitable access to appropriate imaging.7

Specialist Intervention Facilities and Sharing Resources

Only three hospitals in the UK provide 24/7 stroke thrombectomy services, while only four offer MT at the weekend. By contrast, in 62 hospitals, cardiac catheter lab facilities are available for heart attack interventions, 24/7 365 days a year, with dedicated teams of nurses, radiographers, physiologists and consultants delivering reperfusion in 27,000 primary percutaneous interventions (PPCI) for ST-elevation MI (STEMI) per year, the default strategy for occluded coronary vessels since 2009. Current planning regarding the optimal location of stroke thrombectomy centres is that MT should be provided 24/7 at all 24 established neuroscience centres in England with existing interventional radiology services, expertise and a co-located hyperacute stroke service.8,9 A heatmap showing time taken in minutes to travel to one of 24 neuroscience centres, with some regions not well served for emergency access. MT = mechanical thrombectomy. Source: Allen et al. 2019.18 Reproduced with permission from Oxford Academic Health Science Network and OpenStreetMap, from work conducted by the National Institute for Health and Care Research Applied Research Collaboration South West Peninsula (PenARC).

Current recommendations are:

• To offer thrombolysis and thrombectomy for anterior circulation strokes presenting before 6 hours.

• Following the publication of the results of DAWN and DEFUSE III, to

offer thrombectomy for those presenting up to 24 hours with salvageable brain tissue on diffusion-weighted MRI or CT perfusion scanning.5,6

The UK does not provide this care pathway to most suitable patients and remains far behind the best services in Europe in MT provision. While other aspects of MT infrastructure do require attention – and are receiving this via the Integrated Stroke Delivery Networks (ISDNs) – the problem in the UK is manifestly that there are too few trained operators.

Current Infrastructure Challenges Imaging and Reporting

Patients who are face, arm, speech test (FAST) positive are currently recognised pre-admission and conveyed to the nearest hospital by ambulance, along with many ‘stroke mimics’ – patients who present with symptoms initially thought to be secondary to acute cerebral ischaemia but are subsequently found to have an alternative, non-vascular aetiology. Most undergo urgent CT scanning and are assessed by the emergency department (ED) or stroke team as an emergency so that a default strategy of thrombolysis can be considered.

Even if this can be achieved, this will leave some regions without timely cover for treatment, thus requiring between four and seven other nonneuroscience MT centres for full geographical coverage (Figure 1). This process mimics the evolution of PPCI for STEMI, which started in pioneering centres and then spread across the country until all geographical areas were adequately covered. In the meantime, stroke coverage will likely be achieved in some regions by use of the well described ‘drip and ship’ approach.10 The challenge to this approach is familiar to those who witnessed the development of PPCI and the delays involved in a patient being transferred from one ED to another for a time-sensitive intervention. Specifically, the median door-in to door-out time at referring stroke centres is currently 2 hours and 10 minutes, with a further 40 minutes transfer time.1 With the NNT in MT being so much more favourable than for PPCI, and the even more time-sensitive nature of cerebral infarction compared with MI, establishing equitable access to MT facilities for patients across the UK is a priority and one which may only be achieved with radical new approaches involving the sharing of interventional facilities and operator skills.

Workforce Challenges

The composition of the workforce delivering MT varies across the world, with cases delivered by interventional neuroradiologists, interventional vascular radiologists, neurologists, neurosurgeons and cardiologists. By contrast, thrombectomy in the UK has thus far been delivered almost exclusively by interventional neuroradiologists (INRs). While highly expert, their numbers are too few to plausibly deliver 24/7 MT services across the UK.

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Cardiologists and Stroke Thrombectomy At the time of writing, 81 INRs are currently providing MT with 7 INRs scheduled to complete training in 2020 with a further eight completing in 2021. The Royal College of Radiologists has estimated that at least 50 more INRs would need to be trained in the UK to deliver an equitable service, giving 120 in total. Given the paucity of 24/7 rotas in existence for MT, it seems unlikely that round-the-clock coverage will be achieved by simpy adding 50 more INRs. By contrast, to provide a PPCI service to all patients across the UK, 713 consultant ICs are registered in the UK, with the significant majority of those participating in a 24/7 rota at an average intensity of one in seven. The British Cardiovascular Interventional Society (BCIS) Sustainable Workforce document recognises that to maintain a 24/7 rota with a maximum on-call frequency of 1:6 and a half-day compensatory rest after a night on call, a minimum of six (and ideally eight) operators are needed. In addition to the generic challenges of medical workforce expansion, if the UK relied solely on the expansion of the INR team to deliver treatment for stroke, there are a finite number of aneurysms, arteriovenous malformations and fistulae to be addressed. One potential consequence of this could be that the procedural volumes per operator for these other important activities would fall, which may not be desirable. Looking at the workforce calculations from a centre perspective, if MT was to be provided in the 24 neuroscience centres and all thrombectomy operators agree to contribute to an out-of-hours on-call, then between 144 and 192 operators would be needed. For 8,000 cases, this would equate to 40–55 MT cases per operator. Expanding to 30 centres (according to the geographical considerations above), the numbers would be 180 to 240 operators each doing 33–44 thrombectomy cases per year. It becomes obvious that new approaches are going to be needed as there will be insufficient INRs to deliver the service to provide an equitable MT service throughout the UK within the next few years. However, the aspiration to achieve a nationwide 24/7 MT service within the next 2–3 years could be realised if 120 existing willing ICs were trained to contribute to the service. Meanwhile, every 2-year delay in implementing a nationwide service is likely to contribute to more than 10,000 UK stroke patients experiencing avoidable long-term disability. Given that the first major randomised trial to show the life-changing benefits of MT was published on 1 January 2015, further delay should no longer be considered reasonable, in our view, when other mechanisms of delivery have been shown to be safe and successful in other countries.11

Interdisciplinary Solutions

Solutions to this problem have already been conceived and delivered in other countries in Europe and further afield. In St Petersburg, an interventional stroke programme was set up in 2015 using the existing STEMI network, cath labs and ICs.11 This was delivered through a programme of training sessions and masterclasses delivered by neurointerventionalists to the region’s ICs. Prior to this initiative, only 25 patients per year were being treated with MT. Now, by using the combined skills of INRs and ICs, the programme treats 650 cases per year with MT, reporting successful reperfusion in 81% of cases.11 Models and network solutions are likely to vary across different UK regions. For example, in London dedicated interventional neuroradiology centres could provide 24/7 MT by pooling the existing INR teams. In other regions, however, it may be that hybrid services are offered within neuroscience centres by a combination of existing INR teams with

operators from other specialties. Finally, in non-neuroscience centres with geographical barriers to services, using existing coronary/vascular interventional facilities and operators makes more sense, given that many are already providing 24/7 emergency cover and are well placed to provide timely stroke thrombectomy to their own populations. If non-neuroscience centres were to develop, it would require a hub-andspoke network model, with the local hybrid MT team working and training closely with their neuroscience centre colleagues and running a joint programme. This joint working, designed flexibly according to the needs of each region, will help bridge the current gap in available operators. Three hospitals in the UK have successfully implemented an MT service with the joint efforts of INRs, ICs and/or radiologists, the most recent of these being Dundee, where the first patient was treated in November 2020. Thus far, the inability to achieve this elsewhere in the UK is due to lack of capacity in the national training programme and lack of agreement as to exactly how to train non-INRs in MT. The principal proposal by this BCIS Stroke Thrombectomy Focus Group is a two-part bespoke training programme to be made available to interested ICs to expand the available pool of active MT operators:

• Stage 1: training of established consultant ICs. • Stage 2: training in a structured programme, at home or abroad, for

IC trainees after they achieve the certificate of completion of training.

While expanding the trained workforce, BCIS will help to encourage and support the development of solutions for access to patients across the UK, as was undertaken for PPCI.

Why Interventional Cardiologists?

Despite their lack of experience in the cerebrovascular system, ICs have an extensive interventional skill set for the delivery of percutaneous, catheter-based techniques for coronary and valvular procedures. ICs are therefore well placed to be trained in the anatomical and technical challenges associated with MT. Similarly, vascular radiologists are well placed to learn these skills, though there are fewer of them than ICs. It has also been proposed that training could be offered to non-catheter specialists with an interest in stroke, such as neurologists or stroke physicians. There is certainly no theoretical barrier to this, though without a baseline interventional skill set, the training programme would inevitably be much longer than for ICs. Additionally, IC are already highly experienced in emergency, time-sensitive pathways, and the management of critically ill, conscious patients during interventional procedures. In some areas, such as radial artery access, the use of adjunctive antiplatelet medication, and the ongoing investigation of the cardiovascular system to look for the causes of stroke, IC experience could also enrich the current MT pathway. As with INRs, ICs have demonstrated their ability to adapt and excel at the delivery of new procedures as they have evolved. New coronary techniques and valve interventions have advanced rapidly within the timeframe of all practising consultant’s careers. These include the shift of more than 90% of UK PCI procedures from femoral arterial access to radial arterial access and the improvement of chronic total occlusion (CTO) techniques, such that CTO success rates have risen from 50% 10 years ago to over 90% in specialist centres.

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Cardiologists and Stroke Thrombectomy Figure 2: Schematic for Training Interventional Cardiologists in Stroke Thrombectomy Procedures Focused educational programme, such as the EXMINT course Simulator work to accelerate hand skills and decision-making Diagnostic cerebral lists with an INR +/- carotid stenting cases where available Second operator in stroke MT cases First operator in stroke MT cases Independent operator in stroke MT cases EXMINT = European Stroke Course in Minimally Invasive Neurological Therapy; INR = interventional neuroradiologists; MT = mechanical thrombectomy.

ICs have also successfully delivered entirely new fields, such as transcatheter aortic valve implantation, MitraClip, patent foramen ovale closure or percutaneous atrial septal defect closure. Some ICs also have experience in carotid stenting, which is considered advantageous for accelerated training by European training bodies.12 The development of these fields has largely been through workshops and then expert proctoring. Consultants were not asked to take long periods of absence from their existing roles and yet delivered high-quality, safe new services. Crucially, most ICs are also already part of a 24/7 rota and most are content to make this part of their working pattern throughout their consultant career. A recent survey sent to the membership of BCIS revealed that 192 respondents (52%) would be very keen to contribute to a stroke thrombectomy service as part of a 24/7 rota if appropriate training were available, with further respondents also willing to consider it.13 Perhaps the strongest argument for a national interdisciplinary solution is the existing, established, UK-wide emergency interventional cardiology network. It seems unlikely that the country can afford to have another 24/7 team of clinicians, nurses, radiographers and a lab on standby 24/7 in more remote locations, when this already exists to cover the UK for STEMI.

Agreement in Training Interventional Cardiologists

There is an important discussion to be had about the ideal training approach and duration of MT training for an IC consultant. Given the successful programmes elsewhere in the world, we can be confident that the previously proposed estimate of 2–3 years’ training time are unduly pessimistic, but factors that will need to be taken into account during this national discussion will include:

• • • •

Who can dictate how many ICs can or should be trained? How and by whom would competence be certified? How to fit practical training into an IC consultant’s job plan. Can this be replaced by dual accreditation for trainees in the future?

Many of the relevant discussions regarding training are ongoing in other countries.12 Agreement of specialist bodies will be required for medicolegal reasons, and safe and speedy delivery is strongly in the interest of the population. The political challenge regarding the barriers to delivery will require skill and diplomacy from those who oversee the provision of healthcare, given the different perspectives in this area.

Methods of Training Interventional Cardiologists

Given the starting point of low case numbers, the need to train INRs in the UK to be ready to carry out and run MT programmes, and the current job plans and curriculums in cardiology, it is clear that a bespoke programme will be required to train ICs, depending on whether they are based in existing neuroscience centres. A schematic of how such a programme might look is shown in Figure 2. Training a physician with minimal cerebrovascular experience to perform MT on a real patient on day 1 is no longer how contemporary training works. Focused theoretical training followed by simulator work (which has advanced enormously over the past decade) is the standard mechanism of training new operators in interventional procedures in the modern era. Operators could then further develop their skills through diagnostic cerebral work or carotid stenting, where available, before becoming a second operator on MT cases, and then a first operator on stroke MT cases. Pathways such as this have been shown to be successful both inside and outside the UK. Theoretical courses already exist in this area. For example, the European Stroke Course in Minimally Invasive Neurological Therapy (EXMINT) programme is run by the European Society of Minimally Invasive Neurological Therapy and is endorsed by the European Stroke Association.14 This is a 2-week programme, exam and viva assessment covering the anatomy, pathophysiology and imaging components of relevance to highly specialised procedures in the brain. It is specifically designed for the training of non-INRs in MT by experts in the field and the procedure. Simulator training has advanced rapidly in all interventional fields, and MT simulation suites are now available in two locations in the UK, offering a variety of cases from simple to difficult anatomies and allowing training on each procedural step. The operator can select a range of cath lab equipment, including catheters, balloon/aspiration catheters, wires, stents and stent retrievers. The ANGIO Mentor suite (Simbionix) is a human size simulator allowing multidisciplinary stroke team training, and the PROcedure Rehearsal Studio (Simbionix) software enables the creation of an unlimited library of cases based on real patient DICOM data. Neurointerventional simulation training has already been shown to be effective in high-risk endovascular procedures and in-built automated scoring systems within the simulators have even been demonstrated to be able to discriminate between levels of operator proficiency for carotid artery stenting.15–17 Case numbers and credentialling are perhaps the most challenging area in which to achieve consensus before ICs could contribute to an interventional stroke service. In most areas of specialist medical training, evidence has steered us away from a numbers-based assessment to a competency-based one. With such time-sensitive procedures, however, there is no doubt that experience of a variety of scenarios and management of complications will lead to improved performance. A minimum number of simulated cases and real-life second operator MT cases seems appropriate, but personalised, mentored training with assessment of competence by one or more experienced operators is in keeping with contemporary medical and surgical training. Maintaining skills and case numbers is essential but will likely become less of an issue (as will numbers to train on) as the indications for this therapy continue to expand. In addition, while volumes of stroke thrombectomy cases are vital to maintaining skills, once a focused early

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Cardiologists and Stroke Thrombectomy period of training is completed, ICs are high volume catheter specialists already, accessing head and neck vessels when catheterising left and right internal mammary artery grafts, as well as managing radial and femoral access sites, periprocedural anticoagulation, microcatheters, aspiration catheters, stent delivery, specialist wires, telescoping techniques and many other transferrable skills that will support maintenance of MT skills. MT numbers undertaken by operators in comparable European countries would suggest that volumes of approximately 30 per operator per annum are adequate for maintaining skills, which fits well with the workforce calculations outlined above.

Conclusion

The efficacy of MT in patients with anterior circulation stroke caused by large vessel occlusion is long established. Given the life-changing effect of successful MT, equitable access to this therapy is now required. Over 1.

Sentinel Stroke National Audit Programme. Sentinel Stroke National Audit Programme National Results 2020–21. https://www.strokeaudit.org/results/Clinical-audit/NationalResults.aspx (accessed 12 May 2022). Del Zoppo GJ, Poeck K, Pessin MS, et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 1992;32:78–86. https://doi. org/10.1002/ana.410320113; PMID: 1642475. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a metaanalysis of individual patient data from five randomised trials. Lancet 2016;387:1723–31. https://doi.org/10.1016/ S0140-6736(16)00163-X; PMID: 26898852. National Institute of Health and Care Excellence. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management (NG128). London: NICE, 2019. https://www.nice. org.uk/guidance/ng128 (accessed 19 April 2022). Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018;378:708–18. https://doi.org/10.1056/ NEJMoa1713973; PMID: 29364767. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018;378:11–21. https://doi. org/10.1056/NEJMoa1706442; PMID: 29129157. NHS England. National Stroke Service Model. https://www. england.nhs.uk/wp-content/uploads/2021/05/nationalstroke-service-model-integrated-stroke-delivery-networksmay-2021.pdf (accessed 19 April 2022). NHS England. Service Specification: Neurointerventional

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6 years have passed since the first positive randomised controlled trial reported and the UK is still not offering this treatment to the more than four out of five patients who could benefit. This is principally because of a lack of trained operators, as all other barriers are readily surmountable. ICs have transferrable skills in this area, which could significantly shorten the training time required for new catheter specialists to acquire the hand and cognitive skills to train in percutaneous therapies from scratch. Many ICs are willing to provide this vital service in the UK on a 24/7 365 days a year basis, through interdisciplinary, collaborative working. This would also provide additional infrastructure currently used to deliver one of the safest and most comprehensive interventional heart attack services in the world. The BCIS endorses the aims of this document – to facilitate the training of ICs to contribute to the national stroke MT service, offering safe, effective and equitable access to this essential treatment for all of our patients in a timely fashion.

Services for Acute Ischaemic and Haemorrhagic Stroke. 2018. https://www.england.nhs.uk/publication/servicespecification-neurointerventional-services-for-acuteischaemic-haemorrhagic-stroke/ (accessed 19 April 2022). NHS England. Clinical Commissioning Policy 2018: Mechanical Thrombectomy for Acute NHS England. 2018. https://www.england.nhs.uk/publication/clinicalcommissioning-policy-mechanical-thrombectomy-for-acuteischaemic-stroke-all-ages/ (accessed 19 April 2022). Romoli M, Paciaroni M, Tsivgoulis G, et al. Mothership versus drip-and-ship model for mechanical thrombectomy in acute stroke: a systematic review and meta-analysis for clinical and radiological outcomes. J Stroke 2020;22:317–23. https:// doi.org/10.5853/jos.2020.01767; PMID: 33053947. Savello AV, Vozniuk IA, Fiehler J, Orlov KY. How to set up a thrombectomy service. Clin Neuroradiol 2020;30:5–7. https:// doi.org/10.1007/s00062-020-00890-6; PMID: 32193616. Nardai S, Lanzer P, Abelson M, et al. Interdisciplinary management of acute ischaemic stroke: current evidence training requirements for endovascular stroke treatment. Position paper from the ESC Council on Stroke and the European Association for Percutaneous Cardiovascular Interventions with the support of the European Board of Neurointervention. Eur Heart J 2021;42:298–307. https://doi. org/10.1093/eurheartj/ehaa833.12; PMID: 33521827. NHS England and NHS West Midlands Clinical Networks. Stroke Care in the West Midlands: Clinical Review for the Delivery of 7 Day Stroke Services. https://www.england.nhs. uk/midlands/wp-content/uploads/sites/46/2019/05/7-daystroke-service-clinic-review-visits.pdf (accessed 19 April

2022). 14. European Society of Minimally Invasive Neurological Therapy. The European Stroke Course in Minimally Invasive Neurological Therapy (EXMINT). 2018. https://www.esmint. eu/training-education/exmint (accessed 19 April 2022). 15. Pannell J, Santiago-Dieppa DR, Wali AR, et al. Simulatorbased angiography and endovascular neurosurgery curriculum: a longitudinal evaluation of performance following simulator-based angiography training. Cureus 2016;8:e756. https://doi.org/10.7759/cureus.756; PMID: 27733961. 16. Weisz G, Smilowitz NR, Parise H, et al. Objective simulatorbased evaluation of carotid artery stenting proficiency (from Assessment of Operator Performance by the Carotid Stenting Simulator Study [ASSESS]). Am J Cardiol 2013;112:299–306. https://doi.org/10.1016/j. amjcard.2013.02.069; PMID: 23601579. 17. Kurz MW, Ospel JM, Advani R, et al. Simulation methods in acute stroke treatment: current state of affairs and implications. Stroke 2020;51:1978–82. https://doi.org/10.1161/ STROKEAHA.119.026732; PMID: 32568639. 18. Allen M, Pearn K, James M, et al. How many comprehensive and primary stroke centres should the UK have? In: Ford G, James M, White P (eds). Mechanical Thrombectomy for Acute Ischaemic Stroke: An Implementation Guide for the UK. Oxford: Oxford Academic Health Science Network, 2019. https:// www.oxfordahsn.org/wp-content/uploads/2019/07/ Mechanical-Thrombectomy-for-Ischaemic-StrokeAugust-2019.pdf (accessed 19 April 2022).

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