ICR 14.3

Volume 14 • Issue 3 • Winter 2019

www.ICRjournal.com

Contemporary Management of Out-of-hospital Cardiac Arrest in the Cardiac Catheterisation Laboratory: Current Status and Future Directions Nilesh Pareek, Peter Kordis, Ian Webb, Marko Noc, Philip MacCarthy and Jonathan Byrne

Multivalvular Disease: Percutaneous Management in 2019 and Beyond Magdalena Erlebach and Rüdiger Lange

Coronary Calcified Lesions: Introduction to the Focused Issue Nicolas M Van Mieghem

Rotational Atherectomy: A Contemporary Appraisal Tanush Gupta, Michael Weinreich, Mark Greenberg, Antonio Colombo and Azeem Latib Pre-shockwave Post-shockwave

Transfemoral TAVI procedure performed in a female patient

Po

A

B

C

D

E

F

LA = 2.55 mm2 Intravascular lithotripsy used on heavy calcified coronary lesion

2 LA = 6.15 mmafter Stent implantation orbital atherectomy with multiple calcium fractures

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Volume 14 • Issue 3 • Winter 2019

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

Deputy Editors Joost Daemen

Darren Mylotte

Nicolas M Van Mieghem

Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands

Galway University Hospitals, Galway

Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands

Angela Hoye

University Hospital of Wales, Cardiff, UK

Andrew SP Sharp

Castle Hill Hospital, Hull

Editorial Board Fernando Alfonso

Raban Jeger

Crochan J O’Sullivan

Hospital Universitario de La Princesa, Madrid

University Hospital Basel, Switzerland

Triemli Hospital, Zurich

Andrew Archbold

Jaffar Khan

Liesbeth Rosseel

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

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

Galway University Hospitals, Galway, IE

Eduardo Arias

Won Keun Kim Bad Nauheim, Germany

American University of Beirut Medical Center, Beirut, Lebanon

Tim Kinnaird

Alexander Sedaghat

National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico

Rodrigo Bagur London Health Sciences Centre, London, Ontario, Canada

Marco Barbanti Ferrarotto Hospital, Catania

Jonathan Byrne King’s College Hospital, London

Antonio Colombo San Raffaele Hospital, Milan

Pierluigi Costanzo St Michael Hospital/University of Toronto, Toronto, CA

Carlo Di Mario Royal Brompton & Harefield NHS Foundation Trust, London

Ajay Kirtane Columbia University Medical Center and New YorkPresbyterian Hospital, New York

Azeem Latib

University of Bonn, Bonn, DE

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

Lars Søndergaard

San Raffaele Hospital, Milan

Rigshospitalet - Copenhagen University Hospital, Copenhagen

Didier Locca

Gregg Stone

Lausanne University Hospital, Lausanne

Mamas A Mamas

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

University of Keele, Keele, Staffordshire, UK

Corrado Tamburino

Hannah McConkey St. Thomas’ Hospital, London, UK

Ferrarotto & Policlinico Hospital and University of Catania, Catania

Roxana Mehran

Luca Testa

Eric Eeckhout

Mount Sinai Hospital, New York

Centre Hospitalier Universitaire Vaudois, Lausanne

Thomas Modine

Tom Ford

CHRU de Lille, Lille

University of Glasgow, Glasgow, UK

Elmir Omerovic

Sameer Gafoor

Cover image © Shutterstock

University Hospital of Wales, Cardiff

Fadi J Sawaya

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

Renu Virmani CVPath Institute, Maryland

Simon Walsh

CardioVascular Center, Frankfurt

Sahlgrenska University Hospital, Gothenburg, Sweden

Philippe Garot

Peter O’Kane

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

Royal Bournemouth Hospital, Castle Lane East,

Nina C Wunderlich

Bournemouth, UK

Cardiovascular Center Darmstadt, Darmstadt

Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK

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Published by Radcliffe Cardiology.

All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology 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. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2019 All rights reserved ISSN: 1756–1477 • eISSN: 1756–1485

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Established: June 2006 | Frequency: Tri-annual | Current issue: Winter 2019

Aims and Scope

Submissions and Instructions to Authors

• Interventional Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in interventional cardiology practice.

• Interventional Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field.

• Interventional Cardiology Review 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.

• Contributors are identified by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board.

• Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief and Section Editors, formalise the working title and scope of the article.

• The ‘Instructions to Authors’ document and additional submission details are available at www.ICRjournal.com • Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Ashlynne Merrifield ashlynne.merrifield@radcliffe-group.com

Structure and Format • Interventional Cardiology Review is a tri-annual journal comprising review articles, expert opinion articles and guest editorials.

• The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board.

• Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion.

• Each edition of Interventional Cardiology Review is available in full online at www.ICRjournal.com

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Interventional Cardiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by Section Editors and an Editorial Board comprising leading authorities from a variety of related disciplines.

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Interventional Cardiology Review is abstracted, indexed and listed in PubMed, Embase, Scopus and Google Scholar. All articles are published in full on PubMed Central one month after publication.

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• The Managing Editor, following consultation with the Editor-in-Chief, Section Editors and/or a member of the Editorial Board, sends the manuscript to reviewers who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind.

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To support open access publication costs, Radcliffe Cardiology charge an Article Publication Charge (APC) to authors upon acceptance of an unsolicited paper as follows: £1,050 UK | €1,200 Eurozone | $1,369 all other countries.

Online All manuscripts published in Interventional Cardiology Review are available free-to-view at www.ICRjournal.com. Also available at www.radcliffecardiology.com are manuscripts from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including, Arrhythmia and Electrophysiology Review, Cardiac Failure Review, European Cardiology Review and US Cardiology Review.

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Contents

Foreword Simon Kennon

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DOI: https://doi.org/10.15420/icr.2019.14.3.FO1

Coronary Contemporary Management of Out-of-hospital Cardiac Arrest in the Cardiac Catheterisation Laboratory: Current Status and Future Directions

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Nilesh Pareek, Peter Kordis, Ian Webb, Marko Noc, Philip MacCarthy and Jonathan Byrne DOI:https://doi.org/10.15420/icr.2019.3.2

Left Main Coronary Artery Interventions

124

Mirvat Alasnag, Lina Yaqoub, Ammar Saati and Khaled Al-Shaibi DOI: https://doi.org/10.15420/icr.2019.10.R2

Drug-coated Balloons for Small Coronary Vessel Interventions: A Literature Review

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Thomas Nestelberger and Raban Jeger DOI: https://doi.org/10.15420/icr.2019.06.R3

Structural Sex and Transcatheter Aortic Valve Implantation: Impact of Female Sex on Clinical Outcomes

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Alessandra Laricchia, Barbara Bellini, Vittorio Romano, Saud Khawaja, Matteo Montorfano and Alaide Chieffo DOI: https://doi.org/10.15420/icr.2019.07.R1

Multivalvular Disease: Percutaneous Management in 2019 and Beyond

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Magdalena Erlebach and Rüdiger Lange DOI: https://doi.org/10.15420/icr.2019.13.R1

Bioprosthetic Aortic Valve Fracture During Valve-in-valve Transcatheter Aortic Valve Implantation

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John Phineas O’Donnell and Cróchán J O’Sullivan DOI: https://doi.org/10.15420/icr.2019.08.R2

Coronary Calcified Lesions Special Focus Coronary Calcified Lesions: Introduction to the Focused Issue

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Nicolas M Van Mieghem DOI: https://doi.org/10.15420/ icr.2019.14.3.GE1

Contemporary Approach to Heavily Calcified Coronary Lesions

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Carlotta Sorini Dini, Giulia Nardi, Francesca Ristalli, Alessio Mattesini, Brunilda Hamiti and Carlo Di Mario DOI: https://doi.org/10.15420/icr.2019.19.R1

The Value of Intracoronary Imaging and Coronary Physiology When Treating Calcified Lesions

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Yasushi Ueki, Tatsuhiko Otsuka, Kiyoshi Hibi and Lorenz Räber DOI: https://doi.org/10.15420/icr.2019.16.R1

Lesion Preparation with Orbital Atherectomy

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Evan Shlofmitz, Allen Jeremias, Richard Shlofmitz and Ziad A Ali DOI: https://doi.org/10.15420/icr.2019.20.R1

The Coronary Intravascular Lithotripsy System

174

Maria Natalia Tovar Forero and Joost Daemen DOI: https://doi.org/10.15420/icr.2019.18.R1

Rotational Atherectomy: A Contemporary Appraisal

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Tanush Gupta, Michael Weinreich, Mark Greenberg, Antonio Colombo and Azeem Latib Philipp Lurz and Karl Fengler DOI: https://doi.org/10.15420/icr.2019.17.R1

© RADCLIFFE CARDIOLOGY 2019

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Foreword

Simon Kennon is an Interventional Cardiologist and TAVI Operator at the Barts Heart Centre, St Bartholomew’s Hospital, London. He trained at Manchester University, St Bartholomew’s Hospital, the London Chest Hospital and St Vincent’s Hospital, Melbourne. His research interests relate to aortic valve and coronary interventions.

T

his year’s final issue of Interventional Cardiology Review contains a superb section on the assessment and treatment of calcified coronary artery disease. Five articles commissioned by guest editor Nicolas Van Mieghem cover ‘all you need to know but were too scared to ask’ about this ever-relevant subject.

The rest of the issue is evenly split between structural and coronary papers offering, as usual I hope, interesting and useful updates on specific issues that interventional cardiologists are commonly faced with. The coronary section comprises excellent reviews of the contemporary management of cardiac arrest and of left main stem disease, as well as the promise of drug-coated balloons for the treatment of small vessel disease. In the structural section, there is an interesting review of sex and TAVI, as well as a timely review of current thinking regarding the ever-evolving subject of how to treat multi-valve disease. The brutal, but innovative, concept of bioprosthetic valve fracture completes the set.

Finally, I am delighted to welcome Nicolas Van Mieghem, Andrew Sharp and Joost Daemen to the editorial board. I know their enthusiasm and knowledge will enhance the journal and I am looking forward to working with them.

DOI: https://doi.org/10.15420/icr.2019.14.3.FO1

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© RADCLIFFE CARDIOLOGY 2019

Coronary

Contemporary Management of Out-of-hospital Cardiac Arrest in the Cardiac Catheterisation Laboratory: Current Status and Future Directions Nilesh Pareek, 1,2 Peter Kordis, 3 Ian Webb, 1 Marko Noc, 3 Philip MacCarthy 2 and Jonathan Byrne 1,2 1. King’s College Hospital NHS Foundation Trust, London, UK; 2. School of Cardiovascular Medicine & Sciences, BHF Centre of Excellence, King’s College London, UK 3. University Medical Centre, Ljubljana, Slovenia

Abstract Out-of-hospital cardiac arrest (OHCA) is an important cause of mortality and morbidity in developed countries and remains an important public health burden. A primary cardiac aetiology is common in OHCA patients, and so patients are increasingly brought to specialist cardiac centres for consideration of coronary angiography, percutaneous coronary intervention and mechanical circulatory support. This article focuses on the management of OHCA in the cardiac catheterisation laboratory. In particular, it addresses conveyance of the OHCA patient direct to a specialist centre, the role of targeted temperature management, pharmacological considerations, provision of early coronary angiography and mechanical circulatory support.

Keywords Out-of-hospital cardiac arrest, percutaneous coronary intervention, mechanical circulatory support Disclosure: The authors have no conflicts of interest to declare.

Funding: This work was funded by King’s College Hospital R&D Grant, and was supported by the Department of Health via a National Institute for Health Research Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust.

Received: 28 January 2019 Accepted: 22 July 2019 Citation: Interventional Cardiology Review 2019;14(3):113–23. DOI: https://doi.org/10.15420/icr.2019.3.2 Correspondence: Nilesh Pareek, King’s College Hospital NHS Foundation Trust, London, SR5 9RS, UK. E: nileshpareek@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.

Out-of-hospital cardiac arrest (OHCA) is defined as the sudden absence of cardiac mechanical contractility with loss of signs of circulation that occurs within a community setting.1 OHCA affects more than half a million patients globally per year and is one the leading causes of death in developing countries.2 In the US, OHCA affects 350,000 patients per year and is the third leading cause of death.3–6 In the UK, the Ambulance Association reported that there were nearly 60,000 cases of OHCA in 2006, with cardiopulmonary resuscitation (CPR) attempted in less than half these patients.7 When the presenting rhythm is pulseless electrical activity or asystole, the underlying causes are often trauma, metabolic and electrolyte disturbance, drug overdose, subarachnoid haemorrhage, sepsis or pulmonary embolism.8,9 Patients with cardiac arrest and a rhythm that is suitable for defibrillation (i.e. VF or ventricular tachycardia), and where the arrest is witnessed, are more likely to have a cardiac aetiology and are known as the ‘Utstein comparator cohort’.10 Although improvements in prehospital care, exemplified in the ‘chain of survival’, remain central to improving outcomes after OHCA, there is now an increasing appreciation of the role of specialist interventional cardiological services and cardiac arrest centres.11 In this article, we review the contemporary management of OHCA with particular focus on interventional considerations in the cardiac catheterisation laboratory.

© RADCLIFFE CARDIOLOGY 2019

General Considerations Conveyance to Centres: Should the Patient be Taken to a Specialist Centre with Cardiovascular Facilities?

There remains significant regional and temporal variation in outcomes after OHCA, and a combination of resources, centre experience and personnel could account for these disparities.12–19 This indicates that, as with other acute conditions, regionalisation of specialist services has the potential to improve short- and long-term clinical outcomes after OHCA.20,21 The International Liaison Committee on Resuscitation (ILCOR), American Heart Association and NHS England now recommend that all patients with OHCA should be transferred directly to specialist centres, known as cardiac arrest centres, for provision of emergency specialist cardiac services (including interventional cardiology) and experienced critical care services with access to targeted temperature management (TTM).22–24 It is important to note that there is significant variation in the expertise of emergency medical services globally and within health services, which will affect the development of pathways of care. Some emergency medical services are staffed only by paramedics, whereas others are staffed by emergency medicine physicians; in addition, the range of services provided before conveyance varies significantly.

Furthermore, population density, prevalence of disease and transfer times for conveyance to a centre differ considerably, and these factors will have an effect on the delivery of protocols of care.

Access at: www.ICRjournal.com

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Coronary Figure 1: Treatment Pathways for Patients with Out-of-Hospital Cardiac Arrest

support devices may be of benefit, direct conveyance to centres with appropriate levels of care may be particularly pertinent.34,35 Although early angiography can lead to delays in delivery of TTM as observed in the Coronary Angiography After Cardiac Arrest (COACT) study, earlier stratification of patients at high risk of neurological injury could also provide an opportunity to focus early provision of TTM.36

OHCA with sustained ROSC

Post-resuscitation 12-lead ECG

Absence of ST elevation

ST elevation/LBBB

Absence of comorbidities Favourable arrest circumstances

URGENT TRANSFER <2 h

ED stop

No extra-cardiac cause favourable arrest circumstances

STEMI fast-track

Additional history Laboratory values CT scan and TTE

PE SAH Cardiac tamponade Sepsis Haemorrhage

Treat extracardiac cause

Immediate coronary angiography

ED = emergency department; LBBB = left bundle branch block; OHCA, out-of-hospital cardiac arrest; PE = pulmonary embolism; ROSC = return of spontaneous circulation; SAH = subarachnoid haemorrhage; STEMI = ST-elevation MI; TTE = transthoracic echocardiography.

As patients with retained consciousness after return of spontaneous circulation (ROSC) have excellent survival with good neurological recovery (~98%), it is currently recommended that they should be treated as acute coronary syndrome patients without OHCA.25–27 The European Association of Percutaneous Cardiovascular Interventions (EAPCI) currently recommends that all patients with ST elevation (and favourable arrest circumstances, namely witnessed arrest, zero flow time <10 minutes and initial shockable rhythm) should be taken directly to a cardiac arrest centre.28 The current consensus for patients without ST elevation is that they are taken to any emergency department for evaluation of non-cardiac causes and, in the absence of such causes, are urgently transferred to a cardiac catheterisation laboratory, ideally within 2 hours (Figure 1). For patients without ST elevation, this process may lead to delays that could be detrimental, particularly in the presence of haemodynamic instability.

It is also well known that patients with non-cardiac causes of OHCA, such as neurological or renal aetiologies, may exhibit ST changes on the 12-lead ECG. Therefore, it is important that cardiac arrest centres should have 24-hour access to CT scanning, expert neurosurgical care and be able to provide renal replacement therapy, which may not be immediately available in stand-alone primary percutaneous coronary intervention (PCI) centres.

Several observational studies have indicated that direct patient transfer to a cardiac centre may be of benefit in terms of survival and survival with good neurological recovery.13,29–33 However, as with studies evaluating the benefits of early angiography, these retrospective studies are at risk of selection bias. An important potential advantage of direct transfer is access to facilities that can lead to earlier decision making, including expert clinical diagnostics with performance of echocardiography followed by angiography and revascularisation where appropriate.

In cases of cardiogenic shock, where time-critical services such as coronary revascularisation and implantation of mechanical circulatory

114

A major disadvantage of direct conveyance to a specialist cardiac arrest centre is the financial and intensive burden in both acute and more long-term settings. It is known that the average OHCA patient has a hospital cost of £20,000, whereas costs for patients with a moderate to severe neurological disability (Cerebral Performance Category [CPC] 3–4) are significantly higher at £53,000.37 In the absence of clear benefit of the direct transfer of patients to a cardiac arrest centre, these costs may be difficult to justify. This question is currently being addressed

by A Randomised tRial of Expedited transfer to a cardiac arrest centre for non-ST elevation out of hospital cardiac arrest (ARREST), which will randomise approximately 900 patients with OHCA without ST elevation to conveyance either to an emergency department or directly to the cardiac catheterisation laboratory.38

Targeted Temperature Management in OHCA It is well established that interruption of cerebral blood perfusion after a cardiac arrest followed by reperfusion results in a cascade of events resulting in neuronal cell death. These events include astroglial phagocytosis, free radical generation and mitochondrial dysfunction.22 Reducing a patient’s temperature by 1°C decelerates cellular metabolism by 6–7%, and so artificial induction of ‘therapeutic hypothermia’ could provide protection from this deleterious process.39 Animal studies of therapeutic hypothermia in cardiac arrest have suggested that therapeutic hypothermia can be beneficial, but also that early delivery is mandatory to achieve benefit, with even a 15-minute delay after reperfusion injury resulting in more lesions in histopathological studies.40 Two landmark human trials initially suggested that induction of hypothermia could be beneficial. A study by the Hypothermia After Cardiac Arrest Study Group randomised 136 patients to 32–34°C or normothermia and found improved neurological outcome at 6 months in the hypothermia compared with normothermia group. 41 A smaller study randomised 77 patients to 33°C or normothermia and also found improved functional outcome in the hypothermia group (49% versus 29%).42 This approach was extended to patients with a non-VF initial rhythm (in a non-randomised manner) who also appeared to acquire benefit.43 TTM was incorporated into ILCOR guidelines on the basis of these results, but questions remained about whether pyrexia in the normothermia group may have driven poor outcomes in this group.44 The seminal TTM trial aimed to answer these questions by randomising patients to moderate hypothermia (33°C) or mild hypothermia (36°C), and surprisingly found no differences between the two groups in the primary outcome of all-cause mortality or in the secondary outcome of a composite of poor neurologic function or death at 180 days.45 There has been much discussion about the unexpected findings of this trial, focusing on late commencement of TTM (~4 hours), late reaching of target temperature (~10 hours) and rapid rates of rewarming. However, hypothermia is not without its own systemic consequences, including coagulopathy, electrolyte imbalance, haemodynamic changes and altered drug pharmacokinetics.46,47

INTERVENTIONAL CARDIOLOGY REVIEW

Out-of-hospital Cardiac Arrest in the Cath Lab Due in part to the results of the TTM trial and perceptions of risk from hypothermia, current practice is to aim for 36°C in most cases.

The Targeted Hypothermia Versus Targeted Normothermia After Outof-hospital Cardiac Arrest (TTM-2) trial aims to address whether avoidance of pyrexia alone is important by randomising 1,900 patients to hypothermia at 33°C versus ≤37.8°C (NCT02908308).

On the theoretical basis that early initiation of hypothermia is critical to success, with a reported 20% increase in mortality with every hour of delay, intravascular infusion of cold saline has been used in both prehospital and centre settings.48 This holds particular promise in the cardiac catheterisation laboratory, where achievement of rapid hypothermia through conventional means, such as ice packs, can be challenging and lead to significant delays. Although rapid hypothermia can indeed be achieved by this method, this is at the cost of higher rates of re-arrest, pulmonary oedema and diuretic use, as well as lower rates of ROSC.49,50

Management in the Cardiac Catheterisation Laboratory Emergency Angiography and Revascularisation in Primary Cardiac OHCA

These studies confirm an increasing uptake of early coronary angiography, the feasibility and safety of its delivery and an indication that it may improve both survival and neurological recovery. The most contemporary meta-analysis included 15 observational studies and showed that survival was improved in the coronary angiography group compared with the group receiving conservative management (58.8% versus 30.9%; OR 2.77, 95% CI [2.06–3.72]), with a similar result for neurological outcome (58% versus 35.8%; OR 2.20, 95% CI [1.46–3.32]).121 However, these studies are observational and include highly heterogeneous populations, so these findings are susceptible to selection bias.

As with ST elevation, patients without ST elevation and OHCA have not been routinely recruited into RCTs. This group is especially heterogeneous and can include patients ranging from those with a normal ECG to those with profound ST depression. For this reason, both the ESC guidelines and the EAPCI recommend the provision of coronary angiography in patients without ST elevation if there is a high suspicion of a cardiac cause (i.e. chest pain before arrest, history of CAD and abnormal or uncertain ECG results) and in the absence of non-favourable arrest circumstances.28,122

There are numerous causes of OHCA, but a primary cardiac aetiology is common, either from underlying coronary artery disease (CAD) or

A recently reported meta-analysis that included seven observational studies and one RCT and >2,000 patients suggested that early coronary angiography may improve survival compared with delayed

myocardial disease. In post-mortem studies, 79.3% of young patients (mean age 38 years) with sudden cardiac death had a cardiac cause, with 56.7% of the total due to an acute MI; this figure was high as 73.3% in an older, unselected population.51,52 In clinical practice, there are similar rates of significant CAD as in these post-mortem studies.

Spaulding et al. reported very high rates of acute coronary occlusion in a cohort of consecutive patients presenting with OHCA (48%).53 Since then, there have been several retrospective cohort studies that have found rates of CAD between 50% and 80%, although these studies generally included highly selected populations.25,27,54

or no angiography (19.6% versus 35.6%; p<0.001).123 However, these studies are also observational, and this question is currently the subject of several on-going RCTs, including the Pilot RCT of Early Coronary Angiography Versus Delayed Coronary Angiography (PEARL; NCT02387398), Immediate Unselected Coronary Angiography Versus Delayed Triage in Survivors of Out-of-hospital Cardiac Arrest Without ST-segment Elevation (TOMAHAWK; NCT02750462), EMERGEncy Versus Delayed Coronary Angiogram in Survivors of Out-of-hospital Cardiac Arrest (EMERGE; NCT02876458) and Direct or Subacute Coronary Angiography in Out-of-hospital Cardiac Arrest (DISCO; NCT02309151).

One study that systematically evaluated the presence of CAD in a consecutive group of 257 patients with OHCA found rates of obstructive CAD (diameter stenosis >50%) of 63% in patients with ST elevation, 52% in patients with left bundle branch block (LBBB), 54% in patients with ST depression and 31% in patients with no acute changes.55 Rates of culprit lesions have been reported to be as high as 90% in patients with ST-elevation MI (STEMI), but culprit lesions are seen in 25–58% of patients even in the absence of ST-elevation on post-ROSC ECG.27,56,57 However, the high rates of obstructive CAD observed in this patient group do not provide a clear causal link to the cardiac arrest event, especially in the absence of a plaque rupture or the presence of a thrombus.

The COACT study was the first to recruit patients with OHCA without ST elevation into a randomised clinical trial comparing early versus delayed angiography.124 The overall finding of the study was that there was no benefit from early angiography in terms of mortality at 90 days. It is important to note that patients with shock and estimated glomerular filtration rate <30ml/min/1.73m2 were excluded from that study and, perhaps as a result, there was a lower than expected rate of culprit lesions (13%) and higher survival rate in both arms (65%). Nonetheless, most patients died from severe neurological injury regardless of randomisation arm.125

Whether emergency coronary angiography and subsequent PCI are of benefit following OHCA remains unclear, primarily because of a lack of data from randomised control trials (RCTs). OHCA patients have been systematically excluded from almost all clinical trials investigating revascularisation in an acute setting. Nonetheless, for patients with ST elevation or new LBBB at the time of ROSC, both European Society Guidelines (ESC) and American College of Cardiology Foundation/American Heart Association (AHA) guidelines recommend early coronary angiography (Class I, level b recommendation).58,59 Several observational studies and registries have evaluated the role of early angiography in patients with and without STEMI (Table 1).25,26,30,38,53,54,60–120

INTERVENTIONAL CARDIOLOGY REVIEW

It is plausible that provision of early PCI in the presence of an acute thrombotic occlusion or multiple obstructive lesions may limit the extent of cardiogenic shock, leading to improvements in left ventricular function and potentially protection from hypoxic brain injury. The benefits of restoration of coronary flow in this setting have been indicated in large animal studies.126 Current guidelines recommend emergency PCI for an acute occlusion, the presence of thrombus or abnormal flow, and these findings should, where appropriate, be correlated with ECG and echocardiography.28 The relative effects of acute plaque rupture and associated ischaemia in the pathophysiology of OHCA remain unclear.

Intracoronary imaging, particularly optical coherence tomography, may be of some use in illustrating these processes by delineating plaque morphology and identifying plaque rupture and thrombus, which may guide decision making, although the evidence for intracoronary imaging use in the OHCA population is limited.127

115

Coronary Table 1: Roles of Emergency Coronary Angiography and Percutaneous Coronary Intervention in Out-of-Hospital Cardiac Arrest Studies Author

Patients (n)

Comatose (%) STEMI (%)

Undergoing

PCI Success (%)

Surviving (%)

CPC 1â&#x20AC;&#x201C;2 (%)

PCI (%) Khan et al. 1995120

11

7 (64)

11/11 (100)

11 (100)

7/11 (64)

6/11 (55)

6/11 (55)

Spaulding et al. 199753

84

NA

34/84 (40)

37 (44)

28/37 (76)

32/84 (38)

30/84 (36)

Bulut et al. 2000

10

NA

10/10 (100)

10 (100)

10/10 (100)

4/10 (40)

NA

McCollough et al. 2002118

22

NA

22/22 (100)

22 (100)

22/22 (100)

9/22 (41)

NA

Keelan et al. 2003117

15

13 (87)

15/15 (100)

15 (100)

14/15 (93)

11/15 (73)

9/15 (60)

Bendz et al. 2004

40

119

36 (90)

40/40 (100)

40 (100)

38/40 (95)

29/40 (73)

NA

Quintero-Moran et al. 2006115 27

NA

27/27 (100)

27 (100)

23/27 (85)

18/27 (67)

NA

Sunde et al. 200718

47

NA

NA

30 (64)

NA

NA

NA

Gorjup et al. 2007

116

135

85 (64)

135/135 (100)

109 (81)

102/109 (94)

90/135 (67)

74/135 (55)

Garot et al. 2007113

186

NA

186/186 (100)

186 (100)

161/186 (87)

130/186 (70)

89/186 (48)

Richling et al. 2007112

46

NA

46/46 (100)

46 (100)

NA

24/26 (52)

22/46 (48)

25

18 (72)

25/25 (100)

25 (100)

22/25 (88)

19/25 (78)

17/25 (68)

24

NA

NA

13 (54)

NA

16/24 (67)

NA

114

Markusohn et al. 2007

111

Werling et al. 2007110 Hovdenes et al. 2007

49

49 (100)

NA

36 (73)

NA

41/49 (84)

34/49 (69)

Valente et al. 2008108

31

31 (100)

31/31 (100)

31 (100)

NA

23/31 (74)

NA

Mager et al. 2008107

21

NA

21/21 (100)

21 (100)

NA

18/21 (86)

NA

Wolfrum et al. 2008

109

16

16 (100)

16/16 (100)

16 (100)

NA

12/16 (75)

NA

Pleskot et al. 2008105

20

NA

NA

19 (95)

17/19 (89)

NA

NA

Peels et al. 2008104

44

NA

NA

44 (100)

33/44 (86)

22/44 (50)

NA

106

Merchant et al. 2008

30

NA

13/30 (43)

19 (63)

17/19 (89)

22/30 (80)

NA

Hosmane et al. 200926

98

73 (74)

98/98 (100)

64 (65)

62/64 (97)

63/98 (64)

57/98 (58)

Anyfantakis et al. 2009102

72

NA

23/72 (32)

27 (38)

24/27 (89)

35/72 (49)

33/72 (46)

Reynolds et al. 2009

103

96

NA

42/96 (44)

NA

NA

52/96 (54)

NA

Lettieri et al. 2009100

99

NA

99/99 (100)

99 (100)

79/99 (80)

77/99 (78)

72/99 (73)

Pan et al. 2010

101

49

NA

49/49 (100)

49 (100)

42/49 (86)

31/49 (63)

NA

Batista et al. 201098

20

NA

10/20 (50)

20 (100)

NA

8/20 (40)

6/20 (30)

Dumas et al. 201027

435

NA

134 (31)

202 (46)

177/202 (88)

171/435 (39)

160/435 (37)

Stub et al. 2011

99

62

62 (100)

27/62 (44)

31 (50)

29/31 (94)

NA

NA

Tomte et al. 201196

252

NA

NA

NA

NA

140/252 (56)

NA

Radsel et al. 201125

212

171 (82)

158/212 (75)

176 (78)

150/165 (91)

154/212 (73)

108/212 (51)

97

Mooney et al. 2011

101

NA

68/101 (67)

56 (55)

NA

NA

NA

Cronier et al. 201194

91

NA

50/91 (55)

46 (51)

43/46 (93)

60/91 (66)

NA

Mollmann et al. 201193

65

NA

36/65 (55)

65 (100)

64/65 (98)

46/65 (71)

NA

Nanjayya et al. 2012

95

35

35 (100)

31/35 (89)

21 (60)

NA

20/35 (57)

14/35 (40)

Bro-Jeppeson et al. 201291

360

360 (100)

116/360 (32)

122 (33)

101/122 (83)

219/360 (61)

207/360 (58)

Zanuttini et al. 201290

93

93 (100)

32/93 (34)

NA

NA

50/93 (54)

36/93 (39)

Liu et al. 2012

92

81

24 (30)

81/81 (100)

49 (60)

42/49 (46)

36/81 (44)

NA

Zimmermann et al. 201388

48

48 (100)

48/48 (100)

44/49 (92)

37/44 (84)

32/48 (67)

16/48 (33)

Hollenbeck et al. 2013

89

269

269 (100)

0/269 (0)

122 (45)

NA

151/269 (56)

NA

Velders et al. 201385

224

108 (48)

224 (100)

217 (97)

NA

183/218 (84)

168/218 (77)

Fothergill et al. 201486

206

NA

206/206 (100)

NA

NA

131/206 (66)

NA

Zelias et al. 2014

87

405

283 (70)

69/405 (17)

365/405 (90)

256/365 (70)

255/405 (63)

199/405 (49)

Reynolds et al. 201483

273

273 (100)

153/273 (44)

167/273 (49)

159/167 (95)

NA

128/273 (47)

Callaway et al. 201482

3,981

NA

573/3,981 (17.5)

705/3,981 (17)

NA

1,317/3,981 (33)

1,006/3,981 (25.3)

Casella et al. 2015

84

141

141 (100)

48/141 (34)

45/141 (32)

NA

86/141 (65)

61/141 (43)

Dankiewicz et al. 201580

544

544 (100)

0/544 (0)

101/544

NA

255/544

303/544 (56)

Kim et al. 201579

9,762

NA

NA

1,140/9,762 (12)

NA

3,891/9,762 (40)

1,667/9,762 (17)

Geri et al. 2015

1,722

NA

318/1,722

479/1,722 (28)

NA

548/1,722 (32)

NA

746

746 (100)

109/746 (26)

209/746

NA

335/746 (45)

298/746 (40)

78

Kern et al. 201554

81

(Continued)

116

INTERVENTIONAL CARDIOLOGY REVIEW

Out-of-hospital Cardiac Arrest in the Cath Lab Table 1: Cont.

Author

Patients (n)

Comatose (%) STEMI (%)

Undergoing

PCI Success (%)

Surviving (%)

CPC 1â&#x20AC;&#x201C;2 (%)

PCI (%) Kleissner et al. 201577

99

99 (100)

0/99 (0)

20/99 (20)

NA

65/99 (66)

55/99 (56)

Waldo et al. 2015

247

NA

84/247 (43)

NA

NA

NA

NA

Vyas et al. 201575

4,029

NA

NA

NA

NA

2,718/4,029 (67)

1,968/4,029 (49)

Redfors et al. 201574

638

NA

638/638 (100)

NA

NA

204/638 (32)

NA

Demirel et al. 2015

326

NA

326/326 (100)

275/326 (84)

254/276 (92)

270/326 (83)

NA

407,974

NA

82,410 (20)

80,321 (20)

NA

213,877 (52)

NA

76

73

Patel et al. 201672 Chelvanathan et al. 2016

176

176 (100)

45/176 (58)

45/176 (58)

NA

58/176 (33)

42/176 (24)

Garcia et al. 201670

315

191 (61)

104/315

121/315

NA

227/315 (72)

197/315 (63)

Dumas et al. 201669

695

NA

0/695 (0)

199/695 (29)

199/199 (100)

NA

251/695 (36)

Bergman et al. 2016

71

456

333 (73)

456/456 (100)

191/456 (42)

NA

202/456 (44)

NA

Jentzer et al. 201767

599

NA

138/599 (23.1)

158/599 (48)

NA

159/599 (27)

80/599 (13)

Shavelle et al. 201766

422

NA

422/422 (100)

422/422 (100)

NA

159/422 (38)

193/422 (46)

Tateishi et al. 2018

68

155

NA

52/155 (34)

64/155 (41)

60/64 (94)

104/155 (67.1)

74/155 (48)

Moutacalli et al. 201764

160

160 (100)

77/160 (48)

55/150 (34)

50/160 (91)

43/160 (56)

NA

Jeong et al. 201763

765

NA

NA

765/765 (100)

765/765 (100)

489/765 (64)

392/489 (51.2)

Kroupa et al. 2017

65

84

NA

30 (36)

50/84 (69)

46 (92)

44 (52)

37 (36)

Wilson et al. 201762

1,396

NA

NA

195/1,396 (14)

NA

NA

469/1,396 (34)

Patterson et al. 201738

40

NA

4/40 (10)

15/40 (38)

NA

15/40 (38)

NA

507

NA

220/507 (43)

257/507 (51)

NA

163/507 (32)

NA

238

116 (68)

238/238 (100)

238/238 (100)

NA

174/238 (73)

162/238 (68)

30

Staudacher et al. 2018 Taglieri et al. 201860

61

CPC = Cerebral Performance Category; NA = not available; PCI = percutaneous coronary intervention; STEMI = ST-elevation MI. Adapted from: Noc et al. 2014.28 Used with permission from the Europa Group.

Multivessel disease is common in the OHCA population (in up two-thirds of patients) and is associated with higher rates of cardiogenic shock, which itself is observed in approximately 50% of patients with OHCA.128,129 The role of multivessel PCI in the OHCA population has primarily been studied in the presence of cardiogenic shock, which is usually defined as a systolic blood pressure <90 mmHg or the requirement for ionotropic therapy to maintain this blood pressure. In the non-OHCA STEMI population, there have been several recent landmark trials that have suggested that multivessel PCI during the initial admission is safe and may provide clinical benefit.56,130â&#x20AC;&#x201C;132 Results of studies evaluating the role of multivessel PCI in the OHCA population are conflicting, particularly in those patients with cardiogenic shock. Systematic reviews of observational studies have suggested that this approach could be beneficial, although noting inherent selection bias.133,134

respectively).136 At 1 year, there was no difference in mortality between the two arms (50% versus 56.9% for culprit vessel versus multivessel PCI, respectively).137 As with the SHOCK trial, approximately 50% of patients recruited into the CULPRIT-SHOCK trial also had sustained OHCA, suggesting that this strategy may be appropriate in the OHCA population. In practice, a pragmatic approach should be adopted where multivessel PCI is restricted to those exhibiting poor clinical and haemodynamic responses to treatment of the culprit lesion.

Should the Patient be Taken Directly to the Cardiac Catheterisation Laboratory?

The SHould we emergently revascularize Occluded Coronaries in cardiogenic shocK (SHOCK) trial, in which 30% of patients had an OHCA, showed that early coronary revascularisation improved survival at 1 year compared with initial medical stabilisation (46.7% versus 33.6%).135 That study was not reflective of contemporary practice, with high rates of thrombolysis, 80% of patients receiving culprit PCI only and stent placement in only 35.4% of patients.

Decisions to take patients to the cardiac catheterisation laboratory are complex and are currently based on pragmatic assumptions of the likelihood of a culprit lesion, futility and the presence of haemodynamic instability, but with limited supportive clinical evidence. In contrast with previous observational trials in which patients with OHCA were selected for angiography on the basis of clinical discretion, there was a surprisingly low rate of culprit CAD in the COACT randomised clinical trial (i.e. in 13% of patients, with acute atherothrombotic lesions only in 3% of patients).125 Hence, methods of improving prediction of a culprit lesion are urgently required to guide an invasive strategy.

The Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial was a large, contemporary study that included a large proportion of patients following OHCA. In that study, despite improvements in care, advances in PCI techniques and stent technologies, there was limited improvement in mortality (43.3% across all patients) compared with the SHOCK trial.136 Culprit vessel PCI was superior to multivessel intervention alone in the primary endpoint of death or renal replacement therapy at 30 days (45.9% versus 55.4%,

The ACS2 score incorporates clinical features of cardiac arrest (presence of angina and congestive heart failure on admission), initial rhythm and 12-lead ECG findings in order to define the presence of a culprit lesion. In patients with STEMI, the area under the curve (AUC) was 0.88, but the discriminant ability of the ACS2 score was significantly lower in patients without ST elevation (AUC = 0.74).76 Objective prediction of futility on arrival to the cardiac catheterisation laboratory is another important consideration but currently remains

INTERVENTIONAL CARDIOLOGY REVIEW

117

Coronary Table 2: Characteristics of Common Anti-Platelet and Anti-Coagulant Agents Drug

ROA

Loading dose

Time to

Time to

Cooling

EPI (min)

PFR (h)

interaction

Aspirin

Oral, IV

300 mg, 200 mg IV

60

96

Mild

Clopidogrel

Oral

600 mg

360

120

Severe

Prasugrel

Oral

60 mg

90–120

168

Mild

Ticagrelor

Oral

180 mg

60–120

48–120

Mild to moderate

Cangrelor

IV

30 µg/kg bolus

2

0.5

None

Abciximab

IV

0.25 mg/kg bolus 15

24–48

None

Tirofiban

IV

180 µg/kg bolus

15–30

4

None

Eptifibatide

IV

10 µg/kg bolus

15–30

4

None

EPI = effective platelet inhibition (i.e. platelet function inhibited in >50% of patients); PFR = platelet function recovery; ROA = route of administration. Adapted from: Nerla et al. 2015.180 Used with permission from BMJ Publishing Group.

a significant challenge. Risk algorithms and biomarkers hold significant potential in this regard, but these have currently failed to translate to the clinical realm, partly because they have had limited application and validation on arrival, when emergency treatment decisions are made.138 The Cardiac Arrest Hospital Prognosis (CAHP) score is a multivariable nomogram that is used on arrival to the intensive treatment unit (ITU) and predicts poor neurological recovery on ITU discharge.139 A subanalysis of that study indicated that patients with lower predicted risk of neurological injury benefit more from an early invasive approach than those at higher risk.140 This has been replicated in other studies, where patients with the most severe form of cardiac arrest were most likely to die from neurological causes.83,141 Finally, it is accepted that patients with on-going haemodynamic instability may benefit more from revascularisation, as indicated by the results of the SHOCK study.142 However, whether patients after OHCA with cardiogenic shock may additionally benefit from early implantation of mechanical circulatory support devices remains unclear. The CREST model identified five variables in patients without ST elevation that could predict, with moderate accuracy, patients at higher risk of cardiac aetiology death.143 Integration of these risk scores into prospective clinical trials may provide objective information to support decision making on arrival to the cardiac catheterisation laboratory.

Pharmacological Considerations Pharmacological treatment in conscious survivors of OHCA does not differ from management of patients with acute coronary syndrome without cardiac arrest.57 However, comatose survivors of OHCA pose a unique challenge, mostly because they are mechanically ventilated and thus unable to take drugs orally. This can often lead to significant delays in the administration of many drugs until a gastric tube is inserted.

In addition, several other factors may play a role in the efficacy of antiplatelet drugs, including reduced intestinal drug absorption due to gastroparesis and hypoperfusion, therapeutic hypothermia and increased platelet reactivity in response to systemic inflammation following resuscitation.123 These mechanisms place OHCA patients at a particularly high risk of acute and subacute stent thrombosis, ranging from 1.4% up to 31%.144-148 In contrast, as a result of possible injuries due to chest compression, intubation and trauma during the OHCA, these patients are also at an increased risk of bleeding.149

118

Antiplatelet drugs represent the fundamental pharmacological treatment in patients receiving coronary stents. The pharmacological characteristics of the commonly used anti-platelet drugs used are summarised in Table 2. Llitjos et al. reported that 45% of comatose OHCA survivors had an insufficient response to aspirin regardless of the route of administration, possibly due to increased platelet reactivity in the setting of the OHCA.150 Nevertheless, closure time, which is a measure of platelet inhibition in vitro, was significantly increased in the intravenous group, suggesting that a parenteral route of administration is the preferred choice.150 Moreover, the intravenous route is justified not only for initial, but also for subsequent aspirin administration because the absorption of enterally administered aspirin remains affected by hypothermia.151 Oral inhibitors of the ADP P2Y12 receptor, which can be given only via a nasogastric tube, have delayed onset of antiplatelet activity, particularly in the case of clopidogrel.152 Even in the case of novel and more potent agents, such as ticagrelor, there is still a 3- to 4-hour delay until target platelet inhibition is reached.153 The antiplatelet effects of all oral P2Y12 receptor inhibitors, including ticagrelor, are known to be reduced by therapeutic hypothermia, which, in turn, leads to a higher rate of stent thrombosis.154 Prüller et al. compared platelet inhibition in patients in whom the new intravenous P2Y12 inhibitor cangrelor was used to bridge the gap observed with the oral P2Y12 inhibitors and observed a significantly higher anti-aggregation effect with cangrelor after 8 hours without an excess of bleeding.155 Further prospective studies are needed to specifically investigate whether periprocedural treatment with cangrelor can bridge a 3-hour gap in platelet inhibition following administration of the novel oral P2Y12 inhibitors via nasogastric tube in comatose survivors of OHCA. Conversely, the clinical benefits of ticagrelor over clopidogrel in this high-risk subset of patients remain to be robustly proven. A recent meta-analysis showed that there was no difference in the incidence of stent thrombosis (6.1% versus 6.3%), in-hospital mortality or major bleeding between clopidogrel and the newer P2Y12 inhibitors ticagrelor and prasugrel.156 There have been no specific studies regarding anticoagulation in comatose survivors of OHCA undergoing PCI, and currently unfractionated heparin is generally used. Glycoprotein IIb/IIIa inhibitors are used as a bailout strategy at the discretion of the interventional cardiologist, who also has to consider the increased risk of bleeding in these patients.58 In a recent observational study of 71 patients with OHCA treated with therapeutic hypothermia, the use of glycoprotein IIb/IIIa inhibitors was associated with increased bleeding risk with no benefit with regard to thrombotic events.157 Owing to a lack of appropriately sized prospective clinical trials in this area, most studies in this field to date have been insufficiently powered to enable satisfactory conclusions to be drawn.

Mechanical Circulatory Ventricular Support in OHCA-associated Cardiogenic Shock Mechanical circulatory ventricular support devices are potentially useful in the OHCA population with cardiogenic shock, present in approximately half of all patients.128 The putative benefits of such devices are attenuation of cardiogenic shock, which is the cause of death in one-quarter of patients, temporary relief of myocardial dysfunction (‘stunning’) and minimisation of multiorgan dysfunction (Table 3).16

INTERVENTIONAL CARDIOLOGY REVIEW

Out-of-hospital Cardiac Arrest in the Cath Lab Table 3. Features of Mechanical Circulatory Support Devices Device

Access (Fr)

Haemodynamic support (l/min)

Afterload

LV stroke volume

Mechanical work

Coronary perfusion

LV preload

LA pressure

Peripheral perfusion

Active cooling

IABP

7

0.5–1.0

↓

↑

↔

↑

↓

↓

↑

No

Impella LVAD

14

2.5–5.0

↔

↓

↓

↑

↓↓

↓↓

↑↑

No

>4.5

↑

↓

↑↑

Unknown

↑↑

↓↓↓

↑

Yes

VA-ECMO

21

IABP = intra-aortic balloon pump; LA = left atrial; LV = left ventricular; LVAD, left ventricle assist device; VA-ECMO = veno-arterial extracorporeal membranous oxygenation.

Adapted from: Nerla et al. 2015.180 Used with permission from BMJ Publishing Group.

The use of supportive pharmacotherapy is near ubiquitous in cardiogenic shock despite limited evidence supporting its use. The use of catecholamines, such as noradrenaline, adrenaline and dobutamine, improves myocardial contractility and leads to systemic and arterial vasoconstriction. Although this causes a temporary improvement in haemodynamics, it can paradoxically lead to an increase in cardiac work, oxygen consumption and disproportionate arterial vasoconstriction, all of which can have systemic deleterious effects.158 In two randomised controlled trials, noradrenaline had the same effect on cardiac index as adrenaline but with less deleterious effects on heart rate and lactate.159 This led to lower rates of refractory cardiogenic shock in those treated with noradrenaline then adrenaline (37% versus 7%; p=0.008).159 Dobutamine is a powerful inotrope but with a relative vasodilatory effect compared with the other catecholamines

the basis of these results, both ESC and AHA guidelines no longer recommend routine use of IABPs in cardiogenic shock.58,59,122

owing to increased beta-2 action, which may be of particular benefit in patients with cardiogenic shock who exhibit profound systemic vasoconstriction. Dopamine has traditionally been used in cardiogenic shock, but in a large trial of patients with cardiogenic shock its use was associated with higher rates of adverse events than in patients treated with noradrenaline.160

and did not show any difference in mortality at 30 days. Furthermore, the Impella failed to show benefit compared with the IABP in the Initial Management of Patients Receiving a Single Shock (IMPRESS) trial, which was a small trial that recruited 49 patients randomised against the IABP.168 Again, half the patients recruited into that trial had suffered a cardiac arrest, and there was a high rate of neurological injury leading to death. As with ISAR-SHOCK, the IMPRESS trial was significantly underpowered for clinical endpoints. A meta-analysis including 2,483 patients from 13 trials comparing IABPs, the Impella LVAD and conservative therapy in patients with cardiogenic shock found that all strategies had equal outcomes, but that Impella use was associated with higher bleeding rates.169

Nonetheless, current ESC guidelines recommend the use of noradrenaline as a first-line agent with Class IIb, level of evidence B.161,162 Novel agents, such as levosimendan (a calcium sensitiser) and milrinone (a phosphodiesterase inhibitor), have the potential to improve contractility without significantly increasing metabolic requirements whilst inducing an element of vasodilatation. However, there is extremely limited randomised trial data for their use, and studies are required to understand their contemporary use in cardiogenic shock.163 Several devices are currently available, including intra-aortic balloon pumps (IABP), the Impella family of left ventricular assist devices (LVADs; Abiomed) and devices to provide veno-arterial extracorporeal membranous oxygenation (VA-ECMO).

Intra-aortic Balloon Pumps IABPs are counterpulsation devices situated in the descending aorta that inflate in diastole and deflate in systole. This reduces cardiac afterload and increases coronary blood flow, resulting in a small increase in cardiac output (0.5–1 l/min), lowers wall stress and reduces myocardial oxygen consumption, although with a modest reduction in the mechanical work of the heart.164 An IABP was used in 86.1% of patients in the SHOCK trial, and equally in the revascularisation and initial medical stabilisation groups.135 The role of IABPs in cardiogenic shock was specifically studied in the IABP SHOCK II trial, an RCT that recruited 600 patients, nearly half of whom had suffered cardiac arrest. In that study, there was no difference in the primary endpoint of mortality or several secondary endpoints, such as bleeding, sepsis and lactate levels, between the IABP and control groups.165 The timing of implantation before or after PCI had no effect on outcome.166 On

INTERVENTIONAL CARDIOLOGY REVIEW

Impella Left Ventricular Assist Devices The Impella is a percutaneous mini-axial flow LVAD that is placed across the aortic valve and has three different platforms that generate 2.5–5 l/min cardiac output. The Impella LVAD reduces preload and the mechanical work of the heart, and improves haemodynamic parameters.158 The Efficacy Study of LV Assist Device to Treat Patients With Cardiogenic Shock (ISAR-SHOCK) trial compared IABPs and the Impella 2.5 in 26 patients with cardiogenic shock.167 The Impella 2.5 did not significantly improve the cardiac index (from 1.71 l/min/m2 at baseline to 2.20 l/min/m2) compared with the IABP (from 1.73 l/ min/m2 at baseline to 1.81 l/min/m2).167 That study was underpowered

A retrospective study of 287 patients found that early implantation of Impella (prior to PCI) in cardiogenic shock was associated with improved survival (66% when mechanical circulatory support was initiated <1.25 hours from shock onset, 37% when initiated within 1.25–4.25 hours, and 26% when initiated after 4.25 hours; p=0.017).34 In the CULPRIT-SHOCK trial, there were relatively high rates of mechanical circulatory support device implantation, where it was used in 27.4% of patients, of which 42.2% were implanted with the Impella.137 Results from a small consecutive series indicate that Impella use may be of benefit at the time of refractory VF OHCA with on-going CPR.170 In that study, survival with good neurological function was recorded in 50% of patients, but the major vascular complication rate was 50%.170

Extracorporeal Membranous Oxygenation VA-ECMO is a mode of circulatory bypass that can support both ventilatory and circulatory function and can be used in the cardiac catheterisation laboratory but is currently available primarily in supraspecialist units.142 VA-ECMO returns oxygenated blood at high flow rates to the arterial system, achieving a cardiac output of 2.5–5 l/min with a reduction in preload and improvement in systemic tissue perfusion. However, because blood is often returned into the descending aorta, there is an increase in afterload with incomplete unloading of the left ventricle (LV),171 which reduces LV stroke volume

119

Coronary and, in turn, increases LV wall stress and mechanical work of the heart and potentially reduces coronary perfusion.172 Concurrent use of the IABP may enable improved coronary perfusion in diastole, reduced wall stress and improved stroke volume, whereas the Impella device has higher flow rates with more effective unloading of the LV.173 Miniaturisation of ECMO equipment and percutaneous cannulation has made its use increasingly feasible, leading to increased use worldwide.174,175 However, the benefit of ECMO in cardiogenic shock is uncertain owing to a lack of RCTs. Several non-randomised observational studies were included in a pooled analysis of 1,116 patients with cardiogenic shock (of whom 540 had cardiac arrest), with the results suggesting that survival to hospital discharge is in the region of 40% with a better outcome in the cardiogenic shock group than in those following OHCA, possibly because of a higher rate of ‘neurological death’ in the latter group (52.5% versus 36.2%).176 The complication rate with ECMO in that study was high, with 47.4% of patients developing renal impairment, 25% developing infection and 13.1% developing persisting neurological deficits. Although these studies cumulatively include large populations and reflect real-world practice, they are a combination of several small observational studies and have significant selection bias; therefore, the results need to be interpreted with caution.

ECMO can also be used in extracorporeal CPR (ECPR), where mechanical circulatory support is used to augment cardiopulmonary function in cases of refractory cardiac arrest, defined as a failure to respond to conventional CPR. ECPR can be used on admission to a cardiac arrest centre or at the scene. Data from 295 patients in the Extracorporeal Life Support Organization (ELSO) registry found a survival to discharge after ECPR of 27%,177 and a propensity matched study found that use of ECPR was an independent predictor of survival to discharge (HR 0.51, 95% CI [0.35–0.74], p<0.0001) and at 1 year (HR 0.53, 95% CI [0.33–0.83], p=0.006).178 A meta-analysis from 2017 that included six studies and in which 376 patients received ECPR demonstrated an improved survival to discharge compared with conventional treatment (relative risk [RR] 2.37, 95% CI [1.63–3.45], p<0.001) and better long-term neurological outcome (RR 2.79, 95% CI [1.96–3.97], p<0.001).179 However, these findings should be seen as hypothesis generating because they involve highly selected cases. A Comparative Study Between a Pre-hospital and an In-hospital Circulatory Support Strategy (ECMO) in Refractory Cardiac Arrest (APACAR2) (NCT0252703), which is currently recruiting, will evaluate prehospital ECPR versus in-hospital ECMO and provide further insights.

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At present, the use of mechanical circulatory support devices, particularly Impella and ECMO, cannot be recommended in patients with OHCA or in cardiogenic shock on the basis of current evidence.

Identification and risk stratification of patients who may benefit the most from these highly invasive and costly therapies is urgently required. Ongoing controlled trials, such as Testing the Value of Novel Strategy and Its Cost Efficacy in Order to Improve the Poor Outcomes in Cardiogenic Shock (EUROSHOCK; NCT03813134) and Early Initiation of Extracorporeal Life Support in Refractory OHCA (INCEPTION; NCT03101787), may help address the current uncertainties.

Future Directions Urgent clinical trials and translational research to address numerous uncertainties in this field are required. Firstly, the ECG is currently used as the frontline tool for decision making, but this is known to be a poor identifier of CAD in this group of patients, and novel assessment tools or biomarkers may, in future, allow for improved discrimination. Secondly, the effects of hypoxic brain injury overwhelm the potential benefit of PCI in all-comers with OHCA because this remains the leading cause of death. Risk stratification tools and biomarkers validated on arrival to a cardiac centre to identify those at high risk of hypoxic brain injury may enable a more nuanced decision-making process. Thirdly, the role of mechanical circulatory support devices in this population remains unclear.

A better understanding of the relationship between haemodynamic and metabolic phases of shock, together with improved patient stratification, will improve the optimal harnessing of these novel technologies. Finally, in order for tangible improvements in patient outcomes to be realised, an improved evidence base from translational research and well-conducted clinical trials is required to facilitate appropriate patient selection for aggressive invasive and supportive cardiovascular interventions.

Conclusion OHCA remains an important cause of death in developed countries and there is a significant drive to improve early and long-term outcomes. It is common for OHCA to have primary cardiac cause, so pathways of care that convey patients directly to a specialist cardiac centre may be advantageous, and this has been recognised in recent guidelines.22–24 However, bringing all patients with OHCA directly to a cardiac centre will place a significant resource burden on these units with, as yet, limited evidence that outcomes are improved in an unselected population. Observational data suggest that direct conveyance of the Utstein comparator cohort to heart attack centres is beneficial and may set a paradigm for extension to the undifferentiated population. ■

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176. Xie A, Phan K, Tsai YC, et al. Venoarterial extracorporeal membrane oxygenation for cardiogenic shock and cardiac arrest: a meta-analysis. J Cardiothorac Vasc Anesth 2015;29:637– 45. https://doi.org/10.1053/j.jvca.2014.09.005; PMID: 25543217.

177. Thiagarajan RR, Brogan TV, Scheurer MA, et al. Extracorporeal membrane oxygenation to support cardiopulmonary resuscitation in adults. Ann Thorac Surg 2009;87:778–85. https:// doi.org/10.1016/j.athoracsur.2008.12.079; PMID: 19231388.

178. Chen YS, Lin JW, Yu HY, et al. Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis. Lancet 2008;372:554–61. https://doi.org/10.1016/ S0140-6736(08)60958-7; PMID: 18603291.

179. Wang GN, Chen XF, Qiao L, et al. Comparison of extracorporeal and conventional cardiopulmonary resuscitation: a meta-analysis of 2260 patients with cardiac arrest. World J Emerg Med 2017;8:5–11. https://doi.org/10.5847/ wjem.j.1920-8642.2017.01.001; PMID: 28123613.

180. Nerla R, Webb I, MacCarthy P. Out-of-hospital cardiac arrest: contemporary management and future perspectives.

Heart 2015;101:1505–16. https://doi.org/10.1136/ heartjnl-2014-306961; PMID: 26215985.

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Coronary

Left Main Coronary Artery Interventions Mirvat Alasnag 1 , Lina Yaqoub, 2 Ammar Saati 3 and Khaled Al-Shaibi 1 1. King Fahd Armed Forces Hospital, Jeddah, Saudi Arabia; 2. Louisiana State University, LA, US; 3. Brown University, RI, US

Abstract The management of left main coronary artery (LMCA) disease has evolved over the past two decades. Historically, coronary artery bypass grafting (CABG) surgery has been the gold standard for the treatment of LMCA disease. However, with the advancements in percutaneous coronary interventions (PCIs) and stent technology, PCI in select patients has achieved comparable outcomes to CABG. As such, this has led to changes in the American College of Cardiology and European Society of Cardiology guidelines, which recommend that PCI might be an alternative to CABG in select patients. In this review article, we describe the historical perspective and early experience with coronary interventions of LMCA disease, landmark clinical trials and their effect on guidelines, and the role of intravascular imaging in the management of LMCA lesions.

Keywords Left main coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft surgery, left main coronary interventions, intravascular imaging Disclosure: The authors have no conflicts of interest to declare.

Received: 20 February 2019 Accepted: 3 June 2019 Citation: Interventional Cardiology Review 2019;14(3):124–30. DOI: https://doi.org/10.15420/icr.2019.10.R2 Correspondence: Khaled Al-Shaibi, Director Cardiac Center, King Fahd Armed Forces Hospital, PO Box 9862, Jeddah 21159, Saudi Arabia. E: kfalshaibi@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.

Historical Perspective and Early Experience Historically, coronary artery bypass grafting (CABG) surgery has been the gold standard treatment for left main coronary artery (LMCA) disease. However, with the developments and advancements in the interventional cardiology field, percutaneous coronary intervention (PCI) has become a safe alternative management option to CABG in select patients. Today, LMCA disease is identified in about 5% of patients undergoing primary coronary intervention for evaluation of ischaemia.1 The first left main PCI was performed by Andreas Gruntzig in 1978 using plain old balloon angioplasty (POBA). In his initial experience, Gruntzig performed POBA in 50 patients over a period of 18 months; POBA was deemed successful in 32 patients. Using POBA, mean left main stenosis improved from 84% to 34% (p<0.001) with coronary pressure gradient improving from a mean of 58 mmHg to 19 mmHg (p<0.001).2 POBA alone was associated with acute and subacute vessel closure, elastic recoil, late vascular remodelling and re-narrowing of coronary arteries. This led to the development of coronary stents and their progressive refinement from bare-metal stents (BMS) to drugeluting stents (DES). These newer stents addressed the shortcomings of BMS, specifically in-stent restenosis. Furthermore, the development of novel anti-platelet medications has led to significant reductions in the incidence of major adverse cardiac events (MACE).

Important Randomised Clinical Trials

patients were randomised to receive PCI (n=100) or CABG (n=101), with follow-up for 12 months. Mortality and MI rates were comparable, but PCI was associated with higher rates of repeat revascularisation and CABG was associated with higher rates of stroke. The combined primary endpoint was noninferiority in freedom from major adverse cardiac events and the need for target vessel revascularisation within 12 months; this was observed in 13.9% of patients after CABG, as opposed to 19.0% after PCI (p=0.19 for noninferiority).

Combined rates for death and MI were comparable (7.9% in the CABG group versus 5.0% in the PCI group; noninferiority p<0.001), but PCI was inferior to CABG for repeat revascularisation (5.9% versus 14.0%; noninferiority p=0.35). Perioperative complications (including two patients having strokes) were higher after CABG (4% in PCI versus 30% in CABG; p<0.001). Freedom from angina was similar between the groups (p=0.33).3

SYNTAX In 2014, subgroup analysis of the Synergy Between PCI With TAXUS And Cardiac Surgery (SYNTAX) trial compared left main PCI using firstgeneration DES with CABG.4 A total of 357 patients received PCI and 348 patients received CABG. At 5 years, in patients with SYNTAX score <33 (a scoring system that quantifies angiographic lesion complexity) the incidence of MACE was similar in the PCI and CABG groups. However, there was a higher incidence of target vessel revascularisation (TVR) in the PCI group than in the CABG group.

Early Evidence In a 2011 study, Boudriot et al. compared PCI using sirolimus-eluting stents with CABG for the management of LMCA disease.3 Overall 201

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Access at: www.ICRjournal.com

In patients with a high SYNTAX score (≥33), CABG had favourable outcomes compared with PCI. Major adverse cardiac and

© RADCLIFFE CARDIOLOGY 2019

Left Main Coronary Artery Interventions cerebrovascular events (MACCE) rates at 5 years were 36.9% in the PCI arm and 31.0% in the CABG arm (HR 1.23; 95% CI [0.95–1.59]; p=0.12). The mortality rate was 12.8% and 14.6% in the PCI and CABG arms, respectively (HR 0.88; 95% CI [0.58–1.32]; p=0.53). Stroke rate was significantly higher in the CABG arm (PCI 1.5% versus CABG 4.3%; HR 0.33; 95% CI [0.12–0.92]; p=0.03) while repeat revascularisation was significantly higher in the PCI arm (26.7% versus 15.5%; HR 1.82; 95% CI [1.28–2.57]; p<0.01). MACCE was similar between the two arms in patients with low/intermediate SYNTAX scores but significantly higher in PCI patients with SYNTAX scores ≥33.

PRECOMBAT The Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease (PRECOMBAT) trial was published in 2015.5 This multicentre trial in South Korea randomised 300 patients to PCI and 300 patients to CABG. There was no significant difference in rates of MACE in patients undergoing PCI with sirolimuseluting stents compared with patients undergoing CABG over 5 years of follow-up. There was a higher incidence of revascularisation in the PCI group compared with the CABG group.

At 5 years, MACCE occurred in 52 patients in the PCI group and 42 patients in the CABG group (cumulative event rates of 17.5% and 14.3%, respectively; HR 1.27; 95% CI [0.84–1.90]; p=0.26). The two groups did not differ significantly in terms of death from any cause, MI, or stroke as well as their composite (8.4% and 9.6%; HR 0.89; 95% CI [0.52–1.52]; p=0.66). Ischaemia-driven TVR occurred more frequently in the PCI group than in the CABG group (11.4% and 5.5%, respectively; HR 2.11; 95% CI [1.16–3.84]; p=0.012).5

LE MANS The multicentre Left Main Coronary Artery Stenting (LE MANS) trial randomised 105 patients to PCI (n=52) or CABG (n=53). Of those undergoing PCI, only 35% received DES; the majority received BMS. The study showed a favourable but statistically non-significant outcome in favour of PCI compared to CABG over a 10-year follow-up period.

At 10 years, there was a trend towards higher ejection fraction with PCI compared with CABG (54.9% ± 8.3 versus 49.8% ± 10.3; p=0.07), lower mortality (21.6% versus 30.2%; p=0.41) and lower MACCE (51.1% versus 64.4%; p=0.28). Although there were no statistically significant differences between groups, numerically the findings were favour of stenting. Similarly, there was no difference in the occurrence of MI (8.7 versus 10.4%; p=0.62), stroke (4.3 versus 6.3%; p=0.68), and repeat revascularisation rates (26.1% versus 31.3%; p=0.64). The probability of very long-term survival up to 14 years was comparable between PCI and CABG (74.2% versus 67.5%; p=0.34; HR 1.45 95% CI [0.67–3.13]).

However, there was a trend towards higher MACCE-free survival in the PCI group (34.7% versus 22.1%; p=0.06; HR 1.71 95% CI [0.97–2.99]).6

EXCEL and NOBLE More recently the Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) and Nordic-Baltic-British Left Main Revascularization Study (NOBLE) trials were published.7,8 These two multicentre randomised clinical trials were performed to assess the outcomes of second-generation DES in left main PCIs compared with CABG. In the EXCEL trial, a total of 1,905 patients with low–intermediate SYNTAX score of <33 were randomised to PCI versus CABG.7 The primary endpoint was defined as a composite of all-cause death, MI

INTERVENTIONAL CARDIOLOGY REVIEW

and stroke at 3 years. The primary endpoint occurred in 15.4% of the patients in the PCI group and in 14.7% of the patients in the CABG group (difference of 0.7 percentage points; upper 97.5% confidence limit 4.0 percentage points; p=0.02 for noninferiority; HR 1.00; 95% CI [0.79–1.26]; p=0.98 for superiority).

The secondary endpoint was defined as a composite endpoint of all-cause death, MI or stroke at 30 days. It occurred in 4.9% of the patients in the PCI group and in 7.9% in the CABG group (p<0.001 for noninferiority, p=0.008 for superiority). The secondary endpoint event of death, stroke, MI, or ischaemia-driven revascularisation at 3 years occurred in 23.1% of the patients in the PCI group and in 19.1% in the CABG group (p=0.01 for noninferiority, p=0.10 for superiority). In summary, 30-day MACE was lower in PCI group, but similar for both the PCI and CABG at 3-year follow-up.

In the NOBLE trial, a total of 1,201 patients with low–intermediate SYNTAX score were randomised to PCI using biolimus-eluting stents versus CABG.8 The 30-day outcomes were similar to those of the EXCEL trial, but the 5-year outcomes MACCE for PCI were inferior to CABG, mainly due to repeat revascularisation, an endpoint not included in the composite endpoint of EXCEL but in keeping with most of the cumulative literature on this subject in prior randomised trials. At 5 years, estimates of MACCE were 29% for PCI (121 events) and 19% for CABG (81 events), HR 1.48 (95% CI [1.11–1.96]), exceeding the limit for non-inferiority. CABG was significantly better than PCI (p=0.0066). The as-treated estimates were 28% versus 19% (HR 1.55; 95% CI [1.18–2.04]; p=0.0015). Comparing PCI with CABG, 5-year estimates were 12% versus 9% (HR 1.07; 95% CI [0.67–1.72]; p=0.77) for all-cause mortality, 7% versus 2% (HR 2.88; 95% CI [1.40–5.90]; p=0.0040) for non-procedural MI, 16% versus 10% (HR 1.50; 95% CI [1.04–2.17]; p=0.032) for any revascularisation, and 5% versus 2% (HR 2.25; 95% CI [0.93–5.48]; p=0.073) for stroke.

It is important to note that the primary endpoint in EXCEL trial differed from all other major left main trials including NOBLE because it excluded repeat revascularisation as a primary endpoint and added periprocedural MI within the composite endpoint. Furthermore, the NOBLE investigators excluded periprocedural MIs, which were captured by the EXCEL investigators. It is notable that although the primary DES used in NOBLE was the biolimus stent, 10% of patients received a first-generation DES before the switch to biolimus was made. On the other hand, EXCEL exclusively used the second-generation evirolimus stent (Xience).

MAIN-COMPARE Registry In 2018, in the observational cohort study of the Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty versus Surgical Revascularization (MAIN-COMPARE) registry, the 10-year outcomes of PCI and CABG were assessed.9 The overall cohort found that there was no significant difference in the adjusted risk of death and composite outcomes between both groups at 10 years. However, there was a higher rate of TVR in the PCI group.

Meta-analyses Several meta-analyses of these major clinical trials have shown that PCI has similar rates of MACE compared to CABG over 3–5 years in the management of LMCA disease, with PCI being associated with higher repeat revascularisation rates and CABG being associated with higher stroke rates in the early follow-up period. Moreover, these

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Coronary Table 1: Randomised Controlled Trials Included in the Analysis Study

Inclusion criteria

n

PCI (n)

DES (%)

IVUS (%)

CABG (n)

LIMA to LAD (%)

MACCE endpoint

Morice et al.

SYNTAX-LM 20144

>50% ULM stenosis; angina

705

357

100

NR

348

97

Death, MI, CVA, RR 5 years

Ahn et al.

PRECOMBAT 20155

>50% ULM stenosis; angina or ischaemia

600

300

100

91.2

300

93.6

Death, MI, CVA, TVR 5 years

Stone et al.

EXCEL 20167

≥50% ULM stenosis;* angina

1,905

948

99.8

77.2

957

98.8

†

Makikallio et al.

NOBLE 20168

≥70% ULM stenosis

1,194

592

100

74.9

592

93.4

||

‡

§

Death, MI, CVA Median 3 years Death, MI, CVA, RR Median 3.1 years

*Lesions with an FFR ≤0.8 were also included. †Any internal mammary artery graft. ‡Lesions >50% but <70% were included if non-invasive or invasive functional ischaemia demonstrated. §Post-stent implantation only. ||Any arterial graft to LAD. CABG = coronary artery bypass grafts; CVA = cerebrovascular accident; DES = drug eluting stent; IVUS = intravascular ultrasound; LAD = left anterior descending artery; LIMA = left internal mammary artery; MACCE = major adverse cardiac and cerebrovascular events; NR = not reported; PCI = percutaneous coronary intervention; RR = repeat revascularisation; TVR = target vessel revascularisation; ULM = unprotected left main artery. Source: Moore et al. 2017.10 Reproduced with permission from Elsevier.

Table 2: Patient and Procedural Characteristics in Each Study Study

Mean Age (years)

Male (%)

Diabetes (%)

3vCAD (%)

LVEF (%)

Mean

Mean SYNTAX

LMCA bifurcation

Euroscore

score

involvement (%)

Morice et al.

SYNTAX-LM 20144

65.5

73.8

24.7

36.6

–

3.9

29.9

61

Ahn et al.

PRECOMBAT 20155

62.3

76.5

32

40.8

61.2

2.7

25.1

63.8

Stone et al.

EXCEL 20167

65.9

76.9

29.1

18.3

57.2

–

26.5*

80.5

Makikallio et al.

NOBLE 20168

66.2

78.4

14.9

–

60

2†

22.5

81

*As per core laboratory analysis. †Median Euroscore published only. 3vCAD = three vessel coronary artery disease; CABG = coronary artery bypass grafts; LMCA = left main coronary artery; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention. Source: Moore et al. 2017.10 Reproduced with permission from Elsevier.

meta-analyses also showed that the use of second-generation DES was associated with lower revascularisation rates compared to first generation DES. Moore et al. analysed four major clinical trials in their meta-analysis (SYNTAX, PRECOMBAT, EXCEL and NOBLE; Tables 1 and 2). 10 The incidence of MACCE at 3 to 5 years of follow-up was significantly higher with PCI compared to CABG (23.3% versus 18.2%, OR 1.37; 95% CI [1.18–1.58]; p=<0.0001; I2=0%) and was largely driven by more repeat revascularisation procedures among patients treated with PCI. There was no statistically significant difference in rates of mortality, MI or stroke (either individually or when these outcomes were combined as a composite endpoint). Figures 1 and 2 summarise MACCE with an analysis by SYNTAX score and generation of stent.10–12

The CathPCI Registry More recently in 2019, Valle et al. reviewed data from the National Cardiovascular Data Registry (NCDR) CathPCI registry reflecting current left main PCI outcomes in a real-world setting. The investigators compared outcomes collected in the NCDR registry with participants of the EXCEL and NOBEL trials. Patients from the CathPCI registry were significantly older, had more medical comorbidities, more frequently suffered stroke, and intravascular imaging was used less frequently.13

Role of Intravascular Imaging in Left Main Coronary PCI Assessing the severity of stenosis of the LMCA with angiography has challenges. These include a short left main, obscured lesions from overlapping vessels or from reflux of contrast around the catheter in the aortic sinus, overestimation of the severity of the lesion particularly in the left anterior oblique projection with cranial angulation, catheter induced spasm, ambiguous eccentric lesions, underestimation of

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stenosis due to diffuse coronary artery disease and calcification.14 Hence, accurate assessment frequently requires additional evaluation to determine the appropriate revascularisation strategy. For highquality cross-sectional imaging, intravascular ultrasound is particularly useful for assessment of both lumen and wall characteristics, positive remodelling and plaque burden.15 Compared to infrared light of optical coherence tomography (OCT), intravascular ultrasound has a higher tissue penetration and does not have the limitations of OCT in imaging the left main ostium.16 The minimal luminal area (MLA) is the most accepted variable for detecting a significant lesion, with a sensitivity of 93% and of specificity 95%, with MLA <6.0 mm2. Yet this was determined in predominantly western populations. MLA cut-off value can vary within different populations due to difference in body mass and vessel size. In asian patients, MLA <4.8 mm2 and MLA <4.1 mm2 were found to be significant for left main disease and had a sensitivity of 77%, 95% and specificity 82%, 83% respectively.17–19 Another modality to assist in the decision making process is physiological assessment of the lesion using Fractional flow reserve (FFR) with a cut-off of <0.08 indicating an important flow-limiting stenosis. A limitation to FFR is its inability to accurately determine the significance of the stenosis in the presence of tandem lesions. However, FFR may still play a significant role in the treatment of left main coronary artery bifurcation disease.

For example, it can be useful in determining the significance of an ostial stenosis of the side branch (usually the left circumflex artery) and the need for a two-stent strategy.20–21

European and American Guidelines The standard of care for LMCA disease for many years has been CABG over medical therapy because of mortality benefit.22

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Left Main Coronary Artery Interventions Figure 1: Comparison of Major Adverse Cardiac and Cerebrovascular Events Between Percutaneous Coronary Intervention and Coronary Artery Bypass Grafts MACCE Study or Subgroup

PCI Events Total 130 52 121 208

SYNTAX-LM PRECOMBAT NOBLE EXCEL

357 300 592 948

103 42 81 174

2,197

Total (95% CI)

Weight

Odds Ratio M-H, Fixed, 95% CI

Year

22.1%

1.36 [0.99, 1.87]

2014

11.5% 21.4% 45.0%

1.29 [0.83, 2.00] 1.62 [1.19, 2.21]

2015 2016 2016

2,197 100.0%

1.37 [1.18, 1.58]

CABG Events Total 348 300 592 957

1.26 [1.01, 1.58]

Total events 511 400 Heterogeneity: chi2=1.70, df=3, (P=0.64); I2=0% Test for overall effect: z=4.12 (P<0.0001)

Odds Ratio M-H, Fixed, 95% CI

0.01

0.1

1

Favours PCI

10

100

Favours CABG

MACCE by SYNTAX Score

Study or Subgroup

PCI Events Total

CABG Events Total

Weight

Odds Ratio M-H, Fixed, 95% CI

196 201 536 933

35.8% 18.2% 46.0% 100.0%

1.01 [0.66, 1.53] 1.39 [0.80, 2.39] 1.66 [1.20, 2.30] 1.38 [1.09, 1.74]

2014 2015 2016

149 68 56 273

57.4% 23.6% 19.0% 100.0%

2.09 [1.28, 3.42] 1.35 [0.57, 3.16] 1.44 [0.57, 3.66] 1.79 [1.22, 2.64]

2014 2015 2016

Odds Ratio M-H, Fixed, 95% CI

Year

2.1.1 Low to Intermediate SYNTAX Score (≤32) SYNTAX-LM 68 221 60 25 PRECOMBAT 38 231 109 546 70 NOBLE Subtotal (95% CI) 998 215 155 Total events Heterogeneity: chi2=3.41, df=2, (p=0.18); I2=41% Test for overall effect: z=2.70 (p=0.007) 2.1.2 High SYNTAX Score (≥33) SYNTAX-LM 62 14 PRECOMBAT 12 NOBLE Subtotal (95% CI)

135 58 46 239

43 13 11

Total events 88 67 Heterogeneity: chi2=1.03, df=2, (p=0.60); I2=0% Test for overall effect: z=2.97 (p=0.003)

0.01 Test for subgroup differences: chi2=1.33, df=1, (p=0.25); I2=24.8%

0.1

1

Favours PCI

10

100

Favours CABG

MACCE by Stent Generation Study or Subgroup

PCI Events

Total

CABG Events Total

Weight

Odds Ratio M-H, Fixed, 95% CI

348 300 648

65.6% 34.4% 100.0%

1.36 [0.99, 1.87] 1.29 [0.83, 2.00] 1.34 [1.03, 1.73]

2014 2015

592 957 1,549

32.3% 67.7% 100.0%

1.62 [1.19, 2.21] 1.26 [1.01, 1.58] 1.38 [1.15, 1.65]

2016 2016

Odds Ratio M-H, Fixed, 95% CI

Year

7.1.1 First-generation DES SYNTAX-LM PRECOMBAT Subtotal (95% CI)

130 52

357 300 657

103 42

182 145 Total events Heterogeneity: chi2=0.04, df=1, (p=0.84); I2=0% Test for overall effect: z=2.22 (p=0.03) 7.1.2 Second-generation DES 121 592 81 NOBLE 208 948 174 EXCEL 1,540 Subtotal (95% CI) 329 255 Total events Heterogeneity: chi2=1.62, df=1, (p=0.20); I2=38% Test for overall effect: z=3.48 (p=0.0005)

0.01 Test for subgroup differences: Chi2=0.04, df=1, (p=0.84); I2=0%

0.1 Favours PCI

1

10

100

Favours CABG

CABG = coronary artery bypass grafts; DES = drug eluting stent; MACCE = major adverse cardiac and cerebrovascular events; PCI = percutaneous coronary intervention. Source: Moore et al.

2017.10 Reproduced with permission from Elsevier.

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Coronary Figure 2: Comparison of Death, MI and Cerebrovascular Accident (and Their Composite) and Repeat Revascularisation between Percutaneous Coronary Intervention and Coronary Artery Bypass Grafts Death, MI and CVA Study or Subgroup SYNTAX-LM PRECOMBAT EXCEL

PCI Events Total 67 25 137

Total (95% CI)

357 300 948

Weight

Odds Ratio M-H, Fixed, 95% CI

Year

348 300 957

28.8% 13.0% 58.2%

0.93 [0.64, 1.36] 0.88 [0.50, 1.55] 1.03 [0.80, 1.33]

2014 2015 2016

1,605

100.0%

0.98 [0.81, 1.20]

CABG Total Events 69 28 135

1,605

Total events 229 232 Heterogeneity: chi2=0.33, df=2, (p=0.85); I2=0% Test for overall effect: z=0.17 (p=0.86)

Odds Ratio M-H, Fixed, 95% CI

0.01

0.1 1 10 Favours PCI Favours CABG

100

Death Study or Subgroup SYNTAX-LM PRECOMBAT NOBLE EXCEL

PCI Events Total 45 17 36 71

357 300 592 948

CABG Events Total 48 23 33 53

2,197

Total (95% CI)

Weight

Odds Ratio M-H, Fixed, 95% CI

Year

348 300 592 957

29.5% 15.1% 21.5% 33.9%

0.90 [0.58, 1.39] 0.72 [0.38, 1.38] 1.10 [0.67, 1.78] 1.38 [0.96, 1.99]

2014 2015 2016 2016

2,197

100.0%

1.08 [0.86, 1.35]

Total events 169 157 Heterogeneity: chi2=3.84, df=3, (p=0.28); I2=22% Test for overall effect: z=0.66 (p=0.51)

Odds Ratio M-H, Fixed, 95% CI

0.01

0.1 1 10 Favours PCI Favours CABG

100

MI Study or Subgroup SYNTAX-LM PRECOMBAT NOBLE EXCEL

PCI Events Total 28 6 29 72

357 300 592 948

CABG Events Total 16 5 10 77

2,197

Total (95% CI)

Weight

Odds Ratio M-H, Fixed, 95% CI

Year

348 300 592 957

14.9% 4.9% 9.5% 70.7%

1.77 [0.94, 3.33] 1.20 [0.36, 3.99] 3.00 [1.45, 6.21] 0.94 [0.67, 1.31]

2014 2015 2016 2016

2,197

100.0%

1.27 [0.98, 1.65]

135 108 Total events Heterogeneity: chi2=9.52, df=3, (p=0.02); I2=68% Test for overall effect: z=1.80 (p=0.07)

Odds Ratio M-H, Fixed, 95% CI

0.01

0.1

1

Favours PCI

10

100

Favours CABG

CVA Study or Subgroup SYNTAX-LM PRECOMBAT EXCEL NOBLE

PCI Events Total 5 2 20 16

357 300 948 592

CABG Events Total 14 2 26 7

2,197

Total (95% CI)

Weight

Odds Ratio M-H, Fixed, 95% CI

Year

29.1% 4.1% 52.7% 14.2%

0.34 [0.12, 0.95] 1.00 [0.14, 7.15] 0.77 [0.43, 1.39] 2.32 [0.95, 5.68]

2014 2015 2016 2016

2,197 100.0%

0.87 [0.58, 1.32]

348 300 957 592

Total events 43 49 Heterogeneity: chi2=8.00, df=3, (p=0.05); I2=62% Test for overall effect: z=0.63 (p=0.53)

Odds Ratio M-H, Fixed, 95% CI

0.01

0.1

1

Favours PCI

10

100

Favours CABG

Repeat Revascularisation Study or Subgroup SYNTAX-LM PRECOMBAT EXCEL NOBLE Total (95% CI)

PCI Events Total 90 38 114 71

357 300 948 592

CABG Events Total

Weight

Odds Ratio M-H, Fixed, 95% CI

Year

348 300 957 592

23.9% 11.8% 37.7% 26.6%

2.06 [1.40, 3.02] 1.93 [1.10, 3.37] 1.82 [1.32, 2.49] 1.58 [1.07, 2.33]

2014 2015 2016 2016

2,197

100.0%

1.82 [1.50, 2.21]

49 21 67 47

2,197

Total events 313 184 Heterogeneity: chi2=0.94, df=3, (p=0.82); I2=0% Test for overall effect: z=6.08 (p<0.00001)

Odds Ratio M-H, Fixed, 95% CI

0.01

0.1 1 10 Favours PCI Favours CABG

100

CABG = coronary artery bypass grafts; CVA = cerebrovascular accident; PCI = percutaneous coronary intervention. Source: Moore et al. 2017. Reproduced with permission from Elsevier.

10

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Left Main Coronary Artery Interventions Table 3: 2018 European Society of Cardiology/European Association for Cardio-Thoracic Surgery Recommendations Recommendations According to the Extent of CAD

CABG

PCI

Class of

Level of

Class of

Level of

Recommendation

Evidence

Recommendation

Evidence

One-vessel CAD: Without proximal LAD stenosis

IIb

C

I

C

With proximal LAD stenosis

I

A

I

A

Two-vessel CAD: Without proximal LAD stenosis

IIb

C

I

C

With proximal LAD stenosis

I

B

I

C

Left main CAD: Left main disease with low SYNTAX score (0–22)

I

A

I

A

Left main disease with intermediate SYNTAX score (23–32)

I

A

IIa

A

Left main disease with high SYNTAX score (≥33)

I

A

III

B

Three-vessel disease with low SYNTAX score (0–22)

I

A

I

A

Three-vessel disease with intermediate or high SYNTAX score (>22)

I

A

III

A

Three-vessel CAD without diabetes:

Three-vessel CAD with diabetes: Three-vessel disease with low SYNTAX score (0–22)

I

A

IIb

A

Three-vessel disease with intermediate or high SYNTAX score (>22)

I

A

III

A

Recommendations for the type of revascularisation in patients with stable CAD with suitable coronary anatomy for both procedures and low predicted surgical mortality. CABG = coronary artery bypass grafts; CAD = coronary artery disease; EACTS = European Association for Cardio-Thoracic Surgery; ESC = European Society of Cardiology; LAD = left anterior descending artery; PCI = percutaneous coronary intervention. Source: Neumann et al. 2019.25 Reproduced with permission from Oxford University Press on behalf of the European Society of Cardiology.

Over the past decade the treatment of LMCA disease has been the subject of multiple randomised controlled trials that have compared PCI to the gold standard of CABG. Based on results of these trials, the European Society of Cardiology (ESC) and the American College of Cardiology (ACC)/American Heart Association (AHA) have produced recommendations (Table 3).

In the 2014 ESC guidelines, patients with unprotected LMCA disease, stenosis of more than 90% with stable angina or silent ischaemia, or stenosis >50%–90% with documented ischaemia or FFR <0.80, should undergo revascularisation (class I, level of evidence A).23 With low surgical mortality and suitable coronary anatomy, CABG is recommended (Class I, level of evidence B). PCI is also recommended, depending on the SYNTAX score: <22 (class I, level of evidence B); 23–32 (class IIa, level of evidence B); and >32 (class III, level of evidence B).

The ACC/AHA 2014 guidelines indicate that PCI is a reasonable alternative to CABG for LMCA disease in patients with, ostial or trunk LMCA disease and a low SYNTAX score with an increased surgical adverse outcomes Society of Thoracic Surgery predicted mortality 5% (class IIa, level of evidence B).24 PCI is also reasonable in patients with unstable angina/non-ST-elevation MI when the LMCA disease is the culprit lesion and the patient is not a surgical candidate (class IIa, level of evidence B). When a patient presents with ST-elevation-MI and the

1.

2.

3.

agosta M. Left main coronary artery disease: R importance, diagnosis, assessment, and management.

Curr Probl Cardiol 2015;40:93–126. https://doi.org/10.1016/j. cpcardiol.2014.11.003; PMID: 25765453.

Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301:61–8. https://doi.org/10.1056/NEJM197907123010201; PMID: 449946.

Boudriot E, Thiele H, Walther T, et al. Randomized comparison of percutaneous coronary intervention with

INTERVENTIONAL CARDIOLOGY REVIEW

4.

LMCA disease is the culprit lesion with a distal coronary flow is less than thrombolysis in MI grade 3. PCI can be performed more rapidly and safely than CABG (class IIa, level of evidence C). PCI can be an alternative to CABG in select patients for LMCA disease with a low to intermediate risk of PCI procedural complications and an intermediate to high likelihood of good long-term outcomes (class IIb, level of evidence B). These guidelines are based on the SYNTAX trial and other smaller randomised trials that are underpowered, including the LE MANS trial and PRECOMBAT. Results from the EXCEL and NOBLE trials have not yet been incorporated into the guidelines.

Conclusion In conclusion, left main PCI can be performed safely in select patients. The decision to proceed with PCI versus CABG is best made through a multidisciplinary approach consisting of a clinical cardiologist, interventional cardiologist and a cardiac surgeon. It entails consideration of the patient’s preferences and expectations, comorbidities, the estimated surgical risk, the complexity of coronary anatomy and the patient’s ability to comply with dual antiplatelet therapy. Appropriate evaluation of the lesion by coronary angiography and intravascular imaging coupled with operator expertise remains paramount to the decision-making process and strategy. Furthermore, all patients with LMCA disease will require optimal guideline-directed secondary prevention and lifestyle intervention in addition to the chosen revascularisation strategy.

sirolimus-eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis. J Am Coll Cardiol 2011;57:538–45. https://doi.org/10.1016/j.jacc.2010.09.038; PMID: 21272743.

Morice MC, Serruys PW, Kappetein AP, et al. Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial. Circulation 2014;129:2388–94. https://doi.org/10.1161/ CIRCULATIONAHA.113.006689; PMID: 24700706.

5.

6.

hn JM, Roh JH, Kim YH, et al. randomized trial of stents A versus bypass surgery for left main coronary artery disease: 5-year outcomes of the PRECOMBAT Study. J Am Coll Cardiol 2015;65:2198–206. https://doi.org/10.1016/j.jacc.2015.03.033; PMID: 25787197.

Buszman PE, Buszman PP, Banasiewicz-Szkrobka I, et al. Left main stenting in comparison with surgical revascularization: 10-year outcomes of the (left main coronary artery stenting) LE MANS Trial. JACC Cardiovasc Interv 2016;9:318–27. https://doi.org/10.1016/j.jcin.2015.10.044; PMID: 26892080.

129

Coronary 7.

8.

9.

10.

11.

12.

13.

tone GW, Sabik JF, Serruys PW, et al. Everolimus-eluting S stents or bypass surgery for left main coronary artery disease. N Engl J Med 2016;375:2223–35. https://doi. org/10.1056/NEJMoa1610227; PMID: 27797291.

Mäkikallio T, Holm NR, Lindsay M, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial.

Lancet 2016;388: 2743–52. https://doi.org/10.1016/S01406736(16)32052-9; PMID: 27810312.

Park DW, Ahn JM, Yun SC, et al. 10-year outcomes of stents versus coronary artery bypass grafting for left main coronary artery disease. J Am Coll Cardiol 2018;72:2813–22. https://doi. org/10.1016/j.jacc.2018.09.012; PMID: 30261236.

Moore P, Burrage M, Garrahy P, et al. Drug-eluting stents versus coronary artery bypass grafts for left main coronary disease: A meta-analysis and review of randomised controlled trials. Heart Lung Circ 2018;27:1437-45. https://doi. org/10.1016/j.hlc.2017.09.008; PMID: 29102437.

Khan AR, Golwala H, Tripathi A, et al. Meta-analysis of percutaneous coronary intervention versus coronary artery bypass grafting in left main coronary artery disease.

Am J Cardiol 2017;119:1949–56. https://doi.org/10.1016/j. amjcard.2017.03.022; PMID: 28442067.

Giacoppo D, Colleran R, Cassese S, et al. Percutaneous coronary intervention vs coronary artery bypass grafting in patients with left main coronary artery stenosis: a systematic review and meta-analysis. JAMA Cardiol 2017;2:1079–88. https://doi. org/10.1001/jamacardio.2017.2895; PMID: 28903139.

Valle JA, Tamez H, Abbott JD, et al. Contemporary use and trends in unprotected left main coronary artery percutaneous coronary intervention in the United States: An analysis of the national cardiovascular data registry research to practice

130

14.

15.

16.

17.

18.

19.

20.

initiative. JAMA Cardiol 2019;4:100–9. https://doi.org/10.1001/ jamacardio.2018.4376; PMID: 30601910.

Rizik DG, Klassen KJ, Burke RF, et al. Interventional management of unprotected left main coronary artery disease: patient selection and technique optimization. J Interv Cardiol 2015;28:326–38. https://doi.org/10.1111/joic.12211; PMID: 26077351.

De Maria GL, Banning AP. Use of intravascular ultrasound imaging in percutaneous coronary intervention to treat left main coronary artery disease. Interv Cardiol 2017;12:8–12. https://doi.org/10.15420/icr.2017:1:3; PMID: 29588723.

Jasti V, Ivan E, Yalamanchili V, et al. Correlations between fractional flow reserve and intravascular ultrasound in patients with an ambiguous left main coronary artery stenosis. Circulation 2004;110:2831–6. https://doi.org/10.1161/01.CIR.0000146338.62813.E7; PMID: 15492302.

Kang SJ, Lee JY, Ahn JM, et al. Intravascular ultrasound-derived predictors for fractional flow reserve in intermediate left main disease. JACC Cardiovasc Interv 2011;4:1168–74. https://doi. org/10.1016/j.jcin.2011.08.009; PMID: 22115656.

Park SJ, Ahn JM, Kang SJ, et al. Intravascular ultrasoundderived minimal lumen area criteria for functionally significant left main coronary artery stenosis. JACC Cardiovascular Intervention 2014;7:868–74. https://doi.org/10.1016/j. jcin.2014.02.015; PMID: 25147031.

Li J, Patel SM, Parikh MA, Parikh SA. Unprotected left main disease: indications and optimal strategies for percutaneous intervention. Curr Treat Options Cardiovasc Med 2016;18:19. https://doi.org/10.1007/s11936-016-0441-2; PMID: 26874707.

Hamilos M. The use of fractional flow reserve in left main coronary artery lesion assessment. RadcliffeCardiology.com,

2014. https://doi.org/10.15420/rc.2014.wp01 21. R amadan R, Boden WE, Kinlay S. Management of left main coronary artery disease. J Am Heart Assoc 2018;7:e008151. https://doi.org/10.1161/JAHA.117.008151; PMID: 29605817.

22. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994;344:563–70. https:// doi.org/10.1016/S0140-6736(94)91963-1; PMID: 7914958.

23. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541–619. https://doi.org/10.1093/eurheartj/ehu278; PMID: 25173339.

24. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/ AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014;64:1929–49. https://doi.org/10.1016/j. jacc.2014.07.017; PMID: 25077860.

25. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/ EACTS Guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437.

INTERVENTIONAL CARDIOLOGY REVIEW

Coronary

Drug-coated Balloons for Small Coronary Vessel Interventions: A Literature Review Thomas Nestelberger and Raban Jeger Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, University of Basel, Switzerland

Abstract Newer-generation drug-eluting stents (DES) are the standard of care for the treatment of symptomatic coronary artery disease. However, some lack of efficacy has been reported in small coronary arteries based on higher rates of target lesion restenosis, thrombosis and MI resulting in repeated interventions. Drug-coated balloons (DCBs) are an established treatment option for in-stent restenosis in both bare metal stents and DES and they can deliver an anti-proliferative drug into the vessel wall without implanting a stent. DCBs are a promising technique for selected de novo coronary lesions, especially in small vessel disease. In this article, the current evidence for the treatment of small vessel disease with DCBs will be reviewed.

Keywords Coronary artery disease, small vessel disease, drug-coated balloon, drug-eluting balloon, percutaneous coronary intervention Disclosure: TN has received speaker honoraria and personal fees from Beckman-Coulter, Bayer, Orion Pharma and Ortho Clinical Diagnostics. RJ has received speaker honoraria from Cardionovum, Nipro and B Braun and research support from B Braun.

Received: 14 February 2019 Accepted: 30 September 2019 Citation: Interventional Cardiology Review 2019;14(3):131–6. DOI: https://doi.org/10.15420/icr.2019.06.R3 Correspondence: Raban Jeger, Department of Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. E: raban.jeger@usb.ch Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Coronary artery disease (CAD) remains a major cause of morbidity and mortality despite major improvements in primary and secondary prevention strategies. Percutaneous coronary intervention (PCI) or surgical revascularisation may be indicated in many patients with acute or stable CAD.1 Since the first coronary intervention using catheter mounted balloons, percutaneous treatment of CAD has evolved from percutaneous balloon angioplasty, PCI using bare-metal stents (BMS) or firstgeneration drug-eluting stents (DES) to second and newer-generation DES implantation.2–5 The improvements in newer-generation DES have resulted in better safety and efficacy compared with older DES and BMS. However, the efficacy of stents is restricted in small vessel disease (SVD).6–8 SVD is common among patients undergoing PCI and has been documented in up to 30% of cases.9–11 Myocardial revascularisation of small vessels remains challenging owing to increased rates of technical failure following coronary artery bypass graft surgery and an increased risk of restenosis with PCI resulting in repeated interventions.12,13 SVD also remains an independent predictor of major adverse cardiac events (MACE).14 Drug-coated balloons (DCBs) are a novel concept for the treatment of CAD and an established therapeutic option for in-stent restenosis (ISR) of BMS and DES (Figure 1).15,16 The technique is based on the fast delivery of highly lipophilic drugs to the vessel wall after single balloon inflation.6 The efficacy and safety of DCBs in native SVD has recently been demonstrated in a large study with clinical endpoints, which

© RADCLIFFE CARDIOLOGY 2019

showed a similar rate of MACE after 12 months in patients treated either with a DCB or second-generation DES.17

Methods This review includes all English language studies after a detailed search of PubMed according to established methods and in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews and metaanalyses in healthcare interventions.18 The following keywords were used: “small” AND “coronary” AND “drug-eluting stents” OR “DES” OR “DCB” OR “DEB” OR “drug-eluting balloons” OR “drug-coated balloons”.

Databases were screened up until 4 February 2019. The most up to date and inclusive data for each study were used for abstraction.

References of original and review articles were cross-checked.

Definition and Prevalence of Small Vessel Coronary Artery Disease Several definitions of SVD have been proposed. However, most recent studies have identified an angiographic reference vessel <3 mm as the most appropriate cut-off.19 Therefore, it can be stated that any coronary vessel amenable to percutaneous treatment with a 2.75 mm or smaller device should be considered ‘small’.17 Some authors have suggested the term ‘very small vessel coronary artery disease’ for those coronary vessels that are amenable to percutaneous treatment with a 2 mm device.20 Despite varying definitions in the literature, there is universal agreement that SVD is common, being prevalent in up to 30% of patients with symptomatic CAD, and that patients with diabetes or

Access at: www.ICRjournal.com

131

Coronary Figure 1: Drug-coated Balloon

the target segment).20 Thus, the minimum lumen diameter increases significantly after the procedure but decreases at follow-up, mainly because of recoil and hyperplasia phenomena (Figure 2).

SeQuent Please drug-coated balloon during inflation visualising a specific matrix for the fast delivery of highly lipophilic drugs to the vessel wall. Reproduced with permission from B Braun.

Figure 2: Graphical Representation of Late Loss After Percutaneous Coronary Intervention

Stent implantation results in arterial injury, initiating a vasculoproliferative cascade with smooth muscle cell proliferation and migration resulting in neointimal hyperplasia. The amount of neointimal hyperplasia is largely independent of vessel size, and thus the absolute amount of late lumen loss – an angiographic measure of neointimal hyperplasia – is similar across a wide range of vessel diameters.24 Therefore, small vessels are more prone to restenosis than larger vessels because they are less able to accommodate neointimal tissue without compromising blood flow.25 Late lumen loss is defined as the difference between the postprocedural minimum lumen diameter and minimum lumen diameter at follow-up, and ranges between 0.05 and 0.10 mm (for the most effective DES) and 1.0 and 1.5 mm (for balloon-only PCI; Figure 2).20,25 While a low late loss is generally beneficial, it appears even more important in SVD (Figure 3).

Drug-coated Balloons: The Technology DCBs have been developed to overcome some of the limitations of DES, especially for patients with SVD.6,7,8,26 DCBs are semi-compliant Pre-PCI MLD

Post-PCI MLD

Follow-up MLD

Late loss = post-PCI MLD − follow-up MLD Definition of late loss showing the scheme of an artery before, just after and long after PCI, with the definition of angiographic late lumen loss as post-PCI MLD minus follow-up MLD. MLD = minimum lumen diameter; PCI = percutaneous coronary intervention. Source: Alfonso et al.6 Adapted with permission from Europa Digital & Publishing.

Figure 3: Risk of Binary Angiographic Restenosis After Percutaneous Coronary Intervention According to Reference Vessel Diameter of the Target Segment

Small (>2.75 mm)

Medium Large (2.75–3.25 mm) (>3.25 mm)

Balloon-only PCI

35–55%

25–40%

20–35%

Bare-metal stents

25–50%

15–35%

15–20%

30–35%

20–30%

5–12.5%

20–25%

10–20%

2.5–7.5%

10–15%

5–10%

0–5%

Drug-eluting stents with: Relatively high late loss (e.g. ENDEAVOR) Medium late loss (e.g. TAXUS) Low late loss (e.g. CYPHER or XIENCE)

Impact of different late losses on follow-up binary angiographic restenosis after PCI in coronary segments with small (<2.75 mm), medium (2.75–3.25 mm),and large (>3.25 mm) reference vessel diameter. PCI = percutaneous coronary intervention. Source: Biondi-Zoccai et al. 2010.20 Adapted with permission from Elsevier.

chronic renal failure are at even higher risk of developing this type of CAD.21,22 The prognostic implications of SVD are important since a small reference vessel diameter in the coronary segment undergoing PCI is significantly and directly associated with an increased risk of adverse clinical events, including ISR and stent thrombosis (ST) compared with larger reference vessel diameters.9,23 The goal of PCI is to improve the minimum lumen diameter in a given target coronary segment, which has a specific reference vessel diameter (roughly defined as the average of the diameters of apparently normal segments localised proximally and distally to

132

angioplasty balloons covered with an antiproliferative drug that is rapidly released from a lipophilic matrix upon contact with the vessel wall. Mechanical expansion of the vessel is combined with release of an antiproliferative drug without leaving a foreign body. The development of DCBs is complex and factors other than the active drug itself contribute to its effect. The lipophilic matrix must maintain the drug on the balloon during transit to the lesion, while at the site of dilatation it should ensure a rapid and homogenous drug transfer to the vessel wall.

Pharmacokinetic characteristics of each DCB largely depend on the carrier and manufacturing process used to develop the coating. A variety of carrier excipients, such as iopromide, urea and shellac, among others, have been investigated to determine their ability to enhance drug delivery.27 Most currently available DCBs use paclitaxel because of its highly lipophilic profile, potent antiproliferative effect and chemical stability after delivery.28 The -limus drugs (sirolimus and zotarolimus), which are much less lipophilic than paclitaxel, have also shown some efficacy in the suppression of neointimal growth in a limited number of animal models.29,30 Several types of DCBs have been introduced in the market and approved for coronary use (Table 1).

Current research is focused on different coatings and drug delivery technologies using -limus drugs and nanocarriers to identify optimal nanoparticle structure for efficient transfer of drugs to all layers of the vessel wall, achieving high tissue concentrations that persist days after application with a low rate of systemic drug leak.30,31 However, clinical data are still sparse.

The DCB technique has been successfully tested in ISR, where good clinical efficacy was demonstrated in most studies, but not in all.15,16,32–39 Current guidelines recommend the use of DCBs for patients with coronary ISR (class I, level of evidence A).1,40 In addition, DCBs are now increasingly being seen as an attractive option for the treatment of SVD and bifurcation lesions.27,28 Native vessels treated by DCBs, due to absent metallic struts and polymer, keep their vasomotion properties reducing abnormal flow patterns without the risk of ISR and late ST, and remain possible targets for coronary artery bypass grafts.41

INTERVENTIONAL CARDIOLOGY REVIEW

Drug-coated Balloons for Small Coronary Vessel Interventions Table 1: Major Current Drug-coated Balloons Approved for Coronary Interventions Name

Manufacturer

Type

Dosage

Coating Method

Release characteristics

SeQuent Please

B Braun

Paclitaxel

3 μg/mm

Matrix coating: paclitaxel + hydrophilic spacer (iopromide)

Minimum inflation time is 40 s to allow sufficient drug to be released into the vessel wall (4.5% of the drug remains on the balloon)

IN.PACT Falcon

Medtronic

Paclitaxel

3 μg/mm2

Crystalline coating: paclitaxel + urea (FreePac)

Inflate 30–60 s at normal pressure to allow sufficient drug release into the vessel wall (4.7% of the drug remains on the balloon)

Pantera Lux

Biotronik

Paclitaxel

3 μg/mm2

Paclitaxel + butyryl-trihexyl citrate

Minimum inflation time is 30 s to allow sufficient drug to be released into the vessel wall

DIOR-II

Eurocor

Paclitaxel

3 μg/mm2

1:1 mixture of aleuritic and shellolic acid with paclitaxel (shellac coating)

Drug delivery by simple diffusion, inflate 20–30 s at normal pressure

Elutax

Aachen Resonance

Paclitaxel

2 µg/mm2

Two layers of paclitaxel (the first on the inflated balloon and the second as a crystal powder) without any excipient

A maximum of 10% of the drug remains on the balloon after an inflation of 30–60 s

Danubio

Minvasys

Paclitaxel

2.5 µg/mm2

Paclitaxel + butyryl-trihexyl citrate

Minimum inflation time is 30 s to allow sufficient drug to be released into the vessel wall

RESTORE DCB

Cardionovum

Paclitaxel

3 μg/mm2

Shellac

A short-term balloon-to-vessel wall contact time of 45 s is sufficient

Protégé and Protégé NC

Blue Medical

Paclitaxel

3 μg/mm2

Drug component encapsulated in wings using Wing Seal Technology

Load secured to achieve the therapeutic window within 30 s inflation time, also available with non-compliant balloon

MagicTouch

Concept Medical

Sirolimus

1.27 μg/mm2

Sirolimus is encapsulated in a phospholipid bi-layer as drug carrier and in nanocarriers configuration

Balloon should be inflated for at least 45 s if clinically tolerated

Agent

Boston Scientific

Paclitaxel

2 μg/mm2

Balanced hydrophobic and hydrophilic Minimum inflation time is 30 s to allow properties of TransPax, fewer particulates sufficient drug to be released into the are lost distally during the procedure vessel wall

AngiosculptX

Spectranetics

Paclitaxel

3 μg/mm2

Nordihydroguaiaretic acid excipient to facilitate drug transfer to tissue

Minimum inflation time is 30 s, improved dilatation in calcified or resistant lesion using a scoring balloon

Essential

Ivascular

Paclitaxel

3 μg/mm2

Microcrystalline coating

Inflation process must last from 30 s to 1 min

2

After lesion preparation, taking care to avoid geographic mismatch, a DCB is inflated at nominal pressure for at least 30 seconds. Implantation of a DES is recommended in case of a major dissection (type C or higher), a residual stenosis of >30%, or reduced flow (Figure 4).

Although previous studies have not been powered to determine the optimal duration of dual antiplatelet therapy (DAPT), the available data suggests that it is required for a shorter time after DCBs compared with DES, which may be beneficial in many patient groups. The lack of a metallic scaffold and the shorter period of post-procedure inflammation, virtually eliminates the risk of thrombosis.42 Most studies with DCBs in ISR or SVD used a short period of DAPT of only 1 month, without a higher rate of thrombotic events.15,17,33,43 Thus, a short period of DAPT in patients with stable coronary artery disease treated with DCBs alone seems to be safe and effective.

Clinical Trials of Drug-coated Balloons for Small Vessel Coronary Artery Disease In a retrospective analysis by Sinaga et al. in 335 patients receiving either DCB (SeQuent Please, B Braun; n=172) or a second-generation DES (n=163), with a device diameter of ≤2.5 mm,44 there were no differences between baseline demographics or concomitant disease between the groups. There was no difference in MACE (12% versus

INTERVENTIONAL CARDIOLOGY REVIEW

Figure 4: General Principle of Drug-coated Balloon Applicability Lesion preparation Predilatation Conventional semi-compliant balloon, inflation pressure > nominal, balloon-to-vessel ratio 0.8–1.0 Options for complex lesions Non-compliant high-pressure balloons, cutting balloon, scoring balloon, rotablation Additional intravascular imaging (IVUS, OCT), functional measurements (FFR) Acceptable angiographic result No dissection or type A, B TIMI 3 Residual stenosis ≤30%

DCB Ballon-to-vessel ratio 0.8–1.0 Nominal pressure, >30 s

Dissection type C–F TIMI <3 Residual stenosis >30%

DES

DCB = drug-coated balloon; DES = drug-eluting stent; FFR = fractional flow reserve; IVUS = intravascular ultrasound; OCT = optical coherence tomography; TIMI = thrombolysis in MI. Source: Biondi-Zoccai et al.20 Adapted with permission from Elsevier.

12%; p=1.00) and target lesion revascularisation (5% versus 4%; p=0.60) after 12 months. Pre-dilatation was done in all patients. Rates of bailout stenting were not reported.

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Coronary Table 2: Randomised Controlled Studies Comparing Newer-generation Drug-eluting Stent with Drug-coated Balloons in De Novo Small Vessel Disease Study

Device n

Vessel

Vessel

Bailout

DAPT

Balloon

Diameter Diameter, Stenting Duration PreInclusion Mean ± Criteria

Standard

(mm)

Deviation

(n)

Definition of

Clinical Outcome

MACE

Duration of Device Follow-up

(Months) dilatation

(Months)

(n)

(mm) PICCOLETO, DCB 201043

28

≤2.75

2.45 ± 0.28 10 (BMS)

1–3

7

DES

29

≤2.75

2.36 ± 0.25 NA

12

25

DCB

90

<2.8

2.41 ± 0.34 19 (BMS)

2 (1–3)

91

DES

92

<2.8

2.41 ± 0.4

12

81

DCB

382 2.0–3.0

2.75 ± 2.14 19 (DES)

1–12

382

DES

376 2.0–3.0

2.75 ± 0.25 NA

6–12

376

116 2.25–2.75 2.42 ± 0.15 6

>6

116

114 2.25–2.75 2.42 ± 0.18 NA

>6

114

BELLO, 201249

BASKETSMALL 2, 201817

RESTORE DCB SVD, 201851

DES

NA

Death, MI, TLR

Death, MI, TLR

Cardiac death, MI, TLR

MACE: DCB 35.7% versus DES 13.8%, p=0.054 TLR: DCB 32.1% versus DES 10.3%, p=0.15

9

MACE: DCB 14.8% versus DES 25.3%, p=0.08 TLR: DCB 6.8% versus DES 12.1%, p=0.23

24

MACE: DCB 7.3% versus DES 7.5%, p=0.918 HR: 0.97 95% CI [0.58–1.64] TLR DCB: 3.4% versus DES 4.5%, p=0·4375

12

Dior I drug-coated balloon (Eurocor) Paclitaxel-coated stent (Taxus Liberté, Boston Scientific) Paclitaxel-coated balloon (Falcon, Medtronic) Paclitaxel-coated stent (Taxus Liberté) Paclitaxel-coated balloon (SeQuent Please, B Braun) Everolimus-eluting stent (Xience, Abbott Vascular) or paclitaxeleluting stent (Taxus Element, Boston Scientific)

Death, MI, any TLR: DCB 0.2% 30 revascularisation versus DES 1.1% HR: 1.05, 95% CI [0.72–1.53] TLT: DCB 7.0% versus DES 6.2% HR: 0.18, 95% CI [0.04–0.82]

Paclitaxel-coated balloon (SeQuent Please), paclitaxeleluting balloon (In.Pact Falcon, MedtronicInvatec) and paclitaxeleluting balloon (Pantera Lux, Biotronik) Everolimus-eluting stents (Xience, Abbott Vascular) Promus and Synergy (Boston Scientific), zotarolimuseluting stent (Resolute, Medtronic) sirolimuseluting stent (Orsiro, Biotronik), and biolimus-eluting stent (Nobori, Terumo)

BMS = bare metal stent; DCB = drug-coated balloon; DES = drug-eluting stent; DAPT = dual antiplatelet therapy; TLR = target lesion revascularisation; TLT = target lesion thrombosis; MACE = major adverse cardiac events.

Sim et al. retrospectively analysed 287 patients receiving either the SeQuent Please DCB (n=87) or a second-generation DES (n=200).45 Patients received either a 2 mm DCB or a 2 mm DES. Bailout stenting was necessary in seven patients in the DCB group. At 12 months, target lesion revascularisation (5% versus 6%; p=0.74) and death from any cause (5% versus 9%; p=0.24) were similar between the groups.

Venetsanos et al. analysed a large cohort of 7,655 patients who received either a DCB (n=1,197) – SeQuent Please, IN.PACT Falcon (MedtronicInvatec) or Pantera Lux (Biotronik) – or a second-/third-generation DES (n=6,458) – Xience (Abbott Laboratories), Promus and Synergy (Boston Scientific), Resolute (Medtronic), Orsiro (Biotronik) or Nobori (Terumo).46 Median follow-up was 901 days. DCB patients were older with a higher

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cardiovascular risk profile. Bailout stenting after DCB was performed in 8% of lesions. Rate of target lesion revascularisation and target lesion thrombosis was 7.0 versus. 4.9% and 0.2 versus 0.8% for DCB versus DES, respectively. After propensity score matching the adjusted risks of target lesion revascularisation were not significantly elevated (HR 1.05; 95% CI [0.72–1.53]). However, DCB was associated with a significantly lower risk of target lesion thrombosis compared with DES (adjusted HR 0.18; 95% CI [0.04–0.82]).

There are few randomised controlled studies comparing newer generation DES with DCBs in de novo SVD (Table 2). The PaclitaxelCoated Balloon Versus Drug-Eluting Stent During PCI of Small Coronary Vessels (PICCOLETO) study randomised 57 patients with

INTERVENTIONAL CARDIOLOGY REVIEW

Drug-coated Balloons for Small Coronary Vessel Interventions SVD (diameter ≤2.75 mm) in a 1:1 fashion to either a paclitaxeleluting balloon (n=28; Dior, Eurocor) or to a first-generation paclitaxel-eluting stent (n=29; Taxus, Boston Scientific).43 The study was interrupted after including only 57 patients based on an interim analysis which showed a higher rate of target lesion stenosis after 6 months (DCB 44% versus DES 24%, p=0.029) and higher MACE rates (36% in DCB versus 14% in DES, p=0.054), mainly driven by higher target lesion revascularisation rates in DCB versus DES (32% versus 10%, p=0.15). However, this result was felt to reflect a lack of efficacy of the DCB used, rather than a class effect of DCBs overall.47 In first-generation DCBs, adherence of paclitaxel was mediated by the roughened surface of the balloon, providing a significantly lower drug concentration in the tissue and accordingly lower inhibition of neointimal proliferation. Paclitaxel is released more completely and homogenously after the first balloon expansion from newer generation DCBs, resulting in high bioavailability in the target lesion.48 The Balloon Elution and Late Loss Optimization (BELLO) study randomised 182 patients with lesions in small vessels (<2.8 mm) to either paclitaxel-coated balloon (n=90; IN.PACT Falcon and provisional BMS) or paclitaxel-eluting stent (n=92; Taxus Liberté, Boston Scientific), as per standard practice.49 Bailout stenting was required in 20% of patients in the DCB arm. At 6 months, DCBs and DES were associated with similar rates of angiographic restenosis (10% versus 14.6%; p=0.35), target lesion revascularisation (4.4% versus 7.6%; p=0.37), and MACE (10% versus 16.3%; p=0.21). The clinical efficacy of DCBs was confirmed after up to 3 years, showing a trend toward improved outcomes with regard to MACE.50 BELLO demonstrated the importance of routine predilatation, which was performed in 96.8% of interventions compared with 25% in the PICCOLETO study.

In the Basel Kosten-Effektivitäts trial, Drug-Coated Balloons for Small Coronary Artery Disease (BASKET-SMALL 2), 758 patients with SVD (<3 mm) were randomly allocated to receive treatment either with a paclitaxel-coated balloon (n=382; SeQuent Please) or one of two second-generation DES (n=376), the paclitaxel-eluting Taxus Element stent or the everolimus-eluting Xience Stent (Abbott Vascular).17 Lesion preparation was mandatory, and randomisation was only possible if angiographic criteria were met (no high-grade dissection, no reduced blood flow and residual stenosis ≤30%). The rate of MACE after 12 months did not differ between the two groups (7.3% for DCB versus 7.5% for DES, p=0.92). Furthermore, the individual components of

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Grüntzig AR, Senning A, Siegenthaler WE, et al. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301:61–8. https://doi.org/10.1056/NEJM197907123010201; PMID: 449946.

Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease.

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Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxeleluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221–31. doi:10.1056/NEJMoa032441. https://doi. org/10.1056/NEJMoa032441; PMID: 14724301.

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INTERVENTIONAL CARDIOLOGY REVIEW

the primary endpoint did not differ between the two groups (DCB versus DES: cardiac death 3.1% versus 1.3%, p=0.11; non-fatal MI 1.6% versus 3.5%, p=0.11; and target vessel revascularisation 3.4% versus 4.5%, p=0.448). Bailout stenting was required in 5% of patients in the DCB arm. The study was only powered for clinical endpoints, not for angiographic endpoints.

The Drug-Coated Balloon Versus Drug-Eluting Stent for Small-Vessel Disease (RESTORE-SVD) study compared 230 patients with SVD (vessel diameter ≥2.25 mm and ≤2.75 mm) with a new generation paclitaxelcoated balloon (n=116; Restore, Cardionovum) versus a zotarolimuseluting stent (n=114; Medtronic).51 The trial was designed to evaluate non-inferiority of DCB versus DES for a 9-month primary angiographic endpoint, and assessed in-segment percent diameter stenosis, which was similar with 29.6 ± 2.0% versus 24.1 ± 2.0% (p for noninferiority <0.001). There were no differences in target lesion revascularisation, cardiac death, MI and a composite endpoint consisting of all-cause death, MI and any revascularisation. Pre-dilatation was done routinely in all patients. In the DCB group, 5% (6 of 116) needed bailout stenting.

The DCB and DES groups had comparable 1-year rates of target lesion failure (4.4% versus 2.6%, p=0.72).

A meta-analysis of 1,824 patients from seven studies (four randomised controlled trials and three observational studies) compared DCBs (n=759) with other modalities of treating de novo SVD (n=860). DCBs were associated with a similar risk of target lesion revascularisation (OR 0.99; 95% CI [0.54–1.84], p=97) and MACE (OR 0.86; 95% CI [0.51–1.45], p=0.57) during a mean follow-up of 7 ± 1.5 months, compared with DES. DCBs were associated with a significantly lower risk of TLR (OR 0.19; 95% CI [0.04–0.88], p=0.03) and binary restenosis (OR 0.17; 95% CI [0.08–0.37], p=<0.00001) compared with non-coated balloon angioplasty.52

Conclusion The treatment of CAD with DCBs benefits from local drug delivery and a ‘leave nothing behind’ strategy. Many experimental and clinical studies have demonstrated that DCBs are safe and effective for certain indications. While evidence of the value of DCBs in patients presenting with ISR is overwhelming, DCBs also appear promising for selected de novo coronary lesions in SVD. Further studies are required to ascertain the long-term benefits of DCB compared with new-generation DES in this setting before unrestricted use of DCB can be recommended.

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Sex and Transcatheter Aortic Valve Implantation: Impact of Female Sex on Clinical Outcomes Alessandra Laricchia, 1,2 Barbara Bellini, 2 Vittorio Romano, 2 Saud Khawaja, 2 Matteo Montorfano 2 and Alaide Chieffo 2 1. Interventional Cardiology Unit, GVM Care and Research, Maria Cecilia Hospital, Cotignola, Italy; 2. Interventional Cardiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

Abstract Transcatheter aortic valve implantation (TAVI) has emerged as an alternative treatment for severe symptomatic aortic stenosis in patients who are not suitable for surgery or are at high surgical risk. Approximately 50% of patients undergoing TAVI are female and this is reflected by a higher inclusion rate of women in TAVI trials. However, women undergoing TAVI have different baseline clinical characteristics in comparison to men, with fewer comorbidities and a more preserved left ventricular ejection fraction. This translates into favourable outcomes after TAVI, despite a higher rate of peri-procedural complications. This article discusses gender differences in terms of presentation, procedural characteristics and post-procedural results in patients with aortic stenosis undergoing TAVI, with particular focus on possible sex-specific factors affecting outcome.

Keywords Transcatheter aortic valve replacement; women Disclosure: The authors have no conflicts of interest to declare.

Received: 22 February 2019 Accepted: 24 June 2019 Citation: Interventional Cardiology Review 2019;14(3):137–41. DOI: https://doi.org/10.15420/icr.2019.07.R1 Correspondence: Alessandra Laricchia, Interventional Cardiology Unit, GVM Care and Research, Maria Cecilia Hospital, Via Madonna di Genova 1, 48033 – Cotignola, RA, Italy. E: laricchia.a@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.

Transcatheter aortic valve implantation (TAVI) is included in guidelines for the treatment of severe symptomatic aortic stenosis (AS) in patients with intermediate to high risk for standard surgical therapy.1 The gender-related difference in the pathophysiology of heart disease (and consequently in its clinical course and treatment) has already been identified as an issue in interventional cardiology.2 Women are commonly underrepresented in coronary trials, but they constitute nearly half of the population assessed in clinical trials evaluating TAVI.3–5 This raises the need to study the impact of gender, because it is still debated whether sex-specific factors influence and modify the clinical course of AS over time and whether hormonal changes, including a history of pregnancy and age of menopause, can impact TAVI outcomes after implantation.

Female sex is an independent risk factor for mortality after surgical aortic valve replacement and hence is included in the Society of Thoracic Surgeons (STS) risk score model.6 Insights from the Placement of AoRtic TraNscatheTer Valve (PARTNER) trial showed that TAVI may be preferred over surgery for female patients due to a lower rate of late mortality in the TAVI arm.7 Subsequent observational studies and meta-analyses have compared outcomes after TAVI but have found conflicting results in terms of 30-day mortality: some studies did not find any significant difference between the sexes, while others suggested a higher mortality among males.8–11 The aim of this article is to review the literature on this topic, to provide a complete analysis of what is known about female patients undergoing

© RADCLIFFE CARDIOLOGY 2019

TAVI and to clarify the role of potential sex-specific predictors of the main endpoints after TAVI, as defined by the Valve Academic Research Consortium (VARC)-2 criteria.12

Method We searched on PubMed for publications that included the following words in the title: ‘transcatheter aortic valve implantation/replacement (TAVI/TAVR)’, ‘sex/gender’, ‘women’ and ‘outcomes’. References from reviews, registries and meta-analyses were also examined for potentially relevant citations. Articles written in languages other than English, case reports and abstracts were excluded from the analysis.

We looked for gender differences in baseline clinical characteristics, imaging findings and in procedural aspects. We then analysed both short- and long-term outcomes. Reported rates of procedural success and main complications, including mortality, were recorded. We also searched for probable sex-specific predictors of outcomes described in the literature.

Baseline Characteristics Clinical Characteristics Women with severe AS are older than men at presentation. In observational studies performed in the surgical era, this finding was ascribed to a lower awareness of heart disease among women. It was considered that this lack of awareness led women to underestimate their condition and hence seek medical attention later, resulting in a possibly negative impact on outcomes.13 More recent meta-analyses

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Structural Table 1: Main Differences between Women and Men Undergoing Transcatheter Aortic Valve Implantation Women

Men Baseline

↑

Age

↓

↓

Comorbidities

↑

Echo ↑

Ejection fraction

↓

↑

Concentric remodelling

↓

↑

Transvalvular gradient

↓

↓

Valvular area

↑

CT scan ↓

Aortic root

↑

↓

Aortic annulus

↑

↓

Coronary ostia height

↑

↑

Valve calcification

↓

Procedure

The most striking sex-related difference in echocardiographic findings before TAVI is that women usually have a higher left ventricular ejection fraction than men.18,19 Better left ventricular ejection fraction is mainly associated with a lower extent of myocardial fibrosis, potentially indicating a lower burden of irreversible myocardial damage.20 Myocardial response to pressure overload is different in women and men. Female patients have a higher prevalence of concentric remodelling (Figure 1) while male patients show a higher rate of maladaptive remodelling that eventually leads to left ventricle dilation (Figure 2). For this reason, women more frequently present with paradoxical low-flow low-gradient severe AS, while low-flow low-gradient severe AS is more common in men.21 Although both groups have poor outcomes in comparison to patients with normal-flow high-gradient severe AS, low-flow low-gradient severe AS confers the worst prognosis, partially explaining the post-TAVI survival benefit seen in women. Another difference between men and women is that the latter more commonly have worse AS with higher transaortic gradients (mainly related to their better preserved ejection fraction), smaller aortic valve areas and higher pulmonary pressures.19

CT Scan Findings

= Transfemoral

Access

= Transfemoral

= Balloon expandable/ self-expanding

Prosthesis

= Balloon expandable/selfexpanding

Outcomes =↑

VARC-2 success

=↑

=↓

<72-hour mortality

=↓

=↓

Conversion to open surgery

=↓

↓

Valve embolisation

↑

↑

Cardiac tamponade

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↑

Coronary obstruction

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↑

Vascular Complication

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↑

Bleeding

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↑

Stroke

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Residual aortic regurgitation

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Pacemaker implantation

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1-year mortality

↑

↑

Ejection fraction recovery

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VARC-2 = Valve Academic Research Consortium-2.

of TAVI studies have confirmed that women are still older than men at presentation, not only for cultural reasons but also because they become symptomatic later.14 Indeed, a different left ventricular response to pressure overload may be involved, as discussed later.

Women with severe AS are generally ‘healthier’ than men in terms of baseline comorbidities (Table 1). They have a lower prevalence of risk factors, particularly diabetes, as well as concomitant coronary artery disease, history of previous MI and peripheral vascular disease.15 This translates into lower preoperative risk scores for women presenting for TAVI in comparison to men.14 However, even if women are usually healthier than men on presentation, the presence of particular comorbidities can worsen their outcomes after TAVI. For example, a positive history of coronary artery disease at baseline, with or without recent coronary intervention, is associated with adverse 1-year outcomes.16 Similarly, baseline AF is a predictor of increased all-cause and cardiovascular mortality at 12 months (adjusted HR 1.67 and 1.85, respectively) in multivariate analysis.17

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Echocardiographic Findings

Gender differences are also present on CT scans (Figure 3). Women have smaller aortic root dimensions (even after indexing for their smaller body surface area) and their left and right coronary artery ostia are positioned lower than in men. These features might increase the risk of coronary obstruction after TAVI. Conversely, absolute smaller sizes of aorta, subclavian and iliofemoral arteries are not confirmed after indexing for body size.22 Another distinctive feature highlighted on CT scans is that women have smaller aortic annuli.23 This has been related to a higher rate of patient–prosthesis mismatch in women undergoing surgery, but is significantly lower in female patients undergoing TAVI.24,25 This is mainly due to differences in TAVI valve design, such as the supra-annular location of some valve prostheses and the absence of a sewing ring.

The lower incidence of patient–prosthesis mismatch in TAVI patients might make this intervention preferable to surgery in female patients with small aortic annuli.

Finally, it has been demonstrated that the total burden of aortic valve calcification for any given level of AS severity is significantly lower in women than in men; thus, the Agatston coronary artery calcium score cut-off points are 2,065 in men and 1,275 in women.26 These scores are usually used to aid diagnosis in patients with discordant aortic valve area and mean transaortic gradient values. Furthermore, the use of ‘calcium density’ has been shown to be predictive of survival in AS patients independently of clinical and echocardiographic factors.27 The minority of women who show moderate to severe calcifications of the left ventricle outflow tract have an almost two-fold increased risk of mortality or stroke at 1 year.28 In addition, calcium volume in the right coronary cusp is an independent predictor of the need for pacemaker implantation post TAVI.28

Procedural Aspects Access Transfemoral approach is the preferred route of access in the general population undergoing TAVI, particularly in women. However, women have a higher rate of vascular complications following TAVI. This is usually due to an unfavourable sheath-to-artery ratio in women, as the common femoral arteries have a smaller mean diameter and there is increased tortuosity in comparison to men.14

INTERVENTIONAL CARDIOLOGY REVIEW

Sex and Transcatheter Aortic Valve Implantation Prosthesis There are conflicting data about the types of valve implanted in female patients. The meta-analysis by O’Connor et al. including data from five studies and 11,310 patients showed that balloon-expandable (BE) devices were used more frequently and that a higher proportion of women than men received a BE prosthesis.14 In this series only Sapien® and Sapien XT® (Edwards Lifesciences), CoreValve™ (Medtronic) and Portico™ (St. Jude Medical) valves were used.

Figure 1: Left Ventricular Hypertrophy in a Woman with Severe Aortic Stenosis

An even larger meta-analysis by Saad et al. including 47,188 patients confirmed that women were more likely to receive a BE valve compared with men (76.2±38.7% versus 72.7±38.7%; p=0.0001).29 The more frequent use of BE prostheses in women might partially explain the higher incidence of annular rupture, with further contributing factors being smaller annular and aortic root dimensions in females in comparison to males. It might also explain the lower incidence of atrioventricular block requiring permanent pacemaker implantation as well as paravalvular aortic regurgitation (as shown in the next section).

However, a possible confounder is these meta-analyses included many studies referring to initial TAVI experiences, when a reduced armamentarium of devices was available. Consequently, the more common use of BE devices in women at that time can be interpreted as being proportionate to their less frequent employment in men, in whom only self-expanding valves could fit the larger annular sizes.

EDV = end diastolic volume; IVSd = interventricular septal thickness – diastolic; LVIDd = left ventricle internal diameter – diastolic; LVPWd = left ventricle posterior wall thickness – diastolic.

Figure 2: Normal Left Ventricular Wall Thickness in a Man with Severe Aortic Stenosis

A more recent sex-specific registry by Chieffo et al., which enrolled 1,000 women from 19 countries across Europe and North America, found a wider range of devices have been used since the introduction of new-generation prostheses. In this changed scenario, self-expanding (SE) CoreValve prosthesis are now the most commonly used devices (47.2%) while transfemoral is still the preferred route of access.30 The preference for using SE devices in women and patients with smaller annuli and calcified iliofemoral vessels was confirmed by a recent single-centre US study of third-generation devices, reflecting realworld practice.31 The supra-annular design of some of these prostheses may have contributed to this changing scenario as it favours lower post-procedural gradients, thus reducing the incidence of patient– prosthesis mismatch.

Outcomes Procedural Outcomes O’Connor et al. reported a high device success rate (97%) in the whole TAVI population without any gender-related difference (p=0.22), together with a comparable incidence of immediate (<72-hour) peri-procedural mortality (2.2% versus 2.6%, p=0.24) and need for conversion to open surgery (0.9% versus 1.0%, p=0.57). Conversely, valve embolisation is slightly more common in men (1.5% versus 1.0%, p=0.018) while cardiac tamponade has a significantly higher incidence among women (0.7% versus 1.3%, p=0.002).14 Coronary obstruction is a rare but life-threatening complication after TAVI, more often involving the left coronary system. It has been shown to be more frequent in elderly patients, in patients receiving a BE valve, in those with a previous surgical bioprosthesis and, most of all, in women (p<0.001).32 One possible explanation for this finding is the lower coronary artery height observed in women. Other periprocedural endpoint results seem to be consistent, even if there is some heterogeneity in definitions (VARC criteria were applied in most but not all studies).

INTERVENTIONAL CARDIOLOGY REVIEW

EDV = end diastolic volume; IVSd = interventricular septal thickness – diastolic; LVIDd = left ventricle internal diameter – diastolic; LVPWd = left ventricle posterior wall thickness – diastolic.

Despite lower rates of baseline peripheral vascular disease, women are more prone to vascular complications and subsequent bleeding.8,9,33 Female sex is associated with a 1.72-fold increase in major vascular complications, as defined by Stangl et al. in their meta-analysis of 14 studies and 7,973 patients.33 Both Zhao et al. and O’Connor et al. confirm this result and show that women are at a higher risk of major/life-threatening bleeding (15.0% versus 12.7% and 10.5% versus 8.5%, respectively).11,14 This finding has historically been ascribed to the smaller absolute dimensions of the iliofemoral arteries in women, implicating an unfavourable introducer sheathto-femoral artery ratio.34,35 Technical improvements in TAVI procedure have aimed to overcome this problem.

Gender difference in the prevalence of peri-procedural stroke is controversial: some studies consider the incidence to be equally low in both sexes but several studies report a higher stroke rate in women.14,36

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Structural Figure 3: Transfemoral Transcatheter Aortic Valve Implantation Procedure Performed in a Woman

mortality (HR 1.21), together with other risk factors such as advanced age, end-stage renal disease, severe chronic obstructive pulmonary disease, non-transfemoral access, STS score >15% versus <8% and preoperative AF/flutter.37 Similarly, the meta-analysis by O’Connor et al. confirmed a higher mortality for men in comparison to women at a median follow-up of 387 days (21.8% versus 17.3%, respectively). Furthermore, it showed that female patients have a better prognosis on longer-term followup (up to 5 years, when the percentage survival is 43.6% in women versus 38.9% in men). Multivariate analysis also found that female sex is a predictor of better outcome, irrespective of the valve type and the route of access.14

(A–C) Multiplanar CT scan reconstruction showing a small aortic annulus. (D) Angiography showing small femoral access. (E) Aortography. (F) Release of a self-expanding prosthesis.

An analysis of data from the STS/American College of Cardiology Transcatheter Valve Therapies Registry showed that, compared to men, women have a higher risk of stroke (HR 1.40).37 The finding of a higher incidence of stroke in women in some studies is surprising, since women have fewer comorbidities at baseline. The use of a large sheath or the distribution of ascending aortic atheroma might explain these unexpected findings.37 Other important determinants of outcomes after TAVI are the presence of residual aortic regurgitation (AR) and the need for permanent pacemaker implantation. Both are less common in women than in men.

The incidence of post-procedural AR grade ≥2 (where grade 2 is mild) is 20.9% in women and 29.6% in men (p=0.01). This is due to women having a smaller annulus and higher cover index, which is calculated as 100 × ([prosthesis diameter − trans-thoracic echocardiography annulus diameter]/prosthesis diameter).38

Different outcomes between women and men undergoing TAVI can be explained by a complex interaction between baseline characteristics and procedural aspects. The healthier state of female patients at baseline, including better ventricular function, seems to be of primary importance. In men, a higher incidence of coronary artery disease and the consequently wider extent of myocardial fibrosis partially explain this finding.42 Moreover, a lack of oestrogen and high levels of circulating androgens in males contribute to the increase in interstitial fibrosis through up-regulation of the extracellular matrix. 43 As a consequence, when exposed to pressure overload due to AS, male hearts develop systolic dysfunction and heart failure earlier than female hearts, which exhibit a more favourable geometry for the preservation of systolic pump performance. 43–45 The close involvement of sex hormones in cardiac function has been demonstrated in an animal model. Gonadectomy in rats significantly reduces cardiac function, inducing a shift in myosin heavy-chain content to the slower isoform; a pathological effect that can be reversed by hormonal supplementation.46 The combination of all these factors can also directly influence response in terms of recovery of ejection fraction after aortic valve replacement. Morris et al. showed that women have an earlier improvement in ventricular function than men.47

Gender-specific Analysis Permanent atrioventricular block is similarly less common in female than male TAVI patients (9.6% versus 17.2%). The Italian OBSERVANT Registry reported a trend towards significance for female sex as a protective factor (p=0.05; OR 0.61).39 Results are even stronger if focusing on studies in which CoreValve use is dominant, such as the meta-analysis by Zhao et al.11 One suggested explanation for the higher incidence of permanent pacemaker implantation in men as compared to women is the use of larger prostheses.

Long-term Outcomes Although some small studies have shown similar survival between the sexes,9,40,41 large meta-analyses have consistently demonstrated a survival benefit for women at mid-term follow-up after TAVI.17 For example, Stangl et al. and Conrotto et al. assessed mortality and showed that it was higher in men than women at 3 months (25.9% versus 19.7%) and 1 year (34% versus 24%).33,36 The STS/American College of Cardiology Transcatheter Valve Therapies Registry also demonstrated that male sex was significantly associated with 1-year

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The Women’s International Transcatheter Aortic Valve Implantation (WIN-TAVI) Real-World Registry found that increasing age, history of prior stroke, left ventricular ejection fraction <30% and the generation of TAVI device deployed were all independent predictors of 30-day VARC-2 primary safety endpoint (a composite of allcause mortality, stroke, major vascular complication, life-threatening bleeding, acute kidney injury, coronary artery obstruction and repeat procedure for valve-related dysfunction) in women.48 In the effort to identify sex-specific factors that may influence outcomes, a history of pregnancy was found to be protective (OR 0.63). Age of menopause, history of osteoporosis and gynaecological or breast cancers seemed to have no influence on the primary safety endpoint.29 The updated 1-year follow-up demonstrated a univariate but not multivariate protective association of previous history of pregnancy with 1-year incidence of death or stroke; also it failed to demonstrate any association with the VARC-2 composite efficacy endpoint beyond 30 days (a composite of all-cause mortality, all stroke, MI, hospitalisations for valve-related symptoms or worsening congestive heart failure or valve-related dysfunction).48

INTERVENTIONAL CARDIOLOGY REVIEW

Sex and Transcatheter Aortic Valve Implantation Conclusion Percutaneous rather than surgical aortic valve replacement is better for women with AS. The potentially negative impact of some procedural complications in women is counterbalanced by the healthier state of the female population at baseline and the lower incidence of post-

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O’Connor SA, Morice MC, Gilard M, et al. Revisiting sex equality with transcatheter aortic valve replacement outcomes: A collaborative, patient-level meta-analysis of 11,310 patients. J Am Coll Cardiol 2015;66:221–8. https://doi. org/10.1016/j.jacc.2015.05.024; PMID: 26184614.

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INTERVENTIONAL CARDIOLOGY REVIEW

procedural AR and permanent pacemaker implantation. Together these findings lead to the survival benefit observed in women. A history of pregnancy has a protective role against adverse outcomes occurring within 30 days of procedure but has no influence on outcomes in the longer term.

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Multivalvular Disease: Percutaneous Management in 2019 and Beyond Magdalena Erlebach 1,2 and Rüdiger Lange 1,2 1. Department of Cardiovascular Surgery, German Heart Centre, Munich, Germany; 2. Institute of Translational Cardiac Surgery, Department of Cardiovascular Surgery, German Heart Center Munich, Technische Universität München, Munich, Germany

Abstract Patients with multivalvular disease (MVD) are common and often present with heterogeneous valve defects. Evaluation is complicated by interactions among various valve pathologies. Trials and guidelines focus primarily on single-valve disease, providing few recommendations for the treatment of patients with MVD. This article provides an insight into percutaneous treatment possibilities for this heterogeneous patient population.

Keywords Multivalvular disease, transcatheter aortic valve implantation, transcatheter mitral valve repair, intervention Disclosure: RL has received lecture fees and royalties from Medtronic, is a member of Medtronic’s advisory board, has received lecture fees from LivaNova and Abbott and has received lecture fees from and has shares in Highlife. ME has no conflicts of interest to declare.

Received: 1 March 2019 Accepted: 27 September 2019 Citation: Interventional Cardiology Review 2019;14(3):142–6. DOI: https://doi.org/10.15420/icr.2019.13.R1 Correspondence: Magdalena Erlebach, Deutsches Herzzentrum München, Lazarettstrasse 36, 80636 Munich, Germany. E: erlebach@dhm.mhn.de 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.

Patients with multivalvular disease (MVD) can present with a variety of valve pathologies and combinations, often requiring a complex treatment strategy. Both the Euro Heart Survey and the EURObservational Research Programme Valvular Heart Disease Registry (presented at the European Society of Cardiology [ESC] 2018 meeting) demonstrated that more than one-fifth of patients with native valve disease have MVD.1 As these registries solely report left-sided MVD, it seems safe to assume that the number of patients with multiple right- and left-sided valve disease is even higher. Data on the treatment and outcome of such patients is scarce. As most trials and studies concentrate on single-valve pathologies, the MVD patient cohort is also underrepresented in the 2017 ESC/European Association for Cardio-Thoracic Surgery (EACTS) guidelines for the management of valvular heart disease, even more so regarding interventional treatment options.2 This article provides an insight into percutaneous treatment possibilities for this heterogeneous patient population.

Evaluation The clinical presentation of patients with MVD depends on various interacting factors, including the severity of each single valve lesion, the type of lesion (insufficiency or stenosis), volume status, ventricular function and the time of clinical presentation.

Furthermore, patient comorbidities and level of activity can have an effect on symptoms. Auscultation and identification of murmurs can be difficult. In patients with MVD of similar severity, the clinical symptoms may be masked by the haemodynamic effects of the most proximal lesion. A thorough and extensive examination, as well as a comprehensive patient history, is mandatory in order to better understand the leading pathology.

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In addition, ECG is an essential diagnostic tool for valve evaluation.

Yet, most quantification methods have been validated for single-valve disease and so their use in MVD may not yield correct results.

Nonetheless, ECG assessment should include quantitative measurements of valve dynamics, a description of valve morphology and functional indices, such as ventricular function and dimensions and pulmonary pressure.3 In general, measurements that are not affected by volume status, such as planimetric dimensions or measurement of the vena contracta, are preferred.2,3 Further information regarding valve pathology and relation to cardiac structures can be obtained using 3D ECG. Valve pathology, in particular the difference between primary or secondary mitral or TR should be clearly described, because this affects the type of intervention, surgical treatment and possible improvement after treatment of other valves. It must be kept in mind that valve pathologies influence one another, masking or exaggerating the true severity of each lesion. For example, a severely insufficient mitral valve may cause flow reduction across the aortic valve, leading to a decreased gradient, and volume overload due to heart failure in severe aortic stenosis may cause mitral regurgitation. The differentiation can be difficult.

Invasive cardiac catheterisation for pressure and cardiac output measurement should remain restricted to patients in whom non-invasive tests are inconclusive or show a discrepancy with clinical findings.2

Treatment Data about the treatment of MVD are scarce. The 2017 ESC/EACTS guidelines provide only general suggestions as opposed to evidencebased recommendations for the treatment of patients with MVD.2 In general, recommendations for the treatment of concomitant valvular

© RADCLIFFE CARDIOLOGY 2019

Multivalve Disease: Percutaneous Management disease are primarily only Level C recommendations. Briefly, treatment should follow the recommendations for the dominant lesion; and interactions between valve lesions and the higher surgical risk for multiple valve interventions must always be taken into account, including the likelihood of spontaneous changes in tricuspid and mitral regurgitation after surgery.2

thrombosis was uncommon.11 Further studies will help us understand the applicability of this procedure. The sections below describe a small selection of percutaneous devices beyond the spectrum of the known TAVR valves and MitraClip. The diversity and evolution of interventional devices will allow for better patient-adapted therapies, in particular for patients with MVD.

As a key principle, treatment of patients with MVD should be performed by a multidisciplinary heart team in a specialised heart valve centre.2,4 The heart team should include surgeons, interventionalists, echocardiologists, anaesthesiologists and radiologists. The combination of expertise from each discipline will allow for the best possible care of the patient. The rationale for treating patients in a heart valve centre is that such centres provide the logistics and high volume needed to minimise complication rates.4

Percutaneous Mitral Valve Devices

In the setting of patients with MVD, not only is the timing of the intervention important, but even more so is the type of intervention. In the Euro Heart Survey, in-hospital mortality for treatment of MVD was 6.5%, compared with 0.9–3.9% for single-valve disease.1 In the Society of Thoracic Surgeons database, the operative mortality of patients with MVD was twice as high as for patients with single-valve disease (10.7% versus 5.7%, respectively; p=0.0001).5 Furthermore, long-term mortality and, in particular, valve-related mortality in patients undergoing aortic and mitral valve replacement are high.6,7 This higher risk must be taken into account when evaluating patients and deciding on the treatment strategy. The possibility of a single-valve operation as an incomplete surgical correction in order to reduce the risk for selected patients should be taken into account. Conversely, a percutaneous intervention may be a lower-risk single-valve treatment.

The NeoChord DS1000 is a minimally invasive, beating-heart transcatheter system developed for echo-guided neochordae implantation via a transapical access. Procedural and short-term safety and efficacy have been demonstrated, although long-term results are sparse.12

In summary, data and recommendations regarding treatment of MVD are scarce and underrepresented. The guidelines primarily include surgical treatment options and advise concomitant interventional valve procedures because of the invasiveness of surgery. Although interventional valve treatment options have, to date, only been established for selected and single-valve disease (e.g. transcatheter aortic valve replacement [TAVR] and MitraClip [Abbott Vascular]), lessinvasive and possibly staged procedures may play a crucial role in the treatment of patients with MVD. This also provides the possibility of symptomatically treating multimorbid patients, addressing only the dominant valve lesion. By staging interventional procedures, it is possible to treat one lesion and to then re-evaluate the severity of coexisting valvular pathologies in a ‘normalised’ haemodynamic situation.

Percutaneous Interventional Devices Beyond Transcatheter Aortic Valve Replacement and MitraClip TAVR and MitraClip are well-established procedures that will not be described in detail in this article. Numerous studies have proven that the use of TAVR as a valve-in-valve (ViV) procedure in the aortic position can be performed with excellent results.8,9 The clinical use of transcatheter prostheses has also been expanded to include mitral ViV, mitral/tricuspid valve-in-ring (ViR) and valve-in-mitral annular calcification (ViMAC). A recently published study showed excellent results for mitral ViV, despite a high-risk population.10 However, in that study, mitral ViR and ViMAC were associated with a higher rate of adverse events and mid-term mortality than ViV.10 Aside from various case reports, the use of transcatheter prostheses in the tricuspid position has only recently been published. In this high-risk population, mortality was lower than expected and valve dysfunction or

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Aside from the MitraClip, which addresses leaflet coaptation, various transcatheter devices mimicking known surgical strategies have been developed. These include, but are not limited to, the NeoChord DS1000 (NeoChord,) for neochordae implantation, the Cardioband (Edwards Lifesciences) and the Mitralign Percutaneous Annuloplasty System and the Carillon Mitral Contour System (Cardiac Dimension) for mitral valve annuloplasty.

The Cardioband system is a transcatheter direct annuloplasty device, leaning on the known surgical technique of a restrictive annuloplasty.

Results from a feasibility trial and early clinical experience are promising.13,14 At the moment, the Annular Reduction for Transcatheter Treatment of Insufficient Mitral Valve (ACTIVE; NCT03016975) trial is on-going in the US. This is a prospective multicentre randomised controlled and pivotal trial, comparing transcatheter mitral valve repair using the Cardioband system together with medical treatment compared to medical treatment alone in patients with functional MR. The study will randomise 375 patients in a 2 : 1 randomisation scheme.15 The Mitralign Percutaneous Annuloplasty System is a direct annuloplasty technique that applies sutures anterior and posterior of the commissures. By cinching these sutures, annular reduction is achieved. During the first-in-human trial, the device success rate was 70%, with postoperative left ventricular remodelling and improved clinical status.16 Larger series and longer follow-up have not been reported as yet.

The Carillon Mitral Contour System is an indirect annuloplasty device that is inserted in the coronary sinus. Mitral valve leaflet coaptation is achieved by septal–lateral compression of the posterior annulus.

During the Carillon Mitral Annuloplasty Device European Union Study (AMADEUS), the device was only successfully implanted in 30 of 48 patients because of access issues, high residual MR and problems with coronary artery blood flow.17 Subsequent trials (i.e. Transcatheter Implantation of Carillon Mitral Annuloplasty Device [TITAN] and TITAN II) using the second generation device) showed higher device success, a low major adverse event rate and good left ventricular remodelling.18,19 Again, long-term data and larger case series are still needed.

Transcatheter Mitral Valve Replacement Development of transcatheter mitral valve devices has proven to be a greater challenge than that of aortic valve devices. The main challenge lies in the complex anatomy of the mitral valve and its relationship to other anatomical structures. This includes the asymmetrical shape of the mitral annulus, large leaflets, in most cases a lack of calcified structures and the risk of left ventricular outflow tract obstruction.

Access and anchoring are challenging. Table 1 gives a brief overview

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Structural Table 1: Transcatheter Mitral Valves Technologies

Cases

Anchoring

Valve Specifics

in Humans (n)

Access

Ongoing Trials

Transseptal Transapical

Tendyne (Abbott Vascular)

>130

Apical tether

Multiple outer frame sizes, fully retrievable

Medtronic Intrepid (Medtronic)

>70

Radial force

Inner and outer stent frame

(X)

SAPIEN M3 (Edwards Lifesciences)

>15

External anchor; mitral annulus capture

Universal dock system, fully retrievable

X

CardiAQ (Edwards Lifesciences) >23

Mitral annulus capture with native leaflet engagement

Supra-annular

X

Neovasc Tiara (Neovasc)

>52

Fibrous trigone capture with D-shaped native leaflet engagement

HighLife (HighLife)

>15

External anchor; valve in subannular mitral ring

X

SUMMIT prospective randomised trial between TMVR and surgery (NCT03433274)

X

APOLLO prospective randomised trial between TMVR and surgery (NCT03242642)

X X Simultaneous

TMVR = transcatheter mitral valve replacement; X = yes; (X) = under development and will hopefully arrive soon.

Table 2: Tricuspid Percutaneous Devices Annuloplasty Trialign Cardioband (Edwards Lifesciences) Millipede/IRIS (Millipede) Coaptation Enhancement Pascal (Edwards Lifesciences) Clip-based tricuspid repair system (Abbott Vascular) TriCinch (4Tech Cardio) Forma (Edwards Lifesciences) Valve Replacement

moderate to severe mitral valve regurgitation (MR) in patients undergoing TAVR has been reported to occur in approximately 20–30% of patients and has been shown to have a significant effect on mortality. 20–22 In most trials, a significant improvement in MR was reported in 50–60% of patients after TAVR alone.20–22 The results of a large meta-analysis, including primary and secondary MR, indicate that the use of a balloon-expanding valve seems to have a greater effect on MR reduction than the use of a self-expanding valve. 22 Functional MR and the absence of pulmonary hypertension, as well as the absence of AF, had positive effects on MR reduction after TAVR. 23 As residual MR after TAVR has a negative effect on mortality, patients should be followed closely and, if necessary, undergo mitral valve intervention.

Navigate (Navigate Cardiac Structures) TricValve (P&F Products & Features)

of the most established transcatheter mitral valves with no claim to completeness. At the moment, there is no transcatheter mitral valve replacement with CE marking available.

Percutaneous Tricuspid Valve Devices Transcatheter tricuspid valve treatment solutions have recently been emerging. To date, most of devices have been used in small case series or compassionate human case series. Most common has been the off-label use of the MitraClip (see below). As with the mitral valve, dedicated tricuspid valve devices focus on mimicking surgical techniques, such as annuloplasty, leaflet coadaptation or valve replacement. Table 2 gives an overview of this investigational group of devices, again with no claim to completeness.

The type of intervention depends on valve pathology and the applicable devices. A possible percutaneous approach for the treatment of aortic valve stenosis and concomitant MR is TAVR followed by MitraClip implantation. Case series have been able to show the feasibility of this approach, yet rehospitalisation rates and midterm mortality are high, with low functional improvement.24,25 A 2017 study with data from the German Transcatheter Mitral Valve Interventions (TRAMI) registry showed a lower device success rate and a lower survival rate for patients who had previously undergone surgical or interventional aortic valve replacement (AVR; n=28).26 In the TAVR subgroup, survival at 1 year was <50%.26 These results suggest that, at present, this percutaneous treatment combination may be limited to a high-risk subgroup, although larger prospective trials must be established. A further possible percutaneous approach is the combination of TAVR and the Neochord DS1000, which was reported by Gerosa et al. to yield good results.27 Additional data are required to show the feasibility and safety of this approach.

Common Concomitant Valve Pathologies Aortic Valve Stenosis and Mitral Valve Regurgitation

Aortic Stenosis and Mitral Valve Stenosis

Aortic stenosis will lead to remodelling and hypertrophy of the left ventricle, as well as left ventricular dilation. Although primary mitral regurgitation can be present, the changes in left ventricular geometry can lead to secondary mitral regurgitation. Concomitant

The combination of aortic stenosis and mitral stenosis is uncommon in industrialised countries because the haemodynamic situation is not well tolerated and patients present before severe stenosis becomes apparent. The presence of double-valve severe stenosis,

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Multivalve Disease: Percutaneous Management

leading to low cardiac output, will lower the respective gradients and thus lead to an underestimation of the severity of the stenosis.

Here again, valve pathology is of great importance because rheumatic and degenerative mitral stenosis are addressed differently.

Rheumatic mitral stenosis, caused by commissural fusion, can be well treated with percutaneous balloon valvuloplasty. Combined with an underestimated severe aortic stenosis, the sudden increase in preload may lead to heart failure with pulmonary oedema. Conversely, degenerative mitral stenosis is usually caused by progressive annular calcification.28 Treatment options, including surgery, can be difficult.

As mentioned above, ViMAC is an option, but is still undergoing clinical testing.10

Aortic Valve Regurgitation and Mitral Valve Regurgitation Aortic and mitral regurgitation is poorly tolerated, due to severe volume overload, leading to eccentric left ventricular hypertrophy and a reduction in function.29 MR due to volume overload caused by aortic regurgitation is not uncommon. Moderate to severe mitral regurgitation in patients undergoing AVR for aortic regurgitation has a negative effect on survival; simultaneous mitral valve repair improved survival.30 Staged percutaneous interventions allow for reassessment of mitral regurgitation and left ventricular function after treatment of aortic valve regurgitation. Taking certain anatomical criteria into consideration, aortic valve regurgitation can be treated using TAVR devices developed for aortic valve stenosis. A more than moderate paravalvular leak, the need for a second valve due to aortic regurgitation or valve embolisation and a higher rate of pacemaker implantation than usual for TAVR must be taken into account.31 An on-going study of a transfemoral TAVR valve specifically developed for aortic regurgitation will expand therapeutic options.

Left-sided Valve Disease and Tricuspid Regurgitation Significant tricuspid regurgitation (TR) is prevalent in 5–30% of patients undergoing left heart surgery.32 Persistent TR after aortic or mitral valve surgery or intervention has been shown to have a negative effect on survival.33–35 Data concerning improvement of TR after TAVR is variable, with studies reporting TR improvement in 15–50% of patients.32,36 TR has been shown to be significantly reduced after MitraClip implantation, but persistent moderate or severe TR independently predicted death and rehospitalisation for heart failure at 12 months.37 Although data concerning the effect of TR on outcomes for patients undergoing left heart surgery are very diverse, it seems clear that residual regurgitation has a negative effect on outcome.

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Data from the Transcatheter Tricuspid Valve Therapies (TriValve) Registry show that 30% of tricuspid interventions are performed concomitantly with mitral valve intervention, and that 7.5% of patients had previously undergone left heart transcatheter intervention.38 In the largest series on tricuspid clipping, Nickenig et al. reported that 33% of patients undergoing tricuspid valve clipping using the MitraClip had previous interventional valve treatment of the aortic or mitral valve (19% TAVR, 14% MitraClip).39 Twenty-two patients (34%) underwent concomitant mitral valve clipping, and there was a similar reduction in TR and no difference in procedural complications between patients undergoing tricuspid clipping alone and concomitant mitral valve clipping.39 Hypothetically, the combination of TAVR or MitraClip with an interventional device for the tricuspid valve is possible and, with the poor outcomes of residual TR in mind, may be a reasonable treatment option. Further trials and development of transcatheter devices for the tricuspid valve must prove clinical feasibility and efficacy.

Conclusion Patients with MVD are common and present with heterogeneous valve pathologies. Evaluation is complicated by interactions of the various valve pathologies. Trials and guidelines focus primarily on single-valve disease, providing few recommendations for the treatment of patients with MVD. Therefore, a summary of principles is presented below for the diagnosis and intervention of these patients based on our own clinical experience and the sparse available data: • Evaluation should include an extensive clinical examination, a thorough anamnesis and a comprehensive echocardiographic analysis while taking the effects of the various valve pathologies into account.

• Patient risk assessment should be done in a heart team setting, respecting patient comorbidities and treatment goals (complete correction, improvement of quality of life).

• To date, surgical strategies have been the gold standard, yet interventional treatment modalities may offer various advantages, such as being less invasive, staged procedures and solely symptom oriented.

• For percutaneous interventions, the dominant lesion should be addressed first. After a recompensation period, re-evaluation of remaining valve pathologies and the clinical status of the patient is required. Data regarding the outcome of various interventional procedures (e.g. for the tricuspid valve) and, in particular, staged interventions are limited, therefore these treatment strategies should, at present, be used in inoperable or high-risk patients.

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Nickenig G, Kowalski M, Hausleiter J, et al. Transcatheter treatment of severe tricuspid regurgitation with the edgeto-edge MitraClip technique. Circulation 2017;135:1802–14. https://doi.org/10.1161/CIRCULATIONAHA.116.024848; PMID: 28336788.

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Structural

Bioprosthetic Aortic Valve Fracture During Valve-in-valve Transcatheter Aortic Valve Implantation John Phineas O’Donnell 1,2 and Cróchán J O’Sullivan 3,4 1. University Hospital Limerick, Limerick, Ireland; 2. University of Limerick, Limerick, Ireland; 3. Department of Cardiology, Bon Secours Hospital, Cork, Ireland; 4. University College Cork, Cork, Ireland

Abstract The limited durability of surgical bioprostheses, combined with an ageing population, has led to an increasing demand for replacing degenerated bioprosthetic surgical heart valves, which is projected to increase. Valve-in-valve transcatheter aortic valve implantation involves implanting a transcatheter heart valve within a degenerated bioprosthetic surgical heart valve. A significant minority of patients, however, are left with a suboptimal haemodynamic result with high residual gradients. This is more common with smaller surgical bioprostheses, and may be associated with a worse prognosis. The novel concept of fracturing the previously implanted bioprosthetic surgical heart valve during valvein-valve transcatheter aortic valve implantation to create a more favourable haemodynamic profile has shown great promise, particularly in smaller valves. Herein, we describe the benefits, limitations and potential complications of this novel approach.

Keywords Bioprosthetic aortic valve fracture, valve-in-valve, transcatheter aortic valve implantation Disclosure: CJO has received consultant fees from Edwards Lifesciences. JPO has no conflicts of interest to declare.

Received: 13 February 2019 Accepted: 30 September 2019 Citation: Interventional Cardiology Review 2019;14(3):147–51. DOI: https://doi.org/10.15420/icr.2019.08.R2 Correspondence: Cróchán O’Sullivan, Suite 24, The Cork Clinic, Clinic B, Western Road, Cork, Ireland. E: admin@coscardio.ie 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 demand for replacing degenerated bioprosthetic valves (BPVs) is steadily rising owing to the increasing burden of heart disease, ageing populations, advances in surgical intervention and limited durability of current-generation surgical BPVs. The issue is exacerbated by the increasing trend of surgical BPV replacement, especially in younger patients who are likely to require future intervention.1 Transcatheter aortic valve implantation (TAVI) is a safe and effective alternative to surgical aortic valve replacement for patients across the entire risk spectrum, although the importance of the heart team in clinical decision-making remains paramount.2 Structural valve degeneration has bedevilled surgical aortic valve replacement since its inception, and studies have shown high mortality rates associated with redo surgical aortic valve replacement, estimated between 3.8% and 5.2%. Since the first valve-in-valve (VIV) TAVI procedure was performed by Wenaweser et al. in 2007, there is now a less invasive option to treat patients with degenerated BPVs.3 Patient prosthesis mismatch (PPM) following VIV TAVI, however, has emerged as a concern, particularly among patients with smaller BPVs. Bioprosthetic valve fracturing (BVF) of a BPV during VIV TAVI is a novel approach, first described in the aortic position in 2015, involving fracturing the BPV ring with high-pressure balloon inflation to improve postprocedural valvular haemodynamics.4

Valve-in-valve Transcatheter Aortic Valve Implantation The Valve-in-Valve International Data (VIVID) registry, established in 2010, was designed to collect data on VIV TAVI procedures using

© RADCLIFFE CARDIOLOGY 2019

both self-expanding (Medtronic) and balloon-expandable (Edwards Lifesciences) devices. It is the largest of its kind.5 The VIVID registry showed worse outcomes when VIV TAVI was performed in patients with small surgical valve sizes (label size ≤21 mm) and in those with stenosis as the primary mechanism of failure.5 Small surgical valve size (≤21 mm) was associated with a reduced 1-year survival of 74.8% compared with intermediate-sized (21–25 mm) and large (≥25 mm) BPVs, which had survival rates of 81.8% and 93.3%, respectively.5 Patients being treated for BPV stenosis had 30-day mortality rates of 10.5% compared with 4.3% for BPV regurgitation and 7.2% in the combined group (p=0.04).5 One multicentre study (n=47) describes a 30-day mortality rate of 17% after ViV TAVI (mean age 80.3 years; EuroSCORE 35%).6 PPM is assumed to be the cause of increased mortality rates after VIV TAVI and as such is a major concern.5 PPM is generally defined as an indexed effective orifice area (iEOA) ≤0.85 cm2/m2 and can lead to an inadequate cardiac index.7 In one series, PPM was highest among VIV TAVI within smaller BPVs and the incidence of severe PPM (iEOA ≤0.65 cm2/ m2) following VIV TAVI was found to be 31.8 %.5 If, however, one considers that, for example, Mitroflow 19 mm and 21 mm prostheses have true internal diameters of 15.4 mm and 17.3 mm, respectively,5 it is perhaps not surprising that placement of a THV constrained by these diameters may not meet physiological demands. In summary, patients with small surgical BPVs undergoing VIV TAVI have higher residual gradients and higher mortality compared with patients with larger BPVs undergoing VIV TAVI.5

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Structural Table 1: Actuarial Survival and Occurrence of Reoperation and Bleeding after 10 and 20 Years in Patients Receiving a Mechanical (Björk–Shiley) or Bioprosthetic (Porcine) Valve in a Randomised Prospective 20-Year Comparison Trial Valve

10 years (%) 20 years (%) p-value*

Bioprosthetic Valve Fracturing Procedure and Case Series

Björk–Shiley valve

58.7

25.0

Porcine valve

53.6

22.6

Björk–Shiley valve

55.7

23.5

Porcine valve

42.6

6.7

47.0

13.8

37.3

4.8

Björk–Shiley valve

7.1

12.2

Porcine valve

27.0

67.8

BVF fracture directly addresses the issue of inadequate valve diameter by forcefully dismantling the rigid scaffold of the degenerated surgical BPV (Figures 1 and 2). This allows the implantation of a valve size better suited to the patient’s native cardiac index. While the composition of BPVs vary, all are based on similar concepts. For example, the design of the Mitroflow BPV (Sorin Group; Figure 2) incorporates a bovine pericardial sheet sutured to the outside of an acetyl stent to form the leaflets.4 The sewing ring is made from soft radiopaque silicone covered by a Dacron mesh. The acetyl stent ring diameter can be widened via fracturing.4

Björk–Shiley valve

15.3

55.6

Porcine valve

7.5

43.6

Survival All survivors

With original prosthesis intact

Survivors without Björk–Shiley valve a major event Porcine valve

0.39

<0.0001

0.0007

Valve-related Events Reoperation

Bleeding: all episodes

a larger THV size more appropriate to the patient’s cardiac index.4,6–14 At present, it remains unclear as to whether it is the complete expansion of the THV or the implantation of a larger valve that is the main factor contributing to the improved haemodynamics found after BVF.

<0.0001

0.007

*p-value from log rank tests, Bjork-Shiley versus porcine valves at 20 years.

Source: Oxenham et al. 2003.19 Adapted with permission from BMJ Publishing Group.

Figure 1: Fluoroscopic Images of the Stages of Valve-in-valve Transcatheter Aortic Valve Implantation Followed by Bioprosthetic Valve Fracture

Bench tests describe the technique of placing a non-compliant balloon within the surgical bioprosthesis.4,9–11 A high-pressure stopcock is used to separately attach a syringe and an indeflator to the balloon. The balloon is inflated by hand injection at first, and is then completed with high-pressure inflation using the indeflator.9 This results in a single fracture point within the stiff valve ring. An audible snap can be heard with a sudden decrease in inflation pressure. The fracture can usually be confirmed visually by fluoroscopy, but not in Mosaic (Medtronic) and Mitroflow BPVs, because they have no metal ring.12 Haemodynamic measurements and calculation of the valve effective orifice area are performed at baseline, immediately after VIV TAVI and after BVF. Two single-centre case series demonstrate the strategies and haemodynamic results in patients treated with VIV TAVI and BVF.13,14 The majority of these cases were to treat stenotic BPVs, with a mean age of 79 years. Of a combined cohort of 30 patients from the two cases series, 15 patients underwent BVF before TAVI and the other 15 received BVF after TAVI.13,14 This has been clearly summarised in a prior review.12

A: Immediately after valve-in-valve transcatheter aortic valve implantation. B: During bioprosthetic valve fracture before fracture of surgical ring. Note the waist of the balloon at the level of the surgical valve ring. C: During bioprosthetic valve fracture after fracture of the surgical ring. Note the release of the balloon waist. D: Final fluoroscopic results.

Source: Chhatriwalla et al. 2017.13 Reproduced with permission from Wolters Kluwer Health.

Bioprosthetic Valve Fracture Owing to the poorer outcomes among patients undergoing ViV TAVI with smaller diameter BPVs (i.e. 19 mm and 21 mm BPVs), several investigators have begun to consider interventions that might reduce the incidence of PPM. BVF was first described in the aortic position

by Nielsen-Kudsk et al. in 2015.4 The procedure involves fracturing the ring of the structural ring of the surgical BPV using a non-compliant balloon during rapid ventricular pacing to allow for greater expansion of the transcatheter heart valve (THV) and possibly the implantation of

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Interestingly, the 15 cases of TAVI prior to BVF were all in one case series, and allow measurement of haemodynamic improvements following TAVI to be compared with further improvements post BVF.13 In this study, there were initial haemodynamic improvements observed following VIV TAVI, but importantly, further benefits were observed in the same patients following BVF. Mean transvalvular gradients were reduced from 20.5 ± 7.4 mmHg after initial VIV TAVI to 6.7 ± 3.7 mmHg after BVF (p<0.001).13 Accordingly, the mean effective orifice area increased from 1.0 ± 0.4 cm2 after initial VIV TAVI to 1.8 ± 0.6 cm2 after BVF (p<0.001).13 A multicentre case series in which BVF was performed in 75 patients in 21 centres has recently been published. 8 BVF success was defined as when the waist of the balloon released and/or there was a sudden drop in inflation pressure on the indeflator. The outcomes corroborate previous observational studies, and suggest that BVF can be safely performed with balloons ≥3 mm larger than the BPV true internal diameter, thereby achieving significant reductions in transvalvular gradients.8 The series also recommended BVF be performed after VIV TAVI, as this sequence resulted in significantly lower mean gradients as compared with BVF performed before VIV TAVI (8.1 ± 4.8 mmHg versus 16.9 ± 10.1 mmHg; p<0.001). 8 The most

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Bioprosthetic Aortic Valve Fracture significant predictive factors for BVF success were timing of BVF (i.e. post-VIV TAVI BVF) and the use of balloon sizes ≥3 mm larger than the BPV true internal diameter.8

Figure 2: Images from In Vitro Testing Prior to an Early In Vivo Trial

Surgical Bioprosthetic Valve Types In the case series by Chhatriwalla et al. (n=20), both balloon-expandable (n=8) and self-expanding (n=12) THVs were used in Mitroflow (Sorin, Milan, Italy), Carpentier-Edwards Perimount, Magna and Magna Ease (Edwards Lifesciences), Biocor Epic and Biocor Epic Supra (St Jude Medical), and Mosaic (Medtronic Inc., Minneapolis, MN, US) surgical BPVs.18 In the case series by Nielsen-Kudsk (n=10), balloon-expandable THVs were only used in Mitroflow BPVs.14 Bench testing studies in vitro have assessed the durability of specific BPVs and their suitability for BVF.4,9–11 These studies have demonstrated that while the majority of commercially available BPVs can be fractured using high-pressure non-compliant balloon inflation, some surgical BPVs are unsuitable for BVF, including the Trifecta (St Jude Medical) and the Hancock II (Medtronic) BPVs.10,11 In the future, this may influence surgical BPV choice during the index procedure. One could argue that these bench tests are not a truly accurate reflection of the fracturing response of the aforementioned valves, as they have not been tested under pathophysiological conditions; that is, the BPVs tested were in pristine condition. Older valves burdened with pannus and/or calcification may respond differently to high-pressure balloon dilatation with intention to fracture.

Furthermore, the location (supra-annular versus intra-annular) of the previously implanted BPV is potentially important and requires further investigation. It has been hypothesised that there may be less risk in fracturing a BPV in the supra-annular position compared with intraannular located BPVs.13 This warrants further study.

Balloon Type and Size Non-compliant balloons are used (e.g. True Balloon or Atlas Gold balloons [Bard]). Typically, a size 1 mm larger than the labelled diameter of the BPV should be selected in the first instance.14 As mentioned previously, a non-compliant balloon size ≥3 mm larger than the true internal diameter of the BPV has been found to predict BVF success.8

Timing As discussed, opinions differ as to whether BVF should be undertaken before or after implantation of the THV. This decision has generally been left to operator discretion, with no specific recommendations given, and is typically guided according to the specifics of the case.4 There are data to suggest that lower postprocedural mean gradients can be achieved when BVF is performed after VIV TAVI but, nonetheless, there remain theoretical advantages with undertaking BVF prior to TAVI implantation, which should be considered by operators. First, fracture of the BPV ring before VIV TAVI will allow confirmation that the BPV can be fractured. This may also allow for a larger-sized THV to be selected, further increasing the postprocedural effective orifice area. However, as most BPVs can be fractured, this may be unnecessary.10 Second, some have opted for BVF prior to TAVI to avoid theoretical damage to the new THV. It is argued this exposure may impact the longevity of the THV leaflets or even cause immediate damage leading to acute aortic valve regurgitation.

However, it should be noted that balloon-expandable THVs are normally inflated via high-pressure semicompliant balloons at the time of implantation.

INTERVENTIONAL CARDIOLOGY REVIEW

An ATLAS Gold 22 mm high-pressure balloon was gradually inflated inside a 21 mm Mitroflow valve. At a balloon pressure of 11 atm, the acetyl stent ring of the valve fractured with a loud click. A: The outer Dacron ring of the bioprosthesis was intact and no sharp elements protruded. A fracture line could be appreciated by palpation and was visualised by dissection of the valve ring (B and C, arrow). Source: Nielsen-Kudsk et al. 2015.4 Reproduced with permission from Wolters Kluwer Health.

There are, however, concerns that performing BVF first may dislodge embolic material from the degenerated BPV, leaving the patient susceptible to stroke. This may have been the cause of stroke in two patients in the aforementioned large case series.8 Finally, BVF after TAVI deployment is likely to be beneficial in balloon expandable valves as discussed below.

TAVI Valve Type Both self-expanding or balloon-expandable THVs can be used together with BVF. Bench testing studies have shown significant differences between self-expanding and balloon-expandable THV when they were implanted post BVF.9,11 It was shown that the radial force of the self-expanding THV was sufficient for complete expansion within the fractured BPV, thus requiring no additional postdilatation.9 Conversely, suboptimal results were seen when using balloonexpandable THVs (SAPIEN XT and SAPIEN 3; Edwards Lifesciences), where it was found that the delivery semicompliant balloon was not robust enough to fully expand the THV within the previously fractured BPV.9 Therefore, further postdilatation using a non-compliant balloon was required.9 To minimise this risk, fracturing the BPV post VIV TAVI was suggested.

A recent ex vivo bench study evaluated VIV TAVI and BVF with the SAPIEN 3 and ACURATE neo (Boston Scientific) THVs in 19 mm and

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Structural Figure 3: The Constrained Area of a Self-expanding Transcatheter Heart Valve where the Commissures Attach to the Nitinol Frame

results, concerns remain regarding potential risks. Normally, the BPV ring offers protection against aortic annular rupture or aortic dissection during VIV TAVI, but this protection may not apply after forceful BVF. Routine CT imaging was not performed after BVF in these case series, and as such the presence of subclinical injury to the aorta could not be ruled out.

Insufficient numbers of BVF cases have been performed to confidently determine the incidence of complications, but Saxon et al. have published a review specifically highlighting complications associated with BVF.15 Documented complications include acute aortic and mitral valve regurgitation, prosthetic valve destabilisation and migration, coronary artery obstruction, balloon failure, and embolization.16,17 Acute valvular regurgitation is due to damage of the leaflets during balloon dilatation. The Medtronic self-expanding valve is designed with a narrowed area called the constrained area. It is within this area that the commissures attach to the nitinol frame. Therefore, inflating the balloon within the constrained region could potentially tear the leaflets. In an attempt to minimise this risk, one study proposed keeping the superior shoulder of the balloon below the constrained area during inflation (Figure 3).9

Constrained area

A

Bioprosthetic Valve Fracture in Larger Surgical Bioprostheses

B

Constrained diameter is 20 mm for 23 mm Evolut R and 22 mm for 26 mm Evolut R When using a high-pressure balloon larger than the constrained area of a self-expanding transcatheter valve (A), keeping the shoulder of the balloon below the constrained area appears to mitigate the risk of tearing the leaflets and creating aortic regurgitation (B).

Source: Allen et al. 2017.9 Reproduced with permission from Elsevier.

21 mm Mitroflow BPVs.11 It was found that a high implantation was required to enable full expansion of the upper crown of the ACURATE neo and allow optimal leaflet function. Marked underexpansion of the lower crown of this THV within the BPV was also observed. Ultimately, however, valve gradients after BVF were similar for both THVs (8.4 mmHg ACURATE neo versus 7.8 mmHg SAPIEN 3).11 The final iEOAs were 2.1 cm2 with the SAPIEN 3 and 2.2 cm2 with the ACURATE neo.11

Complications of Bioprosthetic Valve Fracture In the aforementioned large case series, two out of 75 patients experienced postprocedural strokes (confirmed by MRI).13 Both patients fully recovered without any permanent neurological sequelae.13 There were no other direct postoperative complications observed with BVF in the three case series published to date.8,13,14 Despite these promising

1.

2.

3.

4.

azine A, Ouzounian M. Aortic valve replacement in young M and middle-aged adults: looking beyond the tree that hides the forest. Ann Transl Med 2017;5:92. https://doi.org/10.21037/ atm.2017.02.06; PMID: 28275637.

Nishimura R, Otto C, Bonow R, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;70:252–89. https://doi.org/10.1016/j.jacc.2017.03.011; PMID: 28315732.

Wenaweser P, Buellesfeld L, Gerckens U, et al. Percutaneous aortic valve replacement for severe aortic regurgitation in degenerated bioprosthesis: the first valve in valve procedure using the Corevalve revalving system. Catheter Cardiovasc Interv 2007;70:760–4. https://doi.org/10.1002/ccd.21300; PMID: 17932876.

Nielsen-Kudsk J, Christiansen E, Terkelsen C, et al. Fracturing the ring of small mitroflow bioprostheses by high-pressure balloon predilatation in transcatheter aortic valve-in-valve implantation. Circ Cardiovasc Interv 2015;8:e002667. https://doi.org/10.1161/CIRCINTERVENTIONS.115.002667; PMID: 26208503.

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Although PPM is more likely in smaller prosthetic valves, there is some evidence to suggest that underexpansion of BPVs may lead to early structural valve degeneration (perhaps because of folds in the BPV leaflets), suggesting that an upfront strategy of BVF in all degenerated surgical valves could, in theory, improve outcomes for all patients undergoing VIV TAVI.15 In the large case series reported by Allen et al., 36 of the 75 cases of successful BVF were in patients with intermediate- to large-sized BPVs (23–26 mm).8,18 This argues the potential feasibility for BVF as an adjunct to VIV TAVI in larger valves. Further clinical experience is required to provide insight into this novel technique.

Conclusion BVF during VIV TAVI results in lower residual mean gradients, and has the potential to improve clinical outcomes among patients undergoing VIV TAVI, particularly those with small diameter surgical BPVs. Recent data suggest that it is preferable to perform BVF after, rather than before, VIV TAVI, and with a larger non-compliant balloon sized ≥3 mm, greater than the true internal diameter for better haemodynamic results. BVF appears to be safe in the limited cases series published to date but more data on larger populations of patients undergoing BVF are required.

5.

vir D, Webb JG, Bleiziffer S, et al. Transcatheter aortic valve D implantation in failed bioprosthetic surgical valves. JAMA 2014;312:162–70. https://doi.org/10.1001/jama.2014.7246; PMID: 25005653.

6. Eggebrecht H, Schäfer U, Treede H, et al. Valve-in-valve transcatheter aortic valve implantation for degenerated bioprosthetic heart valves. JACC Cardiovasc Interv 2011;4:1218– 27. https://doi.org/10.1016/j.jcin.2011.07.015; PMID: 22115663.

7. Pibarot P, Dumesnil JG. Prosthesis-patient mismatch: definition, clinical impact, and prevention. Heart 2006;92:1022–9. https://doi.org/10.1136/hrt.2005.067363; PMID: 16251232.

8. Allen KB, Chhatriwalla AK, Saxon JT, et al. Bioprosthetic valve fracture: technical insights from a multicenter study.

J Thorac Cardiovasc Surg 2019. https://doi.org/10.1016/j. jtcvs.2019.01.073; PMID: 30857820; epub ahead of press.

9. Allen KB, Chhatriwalla AK, Cohen DJ, et al. Bioprosthetic valve fracture to facilitate transcatheter valve-in-valve implantation.

Ann Thorac Surg 2017;104:1501–8. https://doi.org/10.1016/j. athoracsur.2017.04.007; PMID: 28669505.

10. Johansen P, Engholt H, Tang M, et al. Fracturing mechanics before valve-in-valve therapy of small aortic bioprosthetic

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heart valves. EuroIntervention 2017;13:e1026–31. https://doi. org/10.4244/EIJ-D-17-00245; PMID: 28691909.

Sathananthan J, Sellers S, Barlow AM, et al. Valve-in-valve transcatheter aortic valve replacement and bioprosthetic valve fracture comparing different transcatheter heart valve designs. an ex vivo bench study. JACC Cardiovasc Interv 2019;12:65–75. https://doi.org/10.1016/j.jcin.2018.10.043; PMID: 30621980.

Saxon JT, Allen KB, Cohen DJ, et al. Bioprosthetic Valve Fracture During Valve-in-valve TAVI: Bench to Bedside.

Interv Cardiol Rev 2018;13:20–6. https://doi.org/10.15420/ icr.2017:29:1; PMID: 29593832.

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

Nielsen-Kudsk J, Andersen A, Therkelsen C, et al. Highpressure balloon fracturing of small dysfunctional Mitroflow bioprostheses facilitates transcatheter aortic valve-in-valve implantation. EuroIntervention 2017;13:1020–5. https://doi. org/10.4244/EIJ-D-17-00244; PMID: 28691908.

Abbasi M, Azadani AN. Leaflet stress and strain distributions

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Bioprosthetic Aortic Valve Fracture following incomplete transcatheter aortic valve expansion.

J Biomech 2015;48:3663–71. https://doi.org/10.1016/j. jbiomech.2015.08.012; PMID: 26338100.

16. Saxon JT, Allen KB, Cohen DJ, et al. Complications of bioprosthetic valve fracture as an adjunct to valve-in-valve TAVI. Structural Heart 2019;3:92–9. https://doi.org/10.1080/2474 8706.2019.1578446.

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17. H arvey JE, Nicholson WJ, Burlingame MW, et al. Aortic migration of a self-expanding transcatheter heart valve during intended bioprosthetic valve fracture. Structural Heart 2019;3:255–7. https://doi.org/10.1080/24748706.2019.158 3395.

18. Chhatriwalla AK, Saxon JT, Cohen DJ, et al. Is bioprosthetic valve fracture beneficial for patients with larger surgical

valves undergoing valve in valve TAVR? Curr Cardiol Rep 2018;20:95. https://doi.org/10.1007/s11886-018-1035-2; PMID: 30135999.

19. Oxenham H, Bloomfield P, Wheatley D, et al. Twenty year comparison of a Bjork-Shiley mechanical heart valve with porcine bioprostheses. Heart 2003;89:715–21. https://doi. org/10.1136/heart.89.7.715; PMID: 12807838.

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Coronary Calcified Lesions

Coronary Calcified Lesions: Introduction to the Focused Issue Nicolas M Van Mieghem Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands

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

Citation: Interventional Cardiology Review 2019;14(3):152–3. DOI: https://doi.org/10.15420/icr.2019.14.3.GE1 Correspondence: Nicolas M Van Mieghem, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Office Nt 645, Dr Molewaterplein 40 3015 GD, Rotterdam, the Netherlands. E: n.vanmieghem@erasmusmc.nl Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

M

uch has been said about the allegedly final frontiers in interventional cardiology. Is it long-term outcome regarding percutaneous coronary intervention (PCI) for multivessel coronary artery disease? Is it the safety and efficacy of PCI versus coronary artery bypass grafting in patients with diabetes? There is definitely a movement within the interventional cardiology community that says it is the ability to reliably and successfully recanalise chronic total occlusions (CTO), and there are now claims the CTO conundrum is settled and done.

Arguably, controversy remains and, as we move towards precision medicine, attention should shift to an individualised approaches tailored to the specific phenotype of the patient at hand, taking into account substrate complexity, biological age, comorbidities, frailty and the patient’s preference. Precision medicine implies continued iterations and strategies to improve feasibility, safety and efficacy.

There are no final frontiers – only new goals.

despite the fact that the overall tenor of the interventional cardiology community confirms the value of invasive imaging.1 Cost, suboptimal reimbursement policies and the impression of needless procedure prolongation may explain this.

Recent European Society of Cardiology and European Association for Cardio-Thoracic Surgery guidelines on myocardial revascularisation gave only modest and more general recommendations on the use of invasive imaging for PCI, more specifically for left main stem PCI or to detect stent-related mechanical problems leading to restenosis.2 Liberal use of invasive imaging may be of particular use for the management of calcified lesions by streamlining lesion preparation for optimal stent expansion and apposition. Proper stent apposition and expansion require adequate preparation of the lesion that contains excessive calcium.

This Interventional Cardiology Review focused issue revolves around the complexity of coronary calcified lesions and details the value of invasive imaging and coronary physiology, and various treatment modalities and strategies.

A formidable armamentarium for calcified lesion preparation is available, and ranges from specialised balloon technology to atherectomy devices and lithotripsy. This focused issue catalogues the toolbox for complex calcified coronary lesions and may promote a rational selection of technology tailored to the patient and lesion.

Up to a quarter of all patients with significant coronary artery disease have moderate to heavily calcified lesions. It is essential to consider the haemodynamic significance of a calcified lesion before embarking on a technically complex PCI. When in doubt, this requires (invasive) coronary physiology confirmation.

Apart from balloon technology, rotational atherectomy has been available for more than three decades. However, the learning curve proved too long and steep for many interventionalists and its adoption remains restricted to specialised centres and in the hands of experienced operators.

Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) imaging present fundamentally different physical characteristics and generate different images when interacting with calcium. IVUS has less spatial resolution but superior tissue penetration, and therefore seems better suited to determine precise plaque burden and vessel size.

The persisting unmet need for debulking and advanced lesion preparation in calcified disease has fuelled the development of other concepts and resulted in the introduction of orbital atherectomy and intravascular lithotripsy in the last decade.

Paradoxically, in calcified lesions, OCT may be the most accurate modality to quantify total calcium burden because retro-acoustic shadowing with IVUS hinders accurate calcium thickness determination.

The adoption of invasive imaging in clinical practice is still lagging behind its potential to improve PCI procedure success and outcome,

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Orbital atherectomy is reminiscent of rotational atherectomy, but features distinct principles with its one-sized eccentric burr design and bidirectional orbital movement. Intravascular lithotripsy leverages balloon technology to expel pulsatile mechanical energy through sonic pressure waves equivalent to the effect of 50 atm in the media of the vessel where the pulse waves interact with hard (and not soft) tissue components, and therefore calcium.

© RADCLIFFE CARDIOLOGY 2019

Guest Editorial Rotational and orbital atherectomy will create superficial, endothelial fractures and reduce the overall calcium burden starting with the endoluminal calcium – the polishing effect. Intravascular lithotripsy will then interact more with the calcium in the vessel media and poses no or much less risk for major dissections or no-reflow phenomena due to distal debris embolisation.

All these modalities beyond conventional non-compliant and veryhigh pressure balloon dilatation seem complementary rather than competing technologies. Some lesions would benefit more from orbital/rotational atherectomy and others from intravascular lithotripsy.

Indeed, protruding calcified plaques and severe narrowing may require orbital or rotational atherectomy because a low-profile lithotripsy balloon would not be able to negotiate the lesion. Conversely, lesions

1.

2.

that are characterised by excessive circular calcium reaching beyond the intima may be excellent targets for intravascular lithotripsy.

Clearly, operators should incorporate invasive imaging into their routine clinical practice to help assess the overall burden and distribution of calcified lesions so they are able to select the best treatment strategy. This would include optimal lesion preparation before stenting and achieve optimal stent expansion/apposition and overall procedural success.

In anticipation of further research, this Interventional Cardiology Review focused issue on calcified coronary lesions captures contemporary science and knowledge and hopefully serves your clinical practice today.

Koskinas KC, Nakamura M, Raber L, et al. Current use of intracoronary imaging in interventional practice – results of a European Association of Percutaneous Cardiovascular Interventions (EAPCI) and Japanese Association of Cardiovascular Interventions and Therapeutics (CVIT) clinical practice survey. Circ J 2018;82:1360-8. https://doi.org/10.1253/circj.CJ-17-1144; PMID: 29540631.

Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437.

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Coronary Calcified Lesions

Contemporary Approach to Heavily Calcified Coronary Lesions Carlotta Sorini Dini, 1,2 Giulia Nardi, 1 Francesca Ristalli, 1 Alessio Mattesini, 1 Brunilda Hamiti 1 and Carlo Di Mario 1 1. Structural Interventional Cardiology, Careggi University Hospital, Florence, Italy; 2. Cardiology Division, Spedali Riuniti, Livorno, Italy

Abstract Percutaneous treatment of heavily calcified coronary lesions still represents a challenge for interventional cardiology, with higher risk of immediate complications, late failure due to stent underexpansion and malapposition, and consequently poor clinical outcome. Good characterisation of calcium distribution with multimodal imaging is important to improve the successful treatment of these lesions. The use of traditional or new dedicated devices for the treatment of calcified lesions allows better lesion preparation; therefore, it is important that we know the different mechanisms and technical features of these devices.

Keywords Coronary calcified lesion, coronary angioplasty, outcome, intravascular ultrasound, optical coherence tomography, atherectomy, lithotripsy Disclosure: The authors have no conflicts of interest to declare.

Received: 2 July 2019 Accepted: 30 September 2019 Citation: Interventional Cardiology Review 2019;14(3):154–63. DOI: https://doi.org/10.15420/icr.2019.19.R1 Correspondence: Carlotta Sorini Dini, Structural Interventional Cardiology, Careggi University Hospital, Largo G Alessandro Brambilla 3, 50134 Florence, Italy.

E: carlotta.sorinidini@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.

In the 18th century, Edward Jenner and Caleb Hillier Parry, two British physicians, independently noticed that coronary ossification was often present in patients dying of ‘syncope anginosa’.1 Coronary angiography opened the possibility of expanding these observations to living patients and offered revascularisation options. During surgery, it was often possible to modify the position of the distal coronary anastomoses to avoid calcified segments. In terms of percutaneous treatment, heavily calcified coronary lesions still represent a challenge for interventional cardiology, with a greater risk of immediate complications and late failure due to stent underexpansion and malapposition.2 Good characterisation of calcium distribution with multimodal imaging and optimal lesion preparation, facilitated by the introduction of new dedicated devices, are essential for successful treatment of calcified coronary stenoses.3,4

Pathophysiology of the Calcified Coronary Plaque When discussing artery calcification, it is appropriate to distinguish between peripheral and coronary calcifications. In the peripheral arteries of the lower extremities, medial calcification is often found, driven by the action of osteoblast-like cells and due to various factors, such as hypercalcaemia, high phosphate blood concentrations and increased parathyroid hormone concentrations.

Conversely, the mechanism underlying the development of atherosclerotic coronary calcification is different, with dysmorphic calcium precipitation driven by chondrocyte-like cells and linked to expression of inflammatory factors, such as cytokines released by tissue macrophages and foam cells.5 It is likely that inflammation precedes calcification and plays an important role in its progression, with the two processes coexisting and promoting each other.

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The primary cause of the calcification process in atheroma is the death of inflammatory cells and smooth muscle cells (SMCs), with macrophage-derived matrix vesicles also playing a role in this event.

An intense inflammatory response due to cholesterol deposits caught under the endothelium leads to the development of microcalcification over areas ranging in size between 0.5 and 15.0 mm.6 The differentiation of several cell types (e.g. pericytes and vascular SMCs) promotes bone deposition and contributes to necrotic core formation because of the local degradation of collagen fibres.7 The entire process is driven by the fusion of cell debris originating from SMC apoptosis, which then serves as a focus for calcium phosphate crystal formation. A lack of calcification inhibitory factors (e.g. matrix gammacarboxyglutamic acid protein, pyrophosphate, fetuin-A, osteopontin and osteoprotegerin) also plays a role in the imbalance between osteogenic and osteoclastic mechanisms.8 Some drugs, such as phosphate binders or receptor activator of nuclear factor-kappaB ligand blockers, are under investigation to reverse or prevent vascular calcification.7 Microcalcifications can only be detected histopathologically using special stains, such as von Kossa stain and Alizarin red.

Microcalcifications can coalesce into larger masses over time to form speckles and calcified sheets, detectable in vivo using CT or intravascular imaging. In addition to plaque rupture and erosion, the development of subintimal large protruding masses may be a possible cause of plaque destabilisation and thrombus formation, and has been detected in 5% of cases of unstable syndrome and ST-elevation MI. This role of the protruding masses in plaque destabilisation is at odds with the common belief that the substitution of large necrotic cores in positively remodelled arteries with fibrocalcific tissue, also promoted by statin therapy, is a marker of plaque stabilisation.6,9

© RADCLIFFE CARDIOLOGY 2019

Approach to Heavily Calcified Coronary Lesions Coronary Calcification as a Predictor of Events CT allows calculation of the coronary artery calcium score, an independent predictor of coronary events in both asymptomatic and symptomatic individuals, as confirmed by Budoff et al. in the 10-year results of the Multi-Ethnic Study of Atherosclerosis (MESA) study.10–14 Spotty calcifications are associated with unstable plaques and acute coronary syndrome.15 Coronary calcification is also a marker of advanced atherosclerosis and is correlated with multivessel coronary disease and the presence of complex lesions, including long lesions, chronic total occlusions and bifurcations. The SYNTAX score is a method of estimating the complexity of coronary disease. The location and severity of lesions are the main drivers of high scores. Heavy calcification, visible with fluoroscopy, is also considered, adding 2 points per lesion.16–19 In recent registries and meta-analyses, the prevalence of moderate and severe calcific coronary stenoses has been reported to range between 18% and 26%.16–18 In these studies, severe calcific lesions were found to be associated with advanced age, systemic hypertension, dyslipidaemia and diabetes. Chronic kidney disease can also be associated with severe coronary calcification. As a consequence of a progressively aging population and an increase in these comorbidities, we expect a higher frequency of severe coronary calcification in patients undergoing percutaneous coronary intervention (PCI) in coming years.

PCI of coronary calcified lesions is associated with major stent underexpansion and malapposition, with major periprocedural complications and, subsequently, a high rate of target lesion failure, restenosis or thrombosis. Consequently, calcified coronary lesions are a predictor of a worse clinical outcome, associated with higher mortality, major adverse cardiovascular events (MACE) and target vessel failure on multivariate analysis after correction for confounders.19–21 These results were confirmed in a recent registry,17 as well as in a pooled analysis in patients treated exclusively with a second-generation drugeluting stent (DES).18 Late and very late stent thrombosis are also more frequent in patients with calcific stenosis.18–20

Calcium and Imaging Techniques Coronary CT angiography (CCTA) is the most important non-invasive imaging technique used to detect calcium. Calcium is detected as an area of hyperattenuation, defined as an area of at least 1 mm2 with >130 Hounsfield units or ≥3 adjacent pixels using the Agatston method.22 The calcium score is the sum of all coronary calcified lesions (excluding calcium in the valve or aorta) and is a strong prognostic factor for clinical events in the mid to long term in asymptomatic individuals.11,14,15 CCTA is able to characterise coronary plaques; in particular, CCTA can detect spotty calcification, which is one of the four signs of vulnerable plaques (i.e. low CT attenuation, remarkable positive remodelling, spotty calcification and the napkin-ring sign).23 CCTA is also a valuable tool in planning PCI because it allows accurate identification of calcium in coronary lesions and localisation of calcium along coronary vessels, improving procedural success.

Coronary angiography often underestimates calcium, its grading is not accurate and calcium depth within the plaque is not assessed.4 Moderate calcification is defined as radiopacity observed only during the cardiac cycle before injection of contrast medium. Severe calcification is defined as radiopacity observed without cardiac

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motion, visible on both sides of the arterial lumen, as a double track.

Wang et al. assessed 440 lesions with fluoroscopy, intravascular ultrasound (IVUS) and optical coherence tomography (OCT) and showed that IVUS was a particularly sensitive method of detection; in fact, calcium was detected by angiography in 40.2% of lesions, by IVUS in 82.7% of lesions and by OCT in 76.8% of lesions.4 On IVUS, calcium is immediately apparent as bright, hyperechoic lines with acoustic shadowing; deep calcium can also be detected using IVUS because of the high penetration power of ultrasound. 3 Calcified plaques can be assessed semiquantitatively, with calcium arc and calcium length, using this technique; but the thickness of calcium and microcalcifications cannot be detected.

Semiquantitative assessment of calcified plaques with IVUS allows the estimation of calcific burden; in particular, maximum circumferential extension of calcium >180° is associated with a smaller stent area and greater stent eccentricity. 24 OCT features of calcium are subtler, with a low-intensity signal area and well-delineated external contours. OCT can measure calcium thickness and shows calcium disruption better because of its higher resolution, but may miss deep calcifications due to insufficient penetration. With OCT one can perform quantitative assessments of calcified plaques (i.e. calcium arc, length, thickness, area and volume) and detect microcalficiations. 25 Fujino et al. recently proposed an OCT score to grade calcium plaques with a numerical cut-off; calcium arc >180° (2 points), calcium length >5 mm (1 point) and calcium thickness >0.5 mm (1 point) were associated with poor stent expansion (stent expansion <70%).26 IVUS and OCT are two invasive techniques that allow us to better characterise the depth and distribution of calcium in coronary plaques (Table 1).

Percutaneous Coronary Intervention of Complex Calcified Coronary Lesions Either a transfemoral or transradial approach can be used in PCI for heavily calcified lesions, with the choice depending primarily on operator experience. Support wires, buddy wires, guide extensions, lesion predilatation and anchoring of the guide catheter with inflation of a second balloon in a side branch or distal vessel are possible options for the treatment of calcified coronary stenoses.27,28 When successful treatment cannot be obtained using these options, a dedicated device should be used for adequate lesion preparation (Table 2).29

High- and Very High-pressure Non-compliant Balloons Non-compliant (NC) balloons, unlike semicompliant balloons, tolerate high inflation pressures, exhibiting a small increase in diameter. NC balloons allow more uniform balloon expansion and the application of higher forces in a focal segment of a coronary vessel, avoiding dog-bone deformation exerting excessive pressure at the edges and potentially causing coronary dissections or perforations.29,30 Repeated and prolonged inflations with NC balloons should be encouraged as the first choice in mild to moderate calcified stenoses, where the calcium arc is restricted (<90°).

The OPN NC balloon (SIS Medical) uses twin-layer technology to allow super high pressures within the balloon with minimal increases in diameter. This balloon can be inflated with a nominal pressure of 1,010 kPa and a rated burst pressure of 3,546 kPa, but the balloon was tested

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Coronary Calcified Lesions Table 1: Comparisons of Imaging Techniques in for the Detection of Coronary Calcium Technique

Advantages

Disadvantages

Coronary CT

• • • • •

• Contrast medium

Coronary angiography

• Calcium location along coronary vessel detected

• • • • •

Invasive technique Contrast medium Low sensitivity Only qualitative grading of calcium Moderate calcifications are detected only during the cardiac cycle

Intravascular ultrasound

• No contrast medium • Superficial and deep calcium is detected • Semiquantitative grading of calcium: distribution, localisation, length, arc

• • • •

Invasive technique Deep calcium is hidden by acoustic shadow Microcalcifications are not detected Unable to assess calcium thickness

Optical coherence tomography

• Very high resolution • Calcium thickness can be measured • Quantitative grading of calcium: distribution, localisation, thickness, area, volume • Microcalcifications are detected

• Invasive technique • Contrast medium • Limited depth penetration

Non-invasive technique Calcium score in asymptomatic individuals Prognostic role of calcium score Calcium location along coronary vessels detected Spotty calcifications are detected

up to a pressure of 4,560 kPa and many operators report very rare balloon ruptures at pressures as high as 5,573 kPa, the maximal level allowed by the special indeflator provided with the balloon. The OPN NC balloon is available in diameters ranging from 1.5 to 4.5 mm (in 0.5 mm increments) and lengths of 10, 15 and 20 mm. The OPN NC balloon is a dedicated device for the treatment of in-stent restenosis, heavily calcified lesions or other lesions that cannot be dilated. In the past, it was often used for lesion preparation before bioresorbable vascular scaffold (BVS) implantation or to expand the BVS fully, given the small increases in diameter (<0.5 mm) stated by the manufacturer.31,32 In restricted clinical experience, the OPN NC balloon successfully treated >90% of undilatable lesions compared with a conventional NC balloon with a 0.9% rate of coronary rupture.33 The OPN balloon is compatible with 0.014 inch wires and 5 Fr access, but it has a high

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profile (0.028 inches), although this is better than scoring and cutting balloons, and so it is difficult to recross or reuse after inflation.

Cutting and Scoring Balloons The Flextome Cutting Balloon (Boston Scientific), introduced in 1991, is available in monorail or over-the-wire catheter, with the most recent iteration (Wolverine) improved in terms of profile and flexibility.

The Flextome Cutting Balloon is available in diameter sizes ranging from 2.0 to 4.0 mm (in 0.25 mm increments) and lengths of 6, 10 or 15 mm.34 On a cutting balloon, three or four metal microblades are placed longitudinally on the surface of the balloon and the balloon works by cutting the media with radial incisions, thus reducing elastic recoil and minimising neointima proliferation. The microblades also prevent balloon slippage, which is particularly helpful for in-stent restenosis due to intimal hyperplasia.35 Initial clinical experience

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Approach to Heavily Calcified Coronary Lesions Table 2: Technical Features of Dedicated Devices for the Treatment of Coronary Calcified Lesions Very High-pressure

Cutting Balloon

Scoring Balloon

Balloon

Rotational

Orbital Atherectomy

Intravascular

Differential sanding

Pulsatile mechanical energy

Atherectomy

Lithotripsy

Mechanism of action

High pressure with uniform expansion

Radial incision in calcific tissue, prevents balloon slippage

Measurements

Diameter: 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50 mm Length: 10, 15, 20 mm

Diameter: 2.00, 2.25, AngioSculpt (Spectranetics- Burr: 1.25, 1.50, 1.75, 2.50, 2.75, 3.00, 3.25, Philips): 2.00, 2.15, 2.25, 2.38, 2.50, 2.75, 4.00 mm • Diameter: 2.0, 2.5, 3.0, 2.50 mm Length: 6, 10, 15 mm 3.5 mm • Length: 10, 15, 20 mm NSE Alpha (B Braun): • Diameter: 2.0, 2.25, 2.5, 2.75, 3.0, 3.5, 4.0 mm • Length: 14 mm Scoreflex (Orbus Neich): • Diameter: 2.0, 2.5, 3.0, 3.5, 4.0 mm • Length: 10, 15, 20 mm

Classic Crown: 1.25 mm; concentrically positioned on an eccentric bump, no diamond-coated tip Micro Crown: 1.25 mm; eccentrically positioned, diamond-coated tip

Diameter: 2.50, 2.75, 3.00, 3.50, 3.75, 4.00 mm Length: 12 mm

Guide catheter compatibility

5 Fr

6 Fr (<3.50 mm)

AngioSculpt: 6 Fr NSE Alpha: 5 Fr Scoreflex: 5 Fr

5 Fr (1.25 mm burr) 6 Fr (1.50 mm burr) 7 Fr (1.75 mm burr) 8 Fr (2.00, 2.15 mm burrs) 9 Fr (2.25, 2.38 mm burrs) 10 Fr (2.50 mm burr)

6 Fr

5 Fr

Wire

No proprietary wire 0.36 mm

No proprietary wire 0.36 mm

No proprietary wire 0.36 mm

RotaWire (floppy or extra support versions) 0.23 mm

ViperWire 0.30 mm

No proprietary wire 0.36 mm

Balloon crossing profile (mm)

0.71

1.04–1.17

AngioSculpt: 0.91 NSE Alpha: 1.27 Scoreflex: 0.81

–

–

1.09–1.17

Balloon nominal pressure (kPa)

1,013

608

AngioSculpt: 811 NSE Alpha: 608 Scoreflex: 608

–

–

608

Balloon rated burst pressure (kPa)

3,546

1,216

AngioSculpt: 1,621 (3.5 mm), 1,824 (3.00 mm), 2,027 NSE Alpha: 1,419 Scoreflex: 1,621

–

–

1,013

Side branch protection

Yes

Yes

Yes

No

No

Yes

Focal force concentration, prevents balloon slippage

Differential cutting

Ablation type

–

–

–

Unidirectional

Bidirectional

–

Ablation speed (rpm)

–

–

–

135,000–180,000

80,000 or 120,000

–

Particle size (µm)

–

–

–

5–10

<2

–

with cutting balloon angioplasty appeared favourable because it achieved more lumen enlargement compared with traditional balloon angioplasty.35 However, a later large randomised trial showed similar acute procedural success in patients with de novo undilatable lesions treated with cutting balloon or conventional balloon angioplasty, a similar binary restenosis rate at 6 months between the two groups (31.4% versus 30.4%, respectively; p=0.75) and a significantly higher perforation rate in the cutting angioplasty group (0.8% versus 0%; p=0.03).36 These unfavourable clinical results, the large use of coronary stents and the very high crossing profile of cutting balloons

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(0.041–0.046 inches) have discouraged their use in current clinical practice, with a restricted application to resistant lesions in the European Society of Cardiology and American College of Cardiology guidelines.37,38 Scoring balloons are semicompliant balloons encircled by scoring elements. These scoring elements allow focal concentration of the force during inflation and decrease balloon slippage. Scoring balloons have similar indications to cutting balloons, but scoring balloons are more flexible, have a better profile and can achieve a full expansion with a low inflation pressure, with consequently less trauma to vessel walls and a minor risk of coronary dissections.39,40

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Coronary Calcified Lesions Several types of scoring balloons are now available for treatment of mild to moderate calcified lesions. The AngioSculpt (Spectranetics-Philips) is a semicompliant balloon with three spiral rectangular Nitinol scoring elements, also available in a drug-coated version (AngioSculpt X, Spectranetics-Philips).41,42 In a feasibility trial, the AngioSculpt balloon was used for the treatment of de novo lesions prior to BMS implantation and showed very high procedural success and a target lesion revascularisation rate of 10% at 6 months.43 These results were confirmed in an observational study, in which 37 patients treated with AngioSculpt before stent implantation were compared to 145 patients treated with direct stenting and 117 patients with traditional plain old balloon angioplasty before stent implantation.

IVUS assessment showed greater stent expansion in the AngioSculpt group than in the other two groups (89% versus 74% of vessels with an area >5.0 mm2, respectively).44 The NSE Alpha scoring balloon (B Braun) has three triangular flexible nylon elements on the balloon surface attached only at the proximal and distal edges of the balloon. Promising results for predilatation of severe calcified lesions were shown with the leopard-crawl technique.45 The Scoreflex (Orbus Neich) is a semicompliant balloon with two fixed Nitinol wires on opposite sides of the balloon surface.46 Otsuka et al. reported a case series where prolonged inflation of the Scoreflex balloon allowed adequate dilation of severe calcified plaques as shown by the ‘creep phenomenon’, whereby prolonged inflation of the balloon produces a distortion force capable of expanding a resistant calcified lesion.47 Scoring balloons have been considered by cardiologists as an alternative to cutting balloons and, in recent years, have been preferred because of major flexibility and deliverability, although no specific randomised control trials are reported in the literature.

In the PREPARE Severely CALCified Coronary Lesions Trial (PREPARECALC), 200 patients were randomised 1:1 to treatment with either rotational atherectomy (RA) or modified balloons (both cutting and scoring balloons). Lesions treated with the modified balloons had similar late lumen loss at 9 months compared with RA, but high crossover was reported in the study (16% of lesions were untreatable with modified balloons).48

Rotational Atherectomy RA was introduced more than 30 years ago to debulk and modify atherosclerotic plaques as an alternative or adjunctive strategy to percutaneous balloon angioplasty.49 Although initial positive experiences with RA showed short-term lumen enlargement, there was also a high rate of target lesion revascularisation due to cell proliferation and restenosis.50 In the DES era, in-stent restenosis decreased markedly; consequently, RA was reserved for lesion preparation before stent implantation in the case of heavily calcified stenosis, as confirmed by Society for Cardiovascular Angiography and Interventions guidelines in 2011 (Level IIa evidence, Class C recommendation).51 The rotating burr can selectively ablate inelastic calcific atheroma, sparing elastic vascular tissue, but it can also generate microparticles (5–10 µm) that propagate distally in the coronary vessel, with consequent vascular plugging, slow flow or no reflow and increases in myocardial-specific enzymes.52 IVUS analysis after RA showed lumen enlargement with ‘bites’ in the calcific plaque.53 OCT analysis showed plaque modification with a new, larger, smooth lumen vessel created from the rotating burr and fissures or craters in the intima or intima–media wall.54,55

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In a Cochrane review by Wasiak et al. of 12 trials published between 1996 and 2005 and enrolling 3,474 patients, there were no significant differences in restenosis or major adverse cardiac events (MACE) at 6 months or 1 year after the treatment of complex lesions with RA or percutaneous transluminal coronary angioplasty alone, but RA was associated with a higher periprocedural complication rate.56 More recently in the Rotational Atherectomy Prior to TAXUS Stent Treatment for Complex Native Coronary Artery Disease (ROTAXUS) trial, 240 patients with calcified lesions were randomised to RA before stenting or stenting alone (paclitaxel stent).57 This trial showed higher procedural success in the RA group (92.5% versus 83.3%; p=0.03) and better acute lumen enlargement, but a significantly higher late lumen loss at 9 months, although the trial is limited by an 8% crossover rate and the exclusion of more severe calcified lesions.57 Encouraging results have emerged from PREPARE-CALC, published in 2018, in which 200 patients were randomised to treatment with either RA or cutting or scoring balloons.48 In that study, a greater success rate was achieved with RA than with modified balloons (98% versus 81%, respectively), driven primarily by delivery failure of the bulky cutting or scoring balloons, with no significant difference in late lumen loss at 9 months.48 Periprocedural complications were low and similar in the two groups, probably due to highly experienced operators.48 RA should be used in combination with cutting balloons, as reported by Amemiya et al. in single-centre observation study with good results in terms of the number and thickness of calcium fractures, assessed with OCT and stent expansion.58 The Rotablator System (Boston Scientific) is made up of three components: a nickel-plated elliptic burr coated with diamond microscopic crystals that is available in sizes ranging from 1.25 to 2.50 mm diameter; a single advancer that can transmit rotational speed to the burr and is connected with a gas-driven turbine; and a control console and foot pedal (in most recent models, the latter has been replaced by an activator in the connecting handle).59 In recent years, a reduction in burr size and a more standardised protocol with low rotation speeds have decreased periprocedural complications.27,60 A transradial approach is allowed with 1.25, 1.50 or 1.75 mm burrs. An ultrathin (0.009 inch) steerable dedicated guidewire (RotaWire) of length 330 mm is used to cross the calcified lesion; it is available in a floppy version or an extra support version, useful primarily in the treatment of aorto-ostial lesions. These dedicated wires are less torque responsive and more steerable; furthermore, a regular 0.014 inch guidewire can be used to cross the stenosis and the RotaWire can then be inserted through an over-the-wire balloon or microcatheter. The RotaWire must be placed in the main vessel and other guidewires have to be removed from side branches to avoid wire cutting or perforation.

When the burr is proximal to the lesion, rotablation can be started with short burr runs (<20 seconds) at low rotational speed (135,000– 180,000 rpm). Small burrs (1.25 and 1.50 mm; burr-to-artery ratio=0.6) are adequate in most lesions as an initial approach, but occasionally it may be necessary to increase burr size with a step-up approach.

Fluoroscopic, acoustic and tactile signals should be monitored to avoid significant deceleration in rotational speed (>5,000 rpm), which is associated with complications. Possible complications of RA are no reflow or slow flow, treatable with a pharmacological strategy based on intracoronary vasodilators (nitroprusside, adenosine, nicorandil), burr entrapment, coronary perforations and transient atrioventricular

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Approach to Heavily Calcified Coronary Lesions block.61 Prophylactic insertion of a temporary ventricular pacemaker can be considered for long right coronary artery lesions, but atropine before starting burr activation is sufficient to prevent the problem in most other cases. RA is contraindicated in saphenous vein graft stenosis, dissection and in thrombosis, even if a large registry of 1,308 patients with acute coronary syndrome showed the feasibility of RA in this clinical setting.62

OCT has been used to demonstrate the mechanism of action of OA, revealing deeper and longer cuts in calcific plaques with OA than RA. In addition, OA modified calcified plaques more than RA, with consequently better stent apposition and expansion.54 A mean ablation area of 0.55 ± 0.41 mm2 and an ablation volume of 2.68 ± 2.80 mm3 were measured with OCT in a case series of 18 patients, with 18% of intimal dissections reported.67

Although RA is considered the gold standard technique to prepare heavily calcified lesions before stent implantation, particularly when lesions are uncrossable with a balloon device, and it appears to have become safer in recent years, it is used only in 1–3% of PCIs in Europe and is limited to expert operators in high-volume centres,60 probably because of potential complications as well as the costs, which are not negligible, or low insurance recruitment.

The Orbital Atherectomy System in treating de novo calcified coronary lesions (ORBIT I) study was the first-in-human trial to evaluate the safety and performance of OA in 50 patients at two Indian centres, showing a procedural success rate of 94% and a MACE rate of 8% at 30 days.68 The ORBIT II study is a non-randomised trial, enrolling 443 patients with severe calcified lesion in 49 US hospitals.69 ORBIT II showed high procedural success (98.6% of patients with <50% residual stenosis) and good outcomes, namely 4.4% cardiac deaths at 2 years, 8.1% target lesion revascularisation at 2 years and low periprocedural complications (slow flow <1%, coronary dissections 5.9%). Lee et al. reported real-world data for 458 patients treated with OA in three US hospitals, confirming positive results at 1 year.70

Orbital Atherectomy The Diamondback 360 Coronary Orbital Atherectomy (OA) System (Cardiovascular Systems) was approved by the US Food and Drug Administration in 2013 for the treatment of de novo severe calcified coronary stenosis. This device uses the elliptical movement of a single-sized, eccentrically mounted crown to create centrifugal force, differentially sanding the hard component of the plaque and sparing the soft tissue component.63 Comparing OA and RA highlights differences in structural components, mechanisms of action and different anatomical settings in which to use these devices:64–66 • A single-sized crown of 1.25 mm is used in OA to treat vessels with a diameter of 2.5–4.0 mm, regulating rotational speed.

• Two rotational speeds, namely 80,000 rpm (low speed) and 120,000 rpm (high speed), allow different ablation of vessels with different diameters, with the high speed creating greater centrifugal force and a higher orbital diameter.

• In OA, the crown rotation is less concentric; therefore, in aortoostial lesions, where there is a large transition from large to small lumen, OA should be used with caution.

• ViperWire Advance (Cardiovascular Systems) is a dedicated wire for the Diamondback 360 Coronary OA System and is available in one version only (no floppy or extra support versions, as available for the RotaWire) and has 0.012 inch profile.

• In OA, a bidirectional atherectomy is performed, not only anterograde as in RA, with a consequent decrease in crown entrapment.

• Continuous flow of blood and saline solution or other lubricant solutions (e.g. soybean oil, egg yolk) during ablation minimises thermal injury and potentially decreases no-reflow and periprocedural complications.

• The smaller microparticles created by OA (2 µm) have a minimal effect on the microcirculation.

• Device activation is simpler and faster for OA than RA (one-touch activation and 2 minutes, respectively).

Some innovative components of the OA system are now available for clinical use in Japan or for research applications. The Coronary OA Micro Crown (Cardiovascular Systems) has a new diamond-coated tip to better reach the target lesion and a 1.25 mm eccentric crown that allows it to rotate at lower speeds and create an orbit similar to the Classic Crown, which, instead, is located concentrically on an eccentric bump. In addition, a new ViperWire and GlideAssist system are available to easily track the OA device through tortuous coronary vessels.

INTERVENTIONAL CARDIOLOGY REVIEW

The Diamondback 360 Micro Crown has recently been proposed as a technological advancement; it is able to obtain a higher sanding area with lower rotational speed (50,000–70,000 rpm). This new device was used in the Coronary Orbital Atherectomy System Study (COAST), which found that 85% of patients were free of MACE at 30 days.71 The Evaluation of Treatment Strategies for Severe CaLcIfic Coronary Arteries: Orbital Atherectomy vs. Conventional Angioplasty Technique Prior to Implantation of Drug-Eluting StEnts: The ECLIPSE Trial (ECLIPSE; NCT03108456), a large on-going trial in which approximately 2,000 patients with severe calcified lesions will be enrolled to OA or traditional angioplasty groups, will provide scientific evidence regarding OA.72 The Feasibility of Orbital Atherectomy System in Calcified Bifurcation Lesion (ORBID-OA) study is an on-going US observational study in which 30 patients will be assessed with frequency domain OCT.73 While waiting for the results of these trials, new data have emerged from the Manufacturer and User Facility Device Experience (MAUDE) database of a not negligible number of cases of perforations attributed primarily to excessive straightening from the Viper wire and prompting changes in technique.74

Excimer Laser Coronary Atherectomy Excimer laser coronary atherectomy (ELCA) modifies calcified plaques using photochemical and photothermal ablation. The CVX 300 System (Philips) uses xenon chloride to produce a light emitted in the ultraviolet B spectrum (308 nm) with a penetration depth of 30–50 µm to limit medial and adventitia damage. Microparticles (<10 µm) released have a low impact on the microcirculation.75 ELCA catheters are available in four diameters, which are compatible with 6, 7 and 8 Fr catheters; 6 Fr: 0.9 and 1.4, 7 Fr: 1.7 and 8 Fr: 2.0 mm, based on a catheter:vessel diameter ratio of 0.5:0.6, and are compatible with a 0.014 inch guidewire. Initial experience with ELCA treatment for complex coronary artery lesions reported a procedural success rate of 93% and both minor and major periprocedural complications.76,77 In the context of coronary calcified lesions, the use of ELCA is limited to that of a ‘bail-out’ strategy, when lesions are uncrossable for dedicated balloons or for the RotaWire or ViperWire, and its use is limited to a restricted number of centres. A combination of ELCA and RA was recently described (the RASER technique).78 The main application of

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Coronary Calcified Lesions Figure 1: Representative Images Obtained Using the Different Imaging Techniques

A

B

C

D

E

F

G

H

I

J

K

L

A–D: Baseline lesion. B, C: Concentric calcified plaque (calcium arc >270°, calcium thickness 0.90 mm). D: Minimum lumen area (MLA) 2.81 mm2. E–H: Calcified plaque after intravascular lithotripsy treatment. F–H: Deep calcium fracture with lumen enlargement (MLA 6.3 mm2). I–L: Calcified plaque after stent implantation. J–L: Excellent symmetric stent expansion with no stent malapposition (MLA 12.5 mm2). A, E and I: angiographic images. B–D, F–H and J–L: V optical coherence tomography images.

this technique remains in the treatment of severe in-stent restenosis, with positive results reported in a recent OCT study.79

Intravascular Coronary Lithotripsy Intravascular lithotripsy (IVL) is a promising new method for the treatment of heavily calcified coronary lesions that received a CE mark in May 2017. Coronary lithotripsy is based on the fundamental principles of lithotripsy, a technology that has been used to break up kidney stones for over 30 years. Pulsatile mechanical energy is used to fragment selectively amorphous calcium, sparing soft tissue.

The IVL system (Shockwave Medical) is made up of three components: a battery-powered rechargeable generator capable of producing 3 kV energy and preprogramed to deliver a fixed number of pulses per balloon, a cable connector that links the generator with the catheter and a single-use sterile catheter with a semicompliant balloon and three miniaturised lithotripsy emitters distributed along the length of the balloon.80 These emitters convert electrical energy into transient acoustic pressure pulses (1 pulse/s for a maximum of 80 pulses per catheter). IVL balloons are available in sizes ranging from 2.5 to 4.0 mm, with a unique maximum length of 12 mm. After the lithotripsy balloon is inflated to 405 kPa, pulsatile energy is emitted for 10 seconds from two emitters localised within the balloon (the distal emitter is slightly more central to enhance flexibility, whereas the proximal emitter is located near the proximal end of the balloon); the

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balloon is then inflated to 608 kPa. These balloons are compatible with 5 and 6 Fr guide catheters but have a rather large crossing profile of 0.043–0.046 inches. Therefore, in some cases a gentle predilatation with a traditional 1.5 mm or 2.0 mm balloon is necessary before IVL balloon inflation.

The mechanism of action was described by Ali et al., who used OCT in 31 patients with severe coronary calcified lesions treated with IVL.81 In that study, lumen enlargement and single or multiple calcium fractures were observed after IVL in 43% of patients. The Shockwave Coronary Rx Lithoplasty® Study (Disrupt CAD I), a single-arm feasibility trial, enrolled 60 patients with calcified coronary artery disease treated with IVL across seven countries.82 The primary endpoint (residual diameter stenosis <50% after stent implantation without in-hospital MACE) was achieved in 98.5% of patients (residual stenosis mean ± SD: 13.3 ± 11.6%) and acute luminal gain was 1.7 ± 0.6 mm. Analysing data from that study indicated that the technique appeared safe with no major periprocedural complications (no residual dissections, no perforation, no slow flow or no-reflow).

The Disrupt CAD II trial completed enrolment of 120 patients in 15 hospitals in April 2019. 83 Preliminary data indicate successful delivery of the IVL balloon in all patients, with 34% facilitated by predilation. The post-IVL angiographic acute luminal gain was 0.8 ± 0.5 mm and residual stenosis was 29 ± 12%, which further

INTERVENTIONAL CARDIOLOGY REVIEW

Approach to Heavily Calcified Coronary Lesions Figure 2: Decision Algorithm for the Treatment of Calcified Coronary Lesions Coronary angiography

Moderate/severe calcification

Mild calcification

IVUS*/OCT assessment:

Balloon predilatation No

Stent implantation and optimisation with IVUS/OCT

Uncrossable lesion

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)†

Yes

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

3–5 points

1–2 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.

decreased to 12 ± 5% following DES implantation. Residual stenosis <50% was achieved in all patients, with freedom from in-hospital MACE in 94.2% of patients (5.8% of patients had asymptomatic non-Q wave MI without clinical sequelae). Case series (Figure 1) and single-centre registries confirmed the efficacy and safety of this new technique, but no data are currently available from randomised trials comparing IVL with modified balloons or RA.84,85 An Irish retrospective review of 54 patients treated with IVL reported a higher incidence of isolated ventricular capture beats or asynchronous cardiac pacing during shockwave pulse with no clinical events associated with this phenomenon.86

Authors’ Perspectives There have been substantial technological advancements in the treatment of calcified coronary lesions in recent years, with higher procedural success and lower periprocedural complications due to a combination of more reliable, stronger NC balloons, scoring and cutting balloons, RA and, more recently, OA and intravascular coronary lithotripsy.87 Second-generation DESs and more effective antiplatelet agents decrease thrombosis and restenosis. Despite these encouraging data, in clinical practice all the dedicated devices for the treatment of calcified lesions, and especially RA and OA, are grossly underutilised because of a perceived greater procedural risk in the hands of inexperienced operators and substantial costs.

In this context, we believe that IVL has the potential of more widespread adoption because of its efficacy, at least in concentric calcified lesions, safety (with a short learning curve), low periprocedural complications and no risk of coronary perforation. In light of these

INTERVENTIONAL CARDIOLOGY REVIEW

changes, we propose a new algorithm to approach the treatment of coronary calcified lesions after preliminary characterisation based on multimodal imaging. OCT is certainly the preferred intravascular imaging technique for calcified coronary lesions, but it is not feasible in some cases, such as in moderate to severe renal failure or in severe stenoses. In such cases, IVUS can quantify calcium arc and calcium length, but not calcium depth.

For this reason we have modified the OCT score proposed by Fujino et al.26 to enable the use of OCT with IVUS, adding an adjunctive point for lesions with a calcium arc >270° and calcium length >5 mm because, based on our experience, deeper calcified lesions have concomitantly more concentric calcium and longitudinally extended calcium. In addition, another point has been added for lesions with an arc >270° because, based on the literature, the efficacy of IVL was greater in these lesions. Analysing these parameters, a decisional algorithm was proposed to guide the interventional cardiologist to choose the most appropriate device (Figure 2). In case of unsuccessful or partially successful treatment, more devices can be used in sequence, as reported in a recent case of RotaTripsy treatment (a combination of RA and IVL).88

Conclusion The problem of heavily calcified coronary lesions will increase in the future because of an aging population and increased rates of diabetes and chronic renal disease. An approach based on multimodal imaging techniques and the use of dedicated devices is key to improve patient outcomes. Further data will be needed to confirm the efficacy of these new, dedicated devices on long-term clinical outcome.

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77. Holmes DR Jr, Mehta S, George CJ, et al. Excimer laser coronary angioplasty: the New Approaches to Coronary Intervention (NACI) experience. Am J Cardiol 1997;80:99K–105K. https://doi.org/10.1016/S0002-9149(97)00769-8; PMID: 9409697.

78. Fernandez JP, Hobson AR, McKenzie D, et al. Beyond the balloon: excimer coronary laser atherectomy used alone or in combination with rotational atherectomy in the treatment of chronic total occlusions, non-crossable and non-expansible coronary lesions. EuroIntervention 2013;9:243–50. https://doi. org/10.4244/EIJV9I2A40; PMID: 23454891.

79. Lee T, Shlofmitz RA, Song L, et al. The effectiveness of excimer laser angioplasty to treat coronary in-stent restenosis with peri-stent calcium as assessed by optical coherence tomography. EuroIntervention 2019;15:e279–88. https://doi. org/10.4244/EIJ-D-18-00139; PMID: 29769164.

80. D ini CS, Tomberli B, Mattesini A, et al. Intravascular lithotripsy for calcific coronary and peripheral artery stenoses.

EuroIntervention 2019. 10.4244/EIJ-D-18-01056; PMID: 31062700; epub ahead of press.

81. Ali ZA, Brinton TJ, Hill JM, et al. Optical coherence tomography characterization of coronary lithoplasty for treatment of calcified lesions: first description. JACC Cardiovasc Imaging 2017;10;897–906. https://doi.org/10.1016/j.jcmg.2017.05.012; PMID: 28797412.

82. Brinton TJ, Ali Z, Hill J, et al. Feasibility of shockwave coronary intravascular lithotripsy for the treatment of calcified coronary stenoses: first description. Circulation 2019;139:834–6. https://doi.org/10.1161/CIRCULATIONAHA.118.036531; PMID: 30715944.

83. Shockwave Coronary Lithoplasty® Study (Disrupt CAD II). 2017. Available at: https://clinicaltrials.gov/ct2/show/ NCT03328949 (accessed 16 October 2019).

84. Wong B, El-Jack S, Khan A, et al. Treatment of heavily calcified unprotected left main disease with lithotripsy: the first case series. J Invasive Cardiol 2019;31:E143–7. PMID: 31158810.

85. Wong B, El-Jack S, Newcombe R, et al. Shockwave intravascular lithotripsy for calcified coronary lesions: first real-world experience. J Invasive Cardiol 2019;31:46–8. https:// doi.org/10.1016/j.hlc.2019.05.022; PMID: 30765621.

86. Wilson SJ, Spratt JC, Hill J, et al. Coronary intravascular lithotripsy is associated with a high incidence of ‘shocktopics’ and asynchronous cardiac pacing. EuroIntervention 2019. 10.4244/ EIJ-D-19-00484; PMID: 31130523; epub ahead of press.

87. De Maria GL, Scarsini R, Banning AP. Management of calcific coronary artery lesions: is it time to change our interventional therapeutic approach? JACC Cardiovasc Interv 2019;12:1465–78. https://doi.org/10.1016/j.jcin.2019.03.038; PMID: 31395217.

88. 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.

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Coronary Calcified Lesions

The Value of Intracoronary Imaging and Coronary Physiology When Treating Calcified Lesions Yasushi Ueki, 1 Tatsuhiko Otsuka, 1 Kiyoshi Hibi 2 and Lorenz Räber 1 1. Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland; 2. Division of Cardiology, Yokohama City University Medical Centre, Yokohama, Japan

Abstract Heavily calcified coronary artery lesions hinder the delivery of devices and limit stent expansion, resulting in low procedural success and poor clinical outcomes driven by an increase in restenosis and stent thrombosis. Intracoronary imaging provides a more precise assessment of lesions and is a critical step when deciding whether the lesion needs to be prepared with atherectomy devices.

Physiological assessment of lesion significance is an important consideration to avoid unnecessary stenting. This article summarises the current data on the value of intracoronary imaging and functional assessment for coronary calcified lesions and suggests a treatment strategy based on the findings of intracoronary imaging findings.

Keywords Calcified lesion, fractional flow reserve, intravascular ultrasound, optical coherence tomography, rotablation Disclosure: LR has received research grants from Abbott, Biotronik, HeartFlow, Sanofi and Regeneron, and speaker fees from Abbott, Amgen, AstraZeneca, Bayer, Biotronik, CSL Behring and Sanofi. He is also an unpaid principal investigator of a first in-man study conducted by Biotronik. All other authors have no conflicts of interest to declare.

Received: 14 February 2019 Accepted: 9 September 2019 Citation: Interventional Cardiology Review 2019;14(3):164–8. DOI: https://doi.org/10.15420/icr.2019.16.R1 Correspondence: Lorenz Räber, Department of Cardiology, Bern University Hospital, Inselspital, University of Bern, 3010 Bern, Switzerland. E: lorenz.raeber@insel.ch 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.

Heavily calcified coronary artery lesions hinder device delivery and limit stent expansion, which is the most relevant predictor of stent failure.

This may result in low procedural success and poor clinical outcomes.

Coronary angiography has a limited ability to detect calcifications when planning an optimal percutaneous coronary intervention (PCI) strategy.

Intracoronary imaging can provide useful insights for precise lesion assessment including a detailed analysis of the axial, circumferential and longitudinal distribution of calcium.

Physiological lesion assessment is also an important consideration to avoid unnecessary stenting, because severely calcified lesions are often associated with poor outcomes. Inadequate treatment of physiologically non-significant calcification would carry an increased risk of complications. This article aims to summarise the current data on the value of intracoronary imaging and functional assessment for coronary calcified lesions.

Intracoronary Imaging Assessment of Calcified Plaque by Intravascular Ultrasound and Optical Coherence Tomography Intravascular ultrasound (IVUS) imaging is based on ultrasound waves (i.e. acoustic waves) produced by the oscillatory movement of a transducer. IVUS shows calcium as echo dense (hyperechoic) with shadowing and the density is brighter than the reference adventitia.

Calcium generates reverberations, especially after it has been treated with rotablation or orbital atherectomy. This is caused by multiple reflections from the oscillation of ultrasound between the transducer and calcium to create concentric arcs at duplicated distances. Dense

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fibrous tissue is also echo dense and sometimes even creates shadowing, but it does not create reverberations. IVUS is the most reliable diagnostic tool to detect calcium, but the leading edge of the abluminal calcium is often hidden by the calcium shadow which means that calcium thickness cannot be assessed.1 Optical coherence tomography (OCT) imaging is a near-infrared light-based imaging technique. The OCT appearance of calcium is a signal-poor region with a very sharply delineated edge and low attenuation. OCT-detected calcium is often confused with lipid, although the signal-poor regions of lipid rich tissue or a necrotic core show diffuse borders and there is substantial attenuation of the light.

Erroneous categorisation of calcium as thin-cap fibroatheroma (TCFA) or macrophage is a common pitfall due to significant light attenuation behind TCFA or macrophage when calcified plaque is located at the lumen surface.2 Unlike IVUS, OCT can measure calcium thickness, area and volume. The different ways that calcium can appear using IVUS and OCT is presented in Figure 1.

In general, angiography underestimates the amount of calcium compared with intracoronary imaging. Mintz et al. reported that in a study involving 1,155 lesions, angiography detected calcium in 38% of stable lesions (n=440), while IVUS detected 73% (n=841).3 The sensitivity and specificity of IVUS for the detection of calcium, excluding microcalcifications, compared with histology (which is the gold standard for the validation) as a reference has been reported as 89–90% and 97–100%, respectively.4,5

© RADCLIFFE CARDIOLOGY 2019

Intracoronary Imaging and Physiological Assessment in Calcified Lesions Figure 1: Images of Calcified Plaque by Intravascular Ultrasound and Optical Coherence Tomography A

B

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Corresponding frames are shown with the upper panel showing intravascular ultrasound (IVUS) and the lower showing optical coherence tomography (OCT). A–B: IVUS shows the bright leading edge of the calcium with shadowing. In the corresponding OCT frame, a signal-poor region with sharply delineated borders can be seen. A shows superficial calcium with arrowheads; B shows deep calcium with arrowheads. C: IVUS denotes a highly echogenic tissue without shadowing (arrowheads) between spotty calcium (arrows), suggesting dense fibrous plaque or a thin layer of calcium. The corresponding OCT image revealed a macrophage accumulation (with fibrous tissue behind) and no evidence of calcium (arrowheads). D: Calcified nodule (arrowheads). E: OCT depicted an irregular mass protruding to the lumen, which could be misinterpreted as red thrombus. IVUS showed high echogenic mass with shadowing, suggesting a calcified nodule.

Use of Intracoronary Imaging in Calcified Lesions Currently, there is no standardised strategy supported by robust evidence for PCI of calcified coronary lesions. Operators decide on the use of adjunctive atheroablation based on an initial response when using the devices, such as a device unpass or a non-dilatable lesion, or they use visual estimation of calcification on angiography. In principle, plaque modification by atheroablation must be performed before stent implantation because treating stent underexpansion due to a heavily calcified lesion is challenging and should be avoided. In this context, plaque assessment with intracoronary imaging prior to stenting is more important in calcified lesions than other plaque types as poor lesion preparation directly leads to stent underexpansion. Pre-stenting intracoronary imaging delineates plaque constituents and provides accurate measurements of the minimal lumen area, lesion length and reference vessel diameters, as well as calcium arc, length and thickness, which can be used to plan procedures including adequate lesion preparation and stent sizing.

Predictors of Stent Underexpansion and Calcium Fracture

calcified lesion reported that calcium fractures caused by balloon dilatation were associated with smaller residual percentage diameter stenosis (19 ± 27% versus 38 ± 38%, p=0.030) and subsequent lower risk of ischaemic-driven target lesion revascularisation (7% versus 28%, p=0.046).7 These findings indicate that OCT-derived calcium parameters can guide optimal strategies for the preparation of the lesion.

Lesion Preparation According to Intracoronary Imaging Findings Figure 2 shows pre- and post-balloon and post-stent OCT images of calcified lesions. In general, eccentric calcified plaques (<180°) can be expanded only by means of stretching the non-calcified part of the plaques and/or creating dissection at the edge of calcified plaque, while modifications on calcified plaque may not be observed. Consequently, eccentric calcium allows for adequate stent area, although asymmetric expansion may be expected. The localisation of calcium relative to the epicardium at cross-section level should always be considered because stretching the vessel wall at the epicardium side forced by the eccentric calcium at the myocardium side may lead to an increased risk of vessel rupture. In concentric calcified lesions, high-pressure ballooning with non-compliant or scoring balloons can achieve lumen gain by creating fracture at the thinnest part of the calcium or creating dissections at the edges or in gaps in the calcium. In the presence of thick calcium deposits (>500 µm) or if no adequate balloon expansion is achieved, an atherectomy device should be considered to ablate the calcium and make it thinner, allowing the fracture of calcified plaque and further lumen gain. The use of atherectomy devices should be considered before balloon dilatation to avoid too much wire bias in principle because a wire can fit the crack created by a balloon dilatation, leading to an eccentric ablation with a risk of vessel perforation.

Although there is no universal guideline for plaque modification with atheroablation, there is useful evidence that provides practical guidance. Fujino et al. reported an OCT-based scoring system for patients with calcified lesion treated without atherectomy device or scoring device to predict stent underexpansion.6 In the derivation cohort of 128 patients with calcified lesions enrolled in a randomised controlled trial, a multivariable model showed that a calcium angle >180°, a maximum calcium thickness >0.5 mm, and a calcium length >5 mm were independent predictors for stent underexpansion. In the validation cohort including 133 patients undergoing OCT-guided PCI, lesions with a calcium score of 4 (lesions with calcium deposit with maximum angle >180°, maximum thickness >0.5 mm and length >5 mm) emerged as a relevant predictor for stent underexpansion.

Atherectomy Device Selection Based on Intracoronary Imaging Findings

Calcium fracture can be used as a surrogate marker for better stent expansion. A previous study of OCT including 61 patients with a heavily

Rotational atherectomy, orbital atherectomy, lithotripsy and excimer laser coronary angioplasty can be used as atherectomy devices for coronary artery disease. Figure 3 shows OCT recordings after

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A: eccentric calcium (≈90°) was observed at 6 o’clock with a lumen area 1.7 mm2. B: A dissection was observed at the edge of plaque following balloon dilatation. C: Stent expanded to the healthy vessel side with a compression of the vessel wall. D: Concentric calcium with thin (0.3 mm) part. E: After balloon dilatation, calcium fracture was located where the calcium was thinnest. F: Stent was well-expanded with lumen area of 5.3 mm2. G: Concentric thick calcium (>500 µm). H: No fracture, dissection, and luminal gain was observed following balloon dilatation. Stent implantation in such a lesion would ultimately result in underexpansion.

atherectomy by different devices. There are no randomised controlled trials comparing each device and no robust data to support one device over another. Although operators select atherectomy devices based on their preference, their expertise or local availability, findings from intracoronary imaging may help to tailor the device selection more precisely.

In general, rotational atherectomy and orbital atherectomy can effectively ablate the circumferential calcified lesion with a small lumen area.8 A retrospective observational study comparing the effect of rotational atherectomy (n=30) versus orbital atherectomy (n=30) on severely calcified lesions (maximum calcium angle >270°) reported that both devices were associated with greater calcium modifications in smaller lumens (≤4 mm2).8 Considering that the interface of rotational atherectomy is located at the tip of the burr unlike orbital atherectomy, in which the ablative crown is located 6.5 mm proximal to the tip, rotational atherectomy may be the preferred technique for lesions that are balloon impassable. Although the role of the atherectomy device on eccentric calcium lesions and calcified nodule is unclear, an assessment of wire bias may be helpful to predict the effect of plaque modification.

Intravascular lithotripsy, which applies similar principles to urologic lithotripsy which treats kidney stones using pulsatile sonic pressure waves to disrupt vascular calcium. Lithotripsy effectively modifies superficial and deep (medial) calcium without affecting soft tissue

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A–C: Representative case of calcium fracture after orbital atherectomy. Cross-sectional preintervention (A), post-orbital atherectomy (B) and post-stent optical coherence tomography (OCT; C) images were matched. B: Orbital atherectomy led to ablation and thinning of the calcium (double-headed arrow). C: Fracture following balloon use occurred at the position of the ablation (triangles). Maximum fractured calcium thickness throughout a single calcium fracture (double-headed arrow) measured 0.60 mm. D: A round, concave and polished lumen surface was observed after rotational atherectomy. E: OCT identifies severe stent underexpansion secondary to concentric calcification with minimal and maximum calcium thickness of 0.86 mm and 1.35 mm, respectively, and minimal lumen area of 1.09 mm2.

F: Minimal lumen area increased from 1.09 mm2 to 6.47 mm2 following intravascular lithotripsy with OCT resulting in multiple calcium fractures (arrowheads). G–I: Optical frequency domain imaging cross-sectional images showing an underexpanded stent due to calcium: after rotational atherectomy (G); after excimer laser coronary atherectomy (ELCA) with saline flush (H); intimal erosions and minor dissections occurred. However, superficial calcification beneath the stent strut still remained. After ELCA with contrast medium; superficial calcification beneath the stent strut was disrupted well (I). Source: A–C: Yamamoto et al. 2018.22 Adapted with permission from Wiley. E–F: Ali et al. 2018.23 Adapted with permission from Oxford University Press. G–I: Ashikaga et al. 2015.24 Adapted with permission from Wiley.

meaning deep calcium and stent underexpansion due to underlying calcified plaque can be optimal targets, although the use of lithotripsy for in-stent restenosis is not mentioned in the ‘indication for use’.

Recently, a small observational study (n=30) reported that the frequency of calcium fractures per lesion increased in the most severely calcified plaques (highest versus lowest tertile of calcification severity, p=0.009) with a trend toward greater incidence of calcium fracture (77.8% versus 22.2%, p=0.057).9 Lithotripsy may lead to circumferential plaque modification and multiple calcium fracture, rather than localised tubelike effects seen with rotational atherectomy or orbital atherectomy.

This results in a unique plaque modification and improved safety with lower risk of vessel rupture. Disadvantages may include it being more challenging to deliver to the lesion and a probable reduced efficacy in smaller arcs of calcium. Long-term data on intravascular lithotripsy compared with other atherectomy devices are required.

Excimer laser ablates tissues by three mechanisms including photochemical, photothermal and photomechanical effects.10–12 The laser interacts with calcified plaque predominantly by the photomechanical effect. This effect, which is increased if the laser is used with contrast injection, enables the modification of plaque underlying stents because this effect occurs beyond the direct contact. Therefore, the excimer laser is considered beneficial in case of

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Intracoronary Imaging and Physiological Assessment in Calcified Lesions Figure 4: A Case with Severely Calcified Lesion Treated by Rotational Atherectomy and Orbital Atherectomy A

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Figure 6: Treatment Algorithm for a Calcified Lesion Employing Intracoronary Imaging Imaging: Calcium fragility?

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A: Angiography demonstrated severely calcified diffuse stenosis in the left anterior descending artery. B: IVUS (60 MHz) was performed due to renal failure. C and D: Concentric calcification was observed with small lumen areas. After rotablation with a 1.5 mm burr, IVUS showed mild lumen gain with multiple reverberations (arrowheads). Orbital atherectomy was performed to obtain more luminal gain and plaque modification, resulting in a slight increase in lumen area. Balloon dilatation achieved calcium fractures (arrows). Finally, the stent was expanded circumferentially without malapposition. IVUS = intravascular ultrasound, Courtesy of Shunsuke Ozaki, Itabashi Central Hospital, Tokyo, Japan.

Figure 5: A Case with Stent Underexpansion Following Rotational Atherectomy C

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A: Angiography demonstrated diffuse stenosis with severe calcification in the left anterior descending artery (LAD). Rotational atherectomy with a 1.75 mm burr followed by balloon dilatation was performed prior to stent implantation; B: Post-dilatation following stenting in the distal LAD. Balloon was expanded without indentation; C: Post-dilatation following stenting in the proximal LAD. A non-compliant balloon (3.5 mm) was not fully expanded even with high pressure (28 atm) balloon dilatation following stent implantation. D1: optical frequency domain imaging (OFDI) prior to atherectomy showed a concentric calcified plaque with the thinnest part of 500 µm. D2–3: No calcium fractures and only minimal ablation was observed following rotational atherectomy with a 1.75 mm burr and a 2.5 mm noncompliant balloon dilatation. D4: Since the balloon was not fully expanded (C), rotational atherectomy with 1.75 mm burr was performed again. OFDI after re-rotational atherectomy showed that the lower half of the stent had disappeared due to the ablation of stent (arrowheads). D5: Following 3.5 mm non-compliant balloon dilatation with high pressure (26 atm), OFDI confirmed sufficient lumen gain and calcium fracture. E1: Pre-OFDI showed concentric calcified plaque with thickness >500 µm. E2: Rotational atherectomy achieved mild luminal gain, but significant decrease in calcium thickness (arrowheads). E3: Following balloon dilatation, calcium fractures were observed (arrowheads). E4: Finally, the stent was well expanded circumferentially.

under-expanded stents due to underlying severe calcification. Figures 4 and 5 show cases treated by atherectomy devices.

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Rotational atherectomy is considered when an imaging catheter cannot pass the calcified lesion. Lesion modification by atherectomy devices are considered when intracoronary imaging findings indicate criteria associated with risk of stent underexpansion, such as calcium arc (>180°), thickness (>500 µm) and length (>5 mm) or insufficient lesion expansion (remaining indentation) by balloons including NC balloon, OPN balloon and scoring devices.

Once the lesion is pretreated with balloon or atherectomy devices, imaging should be performed to confirm the success of lesion preparation by detecting the presence of fracture and dissection and assessing the stent size. NC = non-compliant.

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Stent underexpansion is a major determinant of stent failure. Stent expansion can be described as either the absolute minimum stent cross-sectional area, or the relative expansion compared with the reference area, i.e. proximal, distal, largest, or average reference area. According to the current European Society of Cardiology (ESC) expert consensus document on intracoronary imaging, absolute minimum stent area >5.5 mm2 (IVUS) and >4.5 mm2 (OCT) or relative expansion (minimal stent area/average reference lumen area) >80% are recommended.13 However, stent underexpansion can persist in calcified lesions despite several post-dilatations, therefore it is important to have adequate lesion modification prior to stenting.

Clinicians should be aware that it is more difficult to achieve uniform struts apposition in calcified lesions compared with other plaque types due to the low conformability of plaque. Although severe malapposition (axial distance <0.4 mm and <1 mm length) is one of the major targets after stenting, further expansion can lead to vessel rupture.13

Treatment Algorithm for Calcified Lesions Figure 6 shows a treatment algorithm for calcified lesions using intracoronary imaging. Rotational atherectomy is considered when the imaging catheter cannot pass the calcified lesion. Lesion modification by atherectomy devices should be considered when: • intracoronary imaging findings indicate criteria associated with the risk of stent underexpansion such as calcium arc (>180°), thickness (>500 µm) and length (>5 mm); or • in case of insufficient lesion expansion and remaining indentation by a non-compliant balloon, OPN balloon and scoring devices.

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Coronary Calcified Lesions Once the lesion has been treated with balloon or atherectomy devices, imaging should be performed to look for the presence of fracture and dissection and assess stent size and the success of lesion preparation.

Functional Assessment of Calcified Lesion Functional assessment by fractional flow reserve (FFR) has become the gold standard for the assessment of coronary artery stenosis and has been shown to improve patient outcomes in previous large randomised controlled trials.14,15 Coronary angiography has been used to determine haemodynamic significance of given arteries; however, it is known that several angiographic factors including lesion location, lesion length, haziness, tandem lesion and bifurcation lesion are associated with positive FFR.16 There is limited data regarding the impact of coronary artery calcification on the value of FFR. In an observational study including 200 patients with intermediate coronary lesion, the correlation between angiographic severity and FFR value decreased as lesion calcification increased (none or mild calcification: R2 = 0.24; moderate calcification: R2 = 0.11; severe calcification: R2 = 0.02).17 These findings may be associated with decreased coronary artery distensibility due to the presence of coronary artery calcium.

1.

2.

3.

4.

5.

6.

7.

8.

ang X, Matsumura M, Mintz GS, et al. In vivo calcium W 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.

Kini AS, Vengrenyuk Y, Yoshimura T, et al. Assessment of fibrous cap thickness by optical coherence tomography in vivo: reproducibility and standardization. J Am Coll Cardiol 2016;69:644–57. https://doi.org/10.1016/j.jacc.2016.10.028; PMID: 27989887.

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 1155 lesions. Circulation 1995;91:1959–65. https://doi. org/10.1161/01.CIR.91.7.1959; PMID: 7895353.

Friedrich GJ, Moes NY, Muhlberger VA, et al. Detection of intralesional calcium by intracoronary ultrasound depends on the histologic pattern. Am Heart J 1994;128:435–41. https://doi. org/10.1016/0002-8703(94)90614-9; PMID: 8074002.

Kostamaa H, Donovan J, Kasaoka S, et al. Calcified plaque cross-sectional area in human arteries: correlation between intravascular ultrasound and undecalcified histology. Am Heart J 1999;137:482–8. https://doi.org/10.1016/S00028703(99)70496-5; PMID: 10047630.

Fujino A, Mintz GS, Matsumura M, et al. A new optical coherence tomography-based calcium scoring system to predict stent underexpansion. EuroIntervention 2018;13:e2182– 9. https://doi.org/10.4244/EIJ-D-17-00962; PMID: 29400655.

Kubo T, Shimamura K, Ino Y, et al. Superficial calcium fracture after PCI as assessed by OCT. JACC Cardiovasc Imaging 2015;8:1228–9. https://doi.org/10.1016/j.jcmg.2014.11.012; PMID: 25797130.

Yamamoto MH, Maehara A, Karimi Galougahi K, et al.

Mechanisms of orbital versus rotational atherectomy plaque modification in severely calcified lesions assessed by optical coherence tomography. JACC Cardiovasc Interv 2017;10:2584–6. https://doi.org/10.1016/j.jcin.2017.09.031; PMID: 29268891.

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There have been several studies which investigated the relationship between defined morphological features from virtual histology-IVUS and FFR, with inconsistent results.18–20 Only one study including 48 patients with non-ST-elevation acute coronary syndrome reported that FFR correlated with necrotic core volume (r = −0.497, p=0.008) and dense calcium volume (r = −0.332, p=0.03),21 while others did not show significant correlations between plaque compositions and FFR value. Further dedicated studies with larger sample sizes are required in this area.

Conclusion Intracoronary imaging plays an essential role in all the steps of calcified lesion treatment, especially pre-lesion assessment. Clinicians should appreciate the inherent limitations of angiography and interpret intracoronary imaging findings in combination with physiological assessment of lesion significance to improve the outcomes for this challenging patient group. Further studies are needed to test the usefulness of the comprehensive treatment algorithm including the choice of atherectomy devices based on intracoronary imaging findings in patients with severely calcified lesions.

li ZA, Brinton TJ, Hill JM, et al. Optical coherence tomography A characterization of coronary lithoplasty for treatment of calcified lesions: first description. JACC Cardiovasc Imaging 2017;10:897–906. https://doi.org/10.1016/j.jcmg.2017.05.012; PMID: 28797412.

Litvack F, Grundfest WS, Goldenberg T, et al. Pulsed laser angioplasty: wavelength power and energy dependencies relevant to clinical application. Lasers Surg Med 1988;8:60–5. https://doi.org/10.1002/lsm.1900080111; PMID: 2965288. van Leeuwen TG, Meertens JH, Velema E, et al. Intraluminal vapor bubble induced by excimer laser pulse causes microsecond arterial dilation and invagination leading to extensive wall damage in the rabbit. Circulation 1993;87:1258–63. https://doi.org/10.1161/01.CIR.87.4.1258; PMID: 8462152.

Esenaliev RO, Oraevsky AA, Letokhov VS, et al. Studies of acoustical and shock waves in the pulsed laser ablation of biotissue. Lasers Surg Med 1993;13:470–84. https://doi. org/10.1002/lsm.1900130412; PMID: 8366748.

Raber L, Mintz GS, Koskinas KC, et al. Clinical use of intracoronary imaging. Part 1: guidance and optimization of coronary interventions. An expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J 2018;39:3281–300. https://doi. org/10.1093/eurheartj/ehy285; PMID: 29790954.

Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24. https://doi. org/10.1056/NEJMoa0807611; PMID: 19144937.

De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991–1001. https://doi. org/10.1056/NEJMoa1205361; PMID: 22924638.

Natsumeda M, Nakazawa G, Murakami T, et al. Coronary angiographic characteristics that influence fractional flow reserve. Circ J 2015;79:802–7. https://doi.org/10.1253/circj.

CJ-14-0931; PMID: 25739718.

17. J ohnson PM, Madamanchi C, Sharalaya ZM, et al.

Angiographic severity does not correlate with fractional flow reserve in heavily calcified coronary arteries. Catheter Cardiovasc Interv 2017;89:226–32. https://doi.org/10.1002/ ccd.26635; PMID: 27465149.

18. Waksman R, Legutko J, Singh J, et al. FIRST: Fractional flow reserve and intravascular ultrasound relationship study.

J Am Coll Cardiol 2013;61:917–23. https://doi.org/10.1016/j. jacc.2012.12.012; PMID: 23352786.

19. Brugaletta S, Garcia-Garcia HM, Shen ZJ, et al. Morphology of coronary artery lesions assessed by virtual histology intravascular ultrasound tissue characterization and fractional flow reserve. Int J Cardiovasc Imaging 2012;28:221–8. https://doi. org/10.1007/s10554-011-9816-3; PMID: 21336551.

20. Rogers JH, Wegelin J, Harder K, et al. Assessment of FFRnegative intermediate coronary artery stenoses by spectral analysis of the radiofrequency intravascular ultrasound signal.

J Invasive Cardiol 2006;18:448–53. PMID: 17042100.

21. Huseyinova G, Aslanger E, Cakir O, et al. Potential contribution of virtual histology plaque composition to hemodynamicmorphologic dissociation in patients with non-ST elevation acute coronary syndrome. Int J Cardiol 2015;187:33–8. https:// doi.org/10.1016/j.ijcard.2015.03.316; PMID: 25828307.

22. Yamamoto MH, Maehara A, Kim SS, et al. Effect of orbital atherectomy in calcified coronary artery lesions as assessed by optical coherence tomography. Catheter Cardiovasc Interv 2019;93:1211–8. https://doi.org/10.1002/ccd.27902; PMID: 30328257.

23. Ali ZA, McEntegart M, Hill JM, Spratt JC. Intravascular lithotripsy for treatment of stent underexpansion secondary to severe coronary calcification. Eur Heart J 2018. https://doi. org/10.1093/eurheartj/ehy747; PMID: 30462174.

24. Ashikaga T, Yoshikawa S, Isobe M. The effectiveness of excimer laser coronary atherectomy with contrast medium for underexpanded stent: The findings of optical frequency domain imaging. Catheter Cardiovasc Interv 2015;86:946-9. https://doi.org/10.1002/ccd.25915; PMID: 25754354.

INTERVENTIONAL CARDIOLOGY REVIEW

Coronary Calcified Lesions

Lesion Preparation with Orbital Atherectomy Evan Shlofmitz, 1 Allen Jeremias, 2,3 Richard Shlofmitz 2 and Ziad A Ali 2,3,4 1. MedStar Washington Hospital Center, Washington, DC, US; 2. St Francis Hospital, Roslyn, New York, NY, US; 3. Cardiovascular Research Foundation, New York, NY, US; 4. Columbia University Medical Center, New York, NY, US.

Abstract Despite significant improvements in stent design, severe coronary calcification continues to impede adequate stent expansion and is associated with worse clinical outcomes. Angiography is limited in its ability to detect and comprehensively characterise calcified plaque.

Intravascular imaging provides information on lesion morphology guiding appropriate treatment strategies. Orbital atherectomy allows for lesion preparation of severely calcified plaque prior to stent implantation. Utilising a unique mechanism of action incorporating centrifugal forces, a standard 1.25 mm eccentrically mounted and diamond-coated burr orbits bi-directionally to ablate calcified plaque. Lesion preparation with orbital atherectomy allows for modification of calcified plaque to facilitate stent expansion.

Keywords Orbital atherectomy, calcified lesions, percutaneous coronary intervention, optical coherence tomography, lesion preparation Disclosure: AJ has received institutional funding (unrestricted education grant) from Philips and Abbott Vascular and has served as a consultant for Philips, Abbott Vascular, Opsens Medical, and Boston Scientific. ZAA received institutional research grants to Columbia University from Abbott and Cardiovascular Systems and is a consultant to Abbott, ACIST Medical Systems, Boston Scientific, Cardinal Health, Medtronic and Canon US. All other authors have no conflicts of interest to declare.

Received: 17 July 2019 Accepted: 1 October 2019 Citation: Interventional Cardiology Review 2019;14(3):169–73. DOI: https://doi.org/10.15420/icr.2019.20.R1 Correspondence: Ziad A Ali, 1700 Broadway, 8th Floor, New York, NY 10019, US. E: zaa2112@columbia.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Coronary calcification has posed challenges to successful revascularisation since the development of percutaneous coronary intervention (PCI).1 Coronary artery calcification worsens clinical outcomes irrespective of the revascularisation strategy.2–4 Despite significant improvements in stent design over the past decades, including an improved ability to deliver a stent, severe calcification continues to impede adequate stent expansion with contemporary PCI. Severe calcification is present in nearly one-third of patients undergoing PCI.5 The degree of coronary lesion calcification impacts stent expansion, which is one of the strongest predictors for in-stent restenosis and stent thrombosis.6–10 Historically, routine use of atherectomy has been reserved for undilatable and uncrossable calcified lesions.11,12 The concept of routine lesion preparation for all heavily calcified lesions prior to stent implantation to prevent stent underexpansion represents a recent change in practice, but is supported by data from intravascular imaging-based studies.6,12–18

Assessment of Coronary Artery Calcification Angiography has been consistently shown to be inadequate for comprehensive assessment of coronary artery calcification.19 In a pivotal analysis of 1,155 coronary lesions, Mintz et al. demonstrated that, while angiography detected calcium in 38% of lesions, intravascular ultrasound (IVUS) was able to detect lesion calcification in 73% of lesions.20 Similar findings were reported in a study that included optical coherence tomography (OCT) in addition to angiography and IVUS.21 Intravascular imaging provides data beyond simple detection of calcified plaque. Lesion morphology, arc of calcification, calcium

© RADCLIFFE CARDIOLOGY 2019

thickness and length are best assessed with intravascular imaging and can be determinant of the optimal revascularisation strategy.22 Figure 1 illustrates calcified plaque identified on OCT.

Role of Calcium Modification Mild or moderate calcification is often adequately treated with balloon angioplasty with either a noncompliant balloon, cutting balloon or scoring balloon. When superficial coronary artery calcification is <0.24 mm thick, a balloon alone is often adequate to create fractures in the calcium plate.23 As calcium thickness increases, achieving calcium fracture with balloon angioplasty alone becomes less likely. In patients with an OCT-based calcium score of 4, indicating the presence of calcium thickness >0.5 mm, an arc of calcium exceeding 180o and a continuous length of calcium >5 mm, adjunctive therapies should be used prior to stent implantation.24 Calcium fracture can facilitate improved stent expansion.16,25 The features of a calcified lesion determine the optimal lesion preparation strategy. The adjunctive therapies that can be utilised for calcium modification as part of PCI can be remembered by the acronym ROLE (Figure 2): Rotational atherectomy, Orbital atherectomy, intravascular Lithotripsy, and Excimer laser coronary atherectomy (ELCA). If a lesion is balloon crossable, intravascular lithotripsy can be used. For lesions that are not balloon crossable, rotational atherectomy or orbital atherectomy are both reasonable options. ELCA can be considered for de novo calcified lesions not amenable to rotational atherectomy, orbital atherectomy or intravascular lithotripsy. 26–29 However, the primary role for ELCA in treating calcified plaque is for in-stent restenosis due to an underexpanded stent with significant

Access at: www.ICRjournal.com

169

Coronary Calcified Lesions Figure 1: Calcified Plaque on Optical Coherence Tomography A

B

A: Optical coherence tomography cross-section with calcified plaque; B: Optical coherence tomography cross-section with calcified plaque highlighted with blue overlay.

Figure 2: The ROLE Acronym for Calcium Modification

Arc >50%

Thickness >0.5 mm

Length >5 mm

ROLE for calcium modification

Rotational atherectomy

Orbital atherectomy

Lithotripsy

Excimer laser coronary atherectomy

In the presence of coronary artery calcification with an arc >50%, thickness >0.5 mm and length >5 mm, adjunctive therapies for calcium modification should be considered.

These include rotational atherectomy, orbital atherectomy, intravascular lithotripsy and excimer laser coronary atherectomy. ROLE = Rotational atherectomy, Orbital atherectomy, intravascular Lithotripsy, and Excimer laser coronary atherectomy.

peri-stent calcification.30,31 An algorithmic approach for the management of calcified lesions can help ensure adequate lesion preparation has been achieved prior to stent implantation (Figure 3). We herein focus on the treatment of calcified plaque with orbital atherectomy.

Orbital Atherectomy Device Setup and Use Orbital atherectomy for coronary arteries utilises the Diamondback 360® orbital atherectomy system (Cardiovascular Systems) which incorporates a 1.25 mm diamond-coated eccentrically mounted crown that is advanced over a dedicated 0.012" ViperWire® Advance Coronary Guide Wire (Cardiovascular Systems) with a 0.014" tip.

ViperSlide® (Cardiovascular Systems) lubricant is infused during treatment to reduce friction from a specialised pump that is mounted on an intravenous pole. The crown is controlled by a hand-held electric powered single-use handle that has two speeds for treatment: low (80,000 rpm) and high (120,000 rpm). The orbital atherectomy system is compatible with a 6 Fr or larger catheter.

Employing centrifugal forces, the 1.25 mm crown orbits as it advances through a coronary artery, allowing for the continuous flow of blood during atheroablation. This unique mechanism of action combined with an average particle size of debris of 2.04 µm – smaller than a red blood cell – may contribute to low rates of no-reflow and transient heartblock with orbital atherectomy.32 A distinguishing feature of orbital atherectomy is its ability to ablate bi-directionally, potentially decreasing the likelihood for burr entrapment.33

170

The 1.25 mm crown size is standard for all coronary arteries and can treat larger-sized lumens by either increasing the speed (high speed) or by slowing the rate of advancement to allow an increase in the diameter of the elliptical orbit. By decreasing the traverse speed to 1 mm/second at high speed, the burr orbit can exceed 2 mm in diameter.34 Low speed should be used for all initial passes with orbital atherectomy. Following treatment at low speed, if an adequate endpoint has not been reached, treatment can be escalated to high speed. High speed is not necessary for all cases, and specifically should be avoided in vessels <3 mm in diameter or excessively tortuous vessels to reduce the risk for perforation. The GlideAssist® feature allows for rotation at 5,000 rpm and may be used to aid in the delivery and removal of the device but should not be used for treating a lesion. GlideAssist can facilitate the use of orbital atherectomy by a single operator.35 The goal of lesion preparation is to modify calcified plaque, changing the vessel compliance to facilitate stent expansion.36 The slower the burr is advanced with orbital atherectomy, the larger the orbit is and greater the likelihood of achieving plaque modification as it is a time dependent therapy. The burr should be advanced at 1–3 mm/second.

Notably, optimal orbital atherectomy technique differs from the standard rapid pecking motion that is characteristic with rotational atherectomy use.

Each pass with orbital atherectomy should be limited to less than 30 seconds. After 25 seconds of continuous treatment, the system emits an audible alert and the crown should be moved to a location outside of the lesion. Rest periods between treatment runs should be for a minimum of duration equal to the preceding run. If the patient becomes symptomatic during treatment, greater rest periods should follow. During atheroablation, pitch changes can be appreciated as the crown engages the hard, calcified plaque. As treatment continues, the pitch change becomes reduced, and tactile resistance decreases.33 Treatment with orbital atherectomy should continue until audible and tactile changes are appreciated, indicating the optimal endpoint has been reached. There is no predefined number of treatment runs that is ideal, and therapy should be adjusted as needed for each specific lesion. While patients have had favourable outcomes following direct stenting after orbital atherectomy, direct stenting in calcified lesions should not be used unless intravascular imaging is performed following lesion preparation confirming an adequate endpoint has been achieved with significant calcium fracture.37 Calcium fracture and the typical smooth, concave ablation seen with orbital atherectomy is readily identified with OCT imaging (Figures 4 and 5).

Clinical Data The first in-human study of coronary orbital atherectomy of 50 patients treated at two centres in India in 2008 was the Safety and Feasibility of Orbital Atherectomy for the Treatment of Calcified Coronary Lesions (ORBIT I) study, which demonstrated device success of 98% with procedural success in 94% of patients.38 Long-term follow-up was reported and the cumulative major adverse cardiac event (MACE) rate at 3-years follow-up was 18.2%.39 Of note, the ORBIT I investigational study occurred prior to device approval and evaluated four different sized burrs, with only 18.4% of patients having been treated with the 1.25 mm burr that is currently available.38 The pivotal Evaluate the Safety and Efficacy of OAS [Orbital Atherectomy System] in Treating Severely Calcified Coronary Lesions (ORBIT II) study evaluated the impact of orbital atherectomy in 443 patients with severe

INTERVENTIONAL CARDIOLOGY REVIEW

Lesion Preparation with Orbital Atherectomy Figure 3: Treatment Algorithm for Calcified Coronary Lesions OCT to assess calcified plaque

Deep

Superficial

Calcification does NOT meet all the following criteria: thickness: >0.5 mm, length: >5 mm, arc: >50%

OCT and balloon uncrossable

Nodular

Calcification meets ALL the following criteria: thickness: >0.5 mm, length: >5 mm, arc: >50%

Balloon crossable

Intravascular lithotripsy

Balloon uncrossable

Orbital atherectomy or rotational atherectomy

NC/scoring/cutting balloonbased lesion preparation Calcium fracture present on OCT

Final OCT

Stent

No

Yes

Stent

Final OCT

An algorithmic approach for the management of calcified lesions can help ensure adequate lesion preparation has been achieved prior to stent implantation. NC = non-compliant; OCT = optical coherence tomography.

coronary artery calcification treated at 49 sites in the US from 2010 to 2012.40 The primary safety endpoint, freedom from 30-day MACE, was met in 89.6% of patients and led to device approval in the US in 2013.40 At 3-year follow-up, the overall cumulative MACE rate was 23.5%, and was comprised of 6.7% cardiac death, 11.2% MI and target vessel revascularisation (TVR) in 10.2% of patients with severe calcification treated with orbital atherectomy.41

Figure 4: Optical Coherence Tomography Cross-section Following Orbital Atherectomy

A real-world multicentre all-comer analysis reported outcomes of 458 patients treated with orbital atherectomy from 2013 to 2015.42 This analysis included a complex cohort of patients that had clinical features that were excluded from the ORBIT II study including unprotected left main disease, low ejection fraction, chronic kidney disease and acute coronary syndrome. Angiographic complications were low with dissection, perforation and no-reflow occurring in less than 1% of cases.42 At 1-year follow-up, the composite rate of major adverse cardiac and cerebrovascular events occurred in 12.6%, with 4.0% all-cause mortality, 1.8% MI rate and TVR rate of 7.5%.43 Multiple studies have reported safety data related to orbital atherectomy in both stand-alone orbital atherectomy studies and in observational studies with comparison to rotational atherectomy.

The rates of dissection, perforation, slow/no-reflow and 30-day TVR in patients treated with orbital atherectomy are presented in Table 1.

Imaging-based Insights In a small, multi-centre OCT-based mechanistic study comparing orbital atherectomy with rotational atherectomy in 60 patients, the investigators found that orbital atherectomy creates greater calcium modification in lesions with larger lumen area.51 Calcium fracture following stent implantation occurred in the majority of cases regardless of atherectomy device used, with similar final stent expansion.51 In a

INTERVENTIONAL CARDIOLOGY REVIEW

Characteristic smooth, concave ablation of calcified surface (white dashed line) with multiple calcium fractures (red arrows).

separate series where OCT was performed at baseline, following orbital atherectomy, and after stent implantation, OCT demonstrated that in thick calcified lesions, orbital atherectomy was effective at creating post-stent fractures in calcium and facilitating stent expansion.52 Calcium modification is commonly noted on OCT following treatment with orbital atherectomy.53,54 Given the characteristic concave-shaped

171

Coronary Calcified Lesions Table 1: Orbital Atherectomy Safety Data Study

Year

N

Dissection, n (%)

Perforation, n (%)

Slow Flow/No

30-day TVR, n (%)

Reflow, n (%) ORBIT I*38

2013

50

6 (12.0)

1 (2.0)

NA

1 (2.0)

ORBIT II

2014

443

10 (2.3)

4 (0.9)

1 (0.2)

6 (1.4)

COAST (NCT02132611)†44

2016

100

2 (2.0)

2 (2.0)

2 (2.0)

1 (1.0)

Lee et al.42

2016

458

4 (0.9)

3 (0.7)

3 (0.7)

0 (0)

COAP-PCI

2018

273

2 (0.7)

1 (0.4)

NA

NA

2018

67

5 (8.0)

NA

NA

NA

40

45

Koifman et al.46 Chambers et al.

2018

78

NA

NA

1 (1.3)

1 (1.3)

Desai et al.48

2018

40

0 (0)

1 (2.5)

1 (2.5)

0 (0)

Whitbeck et al.49

2018

70

0 (0)

1 (1.4)

1 (1.4)

NA

Okamoto et al.

2019

184

3 (1.6)

3 (1.6)

4 (2.2)

NA

47

50

*The 1.25 mm burr was used in 18.4% of patients in the ORBIT I study. The remaining patients were treated with either 1.5 mm, 1.75 mm or 2.0 mm burrs, which are not currently available for commercial use. †Micro-crown orbital atherectomy device. COAP-PCI = Clinical Outcomes of Atherectomy Prior to Percutaneous Coronary Intervention; COAST = Coronary Orbital Atherectomy System Study; NA = not applicable; TVR = target vessel revascularisation.

Figure 5: Optical Coherence Tomography Cross-section Following Stent Implantation After Orbital Atherectomy

except when the distance between the stent strut and vessel wall distance exceeds 0.40 mm.53 The impact of orbital atherectomy on the microcirculation is being evaluated in the prospective Comparison of Orbital Versus Rotational Atherectomy Effects On Coronary Microcirculation in PCI trial (ORACLE; NCT03021577), which randomised 20 patients with calcified coronary artery disease to either orbital or rotational atherectomy and will compare the coronary flow reserve and the volume of myocardial necrosis on serial MRI scans.

Future Directions The Evaluation of Treatment Strategies for Severe CaLcIfic Coronary Arteries: Orbital Atherectomy vs. Conventional Angioplasty Technique Prior to Implantation of Drug-Eluting StEnts trial (ECLIPSE; NCT03108456) is currently enrolling with results expected after 2021. The ECLIPSE trial is randomising approximately 2,000 patients with severe calcific coronary disease undergoing PCI 1:1 to either orbital atherectomy or conventional balloon angioplasty prior to stent implantation. When complete, it will be the largest PCI trial to date in patients with severely calcified coronary artery disease and will assess the role of routine lesion preparation with orbital atherectomy in contemporary PCI and its impact on clinical outcomes.

Multiple calcium fractures are present (red arrows).

Conclusion polishing of the calcium surface with orbital atherectomy, stent strut malapposition may be observed following stent implantation.

Acute stent strut malapposition ≥0.2 mm has been reported as occurring in 7.6% of stent struts at baseline following treatment with orbital atherectomy.53 This typically resolves with neointimal coverage,

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36. Kini AS, Vengrenyuk Y, Pena J, et al. Optical coherence tomography assessment of the mechanistic effects of rotational and orbital atherectomy in severely calcified coronary lesions. Catheter Cardiovasc Interv 2015;86:1024–32. https://doi.org/10.1002/ccd.26000; PMID: 25964009.

37. Shlofmitz E, Martinsen BJ, Behrens AN, et al. Direct stenting in patients treated with orbital atherectomy: an ORBIT II subanalysis. Cardiovasc Revasc Med 2019;20:454–60. https://doi. org/10.1016/j.carrev.2019.03.011; PMID: 30982659.

38. Parikh K, Chandra P, Choksi N, et al. Safety and feasibility of orbital atherectomy for the treatment of calcified coronary lesions: the ORBIT I trial. Catheter Cardiovasc Interv 2013;81:1134– 9. https://doi.org/10.1002/ccd.24700; PMID: 23460596.

39. Bhatt P, Parikh P, Patel A, et al. Orbital atherectomy system in treating calcified coronary lesions: 3-year follow-up in first human use study (ORBIT I trial). Cardiovasc Revasc Med 2014;15:204–8. https://doi.org/10.1016/j.carrev.2014.03.004; PMID: 24746600.

40. Chambers JW, Feldman RL, Himmelstein SI, et al. Pivotal trial

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

to evaluate the safety and efficacy of the orbital atherectomy system in treating de novo, severely calcified coronary lesions (ORBIT II). JACC Cardiovasc Interv 2014;7:510–8. https:// doi.org/10.1016/j.jcin.2014.01.158; PMID: 24852804.

Lee M, Genereux P, Shlofmitz R, et al. Orbital atherectomy for treating de novo, severely calcified coronary lesions: 3-year results of the pivotal ORBIT II trial. Cardiovasc Revasc Med 2017;18:261–4. https://doi.org/10.1016/j.carrev.2017.01.011; PMID: 28162989.

Lee MS, Shlofmitz E, Kaplan B, et al. Real-world multicenter registry of patients with severe coronary artery calcification undergoing orbital atherectomy. J Interv Cardiol 2016;29: 357–62. https://doi.org/10.1111/joic.12310; PMID: 27358246.

Lee MS, Shlofmitz E, Goldberg A, Shlofmitz R. Multicenter registry of real-world patients with severely calcified coronary lesions undergoing orbital atherectomy: 1-year outcomes. J Invasive Cardiol 2018;30:121–4. PMID: 29610442.

Shlofmitz RA, et al. Featured clinical research – part 1.

Presented at: Society for Cardiovascular Angiography and Interventions Scientific Sessions, Orlando, FL, 4–7 May 2016.

Meraj PM, Shlofmitz E, Kaplan B, et al. Clinical outcomes of atherectomy prior to percutaneous coronary intervention: a comparison of outcomes following rotational versus orbital atherectomy (COAP-PCI study). J Interv Cardiol 2018;31:478–85. https://doi.org/10.1111/joic.12511; PMID: 29707807.

Koifman E, Garcia-Garcia HM, Kuku KO, et al. Comparison of the efficacy and safety of orbital and rotational atherectomy in calcified narrowings in patients who underwent percutaneous coronary intervention. Am J Cardiol 2018;121:934–9. https://doi.org/10.1016/j. amjcard.2017.12.041; PMID: 29452688.

Chambers JW, Warner C, Cortez J, et al. Outcomes after atherectomy treatment of severely calcified coronary bifurcation lesions: A single center experience. Cardiovasc Revasc Med 2019;20:569–72. https://doi.org/10.1016/j. carrev.2018.08.017; PMID: 30201481.

Desai R, Mirza O, Martinsen BJ, Kumar G. Plaque modification of severely calcified coronary lesions via orbital atherectomy: Single-center observations from a complex Veterans Affairs cohort. Health Sci Rep 2018;1:e99. https://doi.org/10.1002/ hsr2.99; PMID: 30623053.

Whitbeck MG, Dewar J, Behrens AN, et al. Acute outcomes after coronary orbital atherectomy at a single center without on-site surgical backup: An experience in diabetics versus non-diabetics. Cardiovasc Revasc Med 2018;19(6S):12–5. https:// doi.org/10.1016/j.carrev.2018.05.013; PMID: 29804796.

Okamoto N, Ueda H, Bhatheja S, et al. Procedural and one-year outcomes of patients treated with orbital and rotational atherectomy with mechanistic insights from optical coherence tomography. EuroIntervention 2019;14:1760–7. https://doi.org/10.4244/EIJ-D-17-01060; PMID: 29957595.

Yamamoto MH, Maehara A, Karimi Galougahi K, et al.

Mechanisms of orbital versus rotational atherectomy plaque modification in severely calcified lesions assessed by optical coherence tomography. JACC Cardiovasc Interv 2017;10:2584–6. https://doi.org/10.1016/j.jcin.2017.09.031; PMID: 29268891.

Yamamoto MH, Maehara A, Kim SS, et al. Effect of orbital atherectomy in calcified coronary artery lesions as assessed by optical coherence tomography. Catheter Cardiovasc Interv 2019;93:1211–8. https://doi.org/10.1002/ccd.27902; PMID: 30328257.

Ishida M, Mintz GS, Goldberg A, et al. Neointimal strut coverage and resolution of malapposition after stenting preceded by orbital atherectomy when treating severely calcified lesions. JACC Cardiovasc Interv 2018;11:2548–50. https:// doi.org/10.1016/j.jcin.2018.10.008; PMID: 30573069.

Sotomi Y, Cavalcante R, Shlofmitz RA, et al. Quantification by optical coherence tomography imaging of the ablation volume obtained with the Orbital Atherectomy System in calcified coronary lesions. EuroIntervention 2016;12:1126–34. https://doi.org/10.4244/EIJV12I9A184; PMID: 27753598.

173

Coronary Calcified Lesions

The Coronary Intravascular Lithotripsy System Maria Natalia Tovar Forero and Joost Daemen Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands

Abstract Calcified lesions often mean percutaneous intervention results are suboptimal and increase the risk of procedural complications and future adverse events. Available plaque-modifying devices rely on tissue compression or debulking, with the intention of fracturing calcium and facilitating optimal stent deployment. In contrast, coronary intravascular lithotripsy delivers unfocused, circumferential, pulsatile mechanical energy to safely disrupt the calcium within the target lesion. The present review summarises the evidence available so far on this therapy and includes a practical description of the components and function of the Shockwave Intravascular Lithotripsy System (Shockwave Medical).

Keywords Shockwave Intravascular Lithotripsy System, coronary calcification, coronary plaque modification, coronary lithotripsy.

Disclosure: JD has received institutional research support from Pie Medical, Acist Medical, PulseCath, Medtronic, Boston Scientific and Abbott Vascular, and speaker and consultancy fees from PulseCath, Medtronic, ReCor Medical and Acist Medical. MNTF has no conflict of interest to declare.

Acknowledgements: The authors thank Jason Hokama and Suzanne Wallace from Shockwave Medical for their critical review of the manuscript and supporting material.

Received: 1 July 2019 Accepted: 8 August 2019 Citation: Interventional Cardiology Review 2019;14(3):174–81. DOI: https://doi.org/10.15420/icr.2019.18.R1 Correspondence: Joost Daemen, Department of Cardiology, Room Rg-628, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands.

E: j.daemen@erasmusmc.nl Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The amount of coronary artery calcification increases with age and the presence of cardiovascular risk factors and comorbidities.1,2 Up to 20% of percutaneous coronary intervention (PCI) procedures are challenged by severe calcifications, and coronary calcifications have been shown to be an independent predictor of PCI failure and future adverse cardiac events.3,4 Lesion calcification increases procedural complexity and time. More specifically, calcium localisation (superficial or deep), distribution (focal, circumferential and longitudinal extension) and thickness influence procedural success, stent delivery and deployment.5 Several techniques to treat calcified lesions in native coronary arteries are available, including high-pressure and super-high pressure noncompliant balloons, cutting/scoring balloons, atherectomy devices, both rotational and orbital, and excimer lasers.6 These devices rely on tissue compression and or tissue debulking, and have higher rates of procedural complications, such as dissections, perforations and distal embolisation. Moreover, their success rate is reduced when deep, thick or eccentric calcifications are present, and the induced tissue injury might accelerate uncontrolled neointimal growth and restenosis.6,7 So far, neither specialty balloons nor atherectomy devices have been proved to be superior to high-pressure non-compliant balloons in improving clinical outcomes.8,9 Recently, an alternative way to disrupt calcium has been developed that is based on the lithotripsy concept used to treat kidney and ureteral stones. The Intravascular Lithotripsy (IVL) System (Shockwave Medical) transforms electrical energy into mechanical energy during low-pressure balloon inflation.10 The technology does

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Access at: www.ICRjournal.com

not rely on direct vascular tissue injury for plaque modification but on sonic waves, which travel from the balloon-based catheter to the surrounding tissue with the intention of safely and selectively breaking both superficial and deep calcium deposits with minimal soft tissue impairment, while improving vessel compliance. In contrast to debulking techniques, the calcium fragments resulting from the IVL therapy remain in situ, reducing the likelihood of distal embolisation. The safety and efficacy of the IVL with minimal vessel injury was demonstrated in prospective single-arm studies, where moderate to severely calcified lesions in peripheral artery disease were tackled; these were the Shockwave Lithoplasty Disrupt Trial for PAD 1 and 2 (Disrupt PAD 1 and 2) and Safety and Feasibility of the Shockwave Lithoplasty® System for the Treatment of Peripheral Vascular Stenosis (BTK) trials.11-14

The Coronary Intravascular Lithotripsy System The Shockwave Coronary Rx Lithoplasty® Study (Disrupt CAD I), a multicentre, prospective, single-arm study conducted in seven centres in Europe and Australia, was the first to assess the safety and efficacy of the Shockwave Coronary IVL in 60 patients with severe (100%) calcified lesions in native coronary arteries before drug-eluting stent implantation. The balloon was successfully delivered in 59 patients and stent implantation was successful in all cases, with no major procedural complications, such as slow flow, no reflow, distal embolisation or perforation reported. Device delivery was facilitated by pre-dilatation with a small balloon in 37% of patients. Clinical success was 95%, defined as residual diameter stenosis <50% without in-hospital major cardiac adverse events (MACE; a composite of death, MI and target-

© RADCLIFFE CARDIOLOGY 2019

Coronary Intravascular Lithotripsy System vessel revascularisation) at 30 days; MACE at 6 months increased to 8.5% with three non-Q wave MI events within the first 30 days and two cardiac deaths.15

lesion will depend on lesion resistance; however, the maximum number of pulses to be delivered by each individual catheter is limited to 80 pulses (eight cycles).

An optical coherence tomography sub-study in 31 patients in the Disrupt CAD I trial confirmed the effects of IVL on the vessel wall.16 Calcium fractures were evident in 42.9% of the lesions and multiple circumferential cracks in the same cross-sectional area were witnessed in more than 25% of the cases, with a higher incidence of fractures in heavier calcified plaques (highest tertile versus lowest tertile; p=0.009).

The presence of calcium ruptures allowed to increase acute lumen gain (mean acute area gain = 2.1 mm2) independently of the degree of calcification, enabling successful stent implantation with uniform expansion. Coronary dissections (type B or greater) occurred in four cases during angioplasty and were successfully treated with stent implantation; no other procedural complications were reported. This data provided the first results encouraging the use of the Shockwave Coronary IVL for the treatment of calcified lesions in the coronary vasculature. Following these findings, the device received European CE mark approval in May 2017 for commercial use.

Intravascular Lithotripsy Procedure

The findings of Disrupt CAD I were further confirmed in a small (n=26) real-world study including patients with both stable and unstable disease, either as an upfront calcium modification technique or as a bailout after suboptimal results with standard balloon dilatation.

Angiographic success occurred in all cases (<20% residual stenosis) without procedural complications.17 At present, the results of the Disrupt CAD II (post-market prospective, multicentre, single-arm study), which enrolled 120 patients across Europe, are pending. More recently, the Disrupt CAD III study was announced. The study will aim to enrol 392 patients in 50 centres across the US and Europe with the intention to obtain Food and Drug Administration (FDA) approval.

The IVL procedure does not require high-level additional training for interventional cardiologists. The shockwave balloon must be sized accordingly to the reference vessel diameter (ratio 1:1), placed in the target calcified lesion and inflated up to 4 atm to ensure apposition to the vessel wall; the lithotripsy emitters are then activated to deliver the acoustic pulses by pushing the button on the connector cable. Once a cycle of 10 pulses has been delivered, the balloon can be inflated up to 6 atm (nominal pressure) to increase balloon compliance and to assess symmetrical expansion, confirming calcium modification. Next, the balloon is deflated carefully to allow small air bubbles to escape.

The previous steps must be repeated for each intended IVL cycle and at least two IVL cycles are recommended to treat the target area. For the treatment of lesions longer than 12 mm, the catheter needs to be repositioned and overlapping treatment areas might occur. See Supplementary Videos 1–4.

Due to the slightly higher profile of the shockwave catheter, predilatation with standard balloons might be necessary in some cases to facilitate deliverability and positioning, especially when lumen reduction is severe. Notwithstanding this, the balloon allows the use of guide-catheter extenders and buddy-wire support.18 Furthermore, although the system is labelled 6 Fr compatible, it could be used with a 5 Fr guiding catheter where the radial artery is small.19 The use of dilatation with non-compliant balloons after IVL, although not mandatory, could be considered to expand the lumen further.

Moreover, aggressive plaque modification devices such as cutting/ scoring balloons or atherectomy could be used as adjuvant therapy in challenging lesions to improve results.20

Potential Uses The available studies and case reports on the use of coronary IVL are summarised in Table 1.

The System The Coronary IVL System consists of a portable, rechargeable generator, a connector cable with a push button to allow manually controlled delivery of electric pulses, and a 6 Fr compatible, rapid-exchange, semi-compliant balloon catheter to be used following standard angioplasty practice over a 0.014" guidewire (Figure 1).

The semi-compliant balloon integrates two radiopaque lithotripsy emitters 6 mm apart and two conventional markers at the proximal and distal edges of the balloon. These emitters receive electrical pulses from the generator vaporising the fluid (a standard mixture of 50% NaCl 0.9% and 50% radiopaque contrast) within the balloon and creating a rapidly expanding and collapsing bubble. This bubble can transmit unfocused circumferential pulsatile mechanical energy into the vessel wall, in the form of sonic pressure waves equivalent to approximately 50 atmospheres (atm). The balloons are available in diameters ranging from 2.5 mm to 4.0 mm with a standard length of 12 mm (Table 2); their crossing profiles range from 0.043" to 0.046" (Figure 2).

The IVL therapy consists of a series of 10 pulses (1 cycle) or 10 seconds (1 pulse per second). The number of therapies needed per

INTERVENTIONAL CARDIOLOGY REVIEW

At present, the instructions for use of the Shockwave Coronary IVL System restrict its use to lesion preparation in native coronary arteries (Figure 3). Given it is assumed to be safer than previous approaches, the number of case reports and small case series reporting on its use in more challenging scenarios is increasing.

Acute Coronary Syndromes Calcified lesions in culprit vessels are common in patients presenting with acute coronary syndromes (moderate calcification is found 26.1% of these patients and severe calcification in 5.9%), and their presence is a strong predictor of definite stent thrombosis (HR 1.62; 95% CI [1.14–2.30]; p=0.007) and target lesion revascularisation (HR 1.44; 95% CI [1.17–1.78]; p<0.001).1 The Disrupt CAD study included only patients with stable and unstable angina. Although there is not enough evidence to support the use of the IVL during primary PCI, early experience has shown favourable results.17,21

Unprotected Left Main Calcified Stenosis PCI has become an option for the treatment of left main (LM) disease, with a class IA recommendation for patients with a SYNTAX score ≤22 and class IIA for a SYNTAX score 23–32.22 Calcification increases procedural complexity and therefore the risk of complications. Although atherectomy has previously been proposed as a valid and feasible option, the high-risk profile of those patients means safer approaches would be welcome.23,24

175

176 NA

Case report

Case report

UK

De Silva et al.

201749

Case report

Italy

Tassone et al.

201937

NA

NA

NA

NA

NA

NA

NA

NA

Prospective, multicentre, single arm

1

1

1

3

1

1

1

1

1

1

60

31

Size

Sample

Man

Man

Men

66.6% men

Man

Woman

Man

Man

Man

Man

80% men

80% men

Sex

60

47

67

63, 73 and 81

61

77

74

73

67

69

72 (66–79)

71 ± 10

Age (Years)

0%

0%

0%

0%

100%

0%

0%

0%

0%

0%

0%

0%

NSTEMI/STEMI

OCT

De novo lesion Severe calcification

Stent underexpansion Severe calcification

De novo lesion Severe calcification

Undilatatble lesion Severe calcification

De novo lesion Severe calcification

ISR Severe calcification between stent layers

Stent underexpansion Severe calcification

Stent underexpansion Severe calcification

Stent underexpansion Severe calcification

IVUS

OCT

IVUS

OCT

OCT

IVUS

OCT

OCT

OCT

NA

De novo lesions with severe calcification in 100%

Stent underexpansion Severe calcification

OCT (100%)

Imaging

De novo lesions with severe calcification in 87.1%

Lesion type

ISR = in-stent restenosis; IVUS = intra-vascular ultrasound; IVL = intra-vascular lithotripsy; MACE= major adverse cardiac events; NA = not applicable; OCT = optical coherence tomography.

Case report

Case series

Spain

Rodriguez Costoya et al.

201850

Italy

Case report

Germany

Chen et al.

201845

Soriano et al.

201948

Case report

Italy

Morabito et al.

201833

Case report

Case report

The Netherlands

Tovar Forero et al. 201832

Venuti et al. 201944 Italy

Case report

US

Ali et al. 201839

Watking et al.

201838

NA

Disrupt CAD

International (five countries)

Prospective, multicentre, single arm

Brinton et al.

201715

Disrupt CAD OCT substudy)

International (five countries)

Study Design

Ali et al. 201716

Study

Country

Reference

Table 1: Studies on Coronary Intravascular Lithotripsy

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

6

NA

(Months)

Follow-up

(Continued)

Angiographic and IVUS result: good Acute area gain 4.19 mm2 No complications

Complication: balloon rupture and vessel dissection

Angiographic and IVUS result: good result No complications

Angiographic and OCT result: good No complications

Angiographic and OCT result: good No complications

Angiographic and IVUS result: good; acute gain: 3.83 mm2 No complications

Angiographic and OCT result: good; acute gain: 4.26 mm2 No complications

Angiographic result and OCT result: good; acute gain 5.38 mm2 No complications

Angiographic and OCT result: good No complications

Angiographic result and OCT result: good No complications

Acute gain: mean 1.7 mm (range 1.3–2.1 mm) Angiographic complications: 0% Clinical success (residual stenosis <50% without in-hospital MACE: 95% MACE 30 days: 5% MACE 6 months: 8.3%

Acute area gain 2.08 ± 1.65 mm2

Outcome

Coronary Calcified Lesions

INTERVENTIONAL CARDIOLOGY REVIEW

Coronary Intravascular Lithotripsy System

Country Case report

Study

NA

NA

Study Design

1

1 Man

Woman

Sex

71

73

Age (Years)

100%

0%

NSTEMI/STEMI

De novo lesion Severe calcification

Lesion Type

None

Imaging

Table 1: Cont.

Reference Spain Case report

Sample

López-Lluva et al. 201947 Spain

Stent underexpansion Severe calcification

Follow-up

Case report NA

NA

1

1

1

No info

Woman

Woman

73

74

70

79

100%

100%

0%

100%

De novo lesion Severe calcification

De novo lesion Severe calcification

De novo lesion Severe calcification

De novo Severe calcification.

None

None

IVUS

OCT

IVUS/OCT

OCT

NA

NA

NA

NA

NA

NA

NA

Angiographic result: good No complications

Cardiac pacing secondary to IVL

Angiorgaphic and IVUS result: good No complications

Angiographic and OCT result: good No complications

Angiographic and OCT result: good No complications

Angiographic and OCT result: good Acute gain: 6.27 mm2 No complications

Complication: Balloon rupture and vessel dissection

Outcome

Poland Case report NA Woman

De novo lesion Severe calcification.

(Months)

Legutko et al.

201951 The Netherlands Case report 1

0%

Angiographic result: good No complications.

Size

Salazar et al.

201936

Vainer et al. 201946 Italy NA

74

NA

Sgueglia et al.

201919 Case report Man

None

New Zeland 1

CTO Severe calcification

Cicovic et al.

201941 NA

0%

Case report

62 and 71

Angiographic and IVUS result: good No complications

UK Man

NA

Warisawa et al.

201918 2

IVUS

NA

CTO Severe calcification

Case series

0%

Italy

81

Azzalini et al.

201926

Woman

1

Angiographic and OCT result: good No complications

NA

NA

Case report

OCT

UK

100%

Yeoh et al.

201927

71

Male

NA

1

None

NA

Stent underexpansion Severe calcification

Case report

No information

Spain

51.8%

Retrospective, single centre

54

NA

Stent underexpansion Severe calcification

UK

No capture: No capture: 66.7% 77.2 ± 6.7 Capture: 81% Capture: 71.6 ± 9.3

100%

Wilson et al.

201942

63

Urbano Carillo et al. 201934

IVL provoked ventricular capture in 77.8% of the cases Heart rate <65 bpm increases risk of ventricular pacing (OR 16.3; (95 CI% [2.4–110.8], p=0.004) Man

Angiographic and OCT result: good No complications

1

NA

NA

OCT

Case report

Angiographic result: good No complications

Spain

NA

Angiographic result: good No complications

Alfonso et al.

201935

None

NA

100%

None

61, 70 and 76

66.6%

100%

60, 64 and 96

NA

3

66.6% men

72 ± 8

None

NA

3

69% men

De novo lesions in left main coronary artery Severe calcification

Case series

NA

26

De novo lesions

New Zealand

Case series

NA

54%

Wong et al.

201921

New Zealand

New Zealand

Prospective, single centre, observational

Procedural and clinical success: 100% No complication

De novo lesions (66.6%) Stent underexpansion (33.3%) Severe calcification

Wong et al.

201925 Wong et al.

201917

ISR = in-stent restenosis; IVUS = intra-vascular ultrasound; IVL = intra-vascular lithotripsy; MACE= major adverse cardiac events; NA = not applicable; OCT = optical coherence tomography.

177

INTERVENTIONAL CARDIOLOGY REVIEW

Coronary Calcified Lesions Table 2: Intravascular Lithotripsy Balloon Sizes and Compliance for Coronary Intervention Pressure (atm)

Balloon size 2.5 × 12 mm

2.75 × 12 mm

3.0 × 12 mm

3.25 × 12 mm

3.5 × 12 mm

3.75 × 12 mm

4.0 × 12 mm

4 (IVL)

2.4

2.6

2.9

3.2

3.4

3.7

3.8

5

2.4

2.7

2.9

3.2

3.4

3.7

3.8

6 (NP)

2.5

2.7

2.9

3.2

3.4

3.7

3.9

7

2.5

2.7

3.0

3.3

3.5

3.8

3.9

8

2.5

2.7

3.0

3.3

3.5

3.8

4.0

9

2.5

2.8

3.1

3.3

3.5

3.9

4.1

10 (RBP)

2.5

2.8

3.1

3.4

3.6

3.9

4.1

atm = atmospheres; IVL = intravascular lithotripsy; NP = nominal pressure; RBP = rated burst pressure.

Figure 1: Shockwave Coronary Intravascular Lithoplasty System Generator

procedure is difficult and has a high risk of complications; where standard balloons fail, the Coronary IVL System might be useful in facilitating lumen dilatation and communication with the subintimal space.26,27

Stent Underexpansion due to Underlying Calcification

Push button Connector cable

Lithotripsy catheter (6 Fr compatible)

Of note, the effectiveness of those techniques is limited by the presence of metallic struts, and deeper calcifications therefore remain unaffected. The circumferential sonic waves of the Coronary IVL System, conversely, have the advantage of extending beyond strut layers and fracture deeper calcium deposits (Figure 4). Several case reports have supported the use of the technology for optimising stent expansion without complications.32–39

Source: Adapted with permission from Shockwave Medical.

Figure 2: Intravascular Lithoplasty Therapy

12 mm

Radiopaque markers

Lithotripsy emitters

Balloon fluid NaCl 0.9% (50%) + Radiopaque contrast (50%)

Rapidly expanding bubble

Source: Adapted with permission from Shockwave Medical.

The Coronary IVL System, with controlled pulses delivered under low pressure, might potentially improve plaque modification with a lower risk of vessel closure, perforation or embolisation.25

Chronic Total Occlusions Moderate to severe calcification is frequently found in chronic total occlusions, and debulking devices are usually avoided because the

178

Although the technique has been developed to treat calcified lesions in native coronary arteries before stenting, patients with severe stent underexpansion because of heavy calcification are at a higher risk of stent failure and future adverse events. Until now, undilatable lesions in previously stented segments have been courageously approached with debulking devices such as cutting balloons and atherectomy, with unpredictable results and risks of procedural complications and stent damage.28–31

Of note, the efficacy of the system in segments with multiple layers of stents has not been demonstrated and its impact on stent backbone/ polymer integrity and drug elution is still unknown. Nonetheless, at present, there are no alternative percutaneous options for patients left with underexpanded stents due to heavy calcification.

Effects on Cardiac Rhythm Electric signals similar to pacing spikes on the electrocardiogram (ECG) tracing during pulse-delivery have been described.17,40–42 These so-called ‘shocktopics’ and asynchronous cardiac pacing have been reported in up to 77.8% of the cases, with a 16-fold increased risk in patients with a heart rate <65 BPM. Cardiac pacing has not been linked to any specific number of IVL cycles or coronary artery anatomy, although its frequency is higher when either the left anterior descending artery or the right coronary artery are treated.42 The exact mechanism behind this phenomenon is still unclear.

A potential explanation might be that the transformed mechanical energy reaches and couples with the cardiac conduction system producing ectopic atrial and or ventricular captures. 43 Although no relevant clinical events have been reported, it warrants paying special attention to ECG and aortic pressure waveforms changes during IVL administration; the resulting VOO pacing mode is theoretically

INTERVENTIONAL CARDIOLOGY REVIEW

Coronary Intravascular Lithotripsy System Figure 3: Intravascular Lithoplasty Therapy: Effect on Heavy Calcified Coronary Lesions Pre-shockwave

Post-shockwave

Post-stenting

A

B

C

D

E

F

LA = 2.55 mm2

LA = 6.15 mm2

LA = 8.32 mm2

Angiography left anterior descending coronary artery: a: before intravascular lithotripsy (IVL); b: after IVL; c: after stenting. Red arrow shows severe calcification. Optical coherence tomography: d: before IVL; e: after IVL; f: after stenting. Asterisks show calcium deposits in the vessel wall. Arrows show calcium fractures. LA = lumen area.

pro-arrhythmic (potential R on T phenomenon) and, until further data become available, pacemaker carriers should be assessed for inappropriate device sensing during the IVL cycles and to ensure correct pacing function post-procedure. Further investigation in the matter will be provided by the substudies in the Disrupt CAD III trial.

Challenging Lesions Some lesions might respond better to IVL therapy than to other plaque modification approaches. Reports have pointed out the usefulness of the IVL therapy on creating calcium fractures as assessed with intravascular ultrasound, and achieving optimal stent expansion in undilatable lesions that have been resistant to specialty balloons and rotational atherectomy.44–46 In contrast, some lesions might not be suitable for IVL treatment or may remain resistant after the application of all 80 pulses. Severe tortuosity or angulation, critical lumen reduction, plaque indentation into the lumen and a very low vessel expansion compliance (small vessels and multiple stent layers present), could impact balloon deliverability and positioning.

Up to 46% of the lesions might also require dedicated lesion predilatation and/or post-dilatation with non-compliant balloons or could benefit from adjuvant lesion preparation with conventional devices such as specialty balloons or atherectomy to either facilitate balloon delivery or increase calcium compliance after lithotripsy therapy.17,45

INTERVENTIONAL CARDIOLOGY REVIEW

Figure 4: Intravascular Lithotripsy Therapy Effect on Stent Underexpansion due to Calcified Lesion Pre-shockwave (dog bone effect)

Post-shockwave (complete balloon expansion)

A

B

C

D

LA = 2.92 mm2

LA = 6.34 mm2

Fluoroscopy: A: before intravascular lithotripsy (IVL); B: after IVL. Red arrow shows ‘dog bone’ effect. Optical coherence tomography: C: before IVL d: after IVL. Asterisks show calcium deposits in the vessel wall. Arrows show calcium fractures. LA = lumen area.

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Coronary Calcified Lesions While balloon rupture is uncommon, it can cause vessel complications.

Case reports have described sudden IVL balloon burst during lithotripsy therapy with important vessel dissection; however, it is fair to highlight that either critical stenosis or severe vessel tortuosity were present, which suggests that, in some anatomies, the IVL system might not be suitable or should be used with caution.47,48 Furthermore, vessels with a diameter >4 mm (maximum shockwave balloon size) or important plaque eccentricity preclude appropriate IVL balloon apposition to the vessel wall, and may reduce the efficacy of the therapy. More data are needed on the specific efficacy of IVL in concentric versus eccentric lesions. In the Disrupt CAD study, 22% of the patients had eccentric plaques; nevertheless, overall device success was 98%.15

the need for further adjuvant therapy with conventional devices and potential complications.

Conclusion The Coronary IVL System is a promising new treatment modality to tackle moderate to severe calcified coronary lesions, with a high rate of success and a low risk of complications. Larger studies and longerterm clinical data are needed to confirm the safety and efficacy of this technique with special attention to the effects on cardiac conduction and vessel healing response. Randomised controlled clinical trials are required to evaluate its superiority against currently available calciummodifying devices.

Supplementary data Moreover, performing intracoronary imaging where important coronary calcification is suspected during the angiographic assessment could help to accurately assess calcium distribution, localisation and thickness. The use of intracoronary imaging before and after lithotripsy therapy could not only assist the appropriate selection of IVL balloon sizes but also potentially help to identify IVL responders and identify patients who might need adjuvant therapy from other plaquemodification devices .

Supplementary Video 1: Shockwave Coronary Intravascular Lithotripsy System. Reproduced with permission from Shockwave Medical.

Further clinical data are needed to assess the implications of patient, vessel and lesion characteristics on the effectiveness of this therapy,

Supplementary Video 4: Soft on Soft Tissue (In-vitro Demonstration).

Reproduced with permission from Shockwave Medical.

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enereux P, Redfors B, Witzenbichler B, et al. Two-year G outcomes after percutaneous coronary intervention of calcified lesions with drug-eluting stents. Int J Cardiol 2017;231:61–7. https://doi.org/10.1016/j.ijcard.2016.12.150; PMID: 28040289.

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3. Bourantas CV, Zhang YJ, Garg S, et al. Prognostic implications of coronary calcification in patients with obstructive coronary artery disease treated by percutaneous coronary intervention: a patient-level pooled analysis of 7 contemporary stent trials. Heart 2014;100:1158–64. https://doi. org/10.1136/heartjnl-2013-305180; PMID: 24846971.

4. Lee MS, Shah N. The impact and pathophysiologic consequences of coronary artery calcium deposition in percutaneous coronary interventions. J Invasive Cardiol 2016;28:160–7. PMID: 26301561.

5. Kobayashi Y, Okura H, Kume T, et al. Impact of target lesion coronary calcification on stent expansion. Circ J 2014;78:2209–14. https://doi.org/10.1253/circj.CJ-14-0108; PMID: 25017740.

6. Barbato E, Shlofmitz E, Milkas A, et al. State of the art: evolving concepts in the treatment of heavily calcified and undilatable coronary stenoses – from debulking to plaque modification, a 40-year-long journey. EuroIntervention 2017;13:696–705. https://doi.org/10.4244/EIJ-D-17-00473; PMID: 28844031.

7. Reifart N, Vandormael M, Krajcar M, et al. Randomized comparison of angioplasty of complex coronary lesions at a single center. Excimer Laser, Rotational Atherectomy, and Balloon Angioplasty Comparison (ERBAC) Study. Circulation 1997;96:91–8. https://doi.org/10.1161/01.CIR.96.1.91; PMID: 9236422.

8. de Waha S, Allali A, Buttner HJ, et al. Rotational atherectomy before paclitaxel-eluting stent implantation in complex calcified coronary lesions: two-year clinical outcome of the randomized ROTAXUS trial. Catheter Cardiovasc Interv 2016;87:691–700. https:// doi.org/10.1002/ccd.26290; PMID: 26525804.

9. Mauri L, Bonan R, Weiner BH, et al. Cutting balloon angioplasty for the prevention of restenosis: results of the Cutting Balloon Global Randomized Trial. Am J Cardiol 2002;90:1079–83. https://doi.org/10.1016/S00029149(02)02773-X. PMID: 12423707.

10. Serruys PW, Katagiri Y, Onuma Y. Shaking and breaking calcified plaque: lithoplasty, a breakthrough in interventional armamentarium? JACC Cardiovasc Imaging 2017;10:907–11. https://doi.org/10.1016/j.jcmg.2017.05.011; PMID: 28797413.

11. Brodmann M, Werner M, Brinton TJ, et al. Safety and performance of lithoplasty for treatment of calcified peripheral artery lesions. J Am Coll Cardiol 2017;70:908–10. https://doi.org/10.1016/j.jacc.2017.06.022; PMID: 28797363.

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Supplementary Video 2: IVL Mechanism of Action (In-vitro Demonstration). Reproduced with permission from Shockwave Medical.

Supplementary Video 3: Hard on Hard Tissue (In-vitro Demonstration).

Reproduced with permission from Shockwave Medical.

treated with the shockwave lithoplasty. Clin Med Insights Case Rep 2019;12:1179547619828707. https://doi. org/10.1177/1179547619828707; PMID: 30792580.

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Brodmann M, Werner M, Holden A, et al. Primary outcomes and mechanism of action of intravascular lithotripsy in calcified, femoropopliteal lesions: results of Disrupt PAD II. Catheter Cardiovasc Interv 2019;93:335–42. https://doi. org/10.1002/ccd.27943; PMID: 30474206.

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, Brinton TJ, Hill JM, et al. Optical coherence tomography characterization of coronary lithoplasty for treatment of calcified lesions: first description. JACC Cardiovasc Imaging 2017;10:897–906. https://doi.org/10.1016/j.jcmg.2017.05.012; PMID: 28797412.

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Sgueglia GA, Gioffre G, Piccioni F, Gaspardone A. Slender distal radial five French coronary shockwave lithotripsy.

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Lee MS, Shlofmitz E, Kaplan B, Shlofmitz R. Percutaneous coronary intervention in severely calcified unprotected left main coronary artery disease: initial experience with orbital atherectomy. J Invasive Cardiol 2016;28:147–50. https://doi. org/10.1016/j.jcin.2015.12.054; PMID: 27031936.

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Azzalini L, Bellini B, Montorfano M, Carlino M. Intravascular lithotripsy in chronic total occlusion percutaneous coronary intervention. EuroIntervention. 2019. https://doi.org/10.4244/EIJD-19-00175; PMID: 31012852; epub ahead of press.

Yeoh J, Hill J, Spratt JC. Intravascular lithotripsy assisted chronic total occlusion revascularization with reverse controlled antegrade retrograde tracking. Catheter Cardiovasc Interv 2019;93:1295–7. https://doi.org/10.1002/ccd.28165; PMID: 30838746.

Whiteside HL, Nagabandi A, Kapoor D. Safety and efficacy of stentablation with rotational atherectomy for the management of underexpanded and undilatable coronary stents. Cardiovasc Revasc Med 2019. https://doi.org/10.1016/j. carrev.2019.01.013; PMID: 30685339; epub ahead of press.

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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.

Morabito G, Tripolino C, Tassone EJ, et al. A case of stent under-expansion due to calcified plaque treated with shockwave lithoplasty. Cardiology 2018;141:75–7. https://doi. org/10.1159/000493747; PMID: 30408797.

Urbano Carrillo CA, Cano Garcia M, Munoz Jimenez LD. Coronary lithoplasty in the treatment of stent underexpansion. Rev Esp Cardiol (Engl Ed) 2019. https://doi. org/10.1016/j.rec.2019.04.009; PMID: 31160266; epub ahead of press.

Alfonso F, Bastante T, Antuna P, et al. Coronary lithoplasty for the treatment of undilatable calcified de novo and in-stent restenosis lesions. JACC Cardiovasc Interv 2019;12:497–9. https:// doi.org/10.1016/j.jcin.2018.12.025; PMID: 30772288.

Salazar C, Escaned J, Tirado G, Gonzalo N. Undilatable calcific coronary stenosis causing stent underexpansion and late stent thrombosis: a complex scenario successfully managed with intravascular lithotripsy. JACC Cardiovasc Interv 2019;12:1510–2. https://doi.org/10.1016/j.jcin.2019.02.010;

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39. Ali ZA, McEntegart M, Hill JM, Spratt JC. Intravascular lithotripsy for treatment of stent underexpansion secondary to severe coronary calcification. Eur Heart J 2018. https://doi.org/10.1093/ eurheartj/ehy747; PMID: 30462174; epub ahead of press.

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Venuti G, D’Agosta G, Tamburino C, La Manna A. Coronary lithotripsy for failed rotational atherectomy, cutting balloon, scoring balloon, and ultra-high-pressure non-compliant balloon. Catheter Cardiovasc Interv 2019;94:E111–5. https://doi. org/10.1002/ccd.28287; PMID: 31020765s.

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Coronary Calcified Lesions

Rotational Atherectomy: A Contemporary Appraisal Tanush Gupta, 1,2 Michael Weinreich, 1 Mark Greenberg, 1 Antonio Colombo 3 and Azeem Latib 1,4 1. Division of Cardiology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, US; 2. Department of Cardiology, Columbia University Medical Center, New York, NY, US; 3. GVM Care and Research, Maria Cecilia Hospital, Cotignola, Ravenna, Italy; 4. Division of Cardiology, Department of Medicine, University of Cape Town, Cape Town, South Africa

Abstract Rotational atherectomy (RA) is an atheroablative technology that enables percutaneous coronary intervention for complex, calcified coronary lesions. RA works on the principle of ‘differential cutting’ and preferentially ablates hard, inelastic, calcified plaque. The objective of RA use has evolved from plaque debulking to plaque modification to enable balloon angioplasty and optimal stent expansion. The clinical experience over the past 30 years has informed the current best practices for RA with use of smaller burr sizes, short ablation runs a ‘pecking’ motion, and avoidance of sudden decelerations. This has led to significant improvements in procedural safety and a reduced rate of associated complications. This article reviews the principles, clinical indications, contemporary evidence, technical considerations and complications associated with the use of RA.

Keywords Rotational atherectomy, plaque modification, calcified coronary disease Disclosure: AL serves on the Advisory Board of Medtronic and Abbott Vascular. All other authors have no conflicts of interest to declare.

Received: 22 June 2019 Accepted: 9 September 2019 Citation: Interventional Cardiology Review 2019;14(3):182–9. DOI: https://doi.org/10.15420/icr.2019.17.R1 Correspondence: Azeem Latib, Montefiore-Einstein Center for Heart and Vascular Care, 111 East 210th Street, Bronx, NY 10467, US. E: alatib@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Percutaneous coronary intervention (PCI) is the most commonly used revascularisation modality for obstructive coronary artery disease.1 Despite significant advances in PCI over the past 40 years, severe coronary calcification remains a challenge for successful PCI.2,3 Up to 20% of patients undergoing PCI are estimated to have moderate to severe coronary calcification.4,5 Heavily calcified lesions are difficult to dilate adequately with balloon angioplasty, even with high-pressure inflation.6 Angioplasty balloons are prone to asymmetric expansion and dogboning around the site of severe calcification, increasing the risk of coronary dissection and perforation.7,8 Calcified plaques impede delivery of angioplasty balloons and stents and increase the risk of stent underexpansion and malapposition.9,10 Vigorous advancement of drug-eluting stents (DES) across heavily calcified lesions also poses a risk of damage to the drug coating.

Moreover, there might be inadequate diffusion of the drug through extensive calcium arcs to the subintima limiting the effectiveness of the DES.11 Therefore, even in the contemporary era, moderate to severe lesion calcification is associated with a higher rate of major adverse cardiovascular events (MACE), target lesion revascularisation (TLR) and target vessel revascularisation at follow-up for patients with a DES.12,13 This is likely attributable to both lesion- and patient-specific factors, since significant coronary calcification is more prevalent with advanced age, renal insufficiency, diabetes and previous coronary bypass surgery (CABG), which are independent predictors of adverse ischaemic events.5,14

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The advent of intravascular imaging has provided insights into mechanisms of stent failure and highlighted the importance of optimal lesion preparation prior to stent implantation.15 The interventional devices to modify calcified lesions before balloon angioplasty and stenting can broadly be divided into non-atherectomy and atherectomy strategies.

Non-atherectomy devices, also known as modified balloons (MB; scoring, cutting, or semi-compliant constrained balloons) treat calcified plaques by cutting or targeted dissection. The atherectomy devices are aimed at physical removal of plaque material and include rotational atherectomy (RA), orbital atherectomy and excimer laser coronary angioplasty.5 Table 1 provides a brief comparison of the three atherectomy modalities.

Although there have been no head-to-head randomised comparisons of RA versus orbital atherectomy, observational data suggest equivalence for the two approaches.16,17 Intravascular lithotripsy modifies plaque by causing calcium fracture and is an additional approach currently under investigation in clinical studies.18 The commercially available Rotablator (Boston Scientific) was first introduced by David Auth and colleagues in 1988.19 After initial adoption, the enthusiasm for RA was tempered after reports of high restenosis rates in the pre-DES era.6,20,21 However, with an ageing population and increase in complexity of the patient population being referred for catheterisation for PCI, there has been a resurgence of interest in RA with increased focus on optimal technique.14 The contemporary use of RA in PCI in Europe and the US varies from 1 to 3% of all PCIs performed.22 In this article, we discuss the principles, technical considerations, indications, clinical evidence and complications of the use of RA in modern PCI.

© RADCLIFFE CARDIOLOGY 2019

Rotational Atherectomy Table 1: Comparison of Atherectomy Devices Rotational Atherectomy

Orbital Atherectomy

Laser Atherectomy

Rotational

Orbital

Laser

Diamond-tipped burr spins concentrically on the wire

Eccentrically mounted diamond-coated crown uses centrifugal force to orbit

Multifibre laser catheters transmit ultraviolet energy

Atheroablation via sanding/abrasion

Atheroablation via sanding/abrasion

Photoablation (vapourisation)

To facilitate stent delivery in patients with coronary artery disease who are acceptable candidates for PTCA or stenting owing to de novo, severely calcified coronary artery lesions

A standalone modality or in conjunction with PTCA in patients who are acceptable candidates for coronary artery bypass graft surgery

Mechanism of Action

Clinical Indication A sole therapy or used with adjunctive balloon, angioplasty is indicated in patients with coronary artery disease who are acceptable candidates for coronary artery bypass graft surgery

Moderately calcified lesions In-stent restenosis Technical Features Front-cutting, monodirectional burr

Diamond coated crown, bidirectional treatment

Over the wire and rapid exchange catheters

Multiple burr sizes (8), 1.25–2.5 mm

1.25 mm classic crown orbits to treat larger diameter

Available with concentric and eccentric tip designs

0.009"/0.014" tip RotaWire guidewires

0.012"/0.014" tip ViperWire

0.014" standard coronary guidewire

Power source: pneumatic system, requires console, foot pedal and compressed gas supply; nitrogen tank or room air

Power source: electronic system able to be placed on the operating field connects to a specialised saline pump

Power source: Spectranetics CVX-300 requires console and foot pedal

Speed: 140,000–190,000 rpm during treatment

Speed: 80,000 and 120,000 rpm

Adjustable laser energy settings

PTCA = percutaneous transluminal coronary angioplasty. Source: Chambers et al. 2016.84 Reproduced with permission from Elsevier.

Principles RA ablates calcified plaque using a diamond-encrusted elliptical burr, rotated at speeds of 140,000 to 180,000 rpm by a helical driveshaft, that is advanced across the lesion over a guidewire (Figure 1). The burr causes ‘differential cutting’ and preferentially ablates hard, inelastic, calcified plaque that is unable to stretch away from the RA burr compared with healthy arterial tissue (Figure 2).5 In contrast with balloon angioplasty, which produces intimal and medial dissections in calcified lesions, RA leads to lesser tissue injury and yields relatively smoother luminal surfaces and cylindrical geometry (Figure 3).23–25 The emphasis of the use of RA has shifted over the years from plaque debulking to plaque modification to facilitate balloon angioplasty and stent expansion. The transition in the approach has been driven by the results of the Study to Determine Rotablator and Transluminal Angioplasty Strategy (STRATAS) and Coronary Angioplasty and Rotablator Atherectomy Trial (CARAT) clinical trials. These trials showed that an aggressive strategy with large burrs (burr/artery ratio >0.7) to achieve maximum debulking as a lesion debulking strategy was associated with higher rates of angiographic complications, TLR and peri-procedural creatine kinase-myocardial band (CK-MB) release compared with use of smaller burrs (burr/artery ratio ≤0.7) to modify lesion compliance with a lesion modification strategy without any clinical advantages in terms of procedural success or gain in luminal diameter.26,27 This change in approach has allowed the use of smaller burrs, guide catheters and sheaths without compromising clinical efficacy.

Indications and Clinical Outcomes Indications The principal indication for RA is modification of severely calcified de novo coronary stenoses which are unlikely to expand adequately with balloon angioplasty to allow for complete stent expansion.

INTERVENTIONAL CARDIOLOGY REVIEW

The detection of severe coronary calcification traditionally relied on fluoroscopy but it has been demonstrated that fluoroscopy is less sensitive in calcium detection compared with intravascular imaging.28 Severe coronary calcification on fluoroscopy has been described as radio-opacities noted without cardiac motion before contrast injection involving both sides of the arterial wall.29 With intravascular ultrasound, severe calcification, indicated by bright echodensity causing attenuation of deeper structures, is defined as a large arc of superficial calcium involving ≥3 quadrants.28 On optical coherence tomography (OCT), areas of coronary calcification appear well demarcated and signal-poor. OCT measures of coronary calcification predictive of stent underexpansion include: length >5 mm; arc >180°; and maximum thickness >0.5 mm.30–32 RA can be used as a primary strategy in the presence of severe calcification or as a secondary approach after failure to dilate a lesion with coronary angioplasty. Although long-term outcomes are similar with planned versus bailout RA, planned RA is associated with lower procedure and fluoroscopy time, lower contrast volume and fewer in-hospital MACE.33 Therefore, if there is a strong preprocedural likelihood of the use of RA in severely calcified lesions, operators should have a low threshold for adopting a planned RA strategy. In addition, although rarely an issue, there is concern about performing RA in a lesion that has undergone aggressive balloon angioplasty because of possible unrecognised intimal dissection.

Specific Lesion Subsets There are certain lesion-specific considerations when using RA. RA provides an effective treatment option in patients with calcified unprotected left main (ULM) disease who are not eligible for CABG. In a report of 40 patients undergoing ULM RA, there was one procedural death and 12 deaths at 2-year follow-up.34 In the ROTATE registry, although there were no differences in rates of in-hospital MACE

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Coronary Calcified Lesions between ULM (n=86) compared with non-ULM (n=962) RA (5.8% versus 8.0%; p=0.47), 1-year MACE was higher in the ULM group (26.4% versus 14.9%; p=0.002), largely driven by target vessel revascularisation (20.3% vs 12.7%; p=0.05). Even definite/probable stent thrombosis (ST) was higher in the ULM group (3.9% versus 0.8%; p=0.03).35 Therefore, although feasible, RA of ULM is associated with worse outcomes, likely due to the large territory of jeopardised myocardium, and a meticulous technique should be adopted.

RA is an excellent adjunct in treatment of protected LM disease in patients with previous CABG due to the high prevalence of fibrocalcific disease in this patient population.14 In patients with calcified bifurcation lesions, RA can be useful as plaques at bifurcations can be prone to plaque shift, acute side branch closure and difficult stent delivery.36 In bifurcation lesions with calcification confined to the main branch, RA of the main vessel alone is sufficient. In lesions with severely calcified, undilatable or balloon-uncrossable plaque in side branches >2.5 mm diameter, RA of the side branch should be considered.37 Care must be taken to ensure that only the RotaWire is present in the target vessel to avoid inadvertent cutting of other wires by the RA burr.

If RA of both the main branch and side branch is necessary, a novel technique has been described where after atherectomy of the main branch, the side branch is wired in a standard fashion and a guide extension advanced to the ostium of the side branch to protect the guidewire in the main branch interacting with the RA burr. The rotablator burr can then be advanced through the guide extension catheter to perform RA of the side-branch lesion. This technique does require use of larger guide catheters in order to use larger guide extensions compatible with the desired rotablator burr size.38 In chronic total occlusions, where balloons cannot be delivered after successful guidewire crossing, RA can be used for lesion modification after exchanging the crossing wire for a RotaWire over dedicated microcatheters.14 In chronic total occlusions, cases have also been described where the radiopaque portion of the RotaWire is advanced into the subintimal space or proximal cap and RA used for careful ablation of the refractory proximal cap. This technique is not routinely recommended due to the increased risk of coronary perforation.22 RA is not recommended for routine use in degenerated saphenous vein graft lesions or thrombus, although successful use in nondilatable, calcified vein grafts lesions has been described.39 Other relative contraindications to RA include lack of onsite bypass surgery, severe three-vessel or unprotected left main disease, severe left ventricular dysfunction, lesion angulation >45° and lesion length >25 mm, although successful RA use has been reported with all these conditions.34,35,40 RA has also been successfully applied in ablation of suboptimally expanded stents. In a study of 16 patients treated with RA for severe in-stent restenosis (ISR) due to stent underexpansion resistant to balloon angioplasty, Ferri et al.41 reported an increase in minimal lumen diameter by 2.3 ± 0.8 mm and a decrease in diameter stenosis from 82.17 ± 17.2% to 11.9 ± 9.1%. There was one case of burr entrapment that was managed percutaneously. There is lack of consensus on adjunctive treatment after RA for undilatable severe ISR. In a retrospective analysis of 200 patients undergoing RA for ISR, 12-month TLR rates were lower for drug-coated balloon angioplasty (27.3%) compared with conventional balloon angioplasty (40.7%) or DES implantation (35.0%), suggesting that for severe ISR requiring a debulking strategy, drug-coated balloon angioplasty following RA might be the most effective treatment option.42 Other reports have

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Figure 1: Rotablator System Driveshaft sheath Driveshaft connector CPC connector latch Catheter and burr wireClip® torquer docking port

Thumb rest

Guidewire More stable advancer body

Source: Barbato et al. 2017.3 Reproduced with permission from Europa Digital & Publishing.

Figure 2: Mechanism of Rotational Atherectomy

Direction of motion Elastic tissue deflects Diamond crystal

Direction of motion

Diamond crystal

Forceful mechanical breakdown of matter

Elastic tissue space

Inelastic tissue space

Elastic tissue is able to deflect out of the way

Inelastic tissue is unable to deflect out of the way

Source: Barbato et al. 2017.3 Reproduced with permission from Europa Digital & Publishing.

also reported favourable results with drug-coated balloon angioplasty following RA for severe ISR.43 Nonetheless, stent ablation with RA should be used with extreme caution by highly experienced operators, ideally with on-site surgical backup.22,41

Clinical Evidence In the balloon angioplasty era, studies showed rates of restenosis with RA of approximately 40%, which is similar to using balloon angioplasty alone.20,21 During the bare-metal stent era, although RA use in calcified lesions before stenting was associated with higher procedural success with a trend towards lower restenosis rates, the absolute restenosis rates ranged between 20% and 30%.6 With the advent of DES, neointimal proliferation was significantly inhibited and the rates of restenosis and TLR were reduced in general.44,45 Several studies have reported favourable intermediate and long-term outcomes with adjunctive RA before DES implantation with TLR rates of <10% at 1- to 2-year follow-up.46–51 It is, however, unclear whether adjunctive RA in calcified lesions before DES implantation results in improved outcomes. Observational data have shown conflicting evidence and are limited by selection bias as patients undergoing RA have worse clinical and lesion-specific prognostic factors and the patients who truly benefit from RA, such as those with uncrossable lesions, are correctly not enrolled in these studies.51,52 The Rotational Atherectomy Prior to Taxus Stent Treatment for Complex Native Coronary Artery Disease (ROTAXUS) trial randomised 240 patients with complex calcified coronary disease in a 1:1 ratio to RA versus conventional balloon angioplasty prior to DES implantation. There was

INTERVENTIONAL CARDIOLOGY REVIEW

Rotational Atherectomy Figure 3: Optical Coherence Tomography Findings Before and After Rotational Atherectomy

PRE

POST

has also been reported for stronger back-up support where the operators placed a supportive guidewire (Grand Slam, ASAHI INTECC) in the left anterior descending artery next to the rotablator drive shaft sheath while performing RA in a highly tortuous obtuse marginal artery. Important precautions when using the side-branch buddy-wire technique include positioning the RA burr proximal to the target lesion before wiring the side branch and activating the RA burr only distal to the side branch.55

Wiring

Optical coherence tomography performed before rotational atherectomy in a calcified de novo lesion (left). Following rotational atherectomy (right), optical coherence tomography shows disruption of the arc of calcification, modest luminal enlargement, and a relatively smooth luminal border. Source: Tomey et al. 2014.5 Reproduced with permission from Elsevier © The American College of Cardiology Foundation.

a higher strategy success in the RA group (92.5% versus 83.3%) and a higher crossover in the standard therapy group. Despite an initially higher acute lumen gain (1.56 ± 0.43 versus 1.44 ± 0.49 mm, p=0.01) with RA, in-stent late lumen loss was higher in the RA group (0.4 ± 40.58 versus 0.31 ± 0.52; p=0.04). In-stent binary restenosis, TLR, definite ST and MACE rates were similar in the two groups. The limitations of the ROTAXUS trial included missing angiographic follow-up in approximately 20% of the patients and inclusion of >50% patients with moderate coronary calcification. However, based on the ROTAXUS results, RA use for lesion preparation for calcified coronary lesions could not be routinely recommended.11 The contemporary Comparison of Strategies to PREPARE Severely CALCified Coronary Lesions (PREPARE-CALC) trial randomised 200 patients with severe calcified coronary lesions to RA versus MB (cutting or scoring balloons) angioplasty prior to implantation of third generation sirolimus eluting Orsiro (Biotronik AG) stents. Similar to ROTAXUS, strategy success was more common in the RA group (98% versus 81%). At 9 months, in-stent late lumen loss was not different between RA versus MB groups (0.22 ± 0.40 mm versus 0.16 ± 0.39 mm; p=0.21). TLR, definite/probable ST, and TVF rates were much lower than previously reported and not different between the two groups. The take home conclusions were that in modern PCI, upfront RA prior to contemporary DES in severe calcified coronary lesions was feasible and associated with greater strategy success without increases in late in-stent late lumen loss.53

The RotaWire (Boston Scientific) is available in two versions, the standard Floppy or Extra Support. Both wires are 325 cm long, permitting overthe-wire exchanges and are 0.009 inches in diameter, tapering to 0.005 inches before terminating in a 0.014 inch spring tip. The distal spring tip prevents the burr from travelling beyond the tip of the wire.14 The Floppy wire is more flexible, with a longer taper (over 13 cm) and shorter 2.2 cm spring tip, causes less vessel straightening and wire bias and permits atherectomy at greater curvature of angulated lesions. The Extra Support has a shorter taper (over 5 cm) and longer spring tip (2.8 cm) compared with the floppy wire. It causes more vessel straightening and wire bias and is useful in ablation of plaque at lesser curvature of angulated lesions, aorto-ostial lesions and distal lesions. This wire is rarely used in routine clinical practice.5 Although lesions can be primarily wired with the RA wire, most experts recommend wiring with a suitable coronary guidewire and then exchanging for the RA wire over a microcatheter or over-the-wire balloon. To avoid wire fracture or burr lodging, particular care should be given to positioning the radiopaque tip of the RA wire as distal as possible from the target coronary segment. Also, it is important to loop the tip of the RA wire smoothly to prevent loops or positioning in small distal branches to avoid wire perforations and wire fracture.22

Burr Sizing, Motion and Ablation Speed

Vascular Access

As mentioned above, the smaller burrs with burr:artery ratio <0.7 result in similar angiographic and procedural success compared with larger burrs with fewer angiographic complications, lower CK-MB release, and smaller sheath and guide catheters.26,27 A single 1.5 mm burr suffices for most vessels <3 mm in diameter and a 1.75 mm burr for vessels >3 mm in diameter. Larger burrs may be required for aorto-ostial lesions or larger vessels in which smaller sized burrs would not make physical contact with the plaque. In the presence of extreme tortuosity or angulation, long segments of severe diffuse disease, or inability to pass microcatheter across the lesion, a step-up approach with the careful use of a 1.25 mm burr with subsequent upsizing or more supportive/ larger guide catheters might be required. Smaller burr sizes might also be needed in case of excessive decelerations of larger sized burrs.14,22

Considerations for vascular access should weigh the risk of bleeding and vascular complications with adequate support for performance of RA. A standard 6 Fr guiding system is sufficient for performance of RA with burr sizes up to 1.75 mm. For burr sizes ≥2.0 mm, a 7 Fr or larger system is required. Therefore, most cases requiring RA can be performed with transradial access, which is a proven strategy to mitigate bleeding complications.54 Even for larger burr sizes, transradial access is possible with use of either sheathless guiding catheters or 7 Fr slender sheaths with a 6 Fr outer diameter.14 Although the choice of guide catheters depends on the vessel anatomy and the expected need for back-up support, single curve catheters such as EBU or XB might be associated with less resistance to burr advancement to the catheter tip.22 Using larger guide catheters, deep intubation of guiding catheters, and a guide extension catheter are methods to improve back-up support during RA. A novel ‘buddy-wire’ technique

A pecking motion of the RA burr – a quick-push forward/pull-back movement – is the most widely recommended motion pattern. The following predictors of procedural complications have been described: deceleration during rotablation >5,000 rpm; motion pattern of the burr; speed of rotablation; duration of individual runs.56 The pecking motion minimises the decelerations of the RA burr and shortens the duration of individual runs (recommended <30 seconds). A recent Japanese study of 300 lesions treated with RA reported that 97 had moderate (5,000– 10,000 rpm) and 21 had severe (>10,000 rpm) speed reduction. An ostial RCA lesion and total ablation time were found to be independent predictors of moderate speed reduction and an ostial RCA lesion, use of intra-aortic balloon pump, and higher systolic blood pressure before RA were predictors of a severe speed reduction.57 The ideal rotablation speed is recommended to be about 140,000 to 180,000 rpm with lower

Technical Considerations

INTERVENTIONAL CARDIOLOGY REVIEW

185

Coronary Calcified Lesions speeds being associated with burr entrapment and higher speeds linked to greater platelet activation. A recent study of 100 patients with calcified coronary artery disease randomised 1:1 to low-speed (140,000 rpm) or high-speed (190,000 rpm) RA showed no difference in incidence of slow flow (24% in both groups) or periprocedural MI (6% in both groups), suggesting that high-speed RA can be used safely with an appropriate technique when needed.58 Visual, tactile and auditory feedback provide signals of resistance to burr advancement.

Once the lesion has been fully crossed, a final polishing run should be done, which should be able to be performed without resistance.14,22 Box 1 lists the key elements in optimal techniques of RA.

Box 1: Fundamental Elements of Optimal Rotational Atherectomy Technique

Pharmacology

lesion and patient, more RA in left main) resulting in higher incidence of periprocedural MI but lower rates of repeat revascularisation at 90 days.66 If transient hypotension is encountered periprocedurally during RA, IV infusion of inotropic agents such as dopamine (5–10 µg/ kg/min IV) or dobutamine (2–20 µg/kg/min IV) can be considered.14

Patients undergoing RA should receive antiplatelet and antithrombotic agents similar to standard PCI protocols. Glycoprotein IIb/IIIa that were previously shown to reduced periprocedural CK-MB release and slowflow phenomenon, are no longer recommended routinely but can be considered on a case-by-case basis.22,59

Single burr with burr-to-artery ratio of 0.5:0.6 Rotational speed of 140,000–180,000 rpm Gradual burr advancement using a pecking motion Short ablation runs of 15–20 sec Avoidance of decelerations >5,000 rpm Final polishing run Source: Tomey et al. 2014.5 Adapted with permission from Elsevier © The American College of Cardiology Foundation.

Procedure Completion and Stent Implantation Flush Cocktail The side port of the rotablator advancer is connected to a pressurised flush solution that serves to lubricate device motion, mitigate heat generation and prevent sudden decelerations and flows continuously through the sheath. The traditional flush solution includes heparinised saline, vasodilators and Rotaglide lubricant, a proprietary solution containing egg whites and olive oil.22 In patients with egg allergy, elimination of the lubricant has been described with similar procedural success.60 Vasodilators have been traditionally included in the flush solution to reduce the risk of microvascular obstruction but are associated with side-effects such as bradycardia and hypotension.

The drugs that have been studied include nitroglycerin, verapamil, nicardipine, adenosine, and nicorandil.61–63 There have been recent reports of effective RA eliminating the use of vasodilators while maintaining low rates of slow-flow/no-reflow.64 A recent consensus statement on RA recommends a flush solution comprised of heparinised saline and Rotaglide, reserving vasodilators for provisional use.14

Temporary Pacing Traditionally, the use of temporary pacing during rotablation of the right coronary artery (RCA) or dominant left circumflex artery was considered routine due to concerns for transient conduction blocks with microvascular embolisation. However, with improved technique and provisional use of vasodilators such as adenosine and calcium channel blockers, most operators consider the risks with temporary pacemaker placement to outweigh the purported benefits and favour initial management with atropine (administered 0.4–1.0 mg IV every 3–5 minutes as needed) and vagolytic manoevres.14,22 IV aminophylline use (250–300 mg over 10 minutes) during RA of RCA to prevent bradyarrhythmias has also been described in small case series.65

Mechanical Circulatory Support Use of RA is not by itself an indication for use of mechanical circulatory support. However, when used for haemodynamic indications, mechanical circulatory support can permit more extensive rotablation and more complete revascularisation. In the Prospective, Multi-center, Randomized Controlled Trial of the IMPELLA RECOVER LP 2.5 System Versus Intra Aortic Balloon Pump (IABP) In Patients Undergoing Non Emergent High Risk PCI (PROTECT II) trial, RA was used in 32 patients in the Impella group versus 20 patients in the IABP group. RA was used more aggressively with Impella (longer duration, more passes per

186

RA should be stopped when sufficient plaque modification allows optimal balloon dilation and stent implantation. At the conclusion of RA, the burr should be removed by activating the Dynaglide mode and pressing the brake defeat button. The device is then manually withdrawn while stepping on the foot pedal at low rotational speed while an assistant advances the RotaWire with an aim to maintain the wire position. Cineangiography should be done to exclude angiographic complications and the RotaWire should then be exchanged for a standard guidewire. Balloon angioplasty with an adequately sized non-compliant balloon should then be performed.

A recent OCT-based study compared the effects of calcium modification and stent extension between cutting balloon (n=18) versus conventional balloon (n=23) angioplasty following RA. Final post-stent OCT showed that the number and thickness of calcium fracture were greater after cutting versus conventional balloon, resulting in better stent expansion (78.9% versus 66.7%; p<0.01).

Cutting balloon use was an independent predictor of the presence of calcium fracture and greater stent expansion, suggesting that this might be a superior lesion preparation strategy following RA prior to stent implantation.67 The presence of residual dogboning of angioplasty balloon at low-pressure inflation indicates inadequate plaque modification and merits consideration for a larger sized burr.

Contemporary DES are the standard treatment of choice following RA.14,22 Analysis of the multicentre ROTATE registry showed DES used to be associated with 68% reduction in follow-up MACE after RA.68

New Iteration In 2018, Boston Scientific launched a new generation of the Rotablator system, called the ROTAPRO, aimed at simplifying the use of RA technology.69 The foot pedal has been eliminated and replaced with a button on the top of the burr control knob, similar to the current orbital atherectomy device. The Dynaglide pedal has also been replaced by a button on the side of the advancer. The assembly is easier, more streamlined, with a new digitised display with deceleration indicators on the control console.

Complications of Rotational Atherectomy Table 2 summarises the most common complications of RA and management strategies and Table 3 reports the reported complications rates of RA in the DES era.

INTERVENTIONAL CARDIOLOGY REVIEW

Rotational Atherectomy Table 2: Strategies to Prevent and Manage Complications of Rotational Atherectomy Avoidance

Management

Slow flow

• • • •

Small burrs and low speeds Intermittent runs Optimal antitplatelet and antithrombotic regimen Continuous flush solution

• •

Optimise BP if low (hydration/vasopressors/IABP if needed) Use of intracoronary vasodilators, i.e. nitrates/verapamil/adenosine/ nitroprusside

Dissection

•

Careful case selection to avoid excessive tortuosity

• •

Avoid further RA if dissection identified Maintain wire position and perform angioplasty/stenting as for any PCI

Perforation

•

ommonly related to poor technique (oversizing of burr, • C excessive angulation, high speeds)

tandard technique for treatment of coronary perforation including S cessation of anticoagulation, balloon tamponade, coil embolisation, and covered stents Emergent pericardiocentesis if tamponade

• Burr entrapment

• •

Rare with optimal technique More common with 1.25 mm burr

• • • • •

ulling the RotaWire using its 0.014 inch spring tip combined with P push and pull on the drive shaft Position second wire to allow balloon placement proximal to entrapped burr Deep intubation of guiding catheter or cutting the burr drive shaft with insertion of a mother-in-child catheter Subintimal tracking and reentry with balloon dilatation adjacent to the trapped burr CT surgery consultation if failure of percutaneous retrieval

IABP = intra-aortic balloon pump, PCI = percutaneous coronary intervention, RA = rotational artherectomy. Source: Barbato et al. 2015.22 Reproduced with permission from Europa Digital & Publishing.

Table 3: Complications of Rotational Atherectomy in the Drug-eluting Stent Era Study

n

Death (%)

MI (%)

Dissection (%)

Perforation (%)

Slow Flow/No Reflow (%)

PREPARE-CALC, 2018

53

100

0.0

2.0

3.0

4.0

2.0

Kawamoto et al, 2016

68

1176

0.6

7.4

7.0

1.0

1.1

Sakakura et al, 201683

13,335

0.6

–

–

–

–

Eftychiou et al, 201682

518

0.6

–

–

1.4

0.6

ROTAXUS, 2013

120

1.7

1.7

3.3

1.7

0.0

Abdel-Wahab et al, 201346

205

1.5

2.4

4.4

0.5

2.0

Naito et al, 2012

11

233

0.0

1.3

1.7

0.4

–

Benezet et al, 201147

102

1.0

1.0

2.9

0.0

–

Garcia de Lara et al, 201073

50

4.0

14.0

2.0

2.0

0.0

Rathore et al, 2010

74

391

1.0

6.9

5.9

2.0

2.6

Vaquerizo et al, 201049

63

0.0

3.2

–

–

–

Furuichi et al, 200950

95

0.0

3.2

2.1

1.1

1.1

Clavijo et al, 2006

81

0.0

19.8

1.9

–

–

48

51

Source: Tomey et al. 2014.5 Adapted with permission from Elsevier © The American College of Cardiology Foundation.

Slow Flow/No Reflow Slow-flow/no-reflow results from microvascular embolisation of atherosclerotic debris and thrombi, platelet activation and vasoactive mediators and it is associated with periprocedural MI.70 It has been hypothesised that microcavitations created by the rotating RA burr across the lesion also contribute to slow flow/no reflow. This transient microcavitation phenomenon has been demonstrated in vivo by enhanced myocardial echo contrast effect and directly correlates with rotablation speed, burr size and duration.71,72 The incidence of this complication is up to about 2.5% in contemporary reports.11,46–51,68,73 Technical factors contributing to this complication include use of larger burrs, longer runs and sudden decelerations.22 Optimal technique, use of continuous flush solution, and antithrombotic therapy are preventive strategies. The cornerstone of treatment is administration of intracoronary vasodilators, ideally distally via a microcatheter. It is

INTERVENTIONAL CARDIOLOGY REVIEW

also critical to maintain adequate coronary perfusion pressure with hydration, vasopressors or IABP if needed.14

Dissection and Perforation The incidence of coronary dissection with RA varies from 1.7% to 5.9% in the DES era.5,47,74 Once a severe dissection is identified, RA should be stopped, and focus should be on maintaining wire position in true lumen and completion of PCI with balloon angioplasty and stenting. If the antegrade flow is preserved, the procedure could be stopped, and the procedure reattempted in 3–4 weeks after the dissection heals.22 Coronary perforation due to rotablation is rare with reported incidence of up to 2% and it is usually related to poor technique with oversizing or forceful advancement of burr. It must, however, be noted that coronary perforation rates with PCI with RA are higher than PCI

187

Coronary Calcified Lesions without RA (approximately 0.4%).75 In fact, a report from the British Cardiovascular Intervention Society (BCIS) database identified RA to be an independent predictor of coronary perforation (adjusted OR 2.25 [1.29–3.93]) during PCI of native vessels in patients with prior CABG.76 Lesion-specific predictors of perforation during RA include extreme tortuosity, angulation, long lesion length and location in RCA or left circumflex artery.77 Wire bias related to vessel angulation or tortuosity contributes to both dissection and perforation and can be attenuated by using the more floppy RA wire. Treatment strategies include cessation of anticoagulation, balloon tamponade, coil embolisation and covered stents. Emergent pericardiocentesis might also be required in the presence of pericardial tamponade.14

Burr Entrapment Burr lodging within a lesion is a serious complication of RA that might require surgical intervention.78 Once stalled within a lesion, retrograde ablation is not possible because of the presence of diamond chips on the front but not the rear of the RA burr. This complication is more common with the 1.25 mm burr due to its fusiform shape which can result in sudden forward movement if the tension in the system was not removed before starting RA. Careful, conservative technique with small burr sizes, short duration of runs, short segment ablation and the pecking motion are crucial in preventing burr entrapment.

Percutaneous salvage options include: pulling the RA wire using its 0.014 inch spring tip combined with push and pull on the drive shaft; balloon dilation proximal to the entrapped burr via same or different guide catheter from a different access site; deep intubation of guiding catheter or cutting the burr drive shaft with insertion of a mother-in-child catheter; and subintimal tracking and re-entry with

1.

2.

3.

4.

5.

6.

7.

8.

9.

enereux P, Madhavan MV, Mintz GS, et al. Ischemic G outcomes after coronary intervention of calcified vessels in acute coronary syndromes. Pooled analysis from the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) and ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) TRIALS. J Am Coll Cardiol 2014;63:1845–54. https://doi.org/10.1016/j.jacc.2014.01.034; PMID: 24561145.

Bourantas CV, Zhang YJ, Garg S, et al. Prognostic implications of coronary calcification in patients with obstructive coronary artery disease treated by percutaneous coronary intervention: a patient-level pooled analysis of 7 contemporary stent trials. Heart 2014;100:1158–64. https://doi. org/10.1136/heartjnl-2013-305180; PMID: 24846971.

Barbato E, Shlofmitz E, Milkas A, et al. State of the art: evolving concepts in the treatment of heavily calcified and undilatable coronary stenoses – from debulking to plaque modification, a 40-year-long journey. EuroIntervention 2017;13:696–705. https://doi.org/10.4244/EIJ-D-17-00473; PMID: 28844031.

Lee MS, Yang T, Lasala J, et al. Impact of coronary artery calcification in percutaneous coronary intervention with paclitaxel-eluting stents: two-year clinical outcomes of paclitaxel-eluting stents in patients from the ARRIVE program.

Catheter Cardiovasc Interv 2016;88:891–7. https://doi.org/10.1002/ ccd.26395; PMID: 26756859.

Tomey MI, Kini AS, Sharma SK. Current status of rotational atherectomy. JACC Cardiovasc Interv 2014;7:345–53. https://doi. org/10.1016/j.jcin.2013.12.196; PMID: 24630879.

Moussa I, Di Mario C, Moses J, et al. Coronary stenting after rotational atherectomy in calcified and complex lesions.

Angiographic and clinical follow-up results. Circulation 1997;96:128–36. https://doi.org/10.1161/01.CIR.96.1.128; PMID: 9236427.

Shimony A, Zahger D, Van Straten M, et al. Incidence, risk factors, management and outcomes of coronary artery perforation during percutaneous coronary intervention.

Am J Cardiol 2009;104:1674–7. https://doi.org/10.1016/j. amjcard.2009.07.048; PMID: 19962473.

Fitzgerald PJ, Ports TA, Yock PG. Contribution of localized calcium deposits to dissection after angioplasty. An observational study using intravascular ultrasound. Circulation 1992;86:64–70. https://doi.org/10.1161/01.CIR.86.1.64; PMID: 1617791.

Takebayashi H, Kobayashi Y, Mintz GS, et al. Intravascular ultrasound assessment of lesions with target vessel failure after sirolimus-eluting stent implantation. Am J Cardiol 2005;95:498–502. https://doi.org/10.1016/j.

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balloon dilatation adjacent to the trapped burr.14,79–81 If retrieval is unsuccessful with the above catheter-based techniques, a cardiac surgery consultation will be necessary.

Clinical Predictors of Rotational Atherectomy Complications Optimal RA techniques, as described above, are key to prevent periprocedural complications. A multicentre UK study identified peripheral vascular disease, diabetes, presentation with acute coronary syndromes and higher SYNTAX score to be predictors of major adverse cardiovascular events following RA.82 Similarly, a report from the Japanese PCI (J-PCI) registry of 13,335 RA cases identified older age, impaired kidney function, previous MI, emergent PCI, triple-vessel disease and lower institutional RA volume as independent predictors of worse periprocedural outcomes after RA.83

Conclusion With increasing complexity of the patient population presenting for PCI and improved recognition of severe coronary calcification with the use of intravascular imaging, there is renewed interest in the use of atheroablative strategies for optimal lesion preparation before stent deployment. The accumulated experience in the use of RA over the last several decades has informed the current best practices in optimal technique that minimise associated complications without compromising efficacy. Despite lack of definitive evidence showing superior clinical outcomes in the contemporary DES era, randomised data have shown that RA is associated with greater procedural success in treatment of severely calcified lesions. Therefore, RA remains an integral tool for modern-day complex PCI.

amjcard.2004.10.020; PMID:15695138.

10. V irmani R, Farb A, Burke AP. Coronary angioplasty from the perspective of atherosclerotic plaque: morphologic predictors of immediate success and restenosis. Am Heart J 1994;127:163–79. https://doi.org/10.1016/00028703(94)90522-3; PMID: 8273736.

11. Abdel-Wahab M, Richardt G, Joachim Buttner H, et al. Highspeed rotational atherectomy before paclitaxel-eluting stent implantation in complex calcified coronary lesions: the randomized ROTAXUS (Rotational Atherectomy Prior to Taxus Stent Treatment for Complex Native Coronary Artery Disease) trial. JACC Cardiovasc Interv 2013;6:10–9. https://doi. org/10.1016/j.jcin.2012.07.017; PMID: 23266232.

12. Madhavan MV, Tarigopula M, Mintz GS, et al. Coronary artery calcification: pathogenesis and prognostic implications. J Am Coll Cardiol 2014;63:1703–14. https://doi.org/10.1016/j. jacc.2014.01.017; PMID: 24530667.

13. Shiode N, Kozuma K, Aoki J, et al. The impact of coronary calcification on angiographic and 3-year clinical outcomes of everolimus-eluting stents: results of a XIENCE V/PROMUS post-marketing surveillance study. Cardiovasc Interv Ther 2018;33:313–20. https://doi.org/10.1007/s12928-017-0484-7; PMID: 28726115.

14. Sharma SK, Tomey MI, Teirstein PS, et al. North American Expert Review of Rotational Atherectomy. Circ Cardiovasc Interv 2019;12:e007448. https://doi.org/10.1161/ CIRCINTERVENTIONS.118.007448; PMID: 31084239.

15. Witzenbichler B, Maehara A, Weisz G, et al. Relationship between intravascular ultrasound guidance and clinical outcomes after drug-eluting stents: the assessment of dual antiplatelet therapy with drug-eluting stents (ADAPT-DES) study. Circulation 2014;129:463–70. https://doi.org/10.1161/ CIRCULATIONAHA.113.003942; PMID: 24281330.

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