ICR 13.3 by Radcliffe Cardiology

Interventional Cardiology Review Volume 13 • Issue 3 • Autumn 2018

Volume 13 • Issue 3 • Autumn 2018

www.ICRjournal.com

‘Primary’ Microvascular Angina: Clinical Characteristics, Pathogenesis and Management Gaetano Antonio Lanza, Antonio De Vita and Juan-Carlos Kaski

Culprit Vessel Only Versus Complete Revascularisation in Patients with ST-Segment Elevation Myocardial Infarction – Should we Stay or Stage? Matthias Hasun and Franz Weidinger

Delayed Coronary Occlusion After Transcatheter Aortic Valve Implantation: Implications for New Transcatheter Heart Valve Design and Patient Management Richard J Jabbour, Akihito Tanaka,Antonio Colombo and Azeem Latib

Annular Rupture During Transcatheter Aortic Valve Implantation: Predictors, Management and Outcomes JJ Coughlan, Thomas Kiernan, Darren Mylotte and Samer Arnous

ISSN: 1756-1477

STEMI of the anterior wall

Angiography showing a type III perforation’

Interactive Planning Tool for Calculation of Post Revascularisation FFRCT

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

ICR 13.3_FC + Spine.indd All Pages

06/09/2018 23:20

Orsiro

60 μm1

The new benchmark for DES

Significantly lower TLR rate in the 2nd year BIO-RESORT: Orsiro shows lower event rates than Synergy and Resolute Integrity • Significant TLF and TLR reduction in the second year compared to Resolute Integrity • Landmark analyses provided a signal that the use of Orsiro might reduce the risk of repeat revascularization after the first year of follow-up2

0.6%

TLR in 2nd year

Target Lesion Revascularization (TLR)2 2 – Orsiro – Resolute Integrity – Synergy

p = 0.04*, Difference 1-2 yrs. -0.9 (-1.7;0.0) p = 0.18*, Difference 1-2 yrs. -0.6 (-1.5;0.3)

1.5

4 3 2

1.6 1.5/1.5

1.5

TLR in 2nd year [%]

Cumulative Incidence of TLR [%]

0.9 0.6

0.9

0.6 0

Events in 1st year

Events in 2nd year

Orsiro

Resolute Integrity

Synergy

* Logrank statistical method; 1 ø 2.25 - 3.0 mm; 2 Kok M et al. 2-year outcome of the 3-arm BIO-RESORT randomized trial in all-comer patients treated with contemporary DES. Presented at: EuroPCR; May 23, 2018; Paris, France. Resolute and Integrity are registered trademarks of Medtronic; Synergy is a registered trademark of Boston Scientific

www.orsiro.com

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Volume 13 • Issue 3 • Autumn 2018

www.ICRjournal.com

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

Section Editor – Structural

Section Editor – Coronary

Darren Mylotte

Angela Hoye

Galway University Hospitals, Galway

Castle Hill Hospital, Hull

Fernando Alfonso

A Pieter Kappetein

Hospital Universitario de La Princesa, Madrid

Andrew Archbold

Thoraxcenter, Erasmus University Medical Center, Rotterdam

London Chest Hospital, Barts Health NHS Trust, London

Demosthenes Katritsis

Sergio Baptista

Tim Kinnaird

Hospital CUF Cascais and Hospital Fernando Fonseca, Portugal

Marco Barbanti

Athens Euroclinic, Athens, Greece University Hospital of Wales, Cardiff

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

Ferrarotto Hospital, Catania

Olivier Bertrand Quebec Heart-Lung Institute, Laval University, Quebec

Azeem Latib

Lutz Buellesfeld

Didier Locca

San Raffaele Hospital, Milan

University Hospital, Bern

Jonathan Byrne King’s College Hospital, London

Antonio Colombo San Raffaele Hospital, Milan

Royal Brompton & Harefield NHS Foundation Trust, London Centre Hospitalier Universitaire Vaudois, Lausanne CardioVascular Center, Frankfurt

Sapienza University of Rome, Rome

Andrew SP Sharp Royal Devon and Exeter Hospital and University of Exeter, Exeter

Elliot Smith London Chest Hospital, Barts Health NHS Trust, London Rigshospitalet - Copenhagen University Hospital, Copenhagen

Thomas Modine

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

Corrado Tamburino Ferrarotto & Policlinico Hospital and University of Catania, Catania

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Nicolas Van Mieghem

Keith Oldroyd

Renu Virmani

Golden Jubilee National Hospital, Glasgow

Sameer Gafoor

Gennaro Sardella

Mount Sinai Hospital, New York

Marko Noc

Eric Eeckhout

Beth Israel Deaconess Medical Center, Boston

Lars Søndergaard

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

Carlo Di Mario

Jeffrey Popma

Roxana Mehran

Jeffrey Moses

Imperial College NHS Trust, London

Guy’s & St Thomas’ Hospital and King’s College London, London

Lausanne University Hospital, Lausanne

CHRU de Lille, Lille

Justin Davies

Divaka Perera

Crochan J O’Sullivan

Erasmus University Medical Center, Rotterdam CVPath Institute, Maryland

Mark Westwood

Triemli Hospital, Zurich

London Chest Hospital, Barts Health NHS Trust, London

Thomas Johnson

Nicolo Piazza

Nina C Wunderlich

University Hospitals Bristol, Bristol

McGill University Health Center, Montreal

Cardiovascular Center Darmstadt, Darmstadt

Juan Granada CRF Skirball Research Center, New York

Managing Editor Catherine Hyland • Production Aashni Shah • Senior Designer Tatiana Losinska Sales & Marketing Executive William Cadden • Sales Director Rob Barclay Publishing Director Leiah Norcott • Commercial Director David Bradbury Chief Executive Officer David Ramsey • Chief Operating Officer Liam O’Neill •

Editorial Contact Catherine Hyland catherine.hyland@radcliffe-group.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffe-group.com •

Cover image 3d illustration human body heart. © PIC4U | stock.adobe.com

Cardiology

Lifelong Learning for Cardiovascular Professionals 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 © 2018 All rights reserved ISSN: 1756–1477 • eISSN: 1756–1485

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Established: June 2006 Frequency: Tri-annual Current issue: Autumn 2018

Aims and Scope • 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.

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

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is assessed to ensure the revised version meets quality expectations. The manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • 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, Catherine Hyland catherine.hyland@radcliffe-group.com

Reprints All articles included in Interventional Cardiology Review are available as reprints. Please contact the Publishing Director, Leiah Norcott leiah.norcott@radcliffecardiology.com

Editorial Expertise

Distribution and Readership

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. • Invited contributors who are recognised authorities in their respective fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

Interventional Cardiology Review is distributed tri-annually through controlled circulation to senior healthcare professionals in the field in Europe.

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • 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. • Following review, manuscripts are accepted without modification, accepted pending modification (in which case the manuscripts are returned to the author(s) to incorporate required changes), or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

Abstracting and Indexing 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.

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in Interventional Cardiology Review unless otherwise stated. Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor.

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. n

Cardiology

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Contents

Foreword

106

Simon Kennon Editor-in-Chief, ICR

Coronary

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‘Primary’ Microvascular Angina: Clinical Characteristics, Pathogenesis and Management

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Risk Stratification in Patients with Coronary Artery Disease: a Practical Walkthrough in the Landscape of Prognostic Risk Models

Gaetano Antonio Lanza, Antonio De Vita and Juan-Carlos Kaski

Sergio Buccheri, Paolo D’Arrigo, Gabriele Franchina and Davide Capodanno

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Common and Uncommon CTO complications

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FFRCT for Complex Coronary Artery Disease Treatment Planning: New Opportunities

Johannes Rigger,Colm G. Hanratty and Simon J Walsh

Jonathon Leipsic, Jonathan Weir-McCall and Philipp Blanke

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Culprit Vessel Only Versus Complete Revascularisation in Patients with ST-Segment Elevation Myocardial Infarction – Should we Stay or Stage? Matthias Hasun and Franz Weidinger

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ORBITA: What Goes Around, Comes Around… Or Does It? Matthew Jackson and Azfar Zaman

Structural

137

140

Annular Rupture During Transcatheter Aortic Valve Implantation: Predictors, Management and Outcomes JJ Coughlan, Thomas Kiernan, Darren Mylotte and Samer Arnous

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Alternate Access for TAVI: Stay Clear of the Chest Pavel Overtchouk and Thomas Modine

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CSI FOCUS LAA 2018

LAA WORKSHOP During this 2-day course you will get an overview on all aspects of LAA treatment modality. Clinical studies will be covered and we will also demonstrate how to perform the procedure step by step and how to prevent and manage complications. Live case transmissions are a core of this course and will allow direct attendee-operator interaction to maximize the learning experience.

NOVEMBER 16 â&#x20AC;&#x201C;17, 2018 FRANKFURT, GERMANY www.csi-congress.org/laa

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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.

n this issue of Interventional Cardiology Review there are nine excellent papers, all focusing on issues that have important implications for the clinical practice of interventional cardiologists. Jabbour et al recently published a paper documenting the incidence and possible predictors of delayed coronary obstruction (DCO). Here they summarise the data and go on to discuss how valve design may reduce the incidence of DCO. Coughlan et al discuss another of the feared complications of transcatheter aortic valve implantation (TAVI) – annular rupture. They focus on predictors of annular rupture, as well as its management. The final paper in this issue’s structural section by Modine et al provides an excellent and comprehensive review of non femoral access for TAVI procedures, with particular focus on outcome data. In this issue’s coronary section, Kaski et al provide an excellent review of microvascular angina. Capodan et al review the currently available tools for risk stratifying patients with coronary artery disease, discussing their relative merits and applications. Rigger et al provide an overview of the complications of chronic total occlusion (CTO) procedures, an important consideration when counselling patients regarding such procedures. Coronary computerised tomography (CT) scans are commonly used to diagnose coronary artery disease, but Leipsic et al assess the value of non-invasive FFRct for planning coronary interventions. In this issue, Leipsic et al survey the current status of non-invasive FFRct imaging for planning coronary interventions. Weidinger et al review the current data relating to the management of patients presenting with ST-elevation myocardial infarction (STEMI), specifically with regards to the relative merits of culprit only and complete revascularisation. The autumn issue of ICR concludes with a review by Jackson et al highlighting the initial results from the ORBITA trial. I hope you find these papers as useful as I do! n

DOI: https://doi.org/10.15420/icr.2018.13.3.FO1

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06/09/2018 23:22

Volume 1 • Issue 1 • Spring 2018

www.VERjournal.com

Current State Of The Art In Approaches To Saphenous Vein Graft Interventions Michael Lee and Jeremy Kong

Non-Coronary Interventions: An Introduction To Peripheral Arterial Interventions Brock Cookman, Suhail Allaqab and Tonga Nfor

Endovascular Abdominal Aortic Aneurysm Repair - Patient Selection And Long-Term Outcome Expectations Regula S von AllmenFlorian DickThomas R WyssRoger M Greenhalgh

Saphenous Vein Graft Interventions

Endovascular Abdominal Aortic Aneurysm Repair

Coming soon – September 2018!

Peripheral Arterial Interventions

Vascular

Lifelong Learning for Vascular Professionals

Vascular and Endovascular Review (VER) is a bi-annual journal aimed at assisting time-pressured physicians to stay abreast of key advances and opinions in the vascular and endovascular areas.

Guided by an Editorial Board of leading physicians and led by Editor in Chief, Mr. Stephen Black, Consultant Vascular Surgeon at Guys and St Thomas’ hospital, London; this peer-reviewed journal consists of review articles, technical reviews, expert opinion pieces and special reports contributed by leading vascular surgeons and specialists in the field. Distributed in print and digital format to leading physicians within the community, with free-to-access articles on the website www.VERjournal.com. Radcliffe Vascular combines years of publishing experience, with medical writers, editors and our network of leading KOL advisors across our editorial boards, to harness global expertise to deliver high quality learning materials to vascular and endovascular professionals. Our peer reviewed journals, website and educational platform offer the ideal environment to engage with our audience of 75,000+ global cardiovascular physicians.

Vascular

Lifelong Learning for Vascular Professionals

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Coronary

‘Primary’ Microvascular Angina: Clinical Characteristics, Pathogenesis and Management Gaetano Antonio Lanza 1 , Antonio De Vita 1 and Juan-Carlos Kaski 2 1. Institute of Cardiology, Università Cattolica del Sacro Cuore, Fondazione Policlinico A. Gemelli, Rome, Italy; 2. Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK

Abstract Microvascular angina (MVA), i.e. angina caused by abnormalities of the coronary microcirculation, is increasingly recognised in clinical practice. The pathogenetic mechanisms of MVA are heterogeneous and may involve both structural and functional alterations of coronary microcirculation, and functional abnormalities may variably involve an impairment of coronary microvascular dilatation and an increased microvascular constrictor activity. Both invasive and non-invasive diagnostic tools exist to identify patients with MVA in clinical practice. Prognosis has been reported to be good in primary MVA patients, although the prognostic implications of coronary microvascular dysfunction (CMVD) in more heterogeneous populations of angina patients need further assessment. Management of primary MVA can be challenging, but pharmacological and non-pharmacological treatments exist that allow satisfactory control of symptoms in most patients.

Keywords Microvascular angina, normal coronary arteries, coronary microvascular dysfunction, myocardial ischaemia, clinical outcome, angina therapy Disclosure: The authors have no conflict of interest to declare. Received: 11 May 2018 Accepted: 06 August 2018 Citation: Interventional Cardiology Review 2018;13(3):108–11. DOI: https://doi.org/10.15420/icr.2018.15.2 Correspondence: JC Kaski, Molecular and Clinical Sciences Research Institute,St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK. E: jkaski@sgul.ac.uk

Obstructive coronary atherosclerosis and its complications (e.g. coronary thrombosis) are considered to be the most common causes of myocardial ischaemia. However, up to 50 % of stable angina patients undergoing diagnostic coronary angiography and 10–15 % of those presenting with acute coronary syndrome (ACS) are found to have normal or ‘near-normal’ coronary arteries.1,2 A large body of data indicates that coronary microvascular dysfunction (CMVD) plays an important role in causing myocardial ischaemia in these patients with angina pectoris, despite no obstructive coronary artery disease (CAD). CMVD can be found in many cardiac or systemic diseases, e.g. cardiomyopathies, coronary atherosclerosis, immunological conditions, systemic hypertension. In these patients, CMVD and myocardial ischaemia can result from mechanisms directly related to the underlying disease. In many patients, however, CMVD is the only or the prevailing identifiable mechanism responsible for the occurrence of angina episodes and myocardial ischaemia, a condition defined as ‘primary’ microvascular angina (MVA).3 The term ‘microvascular angina’ was initially proposed by Cannon and Epstein in 19888 to identify patients with myocardial ischaemia triggered not by obstructive CAD but by functional microvascular abnormalities. More recently, the COVADIS group has proposed diagnostic criteria to define MVA.4 In clinical practice, a coronary microvascular origin of typical chest pain symptoms is usually suspected, by exclusion, in patients with angina, typical ischaemic changes on the ECG and/or abnormal findings on non-invasive imaging stress tests, in whom coronary arteriography fails to show obstructive CAD or epicardial coronary artery spasm. This review briefly addresses the clinical presentation,

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mechanisms and management of patients with chronic primary stable MVA.

Clinical Presentation and Clues for Identifying MVA Patients Primary stable MVA is characterised by angina episodes that are exclusively or predominantly triggered by effort or other conditions that increase myocardial oxygen demand. The ECG taken during effort usually shows typical ST-segment depression in most patients, and reversible stress-induced myocardial perfusion defects are usually detectable in over 50 % of patients.5 Of note, at variance with patients with obstructive CAD, conventional stress echocardiography less often shows left ventricular (LV) contractile abnormalities in MVA patients.6 This can be explained by the ‘patchy’ rather than regional nature of CMVD resulting in sparse myocardial perfusion abnormalities, usually affecting thin layers of the myocardium, in contrast with the involvement of large myocardial areas in stress-induced ischaemia caused by flow-limiting epicardial stenoses.7 In MVA patients exercise- and/or stress-induced angina, tends to be longer lasting with a slower resolution (>10–15 min) of chest pain after stopping exercise, and/or following the administration of short-acting nitrates, compared with anginal episodes in CAD patients.8–10 These findings are particularly suggestive of MVA when occurring in peri- or post-menopausal women. Female gender is largely prevalent among patients with primary stable MVA, a finding that has suggested a role for oestrogen deficiency in the pathogenesis of MVA in women.11 When positive for myocardial ischaemia, an ECG exercise stress test is usually unhelpful to distinguish between patients with obstructive

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‘Primary’ Microvascular Angina CAD versus CMVD. In some MVA patients, both the early appearance of ECG abnormalities and/or angina during the stress test and the lack of response to sublingual nitrate administration often suggests a microvascular origin of symptoms. Myocardial perfusion scintigraphy stress testing is often unhelpful for identifying patients with angina related to obstructive CAD versus CMVD. A negative perfusion test or the occurrence of patchy perfusion abnormalities in the presence of typical effort-induced angina may suggest MVA rather than obstructive CAD, but negative findings sometimes occur in the presence of multivessel obstructive CAD. As mentioned above, the occurrence of angina and ST-segment depression, but not LV contractile abnormalities, during echocardiographic dipyridamole or dobutamine stress testing, is suggestive of a microvascular origin of symptoms.12,13 Newer echocardiographic modalities, however, are nowadays more able to detect LV contractile abnormalities in MVA patients.

Assessment of Coronary Microvascular Function A definitive diagnosis of MVA, as also proposed by the COVADIS group,4 requires the demonstration of CMVD. Coronary microvascular function can be examined by both invasive and non-invasive methods.14 The most widely used invasive method for the evaluation of coronary microvascular function is the recording of coronary blood flow velocity using an intracoronary Doppler wire coupled with a pressure/ thermodilution device to allow measurements of both blood flow and coronary microvascular resistance. Among the most reliable and accurate methods for non-invasive assessment of CMVD is positron emission tomography (PET).15 However, its reduced availability in clinical practice and high cost preclude a wider applicability for routine assessment of MVA patients. Cardiovascular magnetic resonance (CMR) imaging, with gadolinium as a flow tracer, is also a very promising tool for the non-invasive assessment of CMVD.16,17 Contrast stress echocardiography is another valuable method for the assessment of CMVD in different myocardial territories;18 it is more widely available and less expensive than other methods for coronary blood flow (CBF) assessment. Although more work is required to fine tune this technique, transthoracic echocardiographic Doppler recording (TTDE), has been shown to be a reliable and accurate methodology.14 This technique, however, is operator-dependent, and limitations also include suboptimal chest windows in some patients and interobserver variability. When assessed, CMVD tests should explore both vasodilator and vasoconstrictor responses of the coronary microcirculation (Figure 1). Coronary microvascular dilator function is investigated by measuring coronary blood flow changes and/or resistance in response to vasodilator stimuli, i.e. adenosine injection, and to constrictor stimuli such as ergonovine or acetylcholine (ACh). Importantly, both endothelium-independent and endothelium-dependent coronary microvascular dilatation should be assessed. Maximal endothelium-independent microvascular dilatation and flow increase (coronary flow reserve, CFR) is usually obtained by intravenous administration of adenosine (0.14 µg/kg/min) or dipyridamole (0.84 mg/kg in 6 min). A CFR <2.0 is considered diagnostic for the presence of CMVD, with values of >2.0 but <2.5 being of borderline diagnostic significance.14 Intracoronary ACh administration – at increasing doses – and the cold pressor test are used to assess endothelium-dependent coronary microvascular dilatation. These tests, however, might not

INTERVENTIONAL CARDIOLOGY REVIEW

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Figure 1: Abnormalities of Coronary Microvascular Function and Tests Suggested to Investigate these Mechanisms in Patients with Suspected Microvascular Angina Coronary microvascular dysfunction

Impaired vasodilation

Increased vasoconstriction

Endothelium independent

Endothelium dependent

• Adenosine • Dipyridamole

• Acetylcholine • Cold pressor test

• Acetylcholine • Ergonovine • Hyperventilation • Mental stress/handgrip

Invasive assessment

induce an adequate increase of CBF because they can cause coronary microvascular constriction, resulting from a direct (ACh) or sympathetically-mediated (cold pressor test) effect on vascular smooth muscle cells. Intracoronary administration of ACh (at increasing doses of up to 200 µg/min) is at present the preferred test to assess the presence of coronary microvascular constriction/spasm in MVA patients. The induction of coronary microvascular constriction might be documented by a reduction of CBF in the absence of flow-limiting epicardial constriction/spasm. Alternatively, an ACh test may be considered positive for coronary microvascular spasm when it triggers typical angina and ischaemic ECG changes in the absence of major epicardial constriction/spasm at angiography.19 Of importance, coronary microvascular spasm can only be assessed during coronary angiography. While ACh is currently the preferred provocative stimulus for coronary microvascular spasm, ergonovine might be a valid alternative (Figure 1).

Evidence for a Role of CMVD in the Pathogenesis of MVA Several studies have demonstrated CMD in patients with stable angina who have normal or near normal epicardial coronary arteries.20–24 Structural abnormalities of the small coronary arteries have been described in several studies, including vascular smooth muscle hypertrophy, capillary rarefaction or vascular wall fibrosis.20,21 Functional changes of the coronary microcirculation appear to be more frequently found to be the mechanism for MVA and include both a reduction of the vasodilator response and increased vasoconstrictor activity, i.e. microvascular spasm.22–24 Initial studies showed an impaired increase of coronary blood flow in response to dilator stimuli such as dipyridamole and atrial pacing using the invasive xenon wash-out and thermodilution methods, respectively. 20–25 Impaired CFR was subsequently confirmed in many studies using various other methods. PET and CMR studies showed abnormal CBF responses and myocardial perfusion abnormalities involving mainly the subendocardium in patients without obstructive CAD, suggesting an involvement of the coronary microcirculation.16 Moreover, using intracoronary Doppler devices, studies in patients with MVA have documented impaired coronary microvascular dilation in response

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Coronary Figure 2: Therapeutic Approach in Patients with Primary Stable Microvascular Angina Traditional anti-ischaemic drugs

ß-blockers Ca2+-antagonists

Second-choice drugs

Symptom persistence

Effective Continue

Ranolazine Ivabradine Symptom Nitrates ACE inhibitors persistence Statins Xanthines Oestrogens* Others

Further forms of treatment

Rehabilitation programmes Imipramine Spinal cord stimulation EECP

Effective Continue

*In selected subgroups of post-menopausal women.

to ACh, a marker of impaired endothelium-dependent vasodilator responses, likely due to a reduced nitric oxide (NO) production by endothelial cells.26 Other studies have shown abnormal constrictor responses of the coronary microcirculation in primary MVA patients, i.e. coronary microvascular spasm.19,27–28 In the 1980s Cannon and Epstein showed for the first time that the administration of ergonovine further impaired the abnormal coronary blood flow responses to atrial pacing in patients with angina despite angiographically normal coronary arteries.25 They proposed the term ‘microvascular angina’ to define these patients. In clinical practice, markers of a possible role of coronary microvascular constriction in MVA include the occurrence of slow coronary blood flow at diagnostic angiography,29 the detection of increased circulating levels of endothelin-1 – the ‘strongest endogenous’ vasoconstrictor stimulus identified to date – both at baseline and after atrial pacing,30 and the occurrence of angina at rest as the prevailing clinical presentation. Furthermore, recent systematic assessment of intracoronary ACh testing in the cath lab in patients presenting with angina despite angiographically normal coronary arteries has shown coronary microvascular spasm in at least 25 % of these patients.19 Notably, a sizeable proportion of MVA patients has also been found to develop epicardial spasm, suggesting a possible contribution of this mechanism to the angina symptoms in at least some MVA patients.

Causes of CMVD in Primary Stable MVA The causal mechanisms of CMVD in patients with primary stable MVA are not fully understood and are likely to be several. Traditional cardiovascular risk factors for CAD are known causes of CMVD, although there is no clear evidence of a direct relationship among risk factors and the severity of CMVD in MVA patients.31 Increased adrenergic activity and/or abnormal function of cardiac sympathetic nerve fibres have been also suggested as causal factors in some studies,32 and inflammatory mechanisms were reported to have a role in MVA.33 Also importantly, oestrogen deficiency has been advocated as a causal mechanism in women with MVA.11

Clinical Outcome Prognosis in primary stable MVA patients showing completely normal coronary arteries has consistently been reported to be good, with rates of major cardiovascular events (i.e. death or acute myocardial infarction) that appear to be similar to those found in the general population. 9,10,34 Larger studies, however, have recently challenged the view that MVA carries a good long-term prognosis.35 These studies,

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however, included more heterogenous groups of patients, with potential markers of worse outcome, including subcritical coronary atherosclerosis, impaired LV function and arrhythmias. Quality of life is, on the other hand, negatively affected by MVA, with many patients needing to retire from work at an early age and restrict their social activities dramatically.

Treatment Treatment of MVA includes full control of cardiovascular risk factors and all other conditions that might impair clinical outcomes (i.e. inflammatory status, oestrogen deficiency, high adrenergic activity). Given the problematic nature of symptoms in these patients, a specific goal in the treatment of stable MVA patients is to reduce angina symptoms and improve quality of life (Figure 2). Symptomatic outcome seems favourable in primary stable MVA patients when pharmacological and non-pharmacological interventions are systematically applied. However, although a sizeable proportion of patients show a significant reduction of symptoms over time,34 some patients report worsening of angina during follow-up, which can be related to a progression of their CMVD, worsening of enhanced pain perception or exacerbation of microvascular spasm. Although conventional antianginals are considered to represent first line treatment for myocardial ischaemia and chest pain in MVA, they are not effective in many patients. A pathophysiologically based approach should be preferred over a ‘first line’ and ‘second line’ recommendation. Identifying the prevailing mechanism for MVA in every individual may help the treating physician decide whether they should try to affect myocardial oxygen demand, microvascular spam or abnormal vasodilation, or all three. Overall, betablockers have been shown to improve angina symptoms, particularly in MVA patients with effort-induced angina and evidence of increased adrenergic activity, e.g. high heart rate at rest and/or rapid increase of heart rate on effort.36 Ivabradine – a bradycardia-inducing drug – may be a suitable alternative option in these patients, albeit no large studies have been conducted in this clinical setting with this agent. Non-dihydropyridine calcium-channel blockers such as diltiazem, are expected to be effective in patients with angina at rest, often triggered by microvascular spasm. Oral nitrates do not appear to be effective in MVA but nicorandil, a potassium channel opener with nitrate-like actions, has been suggested in some studies to have beneficial effects in patients with MVA.37 Promising data have also been reported with the use of ranolazine,38 a recently introduced antianginal drug that acts by reducing the late sodium current in the myocardium, which results in improved diastolic relaxation during and after ischaemia. Other pharmacological options to be considered in patients who do not respond to conventional anti-anginal treatment include xanthine derivatives, as these may favour coronary blood flow redistribution towards ischaemic areas creating an ‘antisteal’ effect,39 ACE inhibitors, which may improve microvascular function by limiting the vasoconstrictor and pro-oxidant effects of angiotensin II,40 alpha-adrenergic blocking drugs that decrease alphamediated adrenergic vasoconstriction,41 statins, which may improve microvascular endothelial function through several mechanisms,42 and, in menopausal women, oestrogen replacement therapy that can correct the abnormal microvascular function caused by oestrogen deficiency.11 In patients with increased algogenic perception and persisting symptoms, pharmacological agents can be used such as imipramine and amytriptiline, which affect areas in the central nervous system that modulate pain perception.43 Furthermore xanthines, which exert an anti- algogenic effect by antagonising cardiac pain nerve fibre

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‘Primary’ Microvascular Angina stimulation by adenosine, may be effective in specific cases.39 In MVA patients with anginal symptoms refractory to all currently available pharmacological agents, an improvement of symptoms and quality of life at long-term follow-up has been reported with the use of spinal cord stimulation,44 which acts both by modulating nociceptive signals and reducing microvascular ischaemia through an anti-adrenergic effect, whereas no changes in clinical status were observed in untreated controls. Enhanced external counterpulsation has been also proposed by some authors, who reported improvement of symptoms and regional ischaemia in treated patients.45

Summary and Conclusions Microvascular angina is being increasingly recognised in clinical practice. The condition affects a larger proportion of individuals than initially thought and, although there is an increased prevalence of MVA in menopausal women, the condition is by no means one

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atel MR, Peterson ED, Dai D, et al. Low diagnostic yield of P elective coronary angiography. N Engl J Med 2010;362:886–95. https://doi.org/10.1056/NEJMoa0907272; PMID: 20220183. Lanza GA, Crea F. Acute coronary syndromes without obstructive coronary atherosclerosis: the tiles of a complex puzzle. Circ Cardiovasc Interv 2014;7:278–81. https://doi.org/10.1161/CIRCINTERVENTIONS.114.001558; PMID: 24944301. Lanza GA, Crea F. Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management. Circulation 2010;121:2317–25. https://doi. org/10.1161/CIRCULATIONAHA.109.900191; PMID: 20516386. Ong P, Camici PG, Beltrame JF, et al; Coronary Vasomotion Disorders International Study Group (COVADIS). International standardization of diagnostic criteria for microvascular angina. Int J Cardiol 2018;259:56. https://doi.org/10.1016/ j.ijcard.2018.02.088; PMID: 29579613. Cavusoglu Y, Entok E, Timuralp B, et al. Regional distribution and extent of perfusion abnormalities, and the lung to heart uptake ratios during exercise thallium-201 SPECT imaging in patients with cardiac syndrome X. Can J Cardiol 2005;21:57–62. PMID:15685304. Nihoyannopoulos P, Kaski JC, Crake T, Maseri A. Absence of myocardial dysfunction during stress in patients with syndrome X. J Am Coll Cardiol 1991;18:1463–70. https://doi. org/10.1016/0735-1097(91)90676-Z; PMID: 1939947. Maseri A, Crea F, Kaski JC, Crake T. Mechanisms of angina pectoris in syndrome X. J Am Coll Cardiol 1991;17:499–506. https://doi.org/10.1016/S0735-1097(10)80122-6; PMID: 1991909. Di Franco A, Milo M, Laurito M, et al. Comparisons of clinical and angina characteristics between patients with cardiac syndrome X and patients with coronary artery disease. It J Practice Cardiol 2012;1:15–21 www.ancecardio.it. Kaski JC, Rosano GMC, Collins P, et al. Cardiac syndrome X: clinical characteristics and left ventricular function: long-term follow-up study. J Am Coll Cardiol 1995;25:807–814. https://doi. org/10.1016/0735-1097(94)00507-M; PMID: 7884081. Lamendola P, Lanza GA, Spinelli A, et al.Long-term prognosis of patients with cardiac syndrome X. Int J Cardiol 2010;140:197–9. https://doi.org/10.1016/j.ijcard. 2008.11.026; PMID: 19070378. Kaski JC. Cardiac syndrome X in women: the role of oestrogen deficiency. Heart 2006;92(suppl 3):5–9. https://doi. org/10.1136/hrt.2005.070318; PMID: 16614266. Lanza GA. Angina pectoris and myocardial ischemia in the absence of obstructive coronary artery disease: role of diagnostic tests. Curr Cardiol Rep 2016;18:15. https://doi. org/10.1007/s11886-015-0688-3; PMID: 26768741. Michelsen MM, Pena A, Mygind ND, et al. Coronary microvascular dysfunction and myocardial contractile reserve in women with angina and no obstructive coronary artery disease. Echocardiography 2018;35:196–203. https://doi. org/10.1111/echo.13767; PMID: 29222822. Lanza GA, Camici PG, Galiuto L, et al; Gruppo di Studio di Fisiopatologia Coronarica e Microcircolazione, Società Italiana di Cardiologia. Methods to investigate coronary microvascular function in clinical practice. J Cardiovasc Med (Hagerstown) 2013; 14:1–18. https://doi.org/10.2459/JCM.0b013e328351680f; PMID: 23222188. Bøttcher M, Bøtker HE, Sonne H, et al. Endothelium dependent and independent perfusion reserve and the effect of L-arginine on myocardial perfusion in patients with syndrome X. Circulation 1999;99:1795–1801. https://doi. org/10.1161/01.CIR.99.14.1795; PMID: 10199874. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med 2002;346:1948–1953. https://doi.org/10.1056/NEJMoa012369; PMID: 12075055.

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that affects women only. CMVD, presenting as abnormal coronary microvascular dilation, microvascular spasm, or both, is the pathogenic mechanism underlying MVA. Both invasive and non-invasive diagnostic tools exist in clinical practice that help identify patients affected by MVA. Prognosis has been reported to be good in patients with MVA in the absence of conditions known to be associated with increased risk. Recent large studies, however, have reported prognosis to be impaired in more heterogeneous populations of patients with angina, despite angiographically normal coronary arteries, with CMVD showing a predictive value for combined cardiovascular end-points. Management of primary MVA can be challenging but pharmacological and nonpharmacological treatments exist that help improve symptoms in a large proportion of patients affected by MVA. Further research is required in areas such as non-invasive assessment of coronary microcirculation, pain perception abnormalities and pharmacological treatments aimed to target specific pathogenic mechanisms. n

17. L anza GA, Buffon A, Sestito A, et al. Relation between stress induced myocardial perfusion defects on cardiovascular magnetic resonance and coronary microvascular dysfunction in patients with cardiac syndrome X. J Am Coll Cardiol 2008; 51:466–72. https://doi.org/10.1016/j.jacc.2007.08.060; PMID: 18222358. 18. Galiuto L, Sestito A, Barchetta S, et al. Noninvasive evaluation of flow reserve in the left anterior descending coronary artery in patients with cardiac syndrome X. Am J Cardiol 2007;99:1378–83. https://doi.org/10.1016/ j.amjcard.2006.12.070; PMID: 17493464. 19. Ong P, Athanasiadis A, Borgulya G, et al. Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Circulation 2014;129:1723–30. https://doi.org/10.1161/ CIRCULATIONAHA.113.004096; PMID: 24573349. 20. Opherk D, Zebe H, Weihe E, et al. Reduced coronary dilator capacity and ultrastructural changes of the myocardium in patients with angina pectoris but normal coronary arteriograms. Circulation 1981;63:817–25. https://doi. org/10.1161/01.CIR.63.4.817; PMID: 7471337. 21. Richardson PJ, Livesley B, Oram S, et al. Angina pectoris with normal coronary arteries: transvenous myocardial biopsy in diagnosis. Lancet 1974;2:677–80. https://doi.org/10.1016/ S0140-6736(74)93260-7; PMID: 4142958. 22. Cannon RO 3rd, Watson RM, Rosing DR, Epstein SE. Angina caused by reduced vasodilator reserve of the small coronary arteries. J Am Coll Cardiol 1983;1:1359–73. https://doi. org/10.1016/S0735-1097(83)80037-0; PMID: 6853894. 23. Motz W, Vogt M, Rabenau O, et al. Evidence of endothelial dysfunction in coronary resistance vessels in patients with angina pectoris and normal coronary angiograms. Am J Cardiol 1991;68:996–1003. https://doi.org/10.1016/00029149(91)90485-4; PMID: 1927940. 24. Chauhan A, Mullins PA, Taylor M, et al. Both endotheliumdependent and endothelium-independent function is impaired in patients with angina pectoris and normal coronary angiograms. Eur Heart J 1997;18:60–8. https://doi. org/10.1093/oxfordjournals.eurheartj.a015119; PMID: 9049516. 25. Cannon RO, Epstein SE. ‘Microvascular angina’ as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol 1988;61:1338–43. https://doi.org/10.1016/00029149(88)91180-0; PMID: 3287885. 26. Egashira K, Inou T, Hirooka Y, et al. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med 1993;328:1659–64. https://doi.org/10.1056/ NEJM199306103282302; PMID: 8487824. 27. Chauhan A, Mullins PA, Taylor G, et al. Effect of hyperventilation and mental stress on coronary blood flow in syndrome X. Br Heart J 1993;69:516–24. https://doi. org/10.1136/hrt.69.6.516; PMID: 8343318. 28. Bortone AS, Hess OM, Eberli FR, et al. Abnormal coronary vasomotion during exercise in patients with normal coronary arteries and reduced coronary flow reserve. Circulation 1989;79:516–527. https://doi.org/10.1161/01.CIR.79.3.516; PMID: 2492909. 29. Fragasso G, Chierchia SL, Arioli F, et al. Coronary slow-flow causing transient myocardial hypoperfusion in patients with cardiac syndrome X: long-term clinical and functional prognosis. Int J Cardiol 2009;137:137–44. https://doi.org/ 10.1016/j.ijcard.2008.06.070; PMID: 18762343. 30. Lanza GA, Luscher TF, Pasceri V, et al. Effects of atrial pacing on arterial and coronary sinus endothelin-1 levels in syndrome X. Am J Cardiol 1999;84:1187–91. https://doi. org/10.1016/S0002-9149(99)00532-9; PMID: 10569328. 31. Wessel TR, Arant CB, McGorray SP, et al; NHLBI Women’s Ischemia Syndrome Evaluation (WISE). Coronary microvascular reactivity is only partially predicted by

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atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women’s Ischemia Syndrome Evaluation (WISE). Clin Cardiol 2007;30:69–74. https://doi.org/10.1002/clc.19; PMID: 17326061. Lanza GA, Giordano AG, Pristipino C, et al. Abnormal cardiac adrenergic nerve function in patients with syndrome X detected by [123I]meta-iodo-benzylguanidine myocardial scintigraphy. Circulation 1997;96:821–6. https://doi. org/10.1161/01.CIR.96.3.821; PMID: 9264488. Arroyo-Espliguero R, Mollichelli N, Avanzas P, et al. Chronic inflammation and increased arterial stiffness in patients with cardiac syndrome X. Eur Heart J. 2003;24:2006–11. https://doi. org/10.1016/j.ehj.2003.09.029; PMID: 14613736. Lanza GA, Filice M, De Vita A, et al. Primary stable microvascular angina: a long-term clinical follow-up study. Circulation 2017;135:1982–84. https://doi.org/10.1161/ CIRCULATIONAHA.117.027685; PMID: 28507253. Pepine CJ, Anderson RD, Sharaf BL, et al. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study. J Am Coll Cardiol 2010;55:2825–32. https://doi.org/10.1016/ j.jacc.2010.01.054; PMID: 20579539. Lanza GA, Colonna G, Pasceri V, Maseri A. Atenolol versus amlodipine versus isosorbide5-mononitrate on anginal symptoms in syndrome X. Am J Cardiol 1999;84:854–6. https://doi.org/10.1016/S0002-9149(99)00450-6; PMID: 10513787. Kaski JC, Valenzuela Garcia LF. Therapeutic options for the management of patients with cardiac syndrome X. Eur Heart J 2001;22:283–93. https://doi.org/10.1053/euhj.2000.2152; PMID: 11161946. Villano A, Di Franco A, Nerla R, et al. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am J Cardiol 2013;112:8–13. https://doi.org/10.1016/ j.amjcard.2013.02.045; PMID: 23558043. Emdin M, Picano E, Lattanzi F, L’Abbate A. Improved exercise capacity with acute aminophylline administration in patients with syndrome X. J Am Coll Cardiol 1989;14:1450–3. https://doi.org/10.1016/0735-1097(89)90380-X; PMID: 2809002. Kaski JC, Rosano G, Gavrielides S, Chen L. Effects of angiotensin converting enzyme inhibition on exerciseinduced angina and ST segment depression in patients with microvascular angina. J Am Coll Cardiol 1994;23:652–7. https://doi.org/10.1016/0735-1097(94)90750-1; PMID: 8113548. Botker HE, Sonne HS, Schmitz O, Nielsen TT. Effects of doxazosin on exercise-induced angina pectoris, ST-segment depression, and insulin sensitivity in patients with syndrome X. Am J Cardiol 1998;82:1352–1356. https://doi.org/10.1016/ S0002-9149(98)00640-7; PMID: 9856918. Fabian E, Varga A, Picano E, et al. Effect of simvastatin on endothelial function in cardiac syndrome X patients. Am J Cardiol 2004;94:652–5. https://doi.org/10.1016/ j.amjcard.2004.05.035; PMID: 15342302. Cannon RO, Quyyumi AA, Mincemoyer R, et al. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med 1994;330:1411–7. https://doi.org/10.1056/ NEJM199405193302003; PMID: 8159194. Sgueglia GA, Sestito A, Spinelli A, et al. Long-term follow-up of patients with cardiac syndrome X treated by spinal cord stimulation. Heart 2007;93:591–7. https://doi.org/10.1136/ hrt.2006.102194; PMID: 17237133. Kronhaus KD, Lawson WE. Enhanced external counterpulsation is an effective treatment for Syndrome X. Int J Cardiol 2009; 135:256–7. https://doi.org/10.1016/j.ijcard.2008.03.022; PMID: 18590931.

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Coronary

Risk Stratification in Patients with Coronary Artery Disease: a Practical Walkthrough in the Landscape of Prognostic Risk Models Sergio Buccheri, 1,2 Paolo D’Arrigo, 1 Gabriele Franchina 1 and Davide Capodanno 1 1. CAST, AOU. Policlinico-Vittorio Emanuele, University of Catania, Catania, Italy; 2. Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden

Abstract Although a combination of multiple strategies to prevent and treat coronary artery disease (CAD) has led to a relative reduction in cardiovascular mortality over recent decades, CAD remains the greatest cause of morbidity and mortality worldwide. A variety of individual factors and circumstances other than clinical presentation and treatment type contribute to determining the outcome of CAD. It is increasingly understood that personalised medicine, by taking these factors into account, achieves better results than “one-size-fitsall” approaches. In recent years, the multiplication of risk scoring systems for CAD has generated some degree of uncertainty regarding whether, when and how predictive models should be adopted when making clinical decisions. Against this background, this article reviews the most accepted risk models for patients with evidence of CAD to provide practical guidance within the current landscape of tools developed for prognostic risk stratification.

Keywords Coronary artery disease, risk score, risk assessment, coronary artery bypass grafting discrimination, clinical outcomes, guidelines, percutaneous coronary intervention, coronary artery bypass graft Disclosure: The authors have no conflicts of interest to declare. Received: 13 May 2018 Accepted: 15 August 2018. Citation: Interventional Cardiology Review 2018;13(3):112–20. DOI: https://doi.org/10.15420/icr.2018.16.2 Correspondence: Davide Capodanno, CAST, AOU Policlinico-Vittorio Emanuele, PO Rodolico, Ed 8, Via Santa Sofia 78, Catania, Italy. E: dcapodanno@gmail.com

Although a combination of multiple strategies to prevent and treat coronary artery disease (CAD) has led to a relative reduction in cardiovascular mortality over recent decades, CAD remains the greatest cause of morbidity and mortality worldwide.1 Based on clinical presentation and prognosis, CAD spans from stable presentations (e.g. chronic angina pectoris) to acute coronary syndromes (ACS), which encompass a variety of clinical scenarios (e.g. unstable angina [UA], non-ST-elevation MI [NSTEMI] and ST-elevation myocardial infarction [STEMI]). Guideline-directed medical therapy and revascularisation using percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) are the main treatment strategies across the spectrum of CAD.2 A variety of individual factors and circumstances other than clinical presentation and treatment type contribute to determining the outcome of CAD. It is increasingly understood that personalised medicine that takes these factors into account achieves superior results than “one-size-fits-all” approaches, which may ignore, for example, individual risk of ischaemia or propensity to bleed with antithrombotics. Directing appropriate treatment strategies to the right individuals is a clinical challenge. In making decisions when more than one treatment is available, physicians may rely entirely on their judgement, use clinical algorithms or be assisted by risk scores. Risk scores can be diagnostic or prognostic, and the latter is more difficult to develop and validate because of the stochastic and time-varying nature of clinical outcomes.3

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An ideal prognostic risk score should satisfy different characteristics (Figure 1). The ability to distinguish between high and low risk is called “discrimination”, and this is mathematically represented by a measure of concordance, the c-statistic (whose values range from 0.5 for worst discrimination and 1.0 for perfect discrimination).4 “Calibration”, which illustrates the similarity between predicted and observed risk, is identified by the Hosmer-Lemeshow goodness-of-fit test, with a chi-squared distribution in which the lower the value, the higher the calibration. The performance of a score, which concerns its accuracy in term of prediction, is measured by the Brier score, with values ranging from 0 (perfect prediction) to 1 (worst prediction). Finally, a risk score should prove to be effective (‘valid’) in similar but independent populations. In recent years, the multiplication of risk scoring systems for CAD has generated some degree of uncertainty regarding whether, when and how predictive models should be adopted in driving clinical decisions. This article aims to review the most accepted prognostic risk models for patients with evidence of CAD. For the sake of clarity, risk scores have been grouped according to the following criteria: logical temporal sequence of CAD management (i.e. pre-treatment, treatment, post-treatment/discharge and followup); clinical presentation (stable CAD undergoing PCI versus ACS presentation); and outcome prognostication (i.e. prediction of ischaemic or bleeding risk) (Figure 2). Risk scores for ruling out the presence of CAD have been discussed in detail elsewhere and are beyond the scope of this article.6

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Risk Scoring in Coronary Artery Disease Assessment of Risk Before Treatment Stable Coronary Artery Disease In patients with stable CAD, a shared multidisciplinary therapeutic decision-making process looking at the identification of the best treatment strategy â&#x20AC;&#x201C; the local heart team discussion â&#x20AC;&#x201C; is standard of care in clinical practice. In contrast with ACS management, where timely intervention is required and prognostically beneficial, stable CAD allows for a detailed diagnostic and therapeutic workup. Different risk scores can be useful aids to better inform the heart team discussion.

Figure 1: Metrics to Assess the Characteristics of a Risk Score

Transportability Discrimination

Calibration

SYNTAX and SYNTAX II score The SYNTAX score evaluates the anatomical burden and complexity of CAD by using a multi-parametric quantification tool based on coronary angiography (i.e. 12 questions ranging from anatomy to characteristics of lesion subsets such as bifurcations or chronic total occlusions). As endorsed by European guidelines, the SYNTAX score should be implemented as a tool to inform the decisionmaking processes between different revascularisation strategies (i.e. percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).7 Based on the results of the landmark SYNTAX trial where a systematic evaluation of its score was used for the first time,8 SYNTAX scores of >22 and >32 should contraindicate (class III) revascularisation by PCI in patients with multivessel or left main disease, respectively. However, the anatomical SYNTAX score has limitations, which result mainly from the variability in assessing and rating complex anatomies (leading to inter-observer variability) and the lack of clinical variables that might affect prognosis. To partly overcome these limitations, the SYNTAX II score has been developed with the aim of integrating the anatomical SYNTAX score with a small array of clinical variables (e.g. unprotected left main coronary artery disease, female sex, chronic obstructive pulmonary disease, age and left ventricular ejection fraction), which differently affect 4-year mortality in patients treated with PCI or CABG. By providing data on the expected mortality for each revascularisation strategy, the SYNTAX II score allows for individualised decision making between CABG and PCI. A userfriendly online calculator of the SYNTAX I and II score is available at www.syntaxscore.com. In the recently published SYNTAX II study, the SYNTAX II score was used to select a cohort of patients with similar predicted risk of mortality for CABG and PCI treatment. In these patients, PCI performed according to a state-of-the-art treatment strategy (i.e. intravascular imaging guidance, functional evaluation of coronary stenosis by fractional flow reserve and optimised secondary prevention) had similar clinical outcomes at one year as a historical and equipoise-derived cohort of patients undergoing CABG in the SYNTAX trial. 9

Functional SYNTAX score Because the anatomical complexity of CAD is a major determinant of prognosis but additional factors contribute to prognosis, a series of iterations and refinements of the anatomical SYNTAX score have recently been proposed. Beyond the above-mentioned SYNTAX II score, which clinically refines the anatomical SYNTAX score, the functional SYNTAX score

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Performance

Validation Workability

evaluates the impact on the total ischaemic burden of different coronary stenoses by using information from fractional flow reserve (FFR) measurements. In the calculation of the functional SYNTAX score, only lesions leading to significant ischaemia are rated while non-functionally relevant stenoses are ignored. This process is used to refine the anatomical SYNTAX score with functional information. The functional SYNTAX score outperformed the anatomical SYNTAX score in patients with multivessel disease enrolled in the FAME trial (n=497), with better discrimination for major cardiac adverse events (MACE) at one year (c-statistic of 0.677 versus 0.630 for functional versus anatomical SYNTAX score respectively; p=0.02). 10 Advances in CT of coronary arteries have recently allowed functional SYNTAX score to be assessed without the need for invasive cardiac catheterisation.11 This approach might be useful to broaden the clinical use of this combined approach looking at the simultaneous assessment of the anatomical and functional relevance of different coronary stenoses in patients with complex CAD. Further studies providing robust validation of this non-invasive technique are awaited.

European System for Cardiac Operative Risk Evaluation (EuroSCORE) II The EuroSCORE II is a prognostic tool to predict the risk of in-hospital mortality in candidates for cardiac surgery. Anticipating the risk of surgery might be helpful to customise heart team indications and widen anatomical thresholds for percutaneous revascularisation when the operative risk becomes clinically unacceptable. The EuroSCORE II encompasses 18 variables, including clinical, laboratory, echocardiographic and planned procedural parameters. Over recent decades, the score has been technically refined. The latest developed version of the EuroSCORE II showed better discrimination than former versions, namely the additive and logistic EuroSCORE models.12 All versions of the EuroSCORE are provided in an online calculator for clinical use, which is available at www.euroscore.org. The EuroSCORE II has been extensively validated in the literature. A recent meta-analysis, based on 22 studies and including 145,592 patients undergoing cardiac surgery, showed a good overall good performance in terms of both discrimination and accuracy.13

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Coronary Figure 2: Scores for Risk Stratification of Patients with Coronary Artery Disease based on Timing of Assessment and Predicted Risk

PRE-TREATMENT

POST-TREATMENT

FOLLOW-UP

BLEEDING RISK

CRUSADE risk score•

SYNTAX score•

CADILLAC risk score

DAPT score•

SYNTAX II score•

PAMI risk score

GUSTO score

EuroSCORE II•

ZWOLLE risk score•

PRECISE-DAPT score• BleeMACS bleeding risk score

STS risk score•

GRACE score at discharge

TIMI risk score•

Dynamic TIMI risk score

SIMPLE risk index•

RISK-PCI score

GRACE risk score•

EPICOR prognostic model

ACTION-GWTG model•

PARIS risk score

APEX-AMI risk score Residual SYNTAX score

Red dots: risk scores endorsed by current guidelines and/or supported by an extensive, rigorous external validation process.

GRACE Risk Score The GRACE risk score was derived from a large, multinational registry of patients with ACS (>20,000 patients). The score, which should be calculated at hospital admission, predicts the risk of mortality at six months. The c-statistics in the derivation and validation cohorts were 0.81 and 0.75 respectively (Table 1).19 The use of the GRACE risk score is advocated by current practice guidelines for the management of patients presenting with NSTEMI to stratify their clinical risk and select the optimal timing for revascularization.20 An online calculator of the score is available at http://gracescore.org/WebSite/Default.aspx.

ACTION–GWTG Model This model, based on the large ACTION Registry-GWTG database, is intended to predict the risk of in-hospital mortality in patients admitted with acute MI. Importantly, patients presenting with cardiac arrest or cardiogenic shock, who have often been excluded during the derivation of other risk scores, are included in this model.21 The c-statistic value for the ACTION-GWTG model was remarkable in both the derivation and the validation cohorts (0.88) (Table 1).

Society of Thoracic Surgeons Risk Score The Society of Thoracic Surgeons (STS) calculator requires the collection of a more extensive array of clinical parameters (http://riskcalc.sts.org). Mortality at 30 days is the primary outcome measure predicted by the score, but the STS database has also been used to derive a series of additional prognostic models for different clinical endpoints.4 The discrimination of the STS score for in-hospital mortality in the CABGonly group is good (Table 1).14

Acute coronary syndromes

Risk Scores After Treatment In patients with CAD, therapeutic strategies aimed at counteracting and relieving ischaemia, the pathophysiological substrate of CAD, are key to sizably improve clinical outcomes either in the early phases after the index event and in the long term. Ignoring the benefits conveyed by effective treatment, such as those of multi-targeted medical therapy and revascularisation may lead to bias and inaccuracy in prediction and risk stratification. Taking this into account, different risk scores have been developed based on the treatment modality received during the index hospitalisation and by incorporating parameters reflecting the response to the treatment itself.

TIMI Risk Score The TIMI risk score is intended to predict 30-day mortality in patients with STEMI who are eligible for fibrinolytic therapy.15 The score was derived from the 14,114 patients enrolled in the InTIME II trial and validated in the TIMI 9 trial.3 The c-statistic values in the derivation and validation cohorts were 0.779 and 0.746 respectively, consistent with moderate discrimination. However, fibrinolysis in Western countries has been largely replaced by primary PCI use. which nowadays is the revascularisation modality recommended by guidelines for patients with STEMI. Nevertheless, the TIMI risk score still provides acceptable discrimination for the prediction of 1-year mortality (c-statistic 0.725) in patients treated with primary PCI.16,17

SIMPLE Risk Index The SIMPLE risk index is a pragmatic, user-friendly score to predict the risk of 30-day mortality in patients with STEMI. The score is calculated by using three clinical variables which are routinely collected at the first medical contact, namely age, heart rate and systolic blood pressure. The SIMPLE risk index was derived using data of patients enrolled in the InTIME II trial3 and externally validated in the TIMI 9A/B trial. Of note, the score is also a robust predictor of mortality occurring within 24 hours from symptoms onset (c-statistic=0.81).18

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CADILLAC risk score The CADILLAC risk score, which has been derived from patients included in the CADILLAC trial,22 aims at stratifying the risk of death at one year in patients with ACS undergoing revascularisation by PCI. The external validation of the score was assesed in patients enrolled in the Stent-PAMI trial23 (Table 2). The score, which includes age >65 years (2 points), Killip class 2/3 (3 points), baseline left ventricular ejection fraction <40 % (4 points), anaemia (2 points), renal insufficiency (3 points), triple-vessel disease (2 points), and post-procedural TIMI flow grade (2 points), has to be calculated in the immediate post-PCI setting. It has three classes of risk: low risk, score 0-2; intermediate risk, score 3-5; and high risk, score ≥6. The score showed good discrimination for predicting both 30-day and 1-year mortality with c-statistic values of 0.81 and 0.78 in the validation cohort, respectively.24 The main limitation of the CADILLAC risk score is the non-contemporary PCI strategy adopted in the trial. Patients in the CADILLAC trial were treated with bare metal stents which are no longer the default strategy during PCI. Therefore, the prognostic performance of the score may be inaccurate since drug-eluting stents (DES), the current standard of modern PCI practice, have demonstrated to significantly improve clinical outcomes in patients undergoing PCI.25

PAMI Risk Score The PAMI risk score has been derived from a pooled analysis of the different PAMI trials, namely PAMI 1 and 2,26,27, AIR PAMI28 and STENT

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Risk Scoring in Coronary Artery Disease Table 1: Risk Score Before Treatment Risk Score

Clinical

Time of Score Use

Predicted Event

Parameters

setting

C-statistic (derived/

Trials/Studies

external Validation)

(Reference)

SYNTAX score

SCAD

Post-angiography

MACCE at 12 months

Angiographic: 11

0.56/0.61

NCT00114972.

SYNTAX score II

SCAD

Post-angiography

4-year mortality

Clinical: 4 Angiographic: 12 Echocardiographic: 1 Laboratory: 1

0.725/0.716

EuroSCORE II

SCAD

Pre-surgery

In-hospital mortality

Clinical: 15 Laboratory: 1 Echocardiographic: 2

0.80/0.79

12,13

Clinical: 25 Echocardiographic: 6 Laboratory: 1 Electrocardiographic: 1 Angiographic: 1

0.81 (mortality for CABG only)

4,14

STS score

SCAD

Pre-surgery

In-hospital mortality and eight other other outcomes

TIMI risk score

STEMI

Hospital admission

30-day mortality

Clinical: 7 Electrocardiographic: 2

0.779/0.746

15,16,17

Simple risk index

STEMI

First medical contact

30-day mortality

Clinical: 3

0.78/0.79

0.81/0.75

19,2

0.88/0.88

GRACE score

NSTEMI

Hospital admission

In-hospital: 6 months mortality

Clinical: 5 Laboratory: 2 Electrocardiographic: 1

ACTION-GWTG model

ACS

Hospital admission

In-hospital mortality

Clinical: 4 Electrocardiographic: 1 Laboratory: 2

Abbreviations: SCAD = stable coronary artery disease; STEMI = ST-elevation MI; NSTEMI = non-ST-elevation MI; ACS = acute coronary syndrome; MACCE = major adverse cardiac and cerebrovascular event; CABG = coronary artery bypass graft.

PAMI23 trials. The score has been designed to predict mortality at six months in patients with acute myocardial infarction treated with primary PCI. The discrimination ability of the score was fairly good (c-statistic 0.78) 3 (Table 2). The same limitations as the CADILLAC score (e.g. non-contemporary PCI practice) must be taken into account when using this score in clinical practice.

ZWOLLE Risk Score The ZWOLLE risk score is simple, based on six clinical and angiographic variables (i.e. Killip class, post-procedural TIMI flow, age, three-vessel disease, anterior infarction and ischaemia >4 hours), which identifies STEMI patients treated by primary PCI at low risk (score ≤3) of 30-day mortality. This score could be used to select patients who can be safely discharged after 48-72 hours of having the procedure. In the validation cohort, the score was robust at predicting 30-day mortality (c-statistic=0.902).29 The predictive value of the ZWOLLE risk score has been confirmed in three randomized controlled trials.30–32

GRACE Score at Hospital Discharge The GRACE score evaluated at hospital discharge to predict long-term mortality (i.e. beyond six months and up to four years) was validated in 1,057 hospital survivors included in the GRACE registry. The GRACE score was a robust predictor of all-cause mortality for all subsets of patients with ACS (STEMI, NSTEMI and unstable angina) at all analysed long-term follow-up time points (6 months, 1 year and yearly up to 4 years) with a c-index >0.75 at all evaluated time points.33

Dynamic TIMI risk score The dynamic TIMI risk score estimates the risk of mortality at 1 year in STEMI patients at hospital discharge. 34 The score was derived from the ExTRACT‐TIMI 25 trial 35 (c-statistic in the derivation cohort of 0.76) and was subsequently validated in 3,534 patients

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with STEMI enrolled in the TRITON‐TIMI 38 trial 36 (c-statistic in the validation cohort of 0.81). The strength of this score is that it reclassifies risk based on the incidence of adverse events occurring during the index hospitalisation, namely recurrent MI, stroke, major bleed, heart failure/shock, arrhythmia or renal failure. The dynamic TIMI risk score is obtained by adding to the baseline TIMI risk score a series of weighted integer points related to the prognostic impact on mortality of each potential in-hospital adverse event. Thus, this model updates the baseline TIMI risk score with clinical determinants of subsequent prognosis. This process statistically translates into an improved prognostic performance of the dynamic TIMI risk score over the baseline TIMI risk score.

RISK-PCI score The RISK–PCI score has been derived from a large cohort of patients treated with primary PCI (n=2,096) with the goal of predicting the risk of MACE and mortality at 30 days. The score – alongside clinical and laboratory parameters (i.e. age >75 years, prior infarction, anterior infarction, complete atrioventricular block, new-onset bundle branch block, left ventricular ejection fraction <40 %, high leucocytes count, glucose ≥6.6 mmol/L, creatinine clearance, pre-procedural TIMI flow = 0) – takes into account the results of the primary PCI procedure (post-procedure TIMI flow <3, reference vessel diameter ≤25 mm). It has shown good discrimination and calibration in the derivation cohort (the c-statistics in the internal validation cohort were 0.83 and 0.87 for MACE and mortality, respectively.37,38

The EPICOR prognostic model Pocock et al. proposed a web-based, user-friendly risk score to predict the risk of two-year mortality in 23,489 consecutive hospital survivors

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Coronary Table 2: Risk Score After Treatment and at Follow-up Risk Score

Clinical

Time of Score

Setting

Use

Predicted Event

Parameters

C-statistic (Derived/

Trials/Studies

External Validation)

(Reference)

CADILLAC risk score

ACS

Post-PCI

1-year mortality

Clinical: 2 Echocardiographic: 1 Laboratory: 2 Angiographic: 1 cTherapeutic: 1

PAMI risk score

ACS

Post-primary PCI

6-month mortality

Clinical: 3 Electrocardiographic: 1

0.78/NR

23,26,27,28

ZWOLLE risk score

STEMI

Post-primary PCI

30-day mortality

Clinical: 3 Angiographic: 3

0.902/0.937

29,30,31,32

GRACE hospital discharge score

All subset of ACS

Pre-discharge

All-cause mortality, from 6 months to 4 years postdischarge

Clinical: 6 Laboratory: 2 Electrocardiographic: 1

0.75/NR

Pre-discharge

1-year mortality

Nine admission variables of TIMI risk score plus parameters during the index hospitalisation: Clinical: 5 Electrocardiographic: 1

0.76/0.81

34,35,36

Clinical: 2 Laboratory: 3 Electrocardiographic: 3 Echocardiographic: 1 Angiographic: 3

0.83 (MACE-internal validation), 0.87 (mortality-internal validation)/NR

37,38

Dynamic TIMI risk score

STEMI

0.79/0.78

22,23,24,25

RISK-PCI score

STEMI

Post-primary PCI

30-day MACE and 30-day mortality

EPICOR prognostic model

ACS

Pre-discharge

1-year mortality

Clinical: 8 Laboratory: 3 Echocardiographic: 1

0.81/0.78

APEX-AMI risk score

STEMI

Post-primary PCI

90-day mortality

Clinical: 4 Electrocardiographic: 2 Laboratory: 1

0.81/NR

Residual SYNTAX score (rSS)

ACS

After PCI

1-year all-cause mortality

Same as baseline SYNTAX score

0.63/NR

DAPT score

All PCI patients on DAPT

12 months after DAPT

Ischaemia and bleeding between 12 and 30 months after PCI

Clinical: 5 Procedural: 3 plus CHF/LVEF<30%

0.70 (ischaemia), 0.68 (bleeding)/0.64 (for both ischaemia and bleeding)

GUSTO score

STEMI

30 days (event-free) after STEMI

1-year mortality

Clinical: 4 ±1 angiographic and heart rate

0.75 and 0.79 (with and without angiographic data)/NR

Abbreviations: STEMI, ST-elevation myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; MACE, major adverse cardiac event; PCI, percutaneous coronary intervention

after an ACS event included in EPICOR and EPICOR Asia prospective cohort studies.39 Twelve independent predictors of mortality were combined into the score, and a good discrimination was achieved (c-statistic 0.81). Consistent with the dynamic TIMI risk score, the EPICOR model also accounts for the incidence of in-hospital adverse events; quality of life before discharge, as assessed by the EQ-5D questionnaire, is also used in the calculation of the score. An online web calculator of the EPICOR prognostic model is available at www.acsrisk.org.

APEX-AMI risk score This APEX-AMI risk score is a prognostic model predicting the risk of mortality at 90 days in patients with STEMI undergoing primary PCI. The model was derived using data from patients enrolled in the APEX-AMI (Assessment of Pexelizumab in Acute Myocardial Infarction) trial. The model had good performance (c-statistic 0.82) and was internally validated, demonstrating a c-statistic value of 0.81.40

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Residual SYNTAX score The residual SYNTAX score (rSS) – calculated by subtracting the score of each successfully treated lesion from the baseline SYNTAX score – was firstly proposed by Généreux et al. in patients with moderateor high-risk ACS undergoing PCI enrolled in the prospective ACUITY trial.41 The rSS is useful to numerically quantify the burden and complexity of residual CAD after PCI and a strong independent predictor of ischaemic outcomes at 1 year, including all-cause mortality, with a c-statistic 0.63. The rSS has been extensively validated in the literature. Farooq et al. found that the rSS was a robust predictor of 5-year mortality in the SYNTAX trial (in eligible patients with 3-vessel or left main coronary artery disease undergoing PCI)42 whereas the authors’ group demonstrated the prognostic value of the rSS as an independent predictor of 2-year cardiac mortality in the setting of unprotected left main PCI.43 The rSS represented an independent predictor of major adverse cardiac and cerebrovascular events (MACCE) at 1 year in

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Risk Scoring in Coronary Artery Disease patients with STEMI and multivessel disease.44 In addition, the rSS has been shown to be a predictor of short-term adverse clinical outcomes (30–day and 6-month all-cause death) in patients with ACS complicated by cardiogenic shock45, while Khan et al. found that an rSS>8 was a predictor of in-hospital death, congestive heart failure, recurrent MI and bleeding in patients treated with primary PCI.

prolonged pharmacological strategies for secondary prevention. Against this background, clinical research has been directed toward the stratification of bleeding risk in patients with CAD and different tools have been recently developed to support clinicians in the difficult clinical task of pinpointing the optimal balance between ischaemic and bleeding risk.

Risk Scores During Follow-Up

CRUSADE risk score

Patients with CAD, despite effective treatment according to current guideline recommendations, are at substantial risk of experiencing recurrent ischaemic adverse events.47 Tailored management of patients during follow-up, based on individual risk profiles, is advisable to customise clinical management strategies for secondary prevention. The use of risk stratification tools might also be useful in secondary prevention.

In patients with NSTEMI, the CRUSADE risk score is intended to predict the risk of major bleeding during the index hospitalisation. It was created by assigning a weighted integer value to each independent predictor of in-hospital bleeding: baseline hematocrit; glomerular filtration rate; sex; heart rate and systolic blood pressure on admission; prior vascular disease; diabetes mellitus; and signs of heart failure on admission.

DAPT score

The final score ranges from 1 to 100 points. Notably, the rate of major bleeding increased by bleeding risk score quintiles are: 3.1 % for score ≤20; 5.5 % for score 21–30; 8.6 % for score 31–40; 11.9 % for score 41–50; and 19.5 % for score >50. C-statistic values for the derivation and validation cohorts were 0.71 and 0.70, respectively.50 (Table 3).

The DAPT score was derived from 11,648 patients enrolled in the DAPT trial and externally validated in the PROTECT trial. The score should be used after 12 months of uncomplicated DAPT, to assess more reliably the benefit-to-risk ratio of prolonging DAPT treatment.48 The DAPT score simultaneously evaluates and weights factors associated with increased risk of bleeding (moderate or severe bleeding according to the GUSTO criteria) and recurrent ischaemic events (stent thrombosis or myocardial infarction) at follow-up. The score ranges from –2 to 9 and patients with a DAPT score of ≥2 may most likely benefit from the prolongation of DAPT. In the derivation cohort, the model had c-statistic values of 0.70 and 0.68 for predicting ischaemic and bleeding risk respectively; in the validation cohort, the c-statistic was 0.64 for both ischaemic and bleeding risk. A user-friendly online calculator of the DAPT score is available at http://tools.acc.org/DAPTriskapp. The DAPT score has some limitations. In particular, stenting was mostly performed with first-generation DES in the DAPT trial, so the risk of stent thrombosis and/or ischaemic events may be overestimated by the DAPT score in light of the high safety standards for the newer generation DES used today.

PARIS risk score The PARIS risk score is a simple and useful tool to predict the risk of ischaemic and bleeding events at two years after PCI with DES. In detail, the two separate scores were developed using data from the PARIS (Patterns of Non-Adherence to Anti-Platelet Regimen in Stented Patients) registry. The first model to predict ischaemic events includes six clinical variables (diabetes mellitus, ACS presentation, current smoking, creatinine clearance <60 ml/minute, prior PCI and prior CABG) with a c-statistic value of 0.70; the second model, predicting major bleeding, also has six clinical variables (age, body mass index, current smoking, anaemia, creatinine clearance <60 ml/min, triple antithrombotic therapy on discharge) with c-statistic of 0.72. External validation was performed in the ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) registry and discrimination was moderate, with c-statistics of 0.65 and 0.64 for ischaemic and bleeding risk scores respectively.51

PRECISE–DAPT Score

GUSTO score In the GUSTO trial, data of STEMI survivors was used to derive two algorithms for predicting 1–year mortality after a 30–day eventfree period: one nomogram is based on only clinical parameters and its c-statistic is 0.70; the other nomogram integrates clinical and angiographic variables and it has a c-statistic value of 0.75. However such models had poor validation in subsequent studies and their use nowadays is generally limited due to the larger proportion of patients treated with primary PCI.49

The PRECISE-DAPT score was developed from a collaborative, individual patient-level analysis including data from eight randomised controlled trials (14,963 patients). The model predicts the risk of bleeding in patients treated with dual antiplatelet therapy (c-statistic of 0.73 for out-of-hospital TIMI major or minor bleeding and 0.71 for TIMI major bleeding within 12 months).52 The following variables are included in the score: age; creatinine clearance; hemoglobin; white blood cell count; and previous spontaneous bleeding. Patients at high bleeding risk are identified by a score of 25 or greater.

Stratification of Bleeding Risk The clinical implementation of potent anti-thrombotic therapies in patients at heightened cardiovascular risk has come at the cost of increasing the risk of bleeding. Despite thrombotic recurrences being the most feared events in patients with CAD, bleeding complications have a detrimental effect on prognosis which, ultimately, may offset the benefits of more intensive/

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In the external validation, obtained in two independent PCI-treated populations from the PLATelet inhibition and patient Outcomes (PLATO) trial and the BernPCI Registry, the PRECISE-DAPT score showed c-statistic values of 0.70 and 0.66 respectively. The PRECISE-DAPT score showed improved integrated discrimination and reclassification performance compared with the PARIS score in both validation cohorts for TIMI major or minor bleeding.

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Coronary Table 3: Bleeding Risk Scores Risk Score

Clinical Setting

Time of Score

Predicted Event

Parameters

Use

C-Statistic (Derived/

Trials/Studies

External Validation)

(Reference)

CRUSADE risk score

NSTEMI

Hospital admission

In-hospital major bleeding

Clinical: 6 Laboratory: 2

07.1/0.70

PARIS score

All PCI patients on DAPT

Post-PCI

Ischaemia and bleeding at 24 months after PCI

Clinical: 6, for coronary thrombosis risk Clinical: 6, for major bleeding risk

0.70 (for ischaemia), 0.72 (for bleeding) / 0.65 (for ischaemia), 0.64 (for bleeding)

PRECISE-DAPT score

All PCI patients on DAPT

Post-PCI

Bleeding at 12 months after PCI

Clinical: 2 Laboratory: 3

0.73/0.70 (PLATO trial), 0.66 (BernPCI registry)

52,53

BleeMACS bleeding risk score

ACS

Pre-discharge

1-year bleeding

Clinical: 5 Laboratory: 2

0.71/0.65

54,55

Abbreviations: NSTEMI, non-ST-elevation myocardial infarction; ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention.

The PRECISE-DAPT score, which can be easily calculated at www.precisedaptscore.com, is endorsed by the 2017 European Society of Cardiology guidelines on optimal DAPT duration in patients under going PCI.53

BleeMACS Bleeding Risk Score The BleeMACS (Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome) registry is a multicentre retrospective registry that enrolled more than 15, 000 patients with ACS who were treated with PCI.54 The BleeMACS bleeding risk score was derived and internally validated in this registry, and demonstrated to be a simple tool for estimating the risk of postdischarge serious bleeding events up to one year. The score includes seven predictors: age; hypertension; vascular disease; history of bleeding; malignancy; creatinine; and haemoglobin. The BleeMACS risk score exhibited good performance in the derivation (c-statistic: 0.71) and internal validation (c-statistic: 0.72) cohorts. The c-statistic in the external validation cohort, performed in the SWEDEHEART registry, was slightly lower (c-statistic of 0.65 for PCItreated patients and 0.63 for patients who did not undergo PCI).55

Selecting a Risk Scoring System in Daily Clinical Practice Undoubtedly, the marked increase in the number of risk scores available to interventional cardiologists, as well as the presence of overlapping risk scores in the same clinical scenarios, make it difficult to select the best risk scoring system in daily clinical practice. In the growing arena of risk assessment tools, however, only a limited number of risk scoring systems have been extensively, rigorously and externally validated. This is a central issue in guiding the selection and supporting the rationale for the use of a specific risk score in daily clinical practice (Figure 2, bottom panel).

patients, the CRUSADE risk score is also robust at predicting the risk of major in-hospital bleeding.50 The ACTION-GWTG model should be clinically implemented to assess the risk of in-hospital mortality in patients admitted with acute MI (it has excellent discrimination – see Table 1).21 After treatment for STEMI, the Zwolle risk score is instrumental at predicting the risk of early (30-day) mortality, thus allowing the selection of patients at low risk of adverse events who can be safely discharged within 72 hours of revascularisation by primary PCI.29–32 Finally, for the optimisation of medical therapy after PCI, the latest European guidelines recommend the use of the PRECISE–DAPT and DAPT scores (class of evidence IIb/A) to properly decide the optimal duration of dual antiplatelet therapy after PCI.53 Even though further research is crucial in this setting, clinicians should take advantage of these tools when facing the difficult clinical task of minimising the risk of bleeding while giving secondary prevention from recurrent ischemic events (Figure 2).

Advancing Risk Stratification in Patients with CAD: a Glimpse into the Future Bedside prognostication using simple and broadly accessible clinical variables, coupled with experience, is the mainstay of risk stratification in medicine. Over recent decades, medicine has drastically evolved in parallel with the implementation and wider clinical use of more advanced diagnostic and therapeutic techniques. Specifically, practice in cardiovascular medicine has been permeated by a large amount of additive information coming from more powerful diagnostic tools (i.e. CT of coronary arteries and invasive coronary diagnostic parameters), biomarker evaluation as well as proteomics and genomics. These data are complementary to the clinical evaluation and, undoubtedly, the integration of clinical and advanced diagnostic data have been instrumental to advance medical practice.

In patients with stable CAD, the SYNTAX I and II,7,9,56 the Euroscore II,12,13 and STS score4 have a central role in clinical decision making. Their applicability is firmly supported by the consistent and reproducible results regarding their overall performance and discrimination ability (as reported in Table 1).

Nevertheless, prognostication remains challenging in specific clinical contexts such as cardiogenic shock. A complex interplay between haemodynamic, metabolic and clinical factors increase the complexity of risk stratification in these patients.

In patients with NSTEMI, the GRACE risk score is particularly useful for the prediction of mid-term clinical outcomes and the identification of the optimal timing of myocardial revascularisation.19,20 In this group of

Recently, a promising risk score to predict 30-day mortality has been developed in this clinical setting using data from the landmark IABPSHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock) trial.57

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Risk Scoring in Coronary Artery Disease In a new era of individualisation and precision in medicine, refinement of existing risk scores by newer diagnostic tools has proven to be of clinical value. As an example, the evaluation of the N–terminal pro–BNP was shown to improve the overall predictive performance of different risk scores (the. Zwolle, TIMI and GRACE risk scores) in patients with STEMI . 58–60 Similarly, in patients with stable CAD, combining clinical variables and biomarkers into a unifying risk score showed potential for improving the stratification of risk for cardiovascular mortality. 61 Moreover, the use of genetic risk scoring in patients with CAD has been recently proposed. 62 Future studies will clarify if and how the use of these advanced techniques will advance our understanding of risk stratification

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in patients with CAD and if this process will finally translate into improved quality of care for PCI and ACS patients.

Conclusion Different tools for risk stratification have been developed and validated in patients with CAD. A stepwise approach, considering the characterisation of both ischaemic and bleeding risk is advisable in these patients to better guide both the immediate and long-term medical management strategies. Further studies are needed to clarify whether further improvements in risk stratification can be obtained by integrating the array of existing clinical risk scores with complementary information coming from more advanced diagnostic techniques. ■

primary PCI: results from the Belgian STEMI registry. EuroIntervention 2014;9(9):1095–101. https://doi.org/10.4244/ EIJV9I9A184. PMID: 24457280. Morrow DA, Antman EM, Charlesworth A, et al. TIMI risk score for ST-elevation myocardial infarction: A convenient, bedside, clinical score for risk assessment at presentation: an intravenous nPA for treatment of infarcting myocardium early II trial substudy. Circulation 2000;102(17):2031–7. https://doi. org/10.1161/01.CIR.102.17.2031. PMID: 11044416. Morrow DA, Antman EM, Giugliano RP, et al. A simple risk index for rapid initial triage of patients with ST-elevation myocardial infarction: an InTIME II substudy. Lancet 2001;358(9293):1571–5. https://doi.org/10.1016/S01406736(01)06649-1. PMID: 11716882. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome estimating the risk of 6-month postdischarge death in an international registry. J Am Med Assoc 2004;291(22):2727–33. https://doi. org/10.1001/jama.291.22.2727. PMID: 15187054. Roffi M, Patrono C, Collet J-P, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37(3):267–315. https://doi.org/10.1093/eurheartj/ehv320. PMID: 26320110. McNamara RL, Kennedy KF, Cohen DJ, et al. Predicting in-hospital mortality in patients with acute myocardial infarction. J Am Coll Cardiol 2016;68(6):626–35. https://doi. org/10.1016/j.jacc.2016.05.049. PMID: 27491907. Tcheng JE, Kandzari DE, Grines CL, et al. Benefits and risks of abciximab use in primary angioplasty for acute myocardial infarction: the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. Circulation 2003;108(11):1316–23. https://doi.org/10.1161/01. CIR.0000087601.45803.86. PMID: 12939213. Grines CL, Cox DA, Stone GW, et al. Coronary angioplasty with or without stent implantation for acute myocardial infarction. Stent Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 1999;341(26):1949–56. https://doi. org/10.1056/NEJM199912233412601. PMID: 10607811. Halkin A, Singh M, Nikolsky E, et al. Prediction of mortality after primary percutaneous coronary intervention for acute myocardial infarction: the CADILLAC risk score. J Am Coll Cardiol 2005;45(9):1397–405. https://doi.org/10.1016/j. jacc.2005.01.041. PMID: 15862409. Sarno G, Lagerqvist B, Fröbert O, et al. Lower risk of stent thrombosis and restenosis with unrestricted use of ‘newgeneration’ drug-eluting stents: a report from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Eur Heart J 2012;33(5):606–13. https://doi.org/10.1093/ eurheartj/ehr479. PMID: 22232428. Grines CL, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. The Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 1993;328(10):673–9. https:// doi.org/10.1056/NEJM199303113281001. PMID: 8433725. Stone GW, Marsalese D, Brodie BR, et al. A prospective, randomized evaluation of prophylactic intraaortic balloon counterpulsation in high risk patients with acute myocardial infarction treated with primary angioplasty. Second Primary Angioplasty in Myocardial Infarction (PAMI-II) Trial Investig. J Am Coll Cardiol 1997;29(7):1459–67. https://doi.org/10.1016/ S0735-1097(97)00088-0. PMID: 9180105. Grines CL, Westerhausen DRJ, Grines LL, et al. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction: the Air Primary Angioplasty in Myocardial Infarction study. J Am Coll Cardiol 2002;39(11):1713–9. https://doi.org/10.1016/ S0735-1097(02)01870-3. PMID: 12039480. De Luca G, Suryapranata H, van ‘t Hof AWJ, et al. Prognostic assessment of patients with acute myocardial infarction treated

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Expert Opinion: Coronary

Common and Uncommon CTO complications Johannes Rigger, 1,2 Colm G. Hanratty 1 and Simon J Walsh 1 1. Cardiology Department, Belfast Health & Social Care Trust, Belfast, Northern Ireland, UK; 2. Kantonsspital, St Gallen, Switzerland

Abstract Despite the ongoing development of technical skills, increasing operator experience and improvements in medical devices, percutaneous coronary interventions (PCI) for chronic total occlusions (CTO) are still the most challenging procedures in interventional cardiology for coronary artery disease. Due to the complexity of the procedury have a higher complication rate than PCI interventions for the treatment of non-occlusive disease. This may significantly increase procedural morbidity and potentially mortality. CTO-PCI related complications include all the usual complications that are seen in routine PCI in addition to unique issues such as inadvertent occlusion of donor vessels or injury of collateral channels causing haemodynamic instability or ischaemia. To minimise the morbidity associated with these procedures, it is important to be aware of potential complications and recognise them in a timely fashion. Should they arise, operators should be able to deal with them in a safe and efficient manner.

Keywords Chronic total occlusions, percutaneous interventions, complications, coronary disease, stents Disclosure: The authors have no conflicts of interest to declare. Received: 1 May 2018 Accepted: 23 July 2018 Citation: Interventional Cardiology Review 2018;13(3):121–5. DOI: https://doi.org/10.15420/icr.2018.10.2 Correspondence: Johannes Rigger, Cardiology Department, Belfast Health & Social Care Trust, Belfast, Northern Ireland, UK; and Kantonsspital, St Gallen, Switzerland. E: johannes.rigger@gmail.com

Chronic total occlusions (CTO) are a common finding at angiography in patients with coronary artery disease (CAD); they are present in ~20 % of cases at angiography (excluding those with acute MI or prior coronary artery bypass graft (CABG).1 Data from the same Canadian registry showed that only 10 % of CTO patients had had a percutaneous coronary intervention (PCI) attempted to treat CTO, with only 7 % successfully revascularised by this procedure. Recent data continue to demonstrate a low rate of CTO PCI in the UK, with approximately 5 % of all PCI lesions being a CTO procedure and ~12–13 % of PCI for stable lesions being a CTO PCI2. The presence of a CTO has historically led patients to be referred for a CABG or a recommendation for medical therapy. Rates of CTO PCI most probably continue to be low because of the perception that these lesions are technically challenging to deal with, and that the procedure has low success rates and higher complication rates. This is despite a large body of evidence demonstrating that high procedural success rates (of ~90 %) are now routine across large groups of patients in different geographies, as well as among operators and centres with varying experience.3–5

Rates of adverse events associated with CTO PCI Traditionally, PCI for non-occlusive disease is viewed as a low-risk procedure for patients with stable CAD. Rates of early Q-wave MI, emergency CABG, cerebrovascular accident (CVA) and mortality are reported at 0.03 %, 0.02 %, 0.04 % and 0.14 %, respectively, in a national audit of >100,000 PCIs annually.2 However, as with all registries, the potential for under-reporting complications (especially events that occur several hours after the

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PCI) should always be borne in mind. For example. in recent large PCI studies, the in-hospital major adverse cardiac events (MACE) rates associated with left main PCI were noted to be ~4 %6 and 5 %7 when there were systematic follow-up and clinical events committees for adjudication. This number is well in excess of the ~0.2 % MACE rate (death, stroke or Q-wave MI) for PCI for stable CAD and non-occlusive disease noted in the UK audit. Rates of inpatient mortality and MACE from a single-centre series of 25 years of CTO PCI has, reassuringly, suggested success rates are increasing while adverse events are declining over time.8 Inpatient adverse events were described among 18,061 patients and 18,941 target CTO vessels in a meta-analysis.9 These data suggest low risks for mortality (0.2 %), emergent coronary bypass graft (0.1 %), stroke (0.01 %) and contrast nephropathy (3.8 %).9 Perforation was reported at 2.0 % with cardiac tamponade in 0.3 %. The approach taken can also influence adverse events, with retrograde procedures being associated with higher numbers of these outcomes.10 While mortality remains low (0.7 %), collateral perforation (6.9 %) and tamponade (1.4 %) were noted amongst 3,482 patients undergoing retrograde CTO PCI procedures. As discussed above, the accuracy of these data (that are almost all registry based) may be limited and, as such, they should be interpreted cautiously. The OPEN CTO registry has been reported recently. In contrast to previous reports of CTO PCI outcome, this study was linked to the National Cardiovascular Data Registry registry to ensure that all consecutive patients were assessed. Furthermore, angiographic core laboratory and central clinical event adjudication were applied for all patients. Under these circumstances of systematic and robust clinical follow-up for contemporary CTO PCI, adverse event rates were noted to be more frequent.5 In-hospital mortality was found to be

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Expert Opinion: Coronary Table 1: Summary of In-Hospital Complications in Patients Undergoing PCI in Non-CTO and CTO Vessels In-Hospital Complications

PCI

CTO PCI

Q-wave myocardial infarction

0.02 %

2.5 %

Emergency CABG

0.03 %

0.1 %

Stroke

0.04 %

0.01 %

Mortality

0.14 %

0.2–0.9 %

Perforation

0.38 %

2–4.8 %

Source: Ludman and British Cardiovascular Intervention Society, 2017; Prasad et al., 2007;9 Patel et al., 2013;10, El Sabbagh et al., 201411

proximal portion of the leaking vessel. If there is a significant bleed while working with a 6F or 7F guide catheter, it is often useful to site a second guide catheter in the same vessel (a “ping-pong guide”). This will allow the operator to maintain control of the bleed, while briefly deflating the occlusion balloon, then reinflating it once equipment has passed distally to facilitate distal intervention. However, a ping-pong guide is not required if a 8 F guide is used when covered stent delivery and continued balloon inflation can be managed via a single guide. Operators should be aware that perforations from epicardial collaterals can be“fed”from multiple sources and that control of continuing bleeding can be challenging.

0.9 % and a coronary perforation requiring intervention was 4.8 %. Modern CTO PCI techniques do afford intervention for much more complex disease and this is likely to be the main factor in an upturn in complications. Nevertheless, these data should be viewed as being derived from a gold standard for outcome reporting. Where outcome data are reported without this level of robust follow-up, discernment with regards to their absolute validity is required. Table 1 gives a summary of in-hospital complications in patients undergoing PCI in non-CTO and CTO vessels. Regardless of the small absolute numbers of serious complications, all operators should be aware of these events and should be able to treat them immediately if needed. CTO-related complications can be considered as acute or late as well as cardiac (coronary and noncoronary) or extracardiac complications (Figure 1).11 Specific risks in CTO PCI include: acute myocardial infarction due to compromise of collateral flow; coronary perforation with pericardial blood extravasation with or without cardiac tamponade; damage of the proximal occluded segment due to deep guide catheter intubation; donor vessel damage (mechanical or thrombotic) during retrograde crossing; and renal failure due to excessive contrast load.11

Perforation and Collateral Channel Injury Coronary perforation is a well-known complication of CTO PCI. Left undiagnosed or untreated, this may become life threatening. The commonest scenario leading to perforation is of a guide wire exiting from the CTO body during attempted antegrade wire escalation (AWE). As long as the wire is not followed by secondary equipment, this is typically a relatively forgiving scenario without significant clinical sequelae.

The next question is whether there is haemodynamic compromise. If the patient has hypotension, an echocardiogram can confirm a diagnosis of cardiac tamponade and aid subsequent pericardiocentesis. With this in mind, it is important that catheter laboratories that perform regular CTO PCI have this equipment to hand with immediate availability in case it is needed for emergent use. Subsequently, the operator needs to identify the exact source of bleeding and the steps that are most appropriate to prevent ongoing blood loss. A specific inventory is necessary to be able to resolve the underlying abnormality. Potential solutions include the injection of autologous fat through a microcatheter (often effective for distal branch wire exits), coils (frequently required for collateral channel perforation), micro-beads, thrombin or covered stents. An appropriate range of this equipment must be available at all CTO PCI centres. Some specific scenarios can arise with collateral channel injury during retrograde approaches that require recognition and different steps for resolution. When there has been exit into a cardiac chamber, these events are almost always benign and self-limiting. It is important that the nature of any ongoing extravasation is understood. Fat, thrombin or micro-beads should never be injected if there is a collateral leak into a left heart chamber as these can potentially embolise and cause a stroke. Very large septal haematomas have also been described, including those that lead to a “dry tamponade”. Occasionally, these will spontaneously decompress12 by forming a self-limiting ventricular septal defect. Where a very large septal haematoma leads to patient compromise, this can be decompressed by percutaneous intervention. Under these circumstances, if the operator can pass a wire from the left coronary side via the haematoma cavity to the right ventricle, passage of a micro-catheter or 2 mm balloon to dilate this connection may allow the haematoma to drain without further compromise to the patient.

Perforations leading to significant bleeding are unusual, but those requiring an intervention (~1–2 % in registries and almost 5 % in OPEN CTO5) are common enough to require familiarity with corrective manoeuvres. In the authors’ experience, those associated with tamponade are most commonly due to collateral channel injury during a retrograde procedure or from unrecognised distal wire exits after antegrade crossing. Other potential causes include passing equipment out of small branches because the operator does not realise they are not in the main vessel architecture, or where stent deployment (or postdilation) leads to contrast extravasation as would also be seen in routine PCI (Figure 2).

Other potential sequelae of collateral channel exit are localised pressure effects, which are seen most often in the patients who have had a CABG. It is not unusual to see right ventricle free wall haematomas form when there has been over-aggressive dissection in the right coronary artery or when there has been dissection into branches with or without equipment exit in a “closed-chest” patient. Typically, supportive measures with intravenous fluids and/or inotropes will be sufficient to support the patient and allow spontaneous resolution. In the post-CABG setting, leaks from atrioventricular groove epicardial collaterals can lead to a left atrial pseudo myxoma and impaired mitral inflow.13 These are often best diagnosed by CT angiography and may require localised drainage using CT guidance13 or open surgery in rare circumstances.

Should a significant perforation occur, the first step is to prevent continuing blood loss. This is usually achieved by inflating a balloon (1:1 sizing) in the

Where retrograde approaches are considered, interventional cardiologists should be mindful of the hierarchical risk associated with

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CTO Complications Figure 1: Possible Complications During CTO-PCI – an Overview

CTO PCI-related complications

Cardiac

Extracardiac

Non coronary

Radiation injury

Aortic dissection

Vascular complications

Contrast induced nephropathy

Periprocedural MI

Coronary

Perforation 1. Main vessel 2. Distal vessel 3. Donor collateral vessel • Septal • Epicardial

Acute vessel closure

Thrombosis

Side branch occlusions

Equipment loss/entrapment

Dissection

Embolisation (including air)

Spasm

Cardiac tamponade Source: El Sabbagh et al (2014)11

each approach. In general, the use of patent (but diseased) vein grafts is safe. Septal collaterals are usually forgiving, and minor perforations tend to be well tolerated. Epicardial channels are less forgiving should a complication occur and should be considered as the last option. The authors would advocate avoiding the use of a left internal mammary artery (especially as a last remaining conduit) where at all possible. Finally, cardiac surgery may be required as a bailout option for percutaneously unresolvable bleeding. Centres that do not have on-site cardiac surgery facilities should strongly consider whether the use of epicardial collaterals and certain techniques is appropriate. In addition, clear pathways should be established for the transfer of patients to surgical centres under emergent circumstances should the need arise.

CTO Strategies, Vascular Access, Radiation Injury and Contrast Nephropathy A number of strategies can be adopted for CTO PCI. Many lesions are amenable to two or more approaches. An algorithmic approach to CTO PCI was first suggested in 2012; this recommends using the anatomy of the lesion to guide the initial strategy to approach the lesion.14 Four key questions guide the operator towards AWE, antegrade dissection and re-entry (ADR), retrograde wire escalation (RWE) or retrograde dissection and re-entry (RDR). An important aspect of a hybrid approach to CTO PCI is that operators must be able to recognise when they are entering a failure mode and efficiently switch between approaches. The main goal of this strategic switching is to minimise procedure duration, radiation exposure and contrast load. The use of the hybrid approach has been shown to be associated with high procedural success rates (~90 % per lesion) with acceptable use of contrast and radiation.3-5,15,16

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Figure 2: Type III Perforation

(a) Angiography showing a type III perforation (black arrow) after stenting of the right coronary artery after CTO revascularisation; (b) after deployment of two covered stents, with complete sealing of the right coronary artery perforation.

Several basic steps can be taken to reduce radiation doses. These include reducing frame rates for both fluoroscopy and acquisition runs, minimising the use of acquisition runs to points in the case where they are both necessary and useful, and strongly encouraging operators to be vigilant around the use of X-rays. Where CTO PCIs are performed in institutions with multiple x-ray systems, performing these procedures with the most modern x-ray equipment is likely to reduce exposure.17 Contrast nephropathy should be considered as a potential adverse event related to CTO PCI. Minimising contrast use is key and, once again, efficient and appropriate use of CTO strategies is pertinent to prevent wasting contrast. However, several peri-procedural manoeuvres can reduce this risk. These include stopping nephrotoxic agents for 48 hours before the procedure (especially angiotensinconverting-enzyme [ACE] inhibitors or angiotensin II receptor blockers

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Expert Opinion: Coronary [ARBs]), pre-hydrating patients with intravenous fluids and/or the use of the RenalGuard system. Historically, the use of certain strategies within PCI led to consideration of the use of 8F guiding systems (especially for ADR). Data have shown an association between sheath size and an increased risk for major bleeding19. Fortunately, the progressive evolution of CTO PCI dedicated technologies means that 8 F-guiding systems are rarely necessary now. Vascular complications related to femoral arterial access still occur in a significant number of cases in contemporary practice (0.3 % of patients required treatment in OPEN CTO, with haematomas noted in 4.3 %5; major vascular complications were noted in 2.5 % of RECHARGE patients4). The routine use of fluoroscopy to guide femoral puncture18 and/or the use of ultrasound may help to minimise adverse events. However, bilateral transradial access will obviate the risk of any femoral bleeding and is now feasible for the vast majority of CTO cases; it should be considered as an option where feasible and indicated.

Donor Vessel Issues In general, if there is no retrograde approach there are limited implications from seating a guide catheter in the non-CTO (contralateral) vessel. Rarely, and often in the context of profound ischaemia with very severe left ventricular dysfunction, bilateral contrast injection can lead to ischaemia or arrhythmia. Under such circumstances, sequential single catheter injections may be safer. Retrograde approaches raise numerous and specific issues related to the donor vessel. Any compromise to this system is potentially catastrophic, as the territory supplied is at risk as well as the CTO territory. Complications can lead to extensive ischaemia and rapid haemodynamic collapse and the operator should always consider this possibility if a patient becomes acutely unwell. Donor-vessel occlusion due to thrombus formation should be avoided at all costs. While this complication can occur in the target vessel during antegrade CTO PCI, the risk is higher for retrograde access. The excess of intracoronary equipment is associated with stasis in the guide catheters. Therefore, meticulous attention must be paid to optimal anticoagulation using the activated clotting time (ACT) to minimise the risk for donor system thrombosis. After an initial bolus of 100 U/kg, the ACT should be monitored to maintain a level >300 seconds (some advocate 350 seconds) to minimise the risk. Back-bleeding of guide catheters and recurrent flushing is also recommended after material exchange. Donor vessel dissection causing occlusion is relatively rare. This complication is most likely to occur as retrograde equipment is withdrawn from the CTO vessel. Under these circumstances, friction and energy that has been stored in the system during micro-catheter crossing is released. An equal and opposite reaction can occur as equipment is brought out of the CTO territory back to the donor guide and the guiding catheter can be sucked into the donor vessel. This is best avoided by withdrawing the donor guide catheter well away from the ostium of the artery as the equipment is being withdrawn, and continuously imaging to ensure that the catheter is not pulled deeply into the donor vessel. The authors would also advocate the simple step of leaving a workhorse guide wire in the distal segment of the donor artery throughout the procedure to facilitate bail-out intervention should a problem arise.

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Occasionally, retrograde approaches can lead to kinking of the donor vessel, especially when the micro-catheter is advanced into a tortuous native vessel with significant angulation into the donor collateral. Under these circumstances, options are limited. If ischaemia and compromise occur, a braided micro catheter (Finecross, Caravel etc) that is more flexible and has a lower profile than a coil-based micro catheter (Corsair, Turnpike etc) may afford continued retrograde manoeuvres. However, if these devices are also associated with compromise of the donor vessel, then the retrograde approach may have to be altered (to an alternative collateral) or abandoned. Equipment loss and entrapment are rare. Stents can come loose from their delivery balloon during attempted delivery through long, calcific and tortuous lesions. Low-threshold use of guide catheter extensions seems to obviate this risk in the majority of CTO PCI. Should this issue occur, retrieval is the same as during routine PCI. Specific to retrograde CTO PCI, guide wires can become knotted after crossing into the CTO territory though this is rare and avoidable. This is a risk where knuckling has been performed, especially if the operator mistakenly “spins” the knuckle wire (this should be avoided). Pushing the retrograde equipment is more likely to free it up than pulling. Swapping the micro-catheter with a retrograde balloon and inflating this at the problem area may loosen any tissue that is entangled with the equipment. Similarly, siting antegrade equipment in the same area and ballooning from this direction may also be helpful.

Myocardial Injury Associated with CTO PCI It is not uncommon to see small increases in cardiac enzymes associated with retrograde approaches. This occurs due to the ischaemia that is invoked by collateral channel occlusion. Usually, this is well tolerated by the patient and not associated with ischaemia on the ECG. A low-level troponin elevation is of questionable clinical relevance. However, if a dominant collateral channel is used and the patient experiences significant cardiac ischaemia and chest pain when this is crossed, the operator should consider an alternative collateral or strategy to prevent significant myocardial infarction. During ADR or RDR procedures, it is imperative that attention is paid to large side branches. These should never be sacrificed by the strategy chosen and, where the loss of a significant vessel is possible or likely, an alternative approach should be taken.

When to Stop Revascularisation It is crucial that the treating physician is capable of recognising futility during the procedure. A contrast (depending on baseline renal function) and radiation limit (many would advocate 4 Gy) should be set and, if no meaningful progress has been made, the procedure should be discontinued. Where a CTO PCI attempt had been made with some progress, dilating the proximal cap and modifying the CTO segment by balloon dilation (an “investment procedure”) can alter the anatomy and facilitate another procedure after a few weeks. Under these circumstances, repeat attempts are associated with very high success rates (~90 %).3

Conclusions The tremendous improvement of equipment in coronary intervention allows practitioners to revascularise a broad range of CTO lesions in contemporary practice. Many of the most complex lesions will require the use of advanced techniques. CTO interventions can

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CTO Complications be performed safely in centres willing to make the commitment to training and education to achieve a high level of success for these challenging procedures. A significant part of modern CTO PCI includes an awareness of the potential pitfalls of the procedure,

efer P, Knudston ML, Cheema AN, et al. Current perspectives F on coronary chronic total occlusions. The Canadian Multicenter Chronic Total Occlusions Registry. J Am Coll Cardiol 2012;59:991–7. https://doi.org/10.1016/j.jacc.2011.12.007. PMID:22402070. Ludman P, British Cardiovascular Intervention Society. BCIS audit returns. Adult interventional procedures January 2016 to December 2016. Available at Available at: www.bcis.org.uk/ resources/audit-results/ (accessed 23 August 2018) Wilson WM, Walsh SJ, Yan AT, et al. Hybrid approach improves success of chronic total occlusion angioplasty. Heart 2016;102:1486–93. https://doi.org/10.1136/ heartjnl-2015-308891. PMID:27164918. Maeremans J, Walsh S, Knaapen P, et al. The hybrid algorithm for treating chronic total occlusions in Europe: the RECHARGE registry. J Am Coll Cardiol 2016;68:1958–70. https://doi. org/10.1016/j.jacc.2016.08.034. PMID:27788851. Sapontis J, Salisbury AC, Yeh RW, et al. Early procedural and health status outcomes after chronic total occlusion angioplasty. A report from the OPEN-CTO Registry (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures). J Am Coll Cardiol Intv 2017;10:1523–34. https://doi.org/10.1016/j.jcin.2017.05.065. PMID:28797429. 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. Stone GW, Sabik JF, Serruys PW, et al for the EXCEL Trial Investigators. Everolimus-eluting stents or bypass surgery for

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being able toto recognise these events promptly when they arise and the ability to resolve them when they do occur. It is important that operators are suitably trained and centres are appropriately equipped for this. n

left main coronary artery disease. N Engl J Med 2016;375:2223– 35. https://doi.org/10.1056/NEJMoa1610227. PMID:27797291. Prasad A, Rihal CS, Lennon RJ. Trends in outcomes after percutaneous coronary intervention for chronic total occlusions. A 25-year experience from the Mayo Clinic. J Am Coll Cardiol 2007;49:1611–8. https://doi.org/10.1016/ j.jacc.2006.12.040. PMID:17433951. Patel VG, Brayton KM, Tamayo A. Angiographic success and procedural complications in patients undergoing percutaneous coronary chronic total occlusion interventions: a weighted meta-analysis of 18,061 patients from 65 studies. JACC Cardiovasc Interv 2013;6:128-136. https://doi.org/10.1016/ j.jcin.2012.10.011. PMID:23352817 El Sabbagh A, Patel VG, Jeroudi OM. Angiographic success and procedural complications in patients undergoing retrograde percutaneous coronary chronic total occlusion interventions: a weighted meta-analysis of 3,482 patients from 26 studies. Int J Cardiol 2014;174: 243–8. https://doi. org/10.1016/j.ijcard.2014.04.004. PMID:24768461. Patel Y, Depta JP, DeMartini TJ. Complications of chronic total occlusion percutaneous coronary intervention. Interv Cardiol 2013;5:567–75. https://doi.org/10.2217/ica.13.48. Fairley SL, Donnelly PM, Hanratty CG, Walsh SJ. Images in cardiovascular medicine. Interventricular septal hematoma and ventricular septal defect after retrograde intervention for a chronic total occlusion of a left anterior descending coronary artery. Circulation 2010;122(20):e518–21. https://doi. org/10.1161/CIRCULATIONAHA.110.976555. PMID:21098463. Wilson WM, Spratt JC, Lombardi WL. Cardiovascular collapse post chronic total occlusion percutaneous coronary intervention due to a compressive left atrial hematoma managed with percutaneous drainage. Catheter Cardiovasc

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Interv 2015;86(3):407–11. https://doi.org/10.1002/ccd.25571. PMID:24909556. Brilakis ES, Grantham JA, Rinfret S, et al. A percutaneous treatment algorithm for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2012;5:367–79. https://doi.org/10.1016/j.jcin.2012.02.006. PMID:22516392. Pershad A, Eddin M, Girotra S, et al. Validation and incremental value of the hybrid algorithm for CTO PCI. Catheter Cardiovasc Interv 2014;84:654–9. https://doi.org/10.1002/ ccd.25370. PMID:24403122. Christopoulos G, Karmpaliotis D, Alaswad K, et al. Application and outcomes of a hybrid approach to chronic total occlusion percutaneous coronary intervention in a contemporary multicenter US registry. Int J Cardiol 2015;198:222–8. https://doi.org/10.1016/j.ijcard.2015.06.093. PMID:26189193; PMCID:PMC4554818. McNeice A, Brooks M, Hanratty CG, et al. A retrospective study of radiation dose measurements comparing different cath lab X-ray systems in a sample population of patients undergoing percutaneous coronary intervention for chronic total occlusions. Catheter Cardiovasc Interv 2018; Feb 7. https://doi.org/10.1002/ccd.27541. PMID: 29411518. Epub ahead of print. Fairley SL, Lucking AJ, McEntegart M, et al. Routine use of fluoroscopic-guided femoral arterial puncture to minimise vascular complication rates in CTO intervention: multicentre UK experience. Heart Lung Circ 2016;25(12):1203–9. https://doi.org/10.1016/j.hlc.2016.04.006. PMID:27265645. Doyle BJ, Ting HH, Bel MR, et al. Major femoral bleeding complications after percutaneous coronary intervention. JACC Cardiovasc Interv 2008;2:202–9. https://doi.org/10.1016/ j.jcin.2007.12.006. PMID:19463301.

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FFR CT for Complex Coronary Artery Disease Treatment Planning: New Opportunities Jonathon Leipsic, Jonathan Weir-McCall and Philipp Blanke St Paul’s Hospital & University of British Columbia, Vancouver, British Columbia, Vancouver, Canada

Abstract Coronary computed tomography (CT) is well established for the assessment of symptomatic patients with suspected but not yet confirmed coronary artery disease with high diagnostic accuracy and risk prediction. Until recently, coronary computed tomography angiography (CTA) has played a limited role in the management of complex coronary artery disease (CAD) and in planning revascularisation strategies. With the advent of FFRCT, enabling anatomy and physiology with a single study and the ability to adjudicate lesion specific pressure loss, the potential of combined coronary CT angiography (CCTA) and fractional flow reserve (FFR) computed from non-invasive CT angiography (FFRCT) to inform treatment decision-making and help guide revascularisation has been recognised. In this review, we highlight the evolving role of FFRCT in the management of complex CAD; the opportunities, the data and the unanswered questions.

Keywords FFRCT, ischaemia, invasive coronary angiography (ICA), coronary CTA, coronary artery disease Disclosure: Jonathon Leipsic receives fellowship support from GE and serves as a consultant to and holds stock options in Circle CVI and Heartflow. Received: 10 May 2018 Accepted: 25 July 2018 Citation: Interventional Cardiology Review 2018;13(3):126-8. DOI: https://doi.org/10.15420/icr.2018.14.3 Correspondence: Jonathon Leipsic, Professor of Radiology and Cardiology UBC Department of Medical Imaging, Centre for Heart Valve Innovation, St Paul’s Hospital, 1081 Burrard St, Vancouver BC V6Z 1Y6, Canada. E: JLeipsic@providencehealth.bc.ca Support: This work has been supported by the Arnold and Anita Silber and Syd and Joanne Belzberg Family Foundations.

Coronary CTA has rapidly gone from a test with potential to be considered a first-line test for patients with stable chest pain.1 It provides robust ability to exclude atherosclerosis and coronary artery stenosis and more recently has been shown to inform and guide clinical treatment making in a fashion that enables a reduction in myocardial infarction when compared to traditional stress testing.2–5 Despite the growing clinical utility data and continued technology improvements, resulting in improved image quality with lower radiation exposure, coronary CTA remains an anatomical test which cannot provide the necessary adjudication of ischaemia needed to guide revascularisation.6 As well, while very robust at ruling out stenosis, the specificity of coronary CTA is limited by spatial resolution, particularly in the setting of significant calcification, which will be a growing issue with CCTA now considered an appropriate first-line test in patients with higher pre-test likelihood of CAD.6 To help manage both of these limitations we have seen the development of both CT perfusion and non-invasive fractional flow reserve (FFRCT) derived from CT. FFRCT was first introduced in 2010 and has undergone significant maturation and validation. The version used clinically, and extensively validated, employs computational fluid dynamics to solve the equations that govern flow and resistance in the coronary arteries while computationally simulating hyperaemia, thereby obviating the need for adenosine administration.7–10 This test is also appealing as it does not require a change in CTA protocols and does not require additional radiation exposure. Through the validation of the technology, FFRCT has been proven to significantly improve the specificity of CTA for the discrimination of ischaemia as defined by invasive FFR. In the most recent large-scale multicentre trial, FFRCT

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accurately reclassified 68 % of CTA false positives to true negatives without a compromise in sensitivity.7 Much of the early clinical trial work and clinical focus has been placed on the avoidance of invasive angiography in patients with anatomical stenoses on CTA. While a meaningful opportunity to help overcome a limitation of clinical CT adoption, it is not the only role for FFRCT in stable chest pain. This is particularly the case as CCTA is being used in patients with higher pre-test likelihood, more coronary calcification and more complicated coronary artery disease (CAD).10 In these patients, FFRCT has been shown to be effective in characterising lesion specific ischaemia despite the higher burden of coronary artery calcium (CACS). Norgaard and colleagues,11 in a sub-analysis of the NXT trial evaluated the diagnostic performance of FFRCT in the setting of higher CACS and noted that while the diagnostic accuracy of FFRCT was slightly lower at CACS >400 it was not significantly so, unlike CCTA alone, the accuracy of which was significantly worsened.

Moving Beyond ICA Deferral Beyond diagnosis and risk stratification, the role of non-invasive imaging has always been to help enrich the population referred to the catheterisation laboratory. It has become increasingly clear that traditional stress testing is not effective in discrimination of those who are likely to be found to have actionable coronary artery disease. Given the apparent disconnect between stress testing and findings at the time of invasive coronary angiography (ICA) and the lack of anatomical information provided by stress testing, there has been little integration of non-invasive imaging in the guidance of revascularisation decisionmaking at the time of ICA. With the maturation of CCTA and the

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FFRCT for Complex CAD integration of FFRCT there is the opportunity to not only rule out disease with CCTA but to help guide and plan ICA and revascularisation strategies on the basis of anatomical stenosis and lesion specific ischaemia. Jensen and colleagues recently confirmed a significant increase in the percutaneous coronary intervention (PCI)/ICA ratio particularly in the higher risk population, importantly with PCI adjudicated by invasive physiology as well.12 In addition, ICA was cancelled more frequently in the high risk population on the basis of FFRCT (75 %) versus CTA alone (45 %). These data introduce the possibility of PCI decisionmaking without needing to adjudicate ischaemia invasively owing to the high concordance between non-invasive and invasive measures of ischaemia. Given the growing evidence of the relatively high frequency of and the increased hazard associated with incomplete revascularisation, the need to develop a more thoughtful approach to revascularisation seems necessary. With this growing and clear need, investigators have begun to explore ways of using non-invasive imaging data to help inform interventional strategies. Collet and colleagues also recently evaluated the potential that a non-invasive approach to adjudication of anatomy and physiology could act as a surrogate in treatment decision-making for invasive evaluation in the SYNTAX II trial (SYNTAX II). Interestingly, the authors found that there was poor correlation between the invasive and non-invasive anatomical syntax but much better correlation between the non-invasive and invasive functional syntax score.13 The anatomical SYNTAX score was overestimated by CTA compared with conventional angiography (27.6 ± 6.4 versus 25.3 ± 6.9; p<0.0001) whereas the calculation of the functional SYNTAX score yielded similar results between the non-invasive and invasive imaging modalities (21.6 ± 7.8 versus 21.2 ± 8.8; p=0.589) (Figure 1). In fact, in patients with three-vessel disease the CTA SYNTAX score almost uniformly overestimates the anatomical SYNTAX score derived from coronary angiography whereas the non-invasive functional SYNTAX score (FSS) was both feasible and yielded similar FSS compared to the invasive FSS and allowed similar reclassification rates. Being able to provide a noninvasive FSS offers significant potential to reduce resource utilisation at the time of ICA through reducing the need for invasive adjudication of ischaemia and by enabling the development of a revascularisation strategy in advance of ICA. In addition, by providing a non-biased threevessel anatomical and physiological mode, the historical anatomical bias that determined whether ischaemia should be adjudicated no longer exist. Given the growing evidence that incomplete ischaemic revascularisation results in worsened event-free survival, tools that allow for effective decision-making that results in a higher likelihood of full ischaemic revascularisation should be considered. This premise has been tested in the SYNTAX III trial which just recently completed enrolling. In this trial, subjects were randomised to non-invasive and invasive physiological adjudication of ischaemia. The results were reported at EuroPCR 2018 with the findings highlighting strong good agreement of treatment decision-making between CTA/ FFRCT and ICA/FFR strategy (Cohen’s kappa=0.82; CI: 0.73–0.91). The heart teams agreed on the coronary segments to be revascularised in 81.1 % of the cases. As well, FFRCT changed the treatment decision in 7 % (14/196) of the patients with 13 patients having a recommendation of surgical revascularisation changed to a percutaneous approach. Importantly, in both of these studies, CTA/FFRCT did not define the treatment but did provide important proof of concept and data to enable the initiation of the SYNTAX IV trial where patients will be randomly assigned to treatment decision-making by CTA/FFRCT

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Figure 1: Non-invasive Anatomical and Functional Assessment with CCTA/FFR CT Enabling the Calculation of a Functional SYNTAX Score Anatomical model

Functional assessment

SYNTAX assessment

Left: 3D anatomical model identifying a proximal LAD stenosis (red circle). Centre: FFRCT calculation yielding both anatomical and functional data. Right: The combination allows for the calculation of a non-invasive functional SYNTAX score.

Figure 2: Interactive Planning Tool for the Calculation of Post Revascularisation FFR CT.

Extracted 3D FFRCT pressure map (left) with a focal stenosis in the mid LAD. Idealised anatomical model following the placement of a mesh thereby remodelling LAD stenosis (centre) and enabling the subsequent recalculation of FFRCT following the resolution of the LAD stenosis (right).

versus the traditional approach of ICA/FFR. This trial represents the next step towards meaningfully embedding non-invasive imaging in interventional and revascularisation planning.

Reinvigoration of the Heart Team Over the last 15 years, we have seen a reinvigoration of the Heart team in the context of transcatheter aortic valve replacement (TAVR). This Heart team strategy has been pivotal in helping TAVR with its rapid evolution and clinical adoption. This collaborative pre-procedural discussion has allowed more informed and collaborative decisionmaking. These discussions have also allowed for deeper integration of non-invasive imaging in the structural space by allowing the imager to better understand the clinical needs and the interventionalists to better understand how non-invasive imaging can help inform decision-making and improve clinical outcomes. Unfortunately, the evolution of percutaneous coronary intervention has largely happened in isolation at least in part owing to the historical lack of meaningful non-invasive imaging to support decision-making. While invasive angiography is the gold standard for anatomy, with the improvements in coronary CTA and now advanced computational analytics offering non-invasive FFR, delta FFRCT, plaque and coronary geometry, it is time to revisit the coronary heart team for coronary artery disease. Perhaps the days of going to the catheterisation laboratory on the basis of symptoms and a nuclear stress test without any knowledge as to the extent, severity, or pattern of CAD are numbered. It would be hard to imagine going to the hybrid surgical suite and performing a TAVR without any baseline imaging or sizing of the annulus nor an assessment of anatomical drivers of procedural complications in the same way surgeons would not go to the operating room without imaging to provide an initial plan. Clearly, the incremental value of CTA FFRCT will need to be proven in a prospective randomised fashion but the opportunity is finally a reality.

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Coronary Recently, the concept of an interventional planner has been introduced where an idealised model is created to simulate the post PCI coronary artery allowing the calculation of a post-PCI FFRCT (Figure 2).14 This pre-procedural calculation of post procedural physiology offers another opportunity to help further guide the interventionalist with revascularisation decision-making. In the original feasibility accuracy study, virtual post FFRCT displayed fairly robust diagnostic performance for the prediction of post-PCI physiology. This initial version was limited in scope and clinical utility owing to the computational requirements which could not be met to allow timely enough modelling to be used for clinical care. With further improvements in computational capacity these idealised models can now be performed by physicians at their site, thereby opening up the opportunity to help inform revascularisation decision-making. Clearly this interactive planner will need further diagnostic performance validation and then ultimately, if proven to be robust, to determine its clinical utility and impact on clinical decisionmaking and downstream clinical outcomes.

for a roadmap prior to invasive evaluation may impact initial test selection amongst symptomatic patients with suspected CAD.

The Way Forward

Challenges

To tackle a disease as complex as CAD, having more information prior to the intervention may help with thoughtful and controlled decisionmaking. Recently, there has been increasing evidence of the incidence and associated risk of incomplete ischaemic revascularisation. Choi and colleagues found that approximately 25 % of patients undergoing multivessel disease revascularisation do not experience complete ischaemic revascularisation. Importantly, these subjects had a significantly higher MACE rate in multivariate analysis (adjusted hazard ratio: 4.17; 95 % confidence interval: 1.85–9.44; p<0.001).15 Whether pre-procedural review of CT anatomical and physiological findings will translate to more complete and appropriate revascularisation has yet to be proven but if so could result in a significant shift in the management of CAD. This hypothesis needs to be tested in a trial setting. SYNTAX IV will help fill the data gap but additional data are required from populations referred for invasive angiography.

There remain challenges with the integration of FFR CT into the clinical paradigm. The technological hurdles regarding computational processing have been significantly reducted in the turnaround time from 24 hours at the time of initial release to <5 hours in the large majority of cases at present. Lack of reimbursement in some healthcare environments has also posed meaningful challenges towards broad adoption. These economic and funding issues will need to continue to be managed globally to see meaningful pervasion into clinical practice. Finally, non-invasive diagnosis of coronary artery disease has long been dependent on ischaemia testing, this established practice pattern has supported the field for decades and shifting practice is not a minor task. It is possible that the demand from an interventional perspective

While it remains early in the clinical adoption of FFRCT and other advanced computational analytics in clinical practice with many outstanding clinical questions, we may be witnessing a paradigm shift in the management of coronary artery disease. It is possible that in the not-so-distant future that the majority of patients will go to the catheterisation laboratory with an interventional strategy in mind with a large majority undergoing ICA and also undergoing PCI. Beyond simply improving catheterisation laboratory efficiency, the ultimate goal is to ensure that those that undergo PCI receive the intended benefit of complete ischaemic revascularisation which the current paradigm is not offering with a high enough frequency. n

illiams M, Shambrook J, Nicol E. The assessment of W patients with stable chest pain. Heart 2018;104:691–9. https://doi.org/10.1136/heartjnl-2017-311212; PMID: 29084808. Williams MC, Moss A, Nicol E, Newby DE. Cardiac CT improves outcomes in stable coronary heart disease: results of recent clinical trials. Curr Cardiovasc Imaging Rep 2017;10:14. https://doi.org/10.1007/s12410-017-9411-7; PMID: 28446942. Foy AJ, Dhruva SS, Peterson B, et al. Coronary Computed Tomography Angiography vs Functional Stress Testing for Patients With Suspected Coronary Artery Disease: A Systematic Review and Meta-analysis. JAMA Intern Med 2017;177:1623–31. https://doi.org/10.1001/jamainternmed. 2017.4772; PMID: 28973101. Williams MC, Hunter A, Shah ASV et al. Use of coronary computed tomographic angiography to guide management of patients with coronary disease. J Am Coll Cardiol 2016;67:1759–68. https://doi.org/10.1016/j.jacc.2016.02.026; PMID: 27081014. SCOT-HEART Investigators. CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial. The Lancet 2015;385:2383–91. https://doi.org/10.1016/S01406736(15)60291-4; PMID: 25788230. Yan RT, Miller JM, Rochitte CE, et al. Predictors of inaccurate coronary arterial stenosis assessment by CT angiography. JACC Cardiovasc Imaging 2013;6:963–72. https://doi.org/10.1016/ j.jcmg.2013.02.011; PMID: 23932641.

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orgaard BL, Leipsic J, Gaur S, et al. Diagnostic performance N of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). J Am Coll Cardiol 2014;63:1145–55. https://doi.org/10.1016/j.jacc.2013.11.043; PMID: 24486266. 8. Koo BK, Erglis A, Doh JH et al. Diagnosis of ischemia-causing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms. Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study. J Am Coll Cardiol 2011;58:1989–97. https://doi.org/10.1016/j.jacc.2011.06.066; PMID: 22032711. 9. Min JK, Leipsic J, Pencina MJ, et al. Diagnostic accuracy of fractional flow reserve fromanatomic CT angiography. JAMA 2012;308:1237–45. https://doi.org/10.1001/2012.jama.11274; PMID: 22922562. 10. Nørgaard BL, Hjort J, Gaur S, et al. Clinical use of coronary CTA-derived FFR for decision-making in stable CAD. JACC Cardiovasc Imaging 2017;10:541–50. https://doi.org/10.1016/ j.jcmg.2015.11.025; PMID: 27085447. 11. Nørgaard BL, Gaur S, Leipsic J, et al. Influence of Coronary Calcification on the Diagnostic Performance of CT Angiography Derived FFR in Coronary Artery Disease:

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A Substudy of the NXT Trial. JACC Cardiovasc Imaging 2015;8:1045–55. https://doi.org/10.1016/j.jcmg.2015. 06.003; PMID:26298072. Møller Jensen J, Erik Bøtker H, Norling Mathiassen O, et al. Computed tomography derived fractional flow reserve testing in stable patients with typical angina pectoris: influence on downstream rate of invasive coronary angiography. Eur Heart J Cardiovasc Imaging 2017;19:405–14. https://doi.org/10.1093/ ehjci/jex068; PMID: 28444153. Collet C, Miyazaki Y, Ryan N, et al. Fractional flow reserve derived from computed tomographic angiography in patients with multivessel CAD. J Am Coll Cardiol 2018;71: 2756–69. https://doi.org/10.1016/j.jacc.2018.02.053; PMID: 29802016. Ihdayhid AR, White A, Ko B. Assessment of serial coronary stenoses with noninvasive computed tomography-derived fractional flow reserve and treatment planning using a novel virtual stenting application. JACC Cardiovasc Interv 10:e223–e225. https://doi.org/10.1016/j.jcin.2017.09.015; PMID: 29153499. Choi KH, Lee JM, Koo BK, et al. Prognostic implication of functional incomplete revascularization and residual functional SYNTAX score in patients with coronary artery disease. JACC Cardiovasc Interv 2018;11:237–45. https://doi.org/10.1016/j.jcin.2017.09.009; PMID: 29361444.

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Culprit Vessel Only Versus Complete Revascularisation in Patients with ST-Segment Elevation Myocardial Infarction – Should we Stay or Stage? Matthias Hasun and Franz Weidinger 2nd Medical Department with Cardiology and Intensive Care Medicine, KA Rudolfstiftung, Vienna, Austria

Abstract Multivessel coronary artery disease (MVCAD) is common in patients with ST-elevation myocardial infarction (STEMI), thereby negatively affecting mortality and outcome. Currently there is increasing evidence that complete revascularisation should be considered in haemodynamically stable patients. There are few larger randomised controlled trials available showing a lower risk of major adverse cardiac events after complete revascularisation, mainly driven by a reduction of repeat revascularisation. However, these trials are not adequately powered to show a mortality benefit or reduced risk of myocardial infarction. As there are several possible strategies, the presence of MVCAD often poses a therapeutic dilemma for interventional cardiologists and there is still ongoing debate on when and how to perform complete revascularisation. Pending further trials that may clarify which strategy is best, an individualised approach should be adopted.

Keywords ST-elevation myocardial infarction, multivessel coronary artery disease, complete revascularisation, repeat revascularisation, mortality Disclosure: The authors have no conflicts of interest to declare. Received: 27 April 2018 Accepted: 25 July 2018 Citation: Interventional Cardiology Review 2018;13(3):129–34. DOI: https://doi.org/10.15420/icr.2018.13.2 Correspondence: Prof Franz Weidinger, 2nd Medical Department with Cardiology and Intensive Care Medicine, Rudolfstiftung Hospital, Juchgasse 25, 1030 Vienna, Austria. E: franz.weidinger@wienkav.at

For ST-segment elevation myocardial infarction (STEMI), there is currently no doubt that primary percutaneous coronary intervention (PPCI) of the infarct related artery (IRA) is the preferred reperfusion strategy.1 In about 50 % of cases, STEMI is associated with multivessel coronary artery disease (MVCAD), defined as a ≥50 % stenosis in at least one non-infarct related epicardial coronary artery (N-IRA, Figure 1).2,3 Like many other factors, the number of diseased coronary arteries (‘disease burden’) influences mortality in STEMI patients, thereby doubling the risk of death in the short (30 days, 4.0 % versus 1.9 %) and long term (1 year, 7.0 % versus 3.0 %) in patients with MVCAD in a retrospective pooled analysis of eight randomised STEMI trials.3 Observational and randomised clinical trials so far showed conflicting results regarding the benefit of complete revascularisation, raising the question whether there is enough evidence to change current clinical practice and guidelines.

Complete Versus Culprit Only Revascularisation Small trials performing intravascular ultrasound (IVUS) have shown differences in plaque characteristics between patients with an acute coronary syndrome (ACS) and stable coronary artery disease (CAD). In ACS, N-IRAs tend to have more high risk features like diffuse CAD and less calcified plaques with thin-cap fibroatheromas and a higher percentage of lipid core, which makes them prone to rupture.4,5 The rationale for complete revascularisation in patients with myocardial infarction (MI) is therefore to reduce the global ischaemic burden and to prevent further cardiovascular events. On the other hand, one might argue that complete revascularisation leads to more procedures, with the associated risks of complications like stent thrombosis, contrast-induced nephropathy (CIN) or stroke, and moreover higher costs.

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The European Society of Cardiology (ESC) guidelines on Myocardial Revascularisation 2014 recommended PPCI for the culprit vessel, but revascularisation of additional lesions only in the case of cardiogenic shock.2 These recommendations were mainly driven by the results of observational trials showing increased in-hospital mortality, CIN and major adverse cardiovascular events (MACE) in case of multivessel PCI (MVPCI).6–8 The Hepacoat for Culprit or Multivessel Stenting for Acute Myocardial Infarction (HELP AMI) study, was one of the first randomised controlled trials (RCTs) to show that MVPCI was safe without any economic disadvantage.9 More recent RCTs showing that complete revascularisation might be beneficial under certain circumstances led to a change in recommendations in the 2017 STEMI guidelines from the former III to a IIa A recommendation (Table 1).1 In the single blind, randomised Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial, a total of 465 patients were evaluated, comparing culprit vessel only PCI (n=231) and immediate MVPCI (n=234) in STEMI. Recruitment was stopped prematurely by the data and safety monitoring board because of highly significant between group differences in favour of preventive PCI.10 The primary composite endpoint, consisting of death from cardiac cause or non-fatal MI or refractory angina, was significantly reduced after MVPCI after a mean follow up (FUP) time of 23 months (HR: 0.35, 95 % CI: 0.21–0.58, p<0.001, 21 versus 53 primary outcomes). This absolute risk reduction of 14 % was evident within 6 months and maintained thereafter. The reduction in risk was similar for the individual secondary endpoints (death from cardiac cause, non-fatal MI, refractory angina, and repeat revascularisation). Of these components, only death from cardiac cause was not significantly different (HR: 0.34, 95 % CI: 0.11–1.08, p=0.07). There was no difference concerning all-cause mortality between the two groups (HR 1.10, 95 % CI 0.38–3.18, p=0.86).

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Coronary Figure 1: STEMI of the Anterior Wall: Single Vessel Disease and Multivessel Disease

A, B: Coronary angiography documented a single vessel disease with a subtotal proximal occlusion of the LAD with TIMI I flow in a 75-year-old patient. C, D: Anterior wall STEMI showing a long segment 95 % stenosis of the proximal LAD (culprit lesion). Coronary angiography documented additional lesions (*) of 50–70 % in the ostial LAD, 70–90 % in the mid and distal LCx, 90 % in the mid RCA and 50–70 % in the distal segment of RCA. LAD = left anterior descending; TIMI = thrombolysis in myocardial infarction; STEMI = ST elevation myocardial infarction; LCx = left circumflex; RCA = right coronary artery.

Procedure time, fluoroscopy dose and contrast volume increased in these patients, thereby not affecting complications like procedurerelated stroke, bleeding and CIN. However, this trial was not designed to address the question of immediate versus staged preventive PCI in STEMI multivessel disease.10 In The Third Danish Study of Optimal Acute Treatment of Patients with STEMI: Primary PCI in Multivessel Disease (DANAMI-3 PRIMULTI), 627 STEMI patients with MVCD were randomly assigned to undergo PPCI of the culprit vessel only (n=313) or staged complete fractional flow reserve (FFR) guided PCI (n=314) before discharge. A FFR value ≤0.80 was considered haemodynamically significant and complete revascularisation was performed a median of 2 days after initial PCI.11 After a median FUP of 27 months the primary combined endpoint of all-cause mortality, re-infarction and ischaemia-driven revascularisation was significantly reduced in the staged FFR-guided complete revascularisation group (HR: 0.56, 95 % CI: 0.38–0.83, 0=0.004). This was mainly driven by a 69 % reduction of repeat revascularisation of the N-IRA (HR: 0.31, 95 % CI: 0.18–0.53, p<0.0001). This effect was more pronounced in young men with anterior MI. However, these subgroups were too small to draw firm conclusions. There was no difference concerning all-cause mortality and non-fatal re-infarction. Furthermore, there were no significant differences of procedure-related complications (MI, bleeding requiring transfusion, stroke or CIN). This trial failed to show differences in hard clinical endpoints like mortality and re-infarction because of a lack of power and like PRAMI, it did not address the question of optimal timing of preventive multivessel PCI.11 Another RCT focusing on preventive MVPCI in STEMI is the Complete versus Lesion-only Primary PCI (CvLPRIT) trial, including 306 patients

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for IRA PCI only (n=146) or complete revascularisation (n=150) during hospital stay, either during PPCI (recommended, 64 %) or staged before discharge. The primary outcome of MACE (all-cause mortality, recurrent MI, heart failure, ischaemia-driven revascularisation) was significantly reduced in favour of preventive PCI (10 % versus 21.2 %, HR 0.45, 95 % CI 0.24–0.84, p=0.009), leading to a 55 % relative risk reduction in the primary endpoint.12 The individual components of the primary outcome were lower in the complete revascularisation arm, although not statistically significant. Again, Kaplan–Meier curves showed early divergence, with a continuing separation of groups during FUP. There were no differences in the occurrence of serious adverse events between the two groups. Similar to PRAMI and DANAMI-3 PRIMULTI, this trial was not powered to show significant differences in hard clinical endpoints. Furthermore, as almost two thirds of patients were revascularised during initial PCI, timing of preventive revascularisations remains unclear. Like in PRAMI, the CvLPRIT trial did not evaluate the role of FFR for MVPCI.12 Finally, the most recent RCT to address this issue was the Comparison Between FFR Guided Revascularization Versus Conventional Strategy in Acute STEMI Patients with MVD (COMPARE-ACUTE) trial, which enrolled 885 patients. Patients were randomly assigned in a 2:1 fashion to receive either FFR-guided complete revascularisation (n=295) or culprit-only revascularisation (n=590).13 Complete revascularisation was performed in 83.4 % of patients during PPCI in lesions with FFR ≤0.80. The primary endpoint was a composite of all-cause mortality, non-fatal MI, any revascularisation, and cerebrovascular events (MACCE) at 12 months. In COMPARE-ACUTE, MACCE was significantly reduced in preventive FFR guided PCI (23 versus 121 patients, HR: 0.35, 95 %: CI 0.22–0.55, p<0.001), an effect which was mainly driven by a decreased need for revascularisation (HR 0.32, 95 % CI 0.20–0.54, p<0.001). The other components of the primary endpoint did not differ significantly. As there were no significant differences in bleeding, cerebrovascular events and stent thrombosis, this study showed that FFR could be safely performed in PPCI. However, also this trial was not powered to show differences in hard clinical end points.13

Timing of Revascularisation So far, four different strategies of revascularisation are possible for treatment of MVCD in STEMI: (1) complete revascularisation at the index procedure; (2) complete revascularisation as a staged procedure before discharge; (3) complete revascularisation as a staged procedure after discharge but within a few weeks (not symptom driven); and (4) culprit vessel only PCI. Of the aforementioned RCTs, none included both staged and immediate complete revascularisation and analysed them separately. Politi et al. conducted a small RCT earlier, randomising 214 patients to IRA PCI only (n=81), complete revascularisation during index procedure (n=65), or staged 2 months after index procedure (n=65).14 Patients undergoing staged or immediate procedures had a 63 % (p=0.003) and a 60 % (p=0.002) risk reduction of MACE after a median FUP of 2.5 years, mainly driven by a lower incidence of in-hospital death, re-PCI and re-hospitalisation. There was no significant difference between the two different MVPCI strategies concerning MACE and the safety outcomes (length of hospital stay, CIN). Primarily this study suffered from a small sample size.14 A post-hoc analysis of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, originally designed to compare bivalirudin to heparin plus GbIIb/IIIa inhibitors during primary P-PCI, retrospectively evaluated 275 patients

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Revascularisation in STEMI Patients Table 1: Overview of RCTs Comparing Culprit Only to Multivessel Revascularisation in Acute STEMI Patients Outcome

Inclusion

Culprit

Complete,

Lesion

Type of complete

Primary

FUP,

period

only (n)

index (n)

staged (n)

criteria (%

revascularisation

endpoint

months

Politi et al.

2003–2007

≥70 % stenosis in ≥2 N-IRAs

Index complete, or staged after 2 months

MACE

63 % relative risk reduction of MACE after immediate complete revascularisation, 60 % after staged revascularisation

PRAMI

2008–2013

231

234

≥50 %

Immediate or no preventive PCI

Composite: death from cardiac cause, MI, refractory angina

65 % relative risk reduction in primary endpoint due to complete revascularisation, no significant difference in death

DANAMI-3 PRIMULTI

2011–2014

313

314

≥50 % in at least 1 N-IRA

Staged FFR guided before discharge

Composite: allcause death, MI, ischemia-driven revascularisation

44 % relative risk reduction in primary endpoint due to reduction in ischaemia-driven revascularisation in complete revascularisation

CvULPRIT

2011–2013

146

≥50 % in 2 vessels, ≥70 % in 1 vessel

Immediate (recommended) or during index admission

MACE (all-cause mortality, MI, heart failure, ischemia-driven revascularisation

55 % relative risk reduction in primary endpoint in the complete revascularisation group

COMPARE ACUTE

2011–2015

590

295

≥50 % + FFR ≤0.80

Immediate FFR guided

Composite: all-cause mortality, MI, any revascularisation, cerebrovascular events

65 % relative risk reduction of primary endpoint in complete revascularisation (revascularisation driven)

RCT

(mean)

stenosis)

RCT = randomized controlled trial; FUP = follow up; N-IRA = non-infarct related artery; MACE = major adverse cardiovascular event; PCI = percutaneous coronary intervention; MI = myocardial infarction; FFR = fractional flow reserve.

undergoing MVPCI during index and 393 patients during staged procedure.15 In this study immediate MVPCI was associated with an increased all-cause mortality (HR 4.1, 95 % CI 1.93–8.86, p<0.0001) and cardiovascular mortality (HR 3.41, 95 % CI 1.35–7.27, p=0.005).15 In order to further address the issue of ideal timing of revascularisation, a recent network meta-analysis was conducted by Elgendy et al. comparing the four treatment strategies.16 The most important quality criteria of included trials were an adequate description of treatment allocation, blinded outcome assessment and description of losses to follow up. In the sensitivity analyses, trials were excluded if they did not include urgent revascularisation as part of MACE, were conducted before 2010, included less than 100 patients, and are yet to be published. A total of 10 trials with 2,285 patients were included in the final analysis. The median FUP time was 25 months (6–38 months). The primary outcome of MACE, defined as in the individual trials, was significantly reduced due to complete revascularisation (index procedure: RR: 0.37, 95 %: CI 0.24–0.59; staged before discharge: RR: 0.49, 95 % CI: 0.27–0.91; staged after discharge: RR 0.58, 95 % CI 0.35–0.97), but there were no differences between the different complete revascularisation strategies. Similar repeat urgent revascularisation was lower in patients fully revascularised, again

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Table 2: 2017 Recommendations of the ESC for STEMI Patients with MVCAD Recommendation

Classa

Levelb

Reference studyc

Routine revascularisation of non-IRA lesions should be considered in STEMI patients with MVD before hospital discharge

IIa

PRAMI, DANAMI-3 PRIMULTI, CvLPRIT, COMPARE-ACUTE

Non-IRA PCI during the index procedure should be considered in patients with cardiogenic shock despite revascularisation of the IRA

IIa

Expert opinion CULPRIT-SHOCK not considered yet

CABG should be considered in patients with ongoing ischaemia and large areas of jeopardised myocardium if PCI of the IRA cannot be performed.

IIa

Expert opinion

N-IRA = non infarct related artery; STEMI = ST elevation myocardial infarction; MVCAD = multivessel coronary artery disease; PPCI = primary PCI; CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention; IRA = infarct related artery. aclass of recommendation, blevel of evidence, crandomised controlled trial supporting the evidence.

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Coronary showing no difference between complete revascularisation at the index procedure or as staged procedure (index procedure: RR: 0.32, 95 % CI: 0.19–0.54; staged before discharge: RR: 0.31, 95 % CI: 0.15–0.65; staged after discharge: RR: 0.46, 95 % CI: 0.25–0.85). There was no difference in the risk of all-cause mortality among the four revascularisation strategies. The authors concluded that each of the three revascularisation strategies has advantages and disadvantages concerning technical and pathophysiological aspects. Furthermore, they stated that 4325 patients (power analysis) would be needed to achieve 80 % power for all-cause mortality.16 Earlier meta-analysis concluded that staged complete revascularisation is associated with the lowest risk of short- and long-term mortality.17,18 However, in contrast to the meta-analysis performed by Elgendy et al., these analyses mainly included observational studies. In a pre-specified subgroup analysis of the CvLPRIT trial, infarct size and left ventricular function in patients who underwent immediate compared to staged complete revascularisation were assessed.19 In a post hoc analysis cardiac magnetic resonance (CMR) scans were performed before discharge, after any staged procedure and after 9 months in 98 patients.20 Patients who were chosen to have staged MVPCI had more visible IRA thrombus, a higher SYNTAX score and more no-reflow after PCI. These differences in baseline characteristics led to larger infarcts, less myocardial salvage and reduced ejection fraction as detected by CMR. A surprising finding of this study was a higher frequency of N-IRA MI (type 4a MI) detected by CMR in patients treated with staged procedure (40 % versus 14 %, p=0.006), which may be related to a greater number of stents implanted in the staged group and different use of adjunctive medication (bivalirudin, Gp IIb/IIIa inhibitors). However, as these patients were not randomised to immediate or staged procedure and due to differences in baseline characteristics, these results can only be considered hypothesis-generating.20 The aim of the most recent meta-analysis by Pasceri et al. was to assess whether complete revascularisation can reduce hard clinical endpoints such as total mortality and MI and to determine the possible role of timing of revascularisation.21 Eleven randomised trials enrolling 3561 patients were included. Patients who had complete revascularisation (immediate or staged) had a 25 % relative risk reduction of all-cause mortality or MI (p=0.04). Taking all 11 RCTs together, immediate complete revascularisation significantly reduced death or MI when compared to staged procedure (p=0.025).21 A possible explanation made by the authors refers to the pathophysiology of the disease as the risk of adverse events in STEMI is higher within the first few days.3 Thus, achieving complete revascularisation as soon as possible might help to reduce the risk of death or MI. However, none of these trials staged patients within the first two days, leaving the question open if early staging is as good as immediate PCI. To summarise these findings, there is currently some evidence that complete revascularisation is beneficial compared to a culprit only strategy, although adequately powered RCTs to assess the impact on all-cause mortality are still missing. There is currently no randomised controlled evidence to prefer one MVPCI strategy over the others as head-to-head comparisons in large cohorts are missing. Furthermore, as most RCTs excluded high risk patients (cardiogenic shock, chronic total occlusion, left main stenosis), evidence in these populations is lacking and they have to be discussed separately.

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STEMI Patients Suffering from Cardiogenic Shock and MVCAD Cardiogenic shock is a serious condition complicating acute MI in 5–10 % of patients and is associated with a short-term mortality of 40–50 %.1 About 80 % of patients suffering from cardiogenic shock have MVCAD, further increasing mortality in these patients.22,23 The main argument in favour of immediate complete PCI in these patients is the improvement of overall myocardial perfusion and function, which is counteracted by the risk of renal impairment due to contrast volume, prolongation of procedure time and volume overload. Meta-analysis of observational trials suggested that immediate MVPCI is harmful in patients with MI and cardiogenic shock and that shortterm mortality is higher.23 This result was intriguing as it challenged the 2017 recommendation of the ESC to consider immediate MVPCI in patients with STEMI and cardiogenic shock (expert opinion). The Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial randomly assigned patients with acute MI (STEMI and NSTEMI) and MVCAD (n=706) to immediate complete or target vessel only PCI (complete revascularisation encouraged). Staged procedure in the latter group was performed on the basis of symptoms of ischaemia, FFR, non-invasive testing, and clinical and neurological status. The study was designed to test the hypothesis that culprit lesion only PPCI is superior in this population. The primary endpoint was a composite of death from any cause and severe renal failure leading to renal replacement therapy within 30 days. The primary endpoint was significantly lower in patients who had target vessel only PCI during index procedure (45.9 versus 55.4 %, RR: 0.83, 95 % CI: 0.71–0.96, p=0.01). Furthermore, relative risk of death (RR: 0.84, 95 % CI: 0.72–0.98, p=0.03) and renal replacement therapy (RR: 0.71, 95 % CI: 0.49–1.03, p=0.07) was reduced in these patients. There were no significant differences in recurrent MI, rehospitalisation for congestive heart failure, bleeding and stroke. The authors concluded that the acute hazards of a prolonged procedure time seem to outweigh any potential negative effects of repeat revascularisation. The main limitations of the study were crossover between groups (although rather infrequent) and the fact that cardiogenic shock management was not standardised.

STEMI Patients Suffering from MVCAD with Chronic Total Occlusion Chronic total occlusion (TO) is found in 10–15 % of STEMI patients.24 There is currently increasing evidence that worse outcome of patients suffering from MVCAD compared with single vessel disease is mainly driven by CTO. In observational trials, revascularisation of CTO lesions led to improvement of LVF and survival. However, PCI is offered only to a minority of patients with CTO (10 %).25,26 The first RCT powered to show differences in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) was the Evaluating Xience and Left Ventricular Function in Percutaneous Coronary Intervention on Occlusions After ST-Segment Elevation Myocardial Infarction (EXPLORE) trial. 27 The hypothesis behind revascularisation of CTO in STEMI patients was restoration of contractile function and an improved healing of infarct border zone. Patients were randomly assigned to staged PCI of CTO within 7 days after STEMI (n=150) or no PCI of CTO (n=154). There were no differences in the two primary endpoints LVEF (CTO PCI: 44.1 ± 12.2 % versus no CTO PCI: 44.8 ± 11.9 %, p=0.6) and LVEDV (CTO PCI: 215.6 ± 62.5 ml versus no CTO PCI: 212.8 ± 60.3 ml, p=0.7) after 4 months evaluated by

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Revascularisation in STEMI Patients cardiac MRI. Furthermore, there was no significant difference in MACE (CTO PCI: 5.4 % versus no CTO PCI: 2.6 %, p=0.25). The adjudicated success rate of CTO PCI was 73 %. However, in a subgroup analysis, PCI in patients with CTO in the left anterior descending artery (LAD) led to a significantly improved LVEF (47.2 ± 12.3 % versus 40.4 ± 11.9 %, p=0.02). An improvement in LVEF was also found in earlier large observational trials.28,29 The main limitations of this trial were the exclusion of high risk patients, a loss of power as the CTO PCI success rate was lower than expected and the trial was not powered to show differences in hard clinical endpoints.

Future Perspectives The variety of trials conducted leaves us with uncertainty on when and how to perform complete revascularisation in STEMI patients. Furthermore, as all the aforementioned RCTs lack power to show differences in relevant clinical endpoints, there is a need for larger trials to address these issues. Three ongoing trials will help to further clarify the role of complete revascularisation in STEMI patients with MVCAD. The Complete Versus Culprit-only Revascularization to Treat Multivessel Disease After PCI for STEMI (COMPLETE) trial was designed to randomly assign STEMI patients to staged complete PCI versus optimal medical treatment 72 hours after PPCI. The trial is estimated to be completed at the end of 2018. The primary outcome is a composite of cardiovascular death or new MI, over a FUP period of 4 years (Clinical Trials.gov Identifier: NCT01740479). The MULTIvessel Immediate Versus STAged RevaScularization in Acute Myocardial Infarction (MULTISTARS AMI) trial estimates to enrol 1200 patients comparing complete revascularisation during the index procedure to culprit lesion only PPCI, but subsequent staged revascularisation of all relevant lesions within 19–45 days. The primary outcome of the trial is a composite endpoint of all-cause death, non-fatal myocardial infarction and unplanned ischaemia-driven revascularisation. The estimated study completion date is December 2019 (Clinical Trials.gov Identifier: NCT03135275). Finally, the FULL REVASC (FFR-Guidance for Complete Non-Culprit Revascularization)

I banez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–177. https://doi. org/10.1093/eurheartj/ehx393; PMID: 28886621. 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. Park D-W, Clare RW, Schulte PJ, et al. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA 2014:312:2019–27. https://doi.org/10.1001/ jama.2014.15095; PMID: 25399277. Pundziute G, Schuijf JD, Jukema JW, et al. Evaluation of plaque characteristics in acute coronary syndromes: noninvasive assessment with multi-slice computed tomography and invasive evaluation with intravascular ultrasound radiofrequency data analysis. Eur Heart J 2008;29: 2373–81. https://doi.org/10.1093/eurheartj/ehn356; PMID: 18682447. Rodriguez-Granillo GA, McFadden EP, Valgimigli M, et al. Coronary plaque composition of nonculprit lesions, assessed by in vivo intracoronary ultrasound radio frequency data analysis, is related to clinical presentation. Am Heart J 2006:151:1020–24. https://doi.org/10.1016/j.ahj.2005.06.040; PMID: 16644327. Rigattieri S, Biondi-Zoccai G, Silvestri P, et al. Management of multivessel coronary disease after ST elevation myocardial infarction treated by primary angioplasty. J Interv Cardiol 2008;21:1–7. https://doi.org/10.1111/j.1540-

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10.

11.

12.

13.

trial will randomise STEMI patients (n=4052) to FFR-guided non-culprit PCI, either immediately or staged. The study is powered to detect differences in 1-year all-cause mortality and MCI (Clinical Trials.gov Identifier: NCT02862119).

Conclusions Complete revascularisation should be considered in patients with STEMI and MVCAD. This recommendation, recently introduced in the STEMI Guidelines 2017 of the ESC (Table 2), is mainly driven by a lower rate of repeat revascularisation in these patients. However, the optimal time point of complete revascularisation in haemodynamically stable patients is still a matter of debate. In cardiogenic shock a ‘culprit vessel only’ strategy during PPCI seems to be beneficial, as prolonged procedures in this setting might be hazardous. Although the role of FFR or imaging techniques like cardiac MRI is still not clear, there is little evidence that FFR guided complete revascularisation could be safely done during the index procedure. In complex lesions such as CTO, staged revascularisation did not prove to have any beneficial effects so far, except in a sub-group of patients with CTO of the LAD. As recent RCTs failed to show differences in hard clinical endpoints, further larger trials are needed to answer the question if we should ‘stay or stage’ in patients with STEMI and MVCAD.

Personal Approach In our own institution, which is part of the Vienna STEMI network, we attempt full revascularisation in a ‘stay AND stage’ fashion, i.e. performing FFR-guided revascularisation of non-culprit lesions in a second sitting within the hospital stay. In stabilised patients, such as those with spontaneously recanalised culprit lesions, there is little reason not to treat an unambiguous tight non-culprit lesion, if proximal and easily accessible. In contrast, patients with complex non-culprit lesions such as left main or complex bifurcations should be treated in a staged procedure. In patients with shock, based on recent data, the decision to treat more than just the culprit lesion should be carefully made based on the morphology and relevant territory of the given lesions. n

8183.2007.00317.x; PMID: 18086133. Hannan EL, Samadashvili Z, Walford G, et al. Culprit vessel percutaneous coronary intervention versus multivessel and staged percutaneous coronary intervention for ST-segment elevation myocardial infarction patients with multivessel disease. JACC Cardiovasc Interv 2010;3:22–31. https://doi. org/10.1016/j.jcin.2009.10.017; PMID: 20129564. Toma M, Buller CE Westerhout, et al. Non-culprit coronary artery percutaneous coronary intervention during acute ST-segment elevation myocardial infarction: insights from the APEX-AMI trial. Eur Heart J 2010;31:1701–7. https://doi. org/10.1093/eurheartj/ehq129; PMID: 20530505. Di Mario C, Mara S Flavio A, et al. Single vs multivessel treatment during primary angioplasty: results of the multicentre randomised HEpacoat for cuLPrit or multivessel stenting for Acute Myocardial Infarction (HELP AMI) Study. Int J Cardiovasc Intervent 2004;6:128–33. https://doi. org/10.1080/14628840310030441; PMID: 16146905. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med 2013;369:1115–23. https://doi.org/10.1056/NEJMoa1305520; PMID: 23991625. Engstrom T, Kelbaek H, Helqvist S, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet 2015; 386:665–71. https://doi.org/10.1016/S0140-6736(15)60648-1; PMID: 26347918. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol 2015;65:963–72. https://doi.org/10.1016/ j.jacc.2014.12.038; PMID: 25766941. Smits PC, Boxma-de Klerk BM. Fractional flow reserve-guided multivessel angioplasty in myocardial infarction. N Engl J Med

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15.

16.

17.

18.

19.

2017;377:397–8. https://doi.org/10.1056/NEJMoa1701067; PMID: 28745981. Politi L, Sgura F Rossi R, et al. A randomised trial of targetvessel versus multi-vessel revascularisation in ST-elevation myocardial infarction: major adverse cardiac events during long-term follow-up. Heart 2010;96:662–7. https://doi. org/10.1136/hrt.2009.177162; PMID: 19778920. Kornowski R. Mehran R, Dangas G, et al. Prognostic impact of staged versus “one-time” multivessel percutaneous intervention in acute myocardial infarction: analysis from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol 2011;58:704–11. https://doi.org/10.1016/j.jacc.2011.02.071; PMID: 21816305. Elgendy IY, Mahmoud AN, Kumbhani DJ, et al. Complete or Culprit-Only Revascularization for Patients With Multivessel Coronary Artery Disease Undergoing Percutaneous Coronary Intervention: A Pairwise and Network Meta-Analysis of Randomized Trials. JACC Cardiovasc Interv 2017;10:315–324. https://doi.org/10.1016/j.jcin.2016.11.047; PMID: 28231899. Vlaar PJ, Mahmoud BS, Homes Jr DR, et al. Culprit vessel only versus multivessel and staged percutaneous coronary intervention for multivessel disease in patients presenting with ST-segment elevation myocardial infarction: a pairwise and network meta-analysis. J Am Coll Cardiol 2011;58:692–703. https://doi.org/10.1016/j.jacc.2011.03.046; PMID: 21816304. Tarantini G, D.Amico G, Brener SJ, et al. Survival After Varying Revascularization Strategies in Patients With ST-Segment Elevation Myocardial Infarction and Multivessel Coronary Artery Disease: A Pairwise and Network Meta-Analysis. JACC Cardiovasc Interv 2016;9:1765–76. https://doi.org/10.1016/ j.jcin.2016.06.012; PMID: 27609250. McCann GP, Khan, JN, Greenwood JP, et al. Complete Versus Lesion-Only Primary PCI: The Randomized Cardiovascular MR CvLPRIT Substudy. J Am Coll Cardiol 2015;66:2713–24. https://doi.org/10.1016/j.jacc.2015.09. 099; PMID: 26700834.

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Coronary 20. K han, JN, Nazir, SA, Greenwood JP, et al. Infarct size following complete revascularization in patients presenting with STEMI: a comparison of immediate and staged in-hospital non-infarct related artery PCI subgroups in the CvLPRIT study. J Cardiovasc Magn Reson 2016;18:85. https://doi.org/10.1186/s12968-0160298-2; PMID: 27842548. 21. Pasceri V, Patti G, Pelliccia F, et al. Complete Revascularization During Primary Percutaneous Coronary Intervention Reduces Death and Myocardial Infarction in Patients With Multivessel Disease: Meta-Analysis and Meta-Regression of Randomized Trials. JACC Cardiovasc Interv 2018;11:833–43. https://doi. org/10.1016/j.jcin.2018.02.028; PMID: 29747913. 22. Webb JG, Lowe AM, Sanborn TA, et al. SHOCK Investigators. Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial. J Am Coll Cardiol 2003;42:1380–6. https://doi. org/10.1016/S0735-1097(03)01050-7; PMID: 14563578 23. de Waha S, Jobs A, Eitel I, et al. Multivessel versus culprit

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lesion only percutaneous coronary intervention in cardiogenic shock complicating acute myocardial infarction: A systematic review and meta-analysis. Eur Heart J Acute Cardiovasc Care 2018;7:28–37. https://doi.org/10.1177/2048872617719640; PMID: 28703046. 24. Claessen BE, van der Schaaf RJ, Verouden NJ, et al. Evaluation of the effect of a concurrent chronic total occlusion on long-term mortality and left ventricular function in patients after primary percutaneous coronary intervention. JACC Cardiovasc Interv 2009;2:1128–34. https://doi.org/10.1016/ j.jcin.2009.08.024; PMID: 19926056. 25. Hoebers LP, Claessen BE, Elias J, et al. Meta-analysis on the impact of percutaneous coronary intervention of chronic total occlusions on left ventricular function and clinical outcome. Int J Cardiol 2015;187:90–6. https://doi.org/10.1016/ j.ijcard.2015.03.164; PMID: 25828320. 26. Grantham JA, Marso, SP, Spertus, MPH, et al. Chronic total

occlusion angioplasty in the United States. JACC Cardiovasc Interv 2009;2:479–86. https://doi.org/10.1016/j.jcin.2009.02.008; PMID: 19539249. 27. Henriques JP, Hoebers LP, Ramunddal T, et al. Percutaneous Intervention for Concurrent Chronic Total Occlusions in Patients With STEMI: The EXPLORE Trial. J Am Coll Cardiol 2016; 68: 1622–32. https://doi.org/10.1016/j.jacc.2016.07.744; PMID: 27712774. 28. Claessen BE, Dangas, GD, Godino, C, et al. Impact of target vessel on long-term survival after percutaneous coronary intervention for chronic total occlusions. Catheter Cardiovasc Interv 2013;82:76–82. https://doi.org/10.1002/ccd.24579; PMID: 22888007. 29. Safley DM, House JA, Marso SP, et al. Improvement in survival following successful percutaneous coronary intervention of coronary chronic total occlusions: variability by target vessel. JACC Cardiovasc Interv 2008;1:295–302. https://doi.org/10.1016/ j.jcin.2008.05.004; PMID: 19463316.

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Expert Opinion: Coronary

ORBITA: What Goes Around, Comes Around… Or Does It? Matthew Jackson and Azfar Zaman Freeman Hospital, High Heaton, Newcastle-Upon-Tyne, UK

Abstract Current guidelines recommend percutaneous coronary intervention (PCI) in patients with ongoing stable angina symptoms despite optimal medical therapy (OMT), although trials have shown no reduction in death or myocardial infarction. The recently published ORBITA trial compared OMT + PCI with OMT + ‘placebo’ PCI in patients with angina and single-vessel coronary artery disease (CAD), and found no significant difference in treadmill exercise time between the two groups after six weeks. The trial concluded that invasive procedures can be assessed with placebo control while numerous editorials interpreted the trial as showing that PCI has no role in the management of stable angina. However, the highly selected patient population, low ischaemic burden and level of symptoms and high proportion of nonflow-limiting stenoses on invasive physiological testing mean that, while ground-breaking in terms of its methodology, ORBITA does not add to the current evidence base supporting ischaemia-guided revascularisation if symptoms are not controlled on medical therapy alone.

Keywords Stable angina, ORBITA, percutaneous coronary intervention, placebo controlled, fraction-flow reserve, coronary artery disease Disclosure: The authors have no conflicts of interest to declare Received: 30 May 2018 Accepted: 9 August 2018 Citation: Interventional Cardiology Review 2018;13(3):135–6. DOI: https://doi.org/10.15420/icr.2018.18.2 Correspondence: Prof Azfar Zaman, Freeman Hospital, High Heaton, Newcastle-Upon-Tyne, NE7 7DN. E: azfar.zaman@nuth.nhs.uk

Medical therapy has been the primary treatment for stable angina since nitroglycerin was first used in 1878. However, since the first successful percutaneous coronary intervention (PCI) procedure was performed in 1977, the role of PCI in patients with stable coronary artery disease (CAD) has been the subject of much study. Numerous trials have shown no reduction in death or myocardial infarction.1–5 However, these trials suggest that PCI is maybe more effective for managing angina symptoms than medical therapy alone. The Angioplasty Compared To Medicine (ACME) study showed that 64 % of 96 patients in the PCI group were angina free compared with 46 % of 102 medically treated patients (p=0.01) at 6 months’ follow-up, supported by a significant increase in exercise tolerance (2.1 minutes versus 0.5 minutes; p<0.0001).1 The Clinical Outcomes Utilising Revascularisation and Aggressive Drug Evaluation (COURAGE) trial showed similar findings (21 % of patients were angina free following PCI versus 10 % who were angina free following medical therapy) at 30 days’ follow-up using more contemporary versions of optimal medical therapy (OMT); however, this improvement was no longer present at 3 years.2,3 Current guidelines recommend titration of several pharmacological agents with complementary mechanisms of action. 6,7 However, analysis of the US National Cardiovascular Data Registry suggests that fewer than half of patients undergoing PCI for stable CAD receive OMT at the time of their PCI.8 Furthermore, the known placebo power of invasive procedures has not been established since the introduction of PCI. Studies in the 1950s and 1960s examined the effects of performing sham operations in patients planned for [internal mammary artery] ligation; one found that all sham patients exhibited improved exercise tolerance and used less glyceryl trinitrate compared with 75 % of patients who underwent IMA ligation;9 another showed

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over half of patients in both groups had subjective improvement at 6 months.10

Trial Summary The Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial is a multicentre, randomised, double-blinded trial enrolling patients with angina, preserved left ventricular systolic function and single-vessel CAD.11 All 230 patients enrolled underwent a 6-week run-in period, during which time medical therapy was optimised with phone contact with a consultant cardiologist up to three times a week. Two hundred patients proceeded to be randomly allocated to PCI or ongoing medical therapy. All patients then underwent invasive physiological measurement of the study lesion. The patients were blinded to whether they underwent PCI or physiological measurement only and the physicians were blinded to the results of the physiological measurements. If patients were randomised to PCI, this was performed with drug-eluting stents with measurement repeated. The primary endpoint was improvement in treadmill exercise time between randomisation and follow up at six-weeks; no significant difference was noted (28.4 seconds after PCI versus 11.8 seconds in the placebo group, p=0.20). Analysis of secondary endpoints – change in peak oxygen uptake, change in exercise time to 1 mm ST-segment depression, angina severity as assessed by Canadian Cardiovascular Society (CCS) class, physical limitation, angina stability and angina frequency assessed with the Seattle Angina questionnaire, quality of life scores and Duke Treadmill score – supported these findings with only a small but statistical significant change in dobutamine stress echocardiography wall motion score index favouring PCI. These results have subsequently been presented as the “final nail in the coffin of PCI”, garnering significant interest in the mainstream media.12

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Expert Opinion: Coronary Discussion The ORBITA trial is the first true comparison between OMT with PCI and OMT with blinded placebo PCI with patients undergoing a sham PCI. The authors suggest PCI is no better than OMT in stable angina. However, closer analysis of the trial design and data casts doubt on the study conclusion. First, the patient population studied is highly selective, excluding those with multi-vessel disease and impaired left ventricular function. The trial recruited at five large PCI centres for almost 4 years; only a small minority of patients planned to undergo PCI were suitable for enrolment. Second, although almost 98 % of patients had CCS II or III angina on enrolment, 23 % in the PCI arm and 25 % in the placebo arm had CCS 0–I angina by the end of the run-in period. Patients were taking three antianginal medications and had a Seattle Angina Questionnaire physical limitation score of around 70, indicating low to moderate limitation. Given this low level of symptoms, it would have been difficult to show an incremental benefit with PCI. The short follow-up period means that the effects of PCI over a longer timespan are unclear; of note, the FAME 2 trial published at the same time, which compared PCI with OMT, showed a reduction of over 50 % in major adverse cardiac events (MACE) following PCI during the three-year follow-up period, although in a different patient population (one with multivessel disease).13 Although ORBITA was not designed to test MACE, we note that studies documenting time to event in the stable angina group suggest such events in patients who are medically managed peak after 12 months, and longer follow-up periods may be required to detect recurrence of angina after the initial ‘honeymoon’ period following the PCI or placebo procedure. Finally, the use of fraction-flow reserve (FFR) is strongly encouraged in current guidelines to guide revascularisation in stable CAD. Fifteen-year outcome data clearly demonstrate postponing PCI in vessels with a FFR >0.75 to be safe and associated with a low rate of clinical endpoints.14 FFR-guided PCI in multivessel disease has also shown greater benefit from revascularisation than OMT.13 The ORBITA study recorded FFR

arisi AF, Folland ED, Hartigan P. A comparison of angioplasty P with medical therapy in the treatment of single-vessel coronary artery disease. Veterans Affairs ACME Investigators. N Engl J Med 1992;326:10–16. https://doi.org/10.1056/ NEJM199201023260102. PMID: 1345754. Weintraub WS, Spertus JA, Kolm P, et al. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med 2008;359:677–87. https://doi.org/10.1056/NEJMoa072771. PMID: 18703470. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503−16. https://doi.org/10.1056/ NEJMoa070829. PMID: 17387127. Frye RL, August P, Brooks M, et al. A randomised trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503-2515. https://doi.org/10.1056/ NEJMoa0805796. PMID: 19502645; PMCid: PMC2863990. Chaitman BR, Hardison RM, Adler D, et al. The BARI 2D randomized trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease. Impact of treatment strategy on cardiac mortality and myocardial infarction. Circulation 2009;120:2529-40. https://doi. org/10.1161/CIRCULATIONAHA.109.913111. PMID: 19920001; PMCid: PMC2830563. 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

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with a mean pre-procedure FFR of 0.67 (normal>0.8), suggesting severe ischaemia that should benefit from PCI, contradicting the above findings, although 28–32 % of randomised subjects had either normal FFR or instantaneous wave-free ratio, signifying a “physiologically normal” or non-flow limiting stenosis. These patients would not be expected to benefit from PCI based on published data although recent analysis of the ORBITA data suggests no significant interaction between lower FFR or instantaneous wave-free ratio (iFR) readings and either angina frequency score or freedom from angina.15

Conclusion The ORBITA trial is a well-conducted trial and includes the novel ‘true’ placebo arm, a first in interventional cardiology. However, it does not significantly add to the current evidence base which suggests ischaemic guided revascularisation is more effective than PCI guided by symptoms and angiographic appearance in stable CAD. Indeed, the COURAGE trial has already shown patients with asymptomatic stable angina and a low ischaemic burden do not benefit from PCI although, like all previous trials in this area, it is not placebo controlled. It also inadvertently raises questions about the role of a placebo procedure, as invasive FFR measurement is not without risk; clinically significant complications occurred in 6.3 % of patients, similar to rates seen in other FFR-guided PCI trials.16,17 Longer-term results from the ORBITA study will be awaited with interest to see whether the initial trial findings are maintained. The ISCHAEMIA trial will also add further evidence in the subgroup of asymptomatic patients with a high ischaemic burden on non-invasive imaging. In summary, while ORBITA has blazed a trail in conducting a true placebo-controlled PCI trial, several limitations to patient selection and trial design limit its extrapolation to everyday clinical practice. Reviewing ORBITA in the context of other studies, it remains the case that FFR-guided PCI continues to be the gold standard treatment for stable CAD in patients whose symptoms are not adequately controlled on OMT. n

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 J Cardiothorac Surg 2014;46:517–92. https://doi.org/10.1093/ejcts/ezu366. PMID: 25173601. 7. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the task force on the management of stable coronary arterydisease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003. https://doi.org/10.1093/ eurheartj/eht296. PMID: 23996286. 8. Borden WB, Redberg RF, Mushlin AI, et al. Patterns and intensity of medical therapy in patients undergoing percutaneous coronary intervention. JAMA 2011;305:1882–89. https://doi.org/10.1001/jama.2011.601. PMID: 21558519. 9. Dimond EG, Kittle CF, Crockett JE. Comparison of internal mammary artery ligation and sham operation for angina pectoris. Am J Cardiol 1960;5:483–6. https://doi. org/10.1016/0002-9149(60)90105-3. PMID: 13816818. 10. Cobb LA, Thomas GI, Dillard D, et al. An evaluation of internal mammary artery ligation by a double blind tecnic. N Engl J Med 1959;260;1115–8. https://doi.org/10.1056/ NEJM195905282602204. PMID: 13657350. 11. Al-Lamee R, Thompson D, Dehbi H-M, et al. Percutaneous coronary intervention in stable angina (ORBITA): a doubleblind, randomised controlled trial. Lancet 2017;391(10115):3–4.

12.

13.

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https://doi.org/10.1016/S0140-6736(17)32714-9. PMID: 29103656. Brown DL, Redberg RF. Last nail in the coffin for PCI in stable angina? Lancet. 2017;391(10115):3–4. http://doi.org/10.1016/ S0140-6736(17)32757-5. PMID: 29103657. Fearon WF, Nishi T, De Bruyne B, et al. Clinical outcomes and cost-effectiveness of fractional flow reserve-guided percutaneous coronary intervention in patients with stable coronary artery disease: three-year follow-up of the FAME 2 Trial (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation). Circulation. 2018;137(5):480–7. https://doi.org/10.1161/CIRCULATIONAHA.117.031907. PMCID:PMC5354083; PMID: 29097450. Zimmerman FM, Ferrara A, Johnson SP, et al. Deferral vs performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15 year follow up of the DEFER trial. Eur Heart J 2015;36: 3182–8. https://doi.org/10.1093/eurheartj/ehv452. PMID: 26400825. Tonino PAL, 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. Curzen N, Rana O, Nicholas Z, et al. Does Routine pressure wire assessment influence management strategy at coronary angiography for diagnosis of chest pain? The RIPCORD study. Circ Cardiovasc Int 2014;7:248–55. https://doi.org/10.1161/ CIRCINTERVENTIONS.113.000978. PMID: 24642999.

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Structural

Delayed Coronary Occlusion After Transcatheter Aortic Valve Implantation: Implications for New Transcatheter Heart Valve Design and Patient Management Richard J Jabbour, 1 Akihito Tanaka, 2,3 Antonio Colombo 2,3 and Azeem Latib 2,3,4 1. Imperial College London, United Kingdom; 2. EMO-GVM Centro Cuore Columbus, Milan, Italy; 3. San Raffaele Scientific Institute, Milan, Italy; 4. University of Cape Town, Cape Town, South Africa

Abstract Transcatheter aortic valve implantation has revolutionised the treatment of patients with severe aortic stenosis and is the preferred treatment option for patients with elevated surgical risk. Outcomes have continually improved, but because of the nature of the procedure infrequent catastrophic complications, such as coronary obstruction, persist. Recently, data were published regarding delayed coronary obstruction (DCO), a phenomenon in which the obstruction occurs after the index procedure. DCO has important consequences for future research. In this article we will explore the implications for new transcatheter heart valve design and approaches to patient management to minimise the risk of DCO occurring.

Keywords Aortic stenosis, coronary, obstruction, TAVI, TAVR, transcatheter Disclosure: Azeem Latib has served on the advisory board of, and as a consultant for, Medtronic, has received speaking honoraria from Abbott Vascular and has received research grants from Medtronic and Edwards Lifesciences. All other authors have no conflicts of interest to declare. Received: 12 July 2018 Accepted: 15 August 2018 Citation: Interventional Cardiology Review 2018;13(3):137–9. DOI: https://doi.org/10.15420/icr.2018.24.2 Correspondence: Azeem Latib, Interventional Cardiology Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. E: alatib@gmail.com

Transcatheter aortic valve implantation (TAVI) has undoubtedly revolutionised the treatment of severe aortic stenosis and has become the preferred treatment option for patients at increased surgical risk.1,2 Although outcomes have improved and complications reduced over time, certain potentially catastrophic complications remain.3,4 Coronary obstruction has long been a feared complication and is classically recognised to occur in the acute setting just after valve deployment.4 However, we recently published data from a large international registry on the incidence and outcomes of delayed coronary obstruction (DCO), a phenomenon in which the obstruction occurs in the hours, days or months following the procedure (Figure 1).5 It is important to mention that coronary obstruction is not solely related to TAVI; both acute coronary obstruction and DCO can occur with conventional surgical aortic valve replacement. The true incidence of surgical coronary obstruction is unknown but historical data have reported it to be as high as 3 %.6,7

Delayed coronary obstruction DCO is defined as: obstruction of the left main or ostial right coronary artery occurring after successful TAVI, with a diagnosis by angiogram, surgery, or autopsy to ensure adequate evidence of obstruction and, importantly, not solely related to coronary artery disease or in-stent restenosis and so directly related to the TAVI procedure or implanted prosthesis. The incidence reported from a large international multicentre registry was 0.22 % (38 cases from a total of 17,092 TAVI procedures), which is typically lower than acute coronary obstruction (up to 1 %).4,5 However, as sudden death could be the first manifestation of DCO outside of hospital and up to one-third of TAVI patients have undergone prior coronary artery bypass graft and so may be protected

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from native coronary obstruction, the real incidence may be higher.8 Certain similarities exist between DCO and acute coronary obstruction. For example, DCO was more frequently observed after valve-in-valve procedures (0.89 % versus 0.18 %; p<0.001) and in two out of three cases the patient had at least one known classical risk factor for acute coronary obstruction (narrow sinus of Valsalva, low coronary height or valve-in-valve procedure).5 DCO occurred more commonly if selfexpanding valves were used during the index procedure rather than balloon expanding valves (0.36 % versus 0.11 %; p<0.01). DCO was most likely to occur within less than, or up to, seven days (n=24, 63.2 %; early DCO), with just over a third of cases occurring ≥60 days (n=14, 36.8 %; late DCO). Early DCO cases were likely to have unstable presentations (cardiac arrest or ST-elevation MI) while late DCO had more stable presentations (stable angina). Percutaneous coronary intervention was attempted in most cases (74.3 % left main; 60.0 % right coronary), and stent implantation was successful in 68.8 % of cases. Similarly to acute coronary obstruction, the in-hospital mortality associated with DCO was high at 50 % (n=19) and higher if DCO occurred within less than, or up to, 7 days of the index procedure (62.5 % versus 28.6 %; p=0.09).5 The absence of cases between seven and 60 days possibly indicates two distinct mechanisms. For example, early DCO may be related to the index procedure, with dislodgement of the native valve leaflets as a result of continuing expansion of the TAVI valve, dissection, haematoma or thrombus formation, while late DCO may be related to persistent inflammation, valve stent endothelisation or thrombus embolisation (Figure 2).5 The pathogenesis is broadly similar to conventional surgical aortic valve replacement, whereby acute coronary obstruction is thought to be predominantly procedurally associated (e.g. ostial cannulation to administer antegrade cardioplegia). In contrast, DCO

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Structural Figure 1: Angiographic Images of Two Delayed Coronary Obstruction Cases

is thought to be a result of persistent inflammation or continuous turbulent flow across the prosthesis leading to fibrous proliferation and intimal thickening in the surrounding regions.6,7 DCO has important implications for future research. As there is a drive towards use of TAVI in lower-risk patients with inevitably longer life expectancy, research is needed to characterise the phenomenon in greater detail and next generation devices should be designed to mitigate the risk.1

Implications for New Transcatheter Heart Valve Design Direct anchoring to native valve leaflets

Upper panel: 71-year-old woman underwent TAVI with a transfemoral Edwards XT device (26 mm). A pre-implantation CT scan revealed a low left coronary height (7 mm). The initial procedure was successful; a post-implant aortogram revealed patent coronary arteries and the patient left the procedure suite haemodynamically stable. Three hours later the patient developed an anterior ST-elevation MI and cardiogenic shock. The patient was transferred back to the procedure suite and an angiogram revealed partial left main occlusion. A 3.5 × 12 mm bare-metal stent was implanted successfully. At four-year follow-up, the patient remains well. Yellow arrowhead demonstrates probable native leaflet occluding the ostium of the left main. Lower panel: 70-year-old woman with previous history of aortic bioprosthetic valve (23 mm Elan) underwent TAVI. Pre-implantation CT reported low left coronary height of 7 mm and no significant disease of the left main trunk. A 23 mm Evolut™ R (Medtronic) was implanted without complication and a final angiogram and aortography confirmed lack of obstruction. At day three post-TAVI, the patient experienced chest pain and then developed cardiac arrest. Coronary angiogram revealed partial left main obstruction. A 3.5 × 12 mm baremetal stent was implanted successfully. However, the patient died in the procedure suite 90 minutes after cardiac arrest. Yellow arrowheads indicate probable native leaflet occluding the ostium of the left main. CT = Computed tomography; TAVI = Transcatheter aortic valve implantation. Source: Images courtesy of Prof Giuseppe Tarantini.

Figure 2: Aetiology and Risk Factors for Delayed Coronary Obstruction CENTRAL ILLUSTRATION: Etiology and risk factors for delayed coronary obstruction Delayed coronary obstruction 0–7 Days

Etiology

Late

Early

coronary obstruction events in 89 transfemoral access patients at oneyear follow-up.13 In contrast, clinical experience using the JenaValve is relatively limited; transfemoral device data are awaited, while initial registry data with the transapical device for the treatment of aortic regurgitation has been encouraging.14 A theoretical limitation of this mechanism is the risk of relatively increased post-procedural gradients, especially in patients with small annulus diameters. Although this has not been reported with ACURATE Neo so far, further data are awaited.9

Increased Cell Size

>7 Days

Etiology Continuing expansion Dissection hematoma

Most of the approved TAVI valves today use a radial force-dependent mechanism to keep the prosthesis fixed in place. However, radial force will not prevent the native aortic valve leaflets from prolapsing and causing coronary obstruction.9 Certain newer generation TAVI devices (ACURATE Neo™ [Boston Scientific], JenaValve™ [JenaValve]) are fixed in place by using a direct anchoring mechanism to either the calcified native leaflets or surgical valve leaflets, which would mitigate the risk future prolapse and coronary obstruction. In an initial early experience with the ACURATE Neo device in 30 patients with high-risk features (mean left main ostial height of only 10.8 mm and sinus of Valsalva:annulus ratio of 1.3 ± 0.8), there were no cases of coronary obstruction.10,11 Furthermore, in the Symetis ACURATE neo Valve Implantation Using Transfemoral Access (SAVI-TF) registry of 1,000 patients, no coronary obstruction events were reported at 30 days.12 Longer-term data from the ‘CE-approval cohort’, reported no

Thrombus Fibrosis endothelialization

Anatomical risk factors

Procedural factors

Pharmacological factors

Narrow SOV low coronary height Excessive calcification

Valve-in-valve Device position

Valve-in-valve

Antiplatelet anticoagulation

Calcium

Low coronary height

Valve-in-Valve

Thrombus

As there is a move towards lower-risk patients with longer life expectancies, coronary angiography or percutaneous coronary intervention after TAVI is becoming an important issue. Although this has been reported to be feasible, it can be technically challenging, especially in the case of self-expanding valves that extend above the coronary ostia.14 By designing valves with larger stent cell sizes (for example, the Portico™ valve [St. Jude Medical]), future access to the coronary circulation can be facilitated. Additionally, the persistence of turbulent flow and inflammation may cause valve stent endothelisation over time. If the cell surface area is increased there is a theoretical likelihood that the degree of coronary obstruction will be lower.

Low Profile Skirt SOV

Definite

Probable

Possible

Jabbour, R.J. et al. J Am Coll Cardiol. 2018;71(14):1513–24.

Delayed coronary obstruction can be divided into two groups: early (up to seven days) and late (over seven days). Early delayed coronary obstruction may be a result of continuing expansion of the implanted valve, or a dissection or haematoma that expands, causing obstruction. In contrast, thrombus or valve stent endothelisation (fibrosis) may cause late delayed coronary obstruction. Late expansion may be a possible additional cause. Definite causes and risk factors are in red, probable in green, and possible in blue. SOV = Sinus of Valsalva. Source: Jabbour RJ, et al., 2018. With permission from Elsevier.

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While valve skirts are important for minimising paravalvular leak, DCO has occurred with self-expanding valves because of prosthesis skirt obstruction.15 Theoretically, the chance of obstruction would be greater in high-implantation cases. Minimising the profile of the skirt could potentially prevent DCO.

Retrievability Newer generation devices (Lotus™ [Boston Scientific], Portico, Evolut™ R [Medtronic]) are retrievable and are advantageous for high-risk acute coronary obstruction cases. Different degrees of retrievability exist, for example the Lotus is retrievable after full implantation,

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Delayed Coronary Occlusion After TAVI while the Portico or Evolut R can only be removed prior to complete deployment. Although retrievability is predominantly beneficial in acute coronary obstruction cases, since a prosthesis can be retrieved if there is immediate angiographic evidence of obstruction, a significant proportion of DCO patients (n=18; 47.4 %) had high implantation depths. Having a device that is fully retrievable even after deployment could be beneficial to obtain an optimal result, which may help to prevent DCO.

an ostial coronary stent was deployed during the index procedure; seven patients (18.4 %) had left main stent insertion during the index procedure and then developed DCO. Possible ways to mitigate this risk, which require evaluation, include excessively protruding ‘chimney’ stents or using stents with greater radial strength to prevent stent deformation from the native valve leaflets or transcatheter heart valve.5

Post-transcatheter Aortic Valve Implantation Low Threshold For Imaging the Coronary System

Patient Management Pre-transcatheter Aortic Valve Implantation Computed Tomography Pre-procedural CT evaluation should now be considered almost mandatory during the TAVI evaluation process. As well as providing valuable information regarding potential vascular accesses and the aortic root, detailed information on risk factors for coronary obstruction — including sinus of Valsalva width, coronary heights, bulky calcium nodules or excessively long leaflets that may obstruct the coronary ostia — can easily be obtained.

BASILICA Technique Recently, a novel technique called the bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction (BASILICA) has been reported. 16 This procedure is performed prior to TAVI insertion with the use of catheters to direct an electrified guidewire to traverse and lacerate through the centre of the aortic valve leaflet. The first-in-human experience was recently reported in seven patients at high risk of coronary obstruction in non-surgical candidates on a compassionate basis. Six patients had failed bioprosthetic valves, two had severe aortic stenosis, three had severe aortic regurgitation, with the remaining two having mixed aortic valve disease. Interestingly, one patient underwent laceration of both left and right coronary cusps. There was no haemodynamic compromise in any patient following the procedure and all patients had successful TAVI, with no major complications occurring and no deaths at 30-day follow-up. Further data are awaited on this promising technique.16,17

During Transcatheter Aortic Valve Implantation Coronary protection In a recently published DCO case series, nine cases (23.7 %) had coronary guidewire protection. Importantly, DCO can occur even if

J abbour RJ, Pagnesi M, Kawamoto H, et al. Transcatheter aortic valve implantation in intermediate- and low-risk populations: An inevitable progression? Int J Cardiol 2016;210:35–7. https://doi.org/10.1016/j.ijcard.2016.02.094; PMID: 26922711. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med 2016;374(17):1609–20. https://doi.org/10.1056/ NEJMoa1514616; PMID: 27040324. Regueiro A, Linke A, Latib A, et al. Association between transcatheter aortic valve replacement and subsequent infective endocarditis and in-hospital death. JAMA 2016; 316:1083–92. https://doi.org/10.1001/jama.2016.12347; PMID: 27623462. Ribeiro HB, Webb JG, Makkar RR, et al. Predictive factors, management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: insights from a large multicenter registry. J Am Coll Cardiol 2013;62:1552–62. https://doi.org/10.1016/j.jacc.2013.07.040; PMID: 23954337. Jabbour RJ, Tanaka A, Finkelstein A, et al. Delayed Coronary Obstruction After Transcatheter Aortic Valve Replacement. J Am Coll Cardiol 2018;71(14):1513–24. https://doi.org/10.1016/ j.jacc.2018.01.066; PMID: 29622157. Pennington DG, Dincer B, Bashiti H, et al. Coronary artery stenosis following aortic valve replacement and intermittent intracoronary cardioplegia. Ann Thorac Surg 1982;33(6):576–84. https://doi.org/10.1016/S00034975(10)60816-8; PMID: 6979984.

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As DCO can occur in the months and years post-TAVI, in patients without risk factors for acute coronary obstruction, clinicians should have a low threshold for imaging the coronary circulation. In stable presentations, coronary CT angiography should be the first-line investigation. If a patient has classical risk factors for acute coronary obstruction (valve-in-valve, low coronary heights, narrow sinus of Valsalva dimensions), increased monitoring in the peri-procedural period is recommended (for example, a CT scan before discharge).5

Anticoagulant Therapy Thrombus embolisation from a prosthetic valve can be a cause of DCO. Also, reduced leaflet motion, which is a presumed surrogate marker of thrombus, was recently reported in 13 % of patients (n=17 from 132) from two pooled registries. So valve thrombosis is an area of intense research and interest. Even though the reduced leaflet motion resolved on follow-up CT in all patients treated with therapeutic anticoagulation, there is no recommendation for routine anticoagulation postTAVI at present.18 The role of anticoagulation is specifically being evaluated in on-going randomised clinical trials, including the AntiThrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis (ATLANTIS) study (NCT02664649) and the Comparison of a Rivaroxaban-based Strategy With an Antiplatelet-based Strategy Following Successful TAVR for the Prevention of Leaflet Thickening and Reduced Leaflet Motion as Evaluated by Four-dimensional, Volumerendered Computed Tomography (GALILEO-4D) trial (NCT02833948). The rapid expansion of TAVI use over the last 15 years is likely to continue as outcomes and operator experience improve. The recent description of DCO is important, as clinician awareness has been raised. Newer valves can be designed to mitigate the risk of DCO because the occurrence of this complication, although infrequent, will be less tolerable in low surgical-risk patients with longer life expectancies. Future studies should monitor this condition to characterise it further. n

aja Y, Routledge HC, Doshi SN. Coronary stenting for R iatrogenic stenosis of the left main coronary artery postaortic valve replacement: an alternative treatment? Eur J Cardiothorac Surg 2011;39(3):398–400. https://doi.org/10.1016/ j.ejcts.2010.07.001; PMID: 20696588. 8. Kleiman NS. Delayed Coronary Obstruction After TAVR: A Call for Vigilance. J Am Coll Cardiol 2018;71(14):1525–7. https://doi. org/10.1016/j.jacc.2018.01.067; PMID: 29622158. 9. Dvir D, Leipsic J, Blanke P, et al. Coronary obstruction in transcatheter aortic valve-in-valve implantation: preprocedural evaluation, device selection, protection, and treatment. Circ Cardiovasc Interv 2015;8(1):e002079. https:// doi.org/10.1161/CIRCINTERVENTIONS.114.002079; PMID: 25593122. 10. Alkhouli M, Badhwar V. Avoiding coronary obstruction after transcatheter aortic valve replacement: Is it the skirt or what’s inside that counts? J Thorac Cardiovasc Surg 2017;153(4):819–20. https://doi.org/10.1016/j. jtcvs.2016.11.034; PMID: 28190608. 11. Chu MW, Bagur R, Losenno KL, et al. Early clinical outcomes of a novel self-expanding transapical transcatheter aortic valve bioprosthesis. J Thorac Cardiovasc Surg 2017;153(4):810–8. https://doi.org/10.1016/j.jtcvs.2016.11.054; PMID: 28073571. 12. Möllmann H, Hengstenberg C, Hilker M, et al. Real-world experience using the ACURATE neo prosthesis: 30-day outcomes of 1,000 patients enrolled in the SAVI TF registry. EuroIntervention 2018;13(15):e1764–70. https://doi.org/10.4244/ EIJ-D-17-00628; PMID: 29131801.

13. M öllmann H, Walther T, Siqueira D, et al. Transfemoral TAVI using the self-expanding ACURATE neo prosthesis: oneyear outcomes of the multicentre ‘CE-approval cohort’. EuroIntervention 2017;13(9):e1040–6. https://doi.org/10.4244/ EIJ-D-17-00187; PMID: 28804056. 14. Yudi MB, Sharma SK, Tang GHL, Kini A. Coronary Angiography and Percutaneous Coronary Intervention After Transcatheter Aortic Valve Repl cement. J Am Coll Cardiol 2018;71(12):1360–78. https://doi.org/10.1016/j.jacc.2018.01.057; PMID: 29566822. 15. Martí D, Del Valle R, Álvarez S, et al. Late Coronary Obstruction After Implantation of Self-expandable Valves. Clinical and Angiographic Features of an Unexpected Complication. Rev Esp Cardiol (Engl Ed) 2017;70(10):880–2. https://doi.org/10.1016/j.rec.2017.02.003; PMID: 28262575. 16. Khan JM, Dvir D, Greenbaum AB, et al. Transcatheter Laceration of Aortic Leaflets to Prevent Coronary Obstruction During Transcatheter Aortic Valve Replacement: Concept to First-in-Human. JACC Cardiovasc Interv 2018;11(7):677–89. https://doi.org/10.1016/j.jcin.2018.01.247; PMID: 29622147. 17. Latib A, Pagnesi M. Tearing Down the Risk for Coronary Obstruction With Transcatheter Aortic Valve Replacement. JACC Cardiovasc Interv 2018;11(7):690–2. https://doi. org/10.1016/j.jcin.2018.01.266; PMID: 29622148. 18. Kodali SK, Thourani VH, Kirtane AJ. Possible Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves. N Engl J Med 2016;374(16):1591. https://doi.org/10.1056/NEJMc1600179; PMID: 27096593.

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Annular Rupture During Transcatheter Aortic Valve Implantation: Predictors, Management and Outcomes JJ Coughlan, Thomas Kiernan, Darren Mylotte and Samer Arnous University Hospital Limerick, Dooradoyle, Co Limerick, Ireland; 2. University Hospital and National University of Ireland, Galway, Ireland

Abstract Transcatheter aortic valve implantation (TAVI) is the treatment of choice in patients with symptomatic severe aortic stenosis who are either inoperable or at high risk for conventional surgical aortic valve replacement. Recent data have also shown favourable outcomes in patients deemed to be at intermediate operative risk, which expands the application of this novel technology. Despite its success, TAVI has been associated with rare life-threatening complications. Of these, aortic annular rupture is considered to be the most devastating. Advances in pre-procedural screening and patient selection have reduced the incidence of annular rupture. When this complication occurs, early recognition and prompt management are essential. This article is intended to provide a comprehensive review of the predictors, management and clinical outcomes of aortic annular rupture.

Keywords Transcatheter aortic valve implantation (TAVI), aortic stenosis, balloon aortic valvuloplasty (BAV), aortic annular rupture, transthoracic echocardiography (TTE), transoesophageal echocardiography (TEE), multislice computed tomography (MSCT), transcatheter heart valve (THV) Disclosure: The authors of this paper have no conflicts of interest to declare. Received: 24 June 2018 Accepted: 9 August 2018 Citation: Interventional Cardiology Review 2018;13(3):140–4. DOI: https://doi.org/10.15420/icr.2018.20.2 Correspondence: JJ Coughlan, Cardiology. University Hospital Limerick, Dooradoyle, Co Limerick, Ireland. E: jjcoughl@gmail.com

Transcatheter aortic valve implantation (TAVI) has emerged as an alternative treatment for symptomatic severe aortic stenosis in patients deemed to be at high operative risk for conventional surgical aortic valve replacement (SAVR). In these patients, TAVI has lower all-cause mortality than SAVR1 and recent data also suggest equipoise between these therapies in intermediate-risk patients.2–5 Similar comparative efficacy trials are under way in patients at low operative risk7–9. Despite the success of TAVI, serious life-threatening complications can occur. Aortic annular rupture is among the most devastating of these. Although uncommon, the high mortality associated with annular rupture mandates careful procedural planning and execution. This will be especially relevant if TAVI is to be successfully expanded to lowerrisk patients. This article discusses the causes, mechanisms and diagnosis of aortic annular rupture. Techniques to minimise the risk of annular rupture and therapeutic strategies to improve outcomes in patients that experience this complication will be examined.

Anatomy of the Aortic Annulus The aortic root is the direct continuation of the left ventricular outflow tract (LVOT) and forms a bridge between the left ventricle and the ascending aorta. It functions as the supporting structure for the aortic valve and is comprised of three main components: the sinutubular junction (STJ); the aortic sinuses (consisting of the sinuses of Valsalva, the surgical aortic annulus [ventriculo-aortic junction] and the leaflets of the aortic valve); and the basal ring. The basal ring, frequently referred to as the “aortic annulus” by those involved in TAVI, is a virtual (rather than anatomic) ring found at the

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insertion point of the basal attachments of the aortic valve leaflets within the LVOT. Despite the use of the term “annulus”, meaning ring, the annulus is neither circular nor oval. The aortic valve leaflets arise from their attachment in the muscular LVOT, which forms the haemodynamic ventriculo-arterial junction, and ascend to come together to form the trileaflet valve at the STJ. The sinuses of valsalva lie distal to the semilunar attachments of the leaflets. The left and right facing sinuses give rise to coronary arteries, usually at or below the level of the STJ. The base of the two coronary aortic sinuses have a crescent of myocardium incorporated, though the greater part of the walls of the sinuses are composed of aortic tissue. The STJ represents the zenith of the aortic root which continues as the ascending aorta. The area of the aortic root and LVOT adjacent to the basal attachment of the valve leaflets is particularly relevant to a discussion on aortic annular rupture. Three triangular fibromuscular extensions, called the interleaflet triangles, are interposed between the leaflets and extend towards the left ventricle. The triangle found between the right and left coronary leaflets is composed of muscular tissue, the triangle between the left coronary and the noncoronary leaflets is a fibrous sheet in continuity with the anterior mitral valve leaflet, and the triangle between the noncoronary and right coronary leaflets comprises the membranous septum. Perforation of the last triangle will create a communication to the right ventricle (a ventricular septal defect), while the first two communicate directly with the pericardial space and perforation here will risk the development of cardiac tamponade. The anatomically weakest region of the muscular LVOT is the region between the left fibrous trigone and the left/right commissure.

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Annular Rupture During TAVI Multislice Computed Tomography Assessment of the Aortic Annulus Multi-slice computed tomography (MSCT) is the method of choice for pre-TAVI assessment of the aortic root and offers a comprehensive 3D image reconstruction of the anatomy. Accurate measurement of the annulus using MSCT is an integral part of pre-procedural planning and accurate transcatheter heart valve (THV)-sizing which is crucial to ensure valve anchoring, sealing and function. Integration of MSCT for THV valve sizing has been shown to reduce paravalvular leak (PVL) compared with 2D echocardiography.10–12

The risk of vascular complications (including annular rupture) is increased in patients with a smaller body surface area.24 Interestingly, even after correcting for smaller body size and weight, women have been have smaller aortic root dimensions than men (mean annulus diameter: 22.9 ± 2.2 mm versus 25.7 ± 2.7 mm; mean sinus of Valsalva diameter: 31.8 ± 4.2 mm versus 36.3 ± 3.8 mm; mean STJ diameter: 26.3 ± 3.4mm versus 29.8 ± 4.2mm).54 This information explains the overrepresentation of women (74 %) in a series of aortic annular ruptures with balloon expandable valves.25

Prosthesis Choice/Sizing As the aortic valve apparatus undergoes dynamic change during systole and diastole, annular measurements vary during the cardiac cycle (with larger dimensions in systole).13–15 Area-based sizing is recommended for balloon-expandable THV; the goal is to oversize the THV relative to the annulus by 0–10 %.16 In contrast, self-expandable valves use perimeter (circumference) based sizing and oversizing of THV relative to the anatomy of 10–25 % is usually recommended, depending on the specific valve system.16,17 Excessive oversizing, particularly of balloonexpandable THV, is closely linked to annular rupture.18 In addition to annulus and root measurements, MSCT allows assessment of aortic root calcification. Koos, et al. validated quantification of aortic valve calcification by MSCT, using the Agatston AVC score, and demonstrated close correlation with in vitro calcification mass determined by atomic absorption spectroscopy.19. As discussed later in this article, some patterns of calcification predispose patients to annular rupture.

Several THV are used routinely in clinical practice. They include balloon-, self-, and mechanical-expandable systems (the Boston Scientific Lotus valve has been temporarily withdrawn from the market). The incidence of annular rupture depends on the type of prosthesis used and, indeed, balloon-expandable valves (SAPIEN XT/3, Edwards Lifesciences) are associated with much higher rates of annular rupture than selfexpandable valves.18,25,29–31 With balloon expandable prostheses, the strongest predictor of annular rupture is MSCT-based area oversizing >20 %.18 Important work by Barbanti et al. found 37 consecutive patients undergoing balloon-expandable TAVI and experiencing root rupture had a greater degree of area-based prosthesis oversizing (30.5 % ± 15.8 % versus 11.3 % ± 19.7 %, p<0.001) and a higher frequency of post-dilatation (22.6 % versus 0.0 %, p=0.005) than those who did not experience this complication.25 This study determined that with balloon-expandable valves, MSCT-based area oversizing ≥20 % predicted an eightfold increased risk of rupture (odds ratio: 8.38; 95 % CI: 2.67–26.33; p<0.001).

Incidence Aortic annular rupture is an umbrella term used to describe a variety of injuries that may occur in the aortic root and LVOT during TAVI. Figure 1 shows the potential locations for aortic annular rupture. Risk factors for rupture, clinical sequelae and management depend on the site involved. The incidence of annular rupture is reported as between 0.4 % and 2.3 %: increasing operator experience and the use of MSCT have seen a considerable decline in the frequency of this complication.20–24

Predictors of Annular Rupture

As such, in patients at high risk of rupture, self-expanding or mechanical expanding valves may be preferable to balloon expandable valves. These prostheses are rarely associated with annular rupture unless excessive balloon pre- or post-dilatation is performed. An alternative technique to reduce the risk of annular rupture in the presence of adverse anatomical features with balloon expandable valves is underfilling of the deployment balloon (by 1–3 ml). This strategy and the now routine slow two-step deployment of the prosthesis have gained popularity, particularly in centres where self-expanding technology is not readily available.

Anatomical Several studies have demonstrated that subannular calcification predisposes patients to annular rupture,25,26 Barbanti et al. described an 11–fold increased risk of rupture with balloon-expandable THV in the presence of moderate to severe LVOT/subannular calcification (odds ratio 10.92; 95 % CI: 3.23–36.91; P<0.001).25 In another study, MSCT analysis of aortic root/LVOT suggested subannular calcification in close proximity to the region of the muscular LVOT between the left fibrous trigone and the left/right commissure in 83 % of patients with subannular perforation.26 A higher burden of LVOT calcification, especially when extending into the LVOT in the non-coronary cusp, has also been associated with aortic root injury during TAVI with balloon-expandable valves.27 Moderate to severe annular calcification is also an independent predictor of ≥mild PVL.28 Although not directly associated with annular rupture, annular calcification with ≥mild PVL usually prompts balloon postdilatation. Excessive or aggressive postdilatation is another risk factor for annular rupture.25

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Procedural technique A few simple procedural techniques can reduce the risk of annular rupture. In particular, a comprehensive understanding of the aortic root anatomy from detailed MSCT can guide valve and balloon size selection. It is of utmost importance to respect the patient’s native anatomy: pre- and post-dilatation balloons should not exceed the mean diameter of the LVOT or sinotubular junction, whichever is smaller. It is recommended to use a balloon to artery ratio of 1.0 for semi-compliant balloons and <1.0 for non-compliant balloons. Failure to respect these “rules” increases the risk of annular rupture.25 Moreover, in patients with severely calcified annular or subannular anatomy, there has been a move towards undersizing the THV relative to the annular dimensions. In such cases, supra-annular sizing is performed using a variety of dedicated techniques and, although the THV is undersized relative to the annulus, it is not undersized relative to the supra-annular structures. This technique is particularly useful and increasingly used in cases of bicuspid aortic valve stenosis, where the presence of a raphe (Siever’s type 1 or type 2) or dense

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Structural Figure 1: Sites and Potential Communications of Annular Rupture

Pericardium

Sinobutubular junction Ventrico-aortic junction Virtual aoric annulus

Ao 3c

1. Intra-annual

LA 2a 2b

LVOT

Schematic demonstrating the sites of, and potential communications arising from, annular repture.

2. Subannular a. Injury of the free myocardial wall b. Injury of anterio mitral valve leaflet c. Injury of intraventricular septum d. Iatrogenic Gerbode defect 3. Supra-annular a. Injury of the sinus of Valsalva b. Injury of the ostium of the coronary artery c. Injury of the sinotubular junction

Ao = aorta; RA = right atrium; RV = right ventricle; LA = left atrium; LV = left ventricle; LVOT = left ventricular outflow tract

leaflet calcification permits relative “downsizing” of the valve. For balloon-expandable THV, this usually manifests as an underfilling of the deployment balloon by 1-3 cc. This technique and further postdilatation, if required, have been shown to reduce the risk of annular rupture without increasing PVL.34 With self-expanding THV, the size of the pre- and post-dilatation balloons and the THV itself may be reduced. To the authors’ knowledge, annular rupture in the absence of post-dilation has not been reported with the self-expanding technology.

including an immediate heart team discussion. In stable patients, reversal of anticoagulation, ensuring the availability of blood products and frequent reassessment of clinical status should be considered. Transoesophageal echocardiography and MSCT can help define the extent of the aortic root disruption.36 Contained rupture usually has a favourable outcome. These events occur more frequently than originally thought; they were identified in 1.2 % of patients after a balloon expandable TAVI in a large multicentre report with systematic computed tomography angiography (CTA) performed after TAVI.39 Subacute progression of the rupture can occur, and late development of aortic pseudoaneurysm has been reported.53 In patients with haemodynamic collapse, associated pericardial effusion and cardiac tamponade, percutaneous pericardial drainage and reversal of systemic anticoagulation should be performed. Not infrequently, these manoeuvres may be sufficient to stabilise the patient, but contingency plans for escalation should be instituted on confirmation of the diagnosis. Auto-transfusion of the pericardial aspirate can reduce the need for blood products when bleeding is extensive. Haemodynamic support or extracorporeal membraneous oxygenation can provide a bridge to surgical repair. When pericardial bleeding cannot be controlled, sternotomy, initiation of cardiopulmonary bypass, and aortic root repair with or without surgical aortic valve replacement is required. In the cases of patients who are not suitable for surgical intervention, recombinant factor VIIa has been reported to reduce bleeding, though the efficacy of this strategy remains controversial.41

Management of Aortic Annular Rupture Diagnosis The clinical manifestations of annular rupture can vary, and depend on the extent and site of the disruption. Rapid haemodynamic collapse is the most common presentation and is due to rupture into the pericardial space and ensuing cardiac tamponade. Ventricular septal defect, fistulae from the left ventricle to the atria (iatrogenic Gerbode defect) and perforation of the anterior mitral valve curtain may be better tolerated acutely, while localised perforation with intramural haematoma can present insidiously or may only be identified on postTAVI imaging.35–37. Hypotension or haemodynamic instability should always arouse suspicion of annular rupture. Haemodynamic instability may manifest as increased central venous pressure, low arterial blood pressure, tachycardia, arrhythmia or frank circulatory collapse with a combination of these features. Patients may report pain due to pericardial irritation. Immediate angiography and echocardiography are the diagnostic modalities of choice. Any evidence of bleeding into the pericardium should arouse suspicion of annular rupture. Serial imaging and examination may be required to confirm or unequivocally exclude the diagnosis.

If the rupture site can clearly be identified as either immediately cranial or caudal to the skirt of the THV, then implantation of a second THV to seal the rupture has been successfully performed.46 In such cases, the second valve is intentionally positioned either cranial or caudal to the initial implant, according to the site of rupture. This has primarily been described in balloon expandable valves.42 In one case, pre-dilation with a 23 mm balloon followed by a 26 mm Edwards valve was performed. Angiography demonstrated an annular tear and cardiac tamponade was demonstrated on echocardiography. Despite pericardiocentesis, auto transfusion and attempted sealing of the annular tear with another valve, the patient died.46 The authors of the study noted that two-thirds of the patients in their series underwent post-dilatation with relatively large balloons. They proposed an initial strategy of postdilatation with a smaller balloon and to proceed further with a larger balloon if necessary. They also proposed choosing a smaller valve size for patients with heavy annular calcification.

Surgical options

Initial Approaches

The development of emergency algorithms to manage life-threatening complications such as annular rupture with TAVI is axiomatic. Clear pathways and protocols need to be designed to streamline care, including expedited transfer to surgical theatre if a hybrid lab is not available.

In patients without haemodynamic compromise, such as those with selfcontained or limited rupture or aortic root haematoma, a conservative management strategy can be adopted after a thorough imaging assessment. In such cases, monitoring the haemodynamic status and reversal of systemic anticoagulation may suffice. Nevertheless, contingency plans and escalation strategies should be prepared,

Intubation, ventilation and emergency sternotomy with exploration of the aortic root to identify and treat the source of bleeding should be considered when persistent uncontrollable haemorrhage occurs. Cardiopulmonary bypass (CPB) maybe required to help stabilise haemodynamics. This can usually be instituted as normothermic

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Annular Rupture During TAVI femoro-femoral cardiopulmonary bypass. Central cardiopulmonary bypass through direct aortic cannulation is an alternative option and may be used in patients with severe peripheral arterial disease. The type of surgical treatment depends on the origin and extent of annular rupture. The standard surgical operation in cases of intraannular rupture comprises of removal of the TAVI prosthesis, excision of the native aortic valve, repair of the ruptured annular lesion with an autologous pericardial patch and aortic valve replacement with a prosthetic valve.31,35 The treatment for supra-annular rupture depends on the site involved. Injury of the coronary ostium can be treated with composite valved graft or aortic valve replacement plus repair of the rupture site. Injuries of the wall of sinus of Valsalva or of the sinotubular junction require repair of the lesion using a pericardial patch or pledgeted sutures and aortic valve replacement. Subannular injury of the interventricular septum or free myocardial wall requires repair or reconstruction using a pericardial or synthetic patch by a transaortic approach, in addition to aortic valve replacement.42–45 Traumatic ventricular septal defects (VSDs) may be well tolerated or, conversely, be associated with subacute or acute haemodynamic compromise. Either a surgical or percutaneous strategy can be effective in such situations depending on the extent and location of the defect, stability of the patient and experience of the institutional heartteam.46 A recent systematic review of iatrogenic VSD following TAVI identified 20 patients from 18 case reports. Of these 20 patients, 13 (65 %) were managed conservatively and seven (35 %) required defect closure.48 Among those requiring intervention, percutaneous techniques were employed in six and one patient underwent surgery. Devices used for closure in these cases included the Amplatzer septal occluder, Amplatzer muscular septal occluder, Amplatzer VSD occluder and the Amplatzer muscular VSD occluder (St Jude Medical). A retrograde technique was used for closure in three cases. While concerns have been expressed regarding the effect of transcatheter VSD closure on TAVR function, no issues with valve function or valve dislodgement were reported in these case reports. Four out of 20 (20 %) patients died in hospital, all of whom were managed conservatively. The reports proposed that risks for VSD after TAVR included: severe asymmetric calcification of the valve; elliptic aortic annulus; valve oversizing; and higher valve placement. The authors also noted that many patients in the study were managed successfully without intervention and proposed that VSD closure should be reserved for patients who had failed conservative management.

iontis GC, Praz F, Pilgrim T, et al. Transcatheter aortic S valve implantation vs. surgical aortic valve replacement for treatment of severe aortic stenosis: a meta-analysis of randomized trials. Eur Heart J 2016;37(47):3503–12. doi: 10.1093/eurheartj/ehw225. https://doi.org/10.1093/eurheartj/ ehw225. PMID: 27389906. Thyregod HG, Søndergaard L, Ihlemann N, et al. The Nordic aortic valve intervention (NOTION) trial comparing transcatheter versus surgical valve implantation: study protocol for a randomised controlled trial. J Am Coll Cardiol 2015;65(20):2184–94. https://doi.org/10.1016/j. jacc.2015.03.014. PMID:23302232;PMCID:PMC3551839. Natarajan D, Makkar R, MacCarthy P, et al. Placement of Aortic Transcatheter Valves (PARTNER) 2 Cohort A trial – transcatheter or surgical aortic-valve replacement in intermediate-risk patients. EuroIntervention 2016;12(6): 805–8. https://doi.org/10.4244/EIJV12I6A131. PMID: 27542796. Barker CM, Reardon MJ. The CoreValve US pivotal trial. Semin Thorac Cardiovasc Surg 2014;26(3):179–86. https://doi. org/10.1053/j.semtcvs.2014.10.001 PMID: 25527011. Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or

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Outcomes Annular rupture can be a catastrophic complication of TAVI. Although mortality varies between studies, high 30-day mortality rates of 49–67 % have been reported. Annular rupture is associated with a seven-fold increase in 30-day mortality. In cases of contained rupture, mortality is lower (~25 %) but nonetheless remains considerable.22,49 Among patients with a rupture proceeding to emergent surgery, specific mortality data is scarce. However, conversion from TAVI to an open surgery has been associated with a 30-day mortality rate of 45 %, regardless of aetiology.45 In a recent study by Eggebrecht et al. on outcomes of patients undergoing emergent cardiac surgery as a result of life-threatening complications during TAVI, annular rupture accounted for 21.2 % of all cases.50 In-hospital mortality for annular rupture was 62 %, which compared poorly with that for the overall population (46 %).

Future Directions As TAVI is offered to younger and lower-risk patients, it is paramount that practitioners remain vigilant in preventing serious complication such as annular rupture. Data on the incidence of annular rupture among younger patients are sparse. In the NOTION 1 trial of intermediate-risk patients treated with first generation TAVI devices, conversion to surgery was required in 2.1 %.51 Importantly, the incidence of bicuspid aortic valve and hence severe valvular calcification is greater in younger patients. It is therefore possible that rates of annular injury could be higher in this patient group. Retrospective registry data has previously reported aortic root rupture rates of 0.7 % in TAVI for bicuspid aortic valves.52 However, there is little prospective data on this topic and further research is needed. Tailored THV sizing strategies in bicuspid aortic valve morphology should mitigate the risk of rupture in these patients.

Conclusions Annular rupture is a rare but serious complication of TAVI. Preprocedural MSCT screening is essential to recognise potential predictors of annular rupture, especially subannular calcification, and to appropriately size the THV. Balloon expandable valves and aggressive balloon dilatation should be avoided in such cases. Prompt management of rupture includes haemodynamic support, reversal of anticoagulation, pericardial drain, consideration of a second THV and emergency surgery. A dedicated protocol should be developed by the institutional heart team for such emergencies. n

transcatheter aortic-valve replacement in intermediaterisk patients. N Engl J Med 2017;376:1321–31. https://doi. org/10.1056/NEJMoa1700456. PMID: 28304219. 6. Anderson RH. Clinical anatomy of the aortic root. Heart 2000;84(6):670–73. https://doi.org/10.1136/heart.84.6.670. PMID: 11083753; PMCID:PMC1729505. 7. Medtronic transcatheter aortic valve replacement in low risk patients NCT02701283. Available at: https://clinicaltrials.gov/ ct2/show/NCT02701283 (accessed 23 August 2018). 8. Comparison of transcatheter versus surgical aortic valve replacement in younger low surgical risk patients with severe aortic stenosis (NOTION-2) NCT02825134. https://clinicaltrials. gov/ct2/show/record/NCT02825134 (accessed 23 August 2018). 9. The PARTNER 3 – trial – the safety and effectiveness of the sapien 3 transcatheter heart valve in low risk patients with aortic stenosis (P3) NCT02675114. https://clinicaltrials.gov/ ct2/show/NCT02675114 (accessed 23 August 2018). 10. de Heer LM, Budde RP, Mali WP, et al. Aortic root dimension changes during systole and diastole: evaluation with ECGgated multidetector row computed tomography. Int J Cardiovasc Imaging 2011;27(8):1195–204. https://doi.org/10.1007/s10554-

011-9838-x. PMID: 21359833; PMCID:PMC3230759. 11. J ilaihawi H, Kashif M, Fontana G, et al. Cross-sectional computed tomographic assessment improves accuracy of aortic annular sizing for transcatheter aortic valve replacement and reduces the incidence of paravalvular aortic regurgitation. J Am Coll Cardiol 2012;59(14):1275–86. https://doi. org/10.1016/j.jacc.2011.11.045. PMID: 22365424. 12. Nguyen G1, Leipsic J. Cardiac computed tomography and computed tomography angiography in the evaluation of patients prior to transcatheter aortic valve implantation. Curr Opin Cardiol. 2013;28(5):497–504. https://doi. org/10.1097/HCO.0b013e32836245c1. PMID: 23877567. 13. Jurencak T, Turek J, Kietselaer BL, Mihl C, Kok M, et al. MDCT evaluation of aortic root and aortic valve prior to TAVI. What is the optimal imaging time point in the cardiac cycle? Eur Radiol. 2015;25(7):1975–83. https://doi.org/10.1007/s00330015-3607-5. PMID: 25708961; PMCID:PMC4457917. 14. Blanke P, Russe M, Leipsic J, et al. Conformational pulsatile changes of the aortic annulus: impact on prosthesis sizing by computed tomography for transcatheter aortic valve replacement. JACC Cardiovasc Interv 2012;5(9):984–94. https://doi.org/10.1016/j.jcin.2012.05.014. PMID: 22995887.

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Structural 15. W illson AB, Webb JG, Labounty TM, et al (2012) 3-dimensional aortic annular assessment by multide-tector computed tomography predicts moderate or severe paravalvular regurgitation after transcatheter aortic valve replacement: a multicenter retrospective analysis. J Am Coll Cardiol 59:1287–94. https://doi.org/10.1016/j.jacc.2011.12.015. PMID: 22365423. 16. Schultz CJ, Moelker A, Piazza N, et al. Three dimensional evaluation of the aortic annulus using multislice computer tomography: are manufacturer’s guidelines for sizing for percutaneous aortic valve replacement helpful? Eur Heart J 2010;31(7):849–856. https://doi.org/10.1093/eurheartj/ehp534. PMID: 19995874. 17. Schultz CJ, Weustink A, Piazza N, et al. Geometry and degree of apposition of the CoreValve revalving system with multislice computed tomography after implantation in patients with aortic stenosis. J Am Coll Cardiol 2009;54(10): 911–918. https://doi.org/10.1016/j.jacc.2009.04.075. PMID: 19712801. 18. Blanke P, Reinöhl J, Schlensak C, et al. Prosthesis oversizing in balloon-expandable transcatheter aortic valve implantation is associated with contained rupture of the aortic root. Circ Cardiovasc Interv 2012;5(4):540–8. doi: 10.1161/ CIRCINTERVENTIONS.111.967349. PMID: 22872051. 19. Koos R, Mahnken AH, Kühl HP, et al. Quantification of aortic valve calcification using multislice spiral computed tomography: comparison with atomic absorption spectroscopy. Invest Radiol 2006;41(5):485–9. https://doi. org/10.1097/01.rli.0000208224.93467.87. PMID: 16625112. 20. Pasic M, Unbehaun A, Buz S, et al. Annular rupture during transcatheter aortic valve replacement: classification, pathophysiology, diagnostics, treatment approaches, and prevention. JACC Cardiovasc Interv 2015;8(1 Pt A):1–9. doi: 10.1016/j.jcin.2014.07.020. https://doi.org/10.1016/j. jcin.2014.07.020. PMID: 25616813. 21. Lembo NJ, King SB, Roubin GS, et al. Fatal aortic rupture during percutaneous balloon valvuloplasty for valvular aortic stenosis. Am J Cardiol 1987;60:733–6. https://doi. org/10.1016/0002-9149(87)90397-3. PMID: 3661448. 22. Walther T, Hamm CW, Schuler G, et al. Perioperative results and complications in 15,964 transcatheter aortic valve replacements: prospective data from the GARY Registry. J Am Coll Cardiol 2015;65(20):2173–80. https://doi.org/10.1016/j. jacc.2015.03.034. PMID: 25787198. 23. Hayashida K, Bouvier E, Lefèvre T, et al. Potential mechanism of annulus rupture during transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2013;82(5):E742–6. https://doi.org/10.1002/ccd.24524. PMID: 22718400. 24. Watanabe Y, Hayashida K, Lefevre T, et al. Transcatheter aortic valve implantation in patients of small body size. Catheter Cardiovasc Interv 2014;84:272–80. https://doi.org/10.1002/ ccd.24970. PMID: 23613222. 25. Barbanti M, Yang T-H, Rodès Cabau J, et al. Anatomical and procedural features associated with aortic root rupture during balloon-expandable transcatheter aortic valve replacement. Circulation 2013;128:244–53. https://doi.org/10.1161/ CIRCULATIONAHA.113.002947. PMID: 23748467. 26. Girdauskas E, Owais T, Fey B, et al. Subannular perforation of left ventricular outflow tract associated with transcatheter valve implantation: pathophysiological background and clinical implications. Eur J Cardiothorac Surg 2017;51(1):91–6. https://doi.org/10.1093/ejcts/ezw252. PMID: 27412343. 27. Hansson NC, Nørgaard BL, Barbanti M, et al. The impact of calcium volume and distribution in aortic root injury related to balloon-expandable transcatheter aortic valve replacement. J Cardio-vasc Comput Tomogr 2015;9(5):382–92. doi: 10.1016/j.jcct.2015.04.002. https://doi.org/10.1016/ j.jcct.2015.04.002. PMID: 26164109.

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28. Y ang TH, Webb JG, Blanke P, et al. incidence and severity of paravalvular aortic regurgitation with multidetector computed tomography nominal area oversizing or undersizing after transcatheter heart valve replacement with the Sapien 3: a comparison with the Sapien XT. JACC Cardiovasc Interv 2015;8(3):462–71. https://doi.org/10.1016/j.jcin.2014.10.014. PMID: 25790764. 29. Lange R, Bleiziffer S, Piazza N, et al. Incidence and treatment of procedural cardiovascular complications associated with trans-arterial and trans-apical interventional aortic valve implantation in 412 consecutive patients. Eur J Cardiothoracic Surg 2011;40:1105–13. PMID: 21515069. 30. Masson JB, Kovac J, Schuler G, et al. Transcatheter aortic valve implantation: review of the nature, management and avoidance of procedural complications. J Am Coll Cardiol Intv 2009;B:811–20. https://doi.org/10.1016/j.jcin.2009.07.005. PMID: 19778768. 31. Pasic M, Unbehaun A, Dreysse S, et al. Rupture of the device landing zone during transcatheter aortic valve implantation: a life-threatening but treatable complication. Circ Cardiovasc Interv 2012;5:424–32. https://doi.org/10.1161/ CIRCINTERVENTIONS.111.967315. PMID: 22589295. 32. Griese DP, Reents W, Kerber S, et al. Emergency cardiac surgery during trans-femoral and transapical aortic valve implantation: incidence, reasons, management, and outcome of 411 patients from a single center. Catheter Cardiovasc Interv 2013;82:E726–33. https://doi.org/10.1002/ccd.25049. PMID: 23765631. 33. Blanke P, Reinöhl J, Schlensak C, et al. Prosthesis oversizing in balloon-expandable transcatheter aortic valve implantation is associated with contained rupture of the aortic root. Circ Cardiovasc Interv 2012;5(4):540–8. https://doi.org/10.1161/ CIRCINTERVENTIONS.111.967349. PMID: 22872051. 34. M. Barbanti, Leipsic J, Binder R, et al. Underexpansion and ad hoc post-dilation in selected patients undergoing balloonexpandable transcatheter aortic valve replacement. J Am Coll Cardiol 2014;63(10):976–81. https://doi.org/10.1016/j. jacc.2013.10.014. PMID: 24211502. 35. Masson JB, Kovac J, Schuler G, et al. Transcatheter aortic valve implantation: review of the nature, management and avoidance of procedural complications. J Am Coll Cardiol Intv 2009;2:811–20. https://doi.org/10.1016/j.jcin.2009.07.005. PMID: 19778768. 36. Olcay A, Paixao A, Marmagkiolos K, et al. Aortic annular rupture during TAVI: mini review. Cardiovasc Revasc Med 2016;17:199–201. https://doi.org/10.1016/j.carrev.2016.03.005. PMID: 27157295. 37. Hiltrop N, Adriaenssens T, Dymarkowski S, et al. Aortic annulus rupture during TAVI: a therapeutic dilemma in the inoperable patient. J Heart Vave Dis 2015;24(4). PMID: 26897812, 38. Vannini L, Andrea R, Sabaté M. Conservative management of aortic root rupture complicated with cardiac tamponade following transcatheter aortic valve implantation. World J Cardiol 2017;9(4):391–5. https://doi.org/10.4330/wjc.v9.i4.391. PMID: 28515859; PMCID:PMC5411975. 39. Breitbart P, Minners J, Pache G, et al. Outcomes in patients with contained ruptures of the aortic annulus after transcatheter aortic valve implantation with balloonexpandable devices. EuroIntervention 2017;pii: EIJ–D–17–00347. https://doi.org/10.4244/EIJ-D-17-00347. PMID: 28781240. 40. Hayashida K, Bouvier E, Lefèvre T. Successful management of annulus rupture in transcatheter aortic valve implantation. J Am Coll Cardiol Intv 2013;6(1):90–1. https://doi.org/10.1016/ j.jcin.2012.08.020. PMID: 23347866. 41. Keenan JE, Vavalle JP, Ganapathi AM, et al. Factor VIIa for annulus rupture after transcatheter aortic valve replacement.

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Ann Thorac Surg 2015;100(1):313–5. https://doi.org/10.1016/ j.athoracsur.2014.09.063. PMID: 26140778. Rezq A, Basavarajaiah S, Latib A, et al. Incidence, management, and outcomes of cardiac tamponade during transcatheter aortic valve implantation: a single-center study. J Am Coll Cardiol Intv 2012;5:1264–72. https://doi.org/10.1016/ j.jcin.2012.08.012. PMID: 23257375. Eker A, Sozzi FB, Civala F, Bourlon F. Aortic annular rupture during transcatheter aortic valve implantation: safe aortic root replacement. Eur J Cardiothorac Surg 2012;41:1205. https:// doi.org/10.1093/ejcts/ezr146. PMID: 22250069. Griese DP, Reents W, Kerber S, et al. Emergency cardiac surgery during transfemoral and transapical transcatheter aortic valve implantation: incidence, reasons, management and outcome of 411 patients from a single center. Catheter Cardiovasc Interv 2013;82(5): E726–33. https://doi.org/10.1002/ ccd.25049. PMID: 23765631. Eggebrecht H, Schmermund A, Kahlert P, et al. Emergent cardiac surgery during transcatheter aortic valve implantation (TAVI): a weighted meta-analysis of 9,251 patients from 46 studies. EuroIntervention 2013;8(9):1072–80. https://doi. org/10.4244/EIJV8I9A164. PMID: 23134947. Yu Y, Vallely M, Ng MK. Valve-in-valve implantation for aortic annular rupture complicating trans-catheter aortic valve implantation. J Invasive Cardiol 2013;25(8):409–10. PMID: 23913607. Mauri L, Aldebert P, Cuisset T, et al. Percutaneous closure of a poorly tolerated post–transcatheter aortic valve implantation ventricular septal defect. Ann Thorac Surg 2014;98:1823–6. https://doi.org/10.1016/j.athoracsur.2013.12.072. PMID: 25441795. Ando T, Holmes AA, Taub CC, et al. Iatrogenic ventricular septal defect following transcatheter aortic valve replacement: a systematic review. Heart Lung Circ 2016;25(10):968–74. https://doi.org/10.1016/j.hlc.2016. 03.012. PMID: 7157312. Hein R, Abdel-Wahab M, Sievert H, et al. Outcome of patients after emergency conversion from transcatheter aortic valve implantation to surgery. EuroIntervention 2013;9(4):446–51. https://doi.org/10.4244/EIJV9I4A73. PMID: 23965349. Eggebrecht H, Vaquerizo B, Moris C, et al. Incidence and outcomes of emergent cardiac surgery during transfemoral transcatheter aortic valve implantation (TAVI): insights from the European Registry on Emergent Cardiac Surgery during TAVI (EuRECS–TAVI). Eur Heart J 2018; 39(8):676–84. doi: 10.1093/eurheartj/ehx713. https://doi.org/10.1093/eurheartj/ ehx713. PMID: 29253177. Thyregod HG, Steinbruchel DA, Ihlemann N, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1–year results from the all-comers NOTION Randomized Clinical Trial. J Am Coll Cardiol 2015;65(20):2184–94. https://doi.org/10. 1016/j.jacc.2015.03.014. PMID: 25787196. Mylotte D, Lefevre T, Sondergaard L, et al. Transcatheter aortic valve replacement in biscuspid aortic valve disease. J Am Coll Cardiol. 2014;64:2330–9. https://doi.org/10.1016/ j.jacc.2014.09.039. PMID: 25465419. Kumar A, Wojciuk J, Morgan KP, et al. Contained aortic rupture as a late complication of transcutaneous aortic valve implantation. JACC: Cardiovascular Interv 2010;3(8):878–9. https:// doi.org/10.1016/j.jcin.2010.02.013. PMID: 20723862. Hamdan A, Barbash I, Schwammenthal E, et al. Sex differences in aortic root and vascular anatomy in patients undergoing transcatheter aortic valve implantation: a computed-tomographic study. J Cardiovasc Comput Tomogr 2017;11(2):87–96. https://doi.org/10.1016/j.jcct.2017.01.006. PMID: 28139364.

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Alternate Access for TAVI: Stay Clear of the Chest Pavel Overtchouk 1 and Thomas Modine 1 1. Centre Hospitalier Regional et Universitaire de Lille, Lille, France

Abstract Transcatheter aortic valve implantation (TAVI) is currently performed through an alternative access in 15 % of patients. The transapical access is progressively being abandoned as a result of its invasiveness and poor outcomes. Existing data does not allow TAVI operators to favour one access over another — between transcarotid, trans-subclavian and transaortic — because all have specific strengths and weaknesses. The percutaneous trans-subclavian access might become the main surgery-free alternative access, although further research is needed regarding its safety. Moreover, the difficult learning curve might compromise its adoption. The transcaval access is at an experimental stage and requires the development of dedicated cavo-aortic crossing techniques and closure devices.

Keywords Alternative access, alternative approach, transapical, transaortic, transcarotid, trans-subclavian, transcaval, TAVI, TAVR Disclosure: Thomas Modine is a consultant for Boston Scientific, Medtronic, Edwards Lifesciences, Cephea, MicroPort Scientific Corporation, GE Healthcare and Abbott; he received a research support grant from Edwards Lifesciences. Pavel Overtchouk has no conflict of interest to declare. Received: 14 July 2018 Accepted: 13 August 2018 Citation: Interventional Cardiology Review 2018;13(3):145–50. DOI: https://doi.org/10.15420/icr.2018.22.1 Correspondence: Thomas Modine, Interventional Cardiology and Cardiovascular Surgery, Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille), 2 Avenue Oscar Lambret, 59037 Lille, France. E: thomas.modine@chru-lille.fr

This article aims to provide an updated comparative review, addressing the respective strengths and weaknesses of different alternative transcatheter aortic valve implantation (TAVI) approaches.

who have previously undergone a coronary artery bypass may be unsuitable for the TAo pathway if they received venous grafts, or for the TS pathway if they received mammal artery grafts.

The transfemoral (TF) access is favoured by international guidelines on TAVI because of its reported superiority to the transthoracic approach.1–3 In spite of the progress in miniaturisation of newgeneration transcatheter heart valves (THV), comorbidities and unfavourable anatomy preclude TF access in 15–20 % of patients according to contemporary registries.4,5 Besides, vascular complications with the TF approach are as high as 6 % in recent randomised Placement of Aortic Transcatheter Valves 2 (PARTNER 2) and Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI) trials, which reflects that some patients could benefit from an alternative approach. Historically, the transapical (TA) approach was the first to be introduced for broad clinical use in TAVI.6 Newer and less invasive pathways have since been proposed and developed, namely transcarotid (TC), transaortic (TAo), trans-subclavian (TS) and transcaval (TCv). However, the relative ‘invasiveness’ of one alternative approach compared with another is subject to debate. Invasiveness relates to the need for a surgical cutdown, general anaesthesia, vascular or heart lesion required for delivery system crossing, and potential impact on the other major systems such as the cerebral, respiratory and renal systems.

Transthoracic Approaches

No randomised trial directly compares the different approaches, and these alternative approaches are more or less subdued to a learning curve.7 Also, patient anatomy and comorbidities often determine eligibility for alternative pathways. Indeed, general anaesthesia for TA or TAo access may be contraindicated in patients with chronic respiratory insufficiency and the TS pathway may be precluded by vascular anatomy, such as tortuosity, stenosis or angulation. Patients

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Transapical TAVI The TA pathway was the first alternative described for when the TF approach is not possible. Therefore, this is the alternative pathway with most abundant data (Figure 1).8 The TA pathway is the only anterograde TAVI approach; it provides easy valve crossing and excellent controllability.9 TA TAVI avoids cardiopulmonary bypass and sternotomy, as it is a beating-heart left transthoracic approach (Figure 2).10 However, TA access requires a surgical cutdown through anterolateral mini-thoracotomy with general anaesthesia and mechanical ventilation. Furthermore, the impact of the crossing by the delivery system through the left ventricle apex and closing after the implantation has been reported to be responsible for apex myocardium stunning and possibly necrosis, which impairs left ventricle function.11 These drawbacks encouraged operators to master other less morbid alternative pathways, and the TA pathway’s use has decreased over time. Indeed, TA access was undertaken in 17.6 % of patients in the early FRench Aortic National CoreValve and Edwards (FRANCE) 2 registry (2010–2012) compared with 4.2 % in the more recent FRANCE TAVI registry (2013–2015). A similar reduction in popularity was noted overseas as reported in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry (Figure 3).4,5 Comparisons between TA and TF TAVI or surgical aortic valve replacement (SAVR) are based on observational prospective studies. TA is inferior to TF TAVI. Indeed, in inoperable and high-risk patients the 30-day mortality with TA TAVI has been reported to

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Structural Figure 1: Timing of published cohorts regarding alternative approaches for transcatheter aortic valve implantation and relative experience with respect to the abundance of data of each alternative approach

First-in-man TAVI Transseptal Anterograde

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Figure 2: Overview of the alternative approaches

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Iliac artery Transfemoral

be close to 5.0 %12,13 compared with 1.6 % for the TF approach in contemporary registries.13 Furthermore, one-year survival was 72 % after TA versus 81 % after TF TAVI in the SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry.14 TA access was associated with particularly worse outcomes in nonagerians; 30-day mortality was as high as 14.2 % (versus 6.5 % with the TF access, HR 2.56; 95 % CI [1.63–4.01])15–17 in a recent meta-analysis of three studies. Vascular complications are twice as few with the TA approach but the rate of major bleeding was twice as high.13 On the other hand, one recent cohort of intermediate- and low-risk patients, showed similar 30-day mortality (1.5 %), stroke (3.5 %) and pacemaker implantation (10.0 %),13 underscoring the need for further research. These remarks should be tempered by the fact that patients treated with TA TAVI often share more comorbidities than those treated with the TF approach. However, comparisons after propensity-matching seem to support these data.18

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Transcaval

Approach

TAVI = transcatheter aortic valve implantation.

Transcarotid

Transsubclavian Percutaneous

TA TAVI yields comparable results to SAVR in inoperable and high-risk patients. One retrospective study with pair matching of 164 high-risk patients (mean logistic EuroScore over 29 %) reported similar one-year survival rates for TA TAVI and SAVR (81 % versus 76 %, respectively; p=0.66). Stroke, pacemaker and indexes of physical and mental quality of life were also similar.19 However, the five-year mortality in highrisk patients favoured SAVR (HR 1.37; 95 % CI [0.98–1.92]).20 In the PARTNER 2 trial that randomised intermediate- and low-risk patients, the outcome of the transthoracic approach group (pooling of patients treated through TA and TAo pathways), was found to be non-inferior to SAVR (HR of composite primary outcome including all-cause death and disabling stroke 1.21; 95 % CI [0.84–1.74]).1 In another cohort, with a long five-year follow-up of low-risk patients, similar survival rates (86 % after SAVR versus 76 % after TA TAVI) were reported, along with similar health related physical or mental quality of life.21 Conversely, the STACCATO trial, which randomised elderly low-risk patients was prematurely stopped after including only 72 patients because of excessive adverse events (death, stroke, acute renal failure, severe paravalvular leakages) in the TA TAVI group.22 A meta-analysis that pooled data from randomised trials with all operative-risk patients (PARTNER 2A, The Nordic aortic valve intervention [NOTION], US CoreValve High Risk and STACCATO or PARTNER 1A) found no difference in two-year mortality risk between TA TAVI and SAVR. Similarly, stroke (RR 1.67; 95 % CI [0.97–2.87]) and acute kidney injury (RR 1.54; 95 % CI [0.77–3.07]) were not different. However, life threatening or disabling bleeding were less frequently observed with TA TAVI (RR 0.53; 95 % CI [0.42–0.67]).1,22–25 Most of these studies included patients treated with the Edwards SAPIEN (Edwards Lifesciences, Irvine, CA, USA) and Medtronic CoreValve (Medtronic, Minneapolis, MN, USA) transcatheter heart valves (THV). However, data are concordant with newer-generation devices. A recent international registry reported results with the TA implanted ACURATE TA™ THV in 500 high-risk patients (Society of Thoracic Surgeons score;

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Alternate Access for TAVI Figure 3: Timely variations of transcatheter aortic valve implantation approach usage in the French, United Kingdom, European and North American registries. 4,5,61–63 100 90 80 70 60 50 40 30 20 10 0

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STS 9.8 ± 8.3 %). Mortality was high (7 % at 30 days and 20 % at 1 year) albeit comparative to registries involving other THV types and similar patient operative risk, the stroke rate was low (2.2 % at 30 days, 3.7 % at one year). Also, only 10 % of patients required a permanent pacemaker and 2 % of patients had echocardiographic paravalvular leakage ≥2+ (none were 3+ or 4+).26,27 These results are encouraging and the TF implantable version of the ACURATE THV (ACURATE Neo™), might benefit from a broader adoption by avoiding the TA pathway drawbacks.28,29 Data with other new-generation devices are reassuring SAPIEN 3, ACURATE TA, Engager, JenaValve™. The design of this newgeneration of THV is interesting and yields low rates of prosthetic regurgitation, but they are not likely to enjoy broad adoption because of the high mortality of the TA approach.13,27,30–33 TA access is being progressively abandoned by TAVI operators because it requires a surgical cutdown, general anaesthesia and intubation. Also, there is growing evidence of inferiority to other pathways and open surgery in the elderly as well as lower-risk patients.

Transaortic Access TAo (or direct aortic) access requires a partial sternotomy or minithoracotomy and no cardiopulmonary bypass as opposed to SAVR. After a 4–5 cm skin incision, a reverse T- or right J-shaped sternotomy down to the second intercostal space or mini-right thoracotomy in the second intercostal space (according to the position of the aorta regarding the sternum on pre-TAVI multi-slice CT) is performed, before puncturing the aorta.34,35 This approach allows excellent controllability and precise THV positioning. SAPIEN and CoreValve THVs have been the most explored devices with the TAo approach.36

Others

2015–16

100 90 80 70 60 50 40 30 20 10 0

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100 90 80 70 60 50 40 30 20 10 0

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Transfemoral

Transapical 2012

2013

2014

Others alternative 2015

TA access.36–39 The risk of stroke is comparable to TF, but the invasive surgical access of the TAo approach yields high rates of life-threatening bleeding complications that are comparable to TA.37,39 In a recent observational study, Arai et al. provided a univariate comparison of 467 patients treated with TF to 289 patients treated with TAo and 42 patients treated with TA approaches. They found 30-day mortality to be 9 % for TAo versus 14 % for TA and 5 % for TF and one-year mortality of 20 % after TAo versus 30 % after TA and 13 % after TF. Strokes were fewer with TF and TAo (both 2 %) than TA (5 %). Acute kidney injury rates were lower after TAo compared with TA, but still higher than TF (13 % versus 31 % versus 5 %, respectively).37 Because no multivariable analysis was performed, these results should be considered with care. These results were consistent with those of McCarthy et al. who also found similar healthcare costs for TAo and TA approaches, although both were more costly than TF, which was partly a result of longer hospital stays.40 A more recent multicentre study reported further favourable outcomes after TAo TAVI with 6.1 % and 1.0 % mortality and stroke rates, respectively.41 Recent propensity-matched data in lower-risk patients are concordant.42 These results support the superiority of TAo over TA access, but not against TF. Indeed, major or life-threatening bleeding at 30 days has recently been reported to be as high as 66.7 % after TAo TAVI, twice as much as in a propensity-matched TF group.39 A meta-analysis by Amrane et al. found concordant 10.0 % 30-day mortality rate across 15 studies and 3.7 % strokes across nine studies.36 The patients included in studies of the TAo approach have mostly been of high surgical risk and further validation in lower-risk categories is warranted. TAo is also yet to be compared with non-TA alternative approaches in methodologically robust studies.

Extra-thoracic Approaches Transcarotid Approach

TAo approach has often been presented as an alternative to TA when TF access is precluded.34 Observational data with high-risk patients suggest that TAo yields lower short-term as well as long-term mortality than the

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The TC approach was first described in 2010.43 Experience with carotid access is important for the surgeon to provide optimal results with the TC approach because of specific anatomical challenges such as the

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Structural Figure 4: Comparative 30-day all-cause mortality, stroke and life-threatening bleeding rates in high-risk patients treated with the different transcatheter aortic valve implantation approaches 14 12 10 8 6 4 2 0 Mortality

Stroke

Transfemoral (Adams et al)

Life-threatening bleeding Transapical (Börgermann et al)

Transsubclavian (Schäfer et al)

Transaortic (Bapat et al)

Transcarotid (Mylotte et al)

Transcaval (Greebaum et al)

Figure 5: Proposed algorithm for alternative approach selection

Trans-subclavian The TS (or transaxillary) approach was one of the first alternative accesses described, and was traditionally considered as mandatory surgical.52,53 The surgical cutdown is performed through an infraclavicular incision and must respect the brachial plexus.52,54,55 However, a percutaneous approach has recently been proposed.56 Conscious sedation with local anaesthesia or general anaesthesia are possible with the TS pathway.47 Most data on TS access feasibility has been

Patient elibigible to TAVI

Yes

TF access favorable

TF TAVI

reported with the Medtronic CoreValve and first-generation Edwards SAPIEN THVs, although some recent reports hinted at favourable outcomes with newer generation SAPIEN 3 and Evolut™ R valving systems.57,58 Recent registry data suggest that the use of the TS approach is declining. Indeed, the alternative TS access was performed in 5.8 % of patients in the FRANCE 2 registry (2010-2012) versus 3.0 % in the more recent FRANCE TAVI registry (2013-2015).2

Carotid and vertebral artery patency Functioning Willis circle

TC access

ER S3

Patient anatomy Local expertise No previous venous CABG

TAo access

No previous mammal CABG Subclavian artery patency

ER S3

TS access

ER S3

TC,TAo,TS approaches precluded

Consider TA access

ER, S3, AT, JV

AT = ACURATE TA; JV = JenaValve; ER = Evolut R; S3 = SAPIEN 3; TA = transapical; TAo = transaortic; TC = transcarotid; TF = transfemoral; TS = trans-subclavian.

presence of the vagus nerve and the respiratory tract. Theoretically, the left carotid access for TAVI should be favoured over the right because it provides superior coaxial alignment with the ascending aorta and optimal positioning for the THV during the device deployment. However, right carotid access has also been successfully used.44,45 Data from the recent FRANCE TAVI registry showed that up to 3.4 % of patients are now treated with the TC approach.5 The TC access has the potential to alleviate some of drawbacks of the other non-femoral approaches, given its minimally-invasive nature.35,46–48 Previous reports demonstrated the feasibility and safety of the TC approach, mostly with the Medtronic CoreValve THV.43,49,50 Our experience with the SAPIEN devices is also reassuring. The minimally-invasive surgery of the TC pathway has been mastered by numerous heart teams and recently it has been reported to have

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similar outcomes to TF access in terms of mortality and morbidity.49 Recent studies reported a mortality of 6.3 % at 30 days and 16.7 % at one year. Furthermore, rates of 30-day cerebrovascular events in our registry were similar to existing data with transfemoral TAVI,51 in particular the rate of 30-day stroke was under 2.5 % with TC TAVI.44,49,50 Preference for local anaesthesia with conscious sedation to general anaesthesia is team-dependent. Azmoun et al. observed in-hospital death in two of the 19 patients treated with TC TAVI under local anaesthesia in their cohort.50 One larger registry reported lower numerical rates of 30-day strokes with local anaesthesia and conscious sedation than general anaesthesia (0.0 % versus 2.2 %), albeit without statistical significance.44 Furthermore, the TC approach permits fast ambulation and short hospital stay (median four days) after the intervention.50 Our team has previously demonstrated the effectiveness and safety of the TC TAVI with the Medtronic CoreValve system44,49 and our practice has provided reassuring feedback with the Edwards SAPIEN system as well.

TS was compared with the TF approach in one small propensitymatched cohort, using the CoreValve THV. The authors found a similar two-year survival (approximately 75 %), along with similar rates of procedural success, major vascular and bleeding complications.59 Another more recent observational report of 202 patients compared TA and TS approaches and found no significant association of access site with mortality in the multivariable analysis. Two-year survival was also comparable (84 % after TS and 75 % in TA) although TA yielded higher perioperative mortality; the latter feature could be linked to a higher risk of major and life-threatening bleeding that was less frequent with the TS approach (11.5 %) than the TA approach (40.0 %).47 The percutaneous approach is relatively recent. It has been reported to be feasible and safe in one German cohort of 100 high-risk patients, mostly through left axillary artery and under general anaesthesia. Thirty-day mortality was 6 % and 1-year mortality was 15 %; no stroke was reported.56 The percutaneous TS approach could potentially become a first-choice alternative pathway by avoiding surgical cutdown. However, manual compression is often ineffective for anatomical reasons, exposing patients to potentially fatal bleeding complications. As a result, some additional complex operative steps are required to avoid cataclysmic bleeding, with the insertion of a wire in the ipsilateral brachial artery externalised through the femoral artery or contralateral brachial artery for balloon occlusion or covered stent implantation in case of failure of the percutaneous closure system, such as the Prostar® (Abbott Vascular) or ProGlide (Abbott Vascular).56

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Alternate Access for TAVI Hence, achieving optimal results will require operators to confront a difficult learning curve. Also, further research is required to validate this approach in intermediate- and low-risk patients.

Transcaval The TCv approach is the most recently described approach for TAVI.60 It aims to avoid the morbidity of the transthoracic (TA and TAo) approaches while providing the favourable operating room ergonomics of the TF access.46 The TCv approach allows large introducer sheath size because of the venous nature of the access without increasing the risk of major bleeding, TCv access use implies the ability to perform a wire crossing from the inferior vena cava into the aorta through the retroperitoneum to allow the passage of the TAVI introducer sheath and delivery system. These steps require precise preoperative planning from the multi-slice CT. Most importantly, the aorta must have few calcifications in the crossing area to avoid tearing of the aortic wall and effective closing of the artificially created cavo-aortic duct after THV implantation. Indeed, the cavo-aortic access requires closing by a cardiac-type occluder device (AMPLATZER™ Duct Occluder or AMPLATZER Ventricular Septal Defect Occluder, St. Jude Medical).46 Experience with the TCv approach was reported in two successive (2013–2014 and 2014–2016) cohorts of 19 and 100 high-risk patients ineligible for the arterial TF as well as TA and TAo pathways, and presenting a suitable cavo-aortic anatomy. The patients were treated with SAPIEN XT and SAPIEN 3 as well as CoreValve and Evolut R THVs, mostly with general anaesthesia although moderate sedation was also allowed.46,60 Retroperitoneal haematoma is the most feared complication specific to the TCv approach. Among the 19 patients of the first cohort, all had persistent aorto-caval flow immediately after the procedure; 16 underwent repeat imaging that showed

L eon MB, Smith CR, Mack MJ, et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med 2016;374(17):1609–20. https://doi.org/10.1056/ NEJMoa1514616; PMID: 27040324. 2. Nishimura RA, Otto CM, Bonow RO, 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(2):252–89. https://doi.org/10.1016/j. jacc.2017.03.011; PMID: 28315732. 3. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017;38(36):2739–91. https://doi.org/10.1093/eurheartj/ ehx391; PMID: 28886619. 4. Grover FL, Vemulapalli S, Carroll JD, et al. 2016 Annual Report of The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. J Am Coll Cardiol 2017;69(10):1215–30. https://doi.org/10.1016/ j.jacc.2016.11.033; PMID: 27956264. 5. Auffret V, Lefevre T, Van Belle E, et al. Temporal Trends in Transcatheter Aortic Valve Replacement in France: FRANCE 2 to FRANCE TAVI. J Am Coll Cardiol 2017;70(1):42–55. https://doi. org/10.1016/j.jacc.2017.04.053; PMID: 28662806. 6. Walther T, Falk V, Borger MA, et al. Minimally invasive transapical beating heart aortic valve implantation — proof of concept. Eur J Cardiothorac Surg 2007;31(1):9–15. https://doi. org/10.1016/j.ejcts.2006.10.034; PMID: 17097302. 7. Henn MC, Percival T, Zajarias A, et al. Learning Alternative Access Approaches for Transcatheter Aortic Valve Replacement: Implications for New Transcatheter Aortic Valve Replacement Centers. Ann Thorac Surg 2017;103(5):1399–405. https://doi.org/10.1016/ j.athoracsur.2016.08.068; PMID: 27765175. 8. Walther T, Dewey T, Borger MA, et al. Transapical Aortic Valve Implantation: Step by Step. Ann Thorac Surg 2009;87(1):276–83. https://doi.org/10.1016/j.athoracsur.2008.08.017; PMID: 19101311. 9. Nakatsuka D, Tabata M. Transapical approach for transcatheter aortic valve implantation. Ann Cardiothorac Surg 2017;6(5):553–4. https://doi.org/10.21037/acs.2017.09.01; PMID: 29062753. 10. Overtchouk P, Modine T. Transcatheter Aortic Valve Implantation (TAVI) Using the Transapical Approach. In: Advances in Treatments for Aortic Valve and Root Diseases [Internet].

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incomplete closure in one of them.60 In the second cohort, the rate of life-threatening or major bleeding was as high as 18 % and the rate of major vascular complications was as high as 19 %, which underscores the bleeding hazard associated with the TCv approach. Device success was achieved in 98 of 100 patients, eight patients died at 30 days and five presented with a stroke in this cohort of high-risk patients (STS mortality risk score 9.6 ± 6.3 %).46 The TCv approach remains an experimental approach, to be performed by expert centres as an option in patients who are ineligible for TF as well as the other alternative approaches, with abdominal anatomy compatible with a cavo-aortic crossing. The TCv access provides favourable operating room ergonomics and is compatible with conscious sedation. Nevertheless, if sufficient improvements of the technology dedicated to cavo-aortic crossing and closing are achieved, the TCv approach might gain popularity among TAVI operators in the future. In conclusion, the perfect alternative pathway should be performed percutaneously, under conscious sedation with local anaesthesia, and yield similar results to the arterial TF access regarding the major complications of perioperative mortality, stroke, and major bleeding. None of the existing approaches satisfy all these criteria (Figure 4). As TAVI indications expand to younger and lower-risk patients, perioperative mortality and stroke will become increasingly intolerable, which might encourage TAVI operators to select approaches with the lowest rates of such complications. Hence, when TF access is precluded, TC and TS approaches might benefit from this expansion of indications in the future. Besides these safety concerns, the choice of one alternative access over another is often a matter of anatomical feasibility as assessed by preoperative imaging and local expertise (Figure 5). n

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Supporting life-long learning for interventional cardiovascular professionals Led by Editor-in-Chief Simon Kennon and underpinned by an editorial board of worldrenowned physicians, Interventional Cardiology Review is a peer-reviewed journal that publishes reviews, case reports and original research. Available in print and online, Interventional Cardiology Reviewâ&#x20AC;&#x2122;s articles are free-to-access, and aim to support continuous learning for physicians within the field.

Call for Submissions Interventional Cardiology Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality. For further information on submitting an article, or for free access to the journal, please visit: www.ICRjournal.com

Radcliffe Cardiology Interventional Cardiology Review is part of the Radcliffe Cardiology family. For further information, including access to thousands of educational reviews from across the speciality, visit: www.radcliffecardiology.com

Cardiology

Lifelong Learning for Cardiovascular Professionals

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Cardiology

Lifelong Learning for Cardiovascular Professionals

www.radcliffecardiology.com A free-to-access community supporting best practice in cardiovascular care

European Cardiology Review Volume 11 • Issue 1 • Summer 2016

Volume 11 • Issue 1 • Summer 2016

www.ECRjournal.com

Resistant Hypertension: A Real Entity Requiring Special Treatment? Stefano Taddei and Rosa Maria Bruno

Advances in Cardiovascular MRI using Quantitative Tissue Characterisation Techniques: Focus on Myocarditis

US Cardiology Review

Rocio Hinojar, Eike Nagel and Valentina O Puntmann

Role of the Thyroid System in the Dynamic Complex Network of Cardioprotection Alessandro Pingitore, Giorgio Iervasi and Francesca Forini

Volume 12 • Issue 1 • Spring 2018

www.USCjournal.com

Atrial Fibrillation, Cognitive Decline and Dementia

Volume 12 • Issue 1 • Spring 2018

Alvaro Alonso and Antonio P Arenas de Larriva

Recognition, Diagnosis,Band Management of A C Heart Failure with Preserved Ejection Fraction

Meshal Soni, MD and Edo Y Birati, MD

Fulminant Myocarditis: A Review of the Current Literature

Artery

Vein Arterioles

Emily Seif, MD, Leway Chen, MD, MPH, and Bruce Goldman, MD

Venules Capillaries

Interventional Echocardiography: Field of Advanced Imaging E F G to Support Structural Heart Interventions

Collagen Adventitial progenitor Smooth muscle cell

Roy Arjoon, MD, Ashley Brogan, MD, and Lissa Sugeng, MD, MPH

Pericyte

Catheter Ablation for Ventricular Tachycardia in Patients with Structural Heart Disease

Endothelial cell Pericyte-derived MSC

ISSN: 1758-3756

Timothy M Markman, MD Daniel A McBride, MD and Jackson J Liang, DO

T1 mapping using the modified look-locker sequence

Adventitia-derived MSC

Sagittal fused PET/ CT showing increased FDG uptake

Origin of potential stem cells

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

ISSN: 1758-3896 • eISSN: 1758-390X

ECR11.1_FC+Spine.indd All Pages

Heart valve surgery for removing expandable transcatheter aortic valve implantation

Anatomic location and sensing vectors of the subcutaneous implantable cardioverterdefibrillator system

29/07/2016 00:08

X-ray showing the correct placement of catheter ablation for atrial fibrillation

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

USC 12.1 FC MOCK.indd All Pages

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ICRjournal.com

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08/05/2018 20:35

R EG I S T ER N OW !

Lisbon, Portugal

September 22-25

CIRSE 2018 MEET

CONNEC T

View the programme and find out more at www.cirse.org

featuring

Preliminary Programme available: www.aorticideas.org

Cardiovascular and Interventional Radiological Society of Europe

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LEADERSHIP IN LIVE CASE DEMONSTRATION

FEBRUARY 14-16, 2019

JOINT INTERVENTIONAL MEETING IN PARTNERSHIP WITH

, Italy w w w . j i m - v a s c u l a r . c o m ORGANIZING SECRETARIAT Victory Project Congressi • Via C. Poma, 2 - 20129 Milan - Italy Phone +39 02 89 05 35 24 • Fax +39 02 20 13 95 • E-mail info@victoryproject.it

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