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Interventional Cardiology Review Volume 13 • Issue 2 • Summer 2018

Volume 13 • Issue 2 • Summer 2018

www.ICRjournal.com

Delayed Coronary Obstruction After Transcatheter Aortic Valve Implantation is not the Structural Equivalent of Late Stent Thrombosis After Percutaneous Coronary Intervention Simon Kennon

Diagnosis and Outcomes of Transcatheter Aortic Valve Implantation in Bicuspid Aortic Valve Stenosis Sung-Han Yoon, Yoshio Maeno, Hiroyuki Kawamori, Masaki Miyasaka, Takahiro Nomura, Tomoki Ochiai, Shadi Nemanpour, Matthias Raschpichler, Rahul Sharma, Tarun Chakravarty and Raj Makkar

Non-vitamin K Antagonist Oral Anticoagulant After Acute Coronary Syndrome: Is There a Role? Paul Guedeney, Birgit Vogel and Roxana Mehran

Right ili

ISSN: 1756-1477

Bicuspid Aortic Valve Stenosis, Type 1

Transcatheter Mitral Valve Implantation

TAVI in Small Anatomy

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Orsiro

Highly deliverable

60 μm

Clinically proven1 Highly deliverable2 Ultrathin 60 μm3 struts

Deliverability is crucial for treatment of complex lesions4 Designed for challenging cases – Primary endpoint* results at 12 months in prospective, large scale, all-comers trials. Complex Lesions

BIOFLOW-III5

5.1% Small Vessels

n = 743 TLF at 12 months [%]

Orsiro n = 731

7.5%

Xience n = 404

5 TLF at 12 months [%]

BIOSCIENCE6 Orsiro n = 679

Orsiro n = 731

5 TVF at 12 months [%]

5 TLF at 12 months [%]

6.0%

Resolute Integrity n = 677

7.9% 0

6.3%

BIO-RESORT7 6.9%

Xience n = 699

n = 731 TLF at 12 months [%]

4.8%

Resolute Integrity n = 677

7.9%

A/B1

BIO-RESORT7

BIOSCIENCE6 Orsiro n = 743

Long Lesions

5.1%

B2/C

8.1%

5 TVF at 12 months [%]

* Target Lesion Failure (TLF) and Target vessel failure (TVF) ; 1 ESC/EACTS Guidelines on myocardial revascularization. European Heart Journal (2014) 35, 2541–2619 doi:10.1093/eurheartj/ehu278; 2 BIOTRONIK data on file; 3 ø 2.25 – 3.0 mm; 4 R. Waksman, Biotronik’s PLLA Biodegradable DES Program. Presented at CRT 2012; Washington, DC, US; 5 Waltenberger et al. BIOFLOW-III, DOI: 10.4244/EIJY15M03_08; 6 Pilgrim et al. BIOSCIENCE, http://dx.doi.org/10.1016/S0140-6736(14)61038-2; 7 von Birgelen et al. BIO-RESORT, http://dx.doi.org/10.1016/S0140-6736(16)31920-1. CAUTION – Investigational device. Limited by the United States law to investigational use. Xience is a registered trademark of Abbott Cardiovascular Systems Inc. Resolute and Resolute Integrity are registred trademarks of Medtronic.

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Volume 13 • Issue 2 • Summer 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 Lindsey Mathews • Production Helena Clements • 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 Lindsey Mathews lindsey.mathews@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 there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. 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: Summer 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, Lindsey Mathews lindsey.mathews@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

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

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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

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Contents

Foreword

Simon Kennon Editor-in-Chief, ICR

Structural

Delayed Coronary Obstruction After Transcatheter Aortic Valve Implantation is not the Structural Equivalent of Late Stent Thrombosis After Percutaneous Coronary Intervention Simon Kennon

Transcatheter Aortic Valve Implantation in Small Anatomy: Patient Selection and Technical Challenges Makoto Nakashima and Yusuke Watanabe

Coronary Revascularisation in Transcatheter Aortic Valve Implantation Candidates: Why, Who, When? Davide Cao, Mauro Chiarito, Paolo Pagnotta, Bernhard Reimers and Giulio G Stefanini

Transseptal Transcatheter Mitral Valve Replacement for Post-Surgical Mitral Failures Marvin H Eng and Dee Dee Wang

Coronary

‘Combat’ Approach to Cardiogenic Shock

Anticoagulant Therapy for Acute Coronary Syndromes

Non-vitamin K Antagonist Oral Anticoagulant After Acute Coronary Syndrome: Is There a Role?

Alexander G Truesdell, Behnam Tehrani, Ramesh Singh, Shashank Desai, Patricia Saulino, Scott Barnett, Stephen Lavanier and Charles Murphy

Eunice NC Onwordi, Amr Gamal and Azfar Zaman

Paul Guedeney, Birgit Vogel and Roxana Mehran

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Erratum

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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.

his issue of the journal – as it often does – reflects areas of interventional cardiology at different stages of maturity. The majority of patients undergoing percutaneous coronary intervention do so in the context of acute coronary syndromes and the cardiovascular community has been striving for decades to achieve the perfect balance between preventing thrombus generation on the one hand and eliminating bleeding risk on the other. In this sphere, Onwordi et al and Guedeney et al get this month’s joint prize for the “all you needed to know but were too afraid to ask” papers on antithrombotic therapy in general, and novel oral anticoagulant therapy specifically, in acute coronary syndromes. Four papers on transcatheter aortic valve implantation (TAVI) demonstrate that this procedure remains under intense scrutiny and that operators continue to strive for optimal treatment for all patients with aortic valve disease. I have provided what I hope is a reasoned overview of the “newest” TAVI complication: delayed coronary obstruction. Yoon et al and Nakashima and Watanabe review data relating to TAVI procedures for bicuspid aortic valves and for small anatomy, respectively. In the absence of any definitive trial data regarding coronary revascularisation in TAVI candidates, an update of available evidence and experience from Cao et al is welcome. Transcatheter treatment of mitral valve disease is certainly at an early stage of development but Eng and Wang provide an excellent review of transcatheter mitral valve replacement for post-surgical mitral failures, a procedure that for many will be the entry point to transcatheter mitral interventions and a procedure that all structural services are now being asked to undertake. Finally, cardiogenic shock has always been a feared complication of cardiac disease – and of cardiac interventions – but its treatment outside of transplantation centres has only relatively recently been approached in a scientific and systematic fashion. Truesdell et al tell us how lessons learnt in the heat of battle can be applied to our approach to the treatment of what remains a frequently fatal condition. 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

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Structural

Editorial Delayed Coronary Obstruction After Transcatheter Aortic Valve Implantation is not the Structural Equivalent of Late Stent Thrombosis After Percutaneous Coronary Intervention Simon Kennon Barts Heart Centre, St Bartholomew’s Hospital, London, UK; Editor-in-Chief, Interventional Cardiology Review

Citation: Interventional Cardiology Review 2018;13(2):60–1. DOI: https://doi.org/10.15420/icr.2017:35:3 Correspondence: Simon Kennon, Barts Heart Centre, St Bartholomew’s Hospital, West Smithfield, London, EC1A 7BE, UK. E: simon.kennon@bartshealth.nhs.uk

eports of late stent thrombosis following percutaneous coronary intervention (PCI) with drug-eluting stents started to emerge in 2005 and 2006, causing widespread alarm and a substantial reduction in their use.1,2 Research-led advances in pharmacology and stent design have done much to allay this alarm, but nevertheless late stent thrombosis (LST) remains a concern for coronary interventionists and a focus for ongoing research. Until recently, delayed coronary obstruction (DCO) following transcatheter aortic valve implantation (TAVI) was the subject of occasional case reports,3–8 but following publication of data from a

large registry,9 there are now concerns that DCO may be the structural equivalent of late stent thrombosis. Are these concerns justified? Certainly DCO, like late stent thrombosis, has a high mortality. In 2005, Iakovou et al. documented an incidence of LST of 1.3 % at 9 months with a mortality of 45 %.1 The recently published paper by Jabbour et al. documents 38 patients presenting with DCO out of a total of 17,092 TAVI procedures, an incidence of 0.22 %, with a mortality of 50 %.9 This though, by and large, is where the similarities end. The British Cardiovascular Intervention Society annual audit (www.bcis.org.uk) documented 70,142 PCI procedures undertaken in the UK in 2005, in the absence of any evidence at the time that PCI conferred a mortality benefit. In 2016 (the most recent year for which data are available), 100,483 procedures were undertaken: 26.1 % of which were for STEMI for which there is clear evidence of benefit;10 37.8 % for NSTEMI where evidence is more mixed;11 and 32.7 % for stable coronary artery disease for which there is no evidence of mortality benefit.12 In 2016, the largest UK centre carried out 3,600 PCI procedures; in contrast, in the same year, 3,250 TAVI procedures were undertaken across the UK, supported by randomised controlled trial data demonstrating mortality benefit for TAVI compared with conservative and surgical treatment for high- and intermediate-risk patients.13–15 TAVI is undertaken less commonly in the UK than other developed countries, but it is clear the number of PCI procedures being

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ICR_Kennon_FINAL.indd 60

undertaken is an order of magnitude larger than TAVI procedures. Thus, late stent thrombosis is a complication of a commonly undertaken procedure for which, in many cases, there is no evidence of mortality benefit, whereas TAVI is undertaken relatively rarely and in the context of clear evidence of prognostic benefit. In addition, late stent thrombosis occurs more commonly in patients with diabetes, renal failure and impaired left ventricular function, and is more common following premature discontinuation of antiplatelet therapy and intervention to bifurcation lesions.1 In the recently published registry by Jabbour et al., however, the 38 cases of DCO occurred more commonly in valve-in-valve procedures (6 out of 9 were Mitroflow prosthetic valves [Sorin Group]) and in those using self-expanding devices. There was <3mm difference between sinus of Valsalva diameter and device diameter in 59.3 % of cases; the left main stem was protected with guide wires in 23.7 % (n=9) of cases; and severe aortic regurgitation necessitated deployment of a second valve in two cases. Thus, predictors of late stent thrombosis are common in patients undergoing PCI, whereas DCO seems to occur in more circumscribed and largely structural or anatomical subgroups. It is clear therefore that DCO does not reflect a fundamental problem with TAVI. It does, however, join a list of adverse events that occur more commonly after TAVI than aortic valve replacement surgery (AVR), the others being paravalvular aortic regurgitation, the need for permanent pacemaker implantation, annular rupture, prosthetic valve thrombosis, and cerebral embolism.13–16 These may be partly a reflection of the demographic and clinical profiles of patients who undergo TAVI, and advances in technology – valve design, pharmacology, cerebral protection – are steadily reducing their incidence,17,18 but they are nonetheless factors that need to be considered, particularly in intermediate-risk patients. That said, late stenosis of coronary ostia has been noted following AVR, although its incidence is not well defined.19,20 Other disadvantages of AVR compared to TAVI include smaller prosthetic valve areas, the requirement for cardiopulmonary bypass in all patients, for sternotomy in most cases and substantially longer intensive therapy unit stay, in-patient stay and recovery period in almost all cases.13–15,17

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Delayed Coronary Obstruction after TAVI

In conclusion, the paper by Jabbour et al. confirms the need for vigilance not alarm. Advances in pharmacology and valve design will reduce the incidence of all complications of both TAVI and AVR.

I akovou I, Schmidt T, Bonizzoni E,et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126–30. https://doi. org/10.1001/jama.293.17.2126; PMID: 15870416. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006;48:2584–91. https://doi.org/10.1016/j.jacc.2006.10.026; PMID: 17174201. Durmaz T, Ayhan H, Keles T, et al. Left main coronary artery obstruction by dislodged native-valve calculus after transcatheter aortic valve replacement. Tex Heart Inst J 2014;41:414–7. https://doi.org/10.14503/THIJ-13-3410; PMID: 25120396. Giustino G, Montorfano M, Chieffo A, et al. Tardive coronary obstruction by a native leaflet after transcatheter aortic valve replacement in a patient with heavily calcified aortic valve stenosis. J Am Coll Cardiol Intv 2014;7:e105–7. https://doi. org/10.1016/j.jcin.2014.01.173; PMID: 25147045. Jategaonkar SR, Dimitriadis Z, Hakim-Meibodi K, et al. Delayed coronary ischemia after transfemoral aortic valve implantation. J Heart Valve Dis 2013;22:762–6. PMID: 24597395. Freixa X, Bonan R, Asgar AW. Unusual coronary occlusion post transcatheter aortic implantation: the importance of clinical assessment. Can J Cardiol 2013;29:1014.e5–6. https:// doi.org/10.1016/j.cjca.2012.09.018; PMID: 23265096. Kukucka M, Pasic M, Dreysse S, Hetzer R. Delayed subtotal coronary obstruction after transapical aortic valve implantation. Interact Cardiovasc Thorac Surg 2011;12:57–60. https://doi.org/10.1510/icvts.2010.252866; PMID: 21098421.

INTERVENTIONAL CARDIOLOGY REVIEW

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10.

11.

12.

13.

14.

In the meantime, the decision to proceed with transcatheter or surgical aortic valve intervention should take into account the relative merits of both procedures. n

euss M, Kaneko H, Tambor G, et al. Fatal thrombotic N occlusion of left main trunk due to huge thrombus on prosthetic aortic valve after transcatheter aortic valve replacement. J Am Coll Cardiol Intv 2016;9:2257–8. https://doi. org/10.1016/j.jcin.2016.08.027; PMID: 27744041 Jabbour RJ, Tanaka A, Finkelstein A, et al. Delayed coronary obstruction after transcatheter aortic valve replacement. J Am Coll Cardiol 2018;71:1513–24. https://doi.org/10.1016/j. jacc.2018.01.066; PMID: 29622157. Schömig A, Kastrati A, Dirschinger J, et al. Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction. Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction Study Investigators. N Engl J Med 2000;343:385–91. https://doi.org/10.1056/ NEJM200008103430602; PMID: 10933737. Wallentin L, Lindhagen L, Ärnström E, et al.Early invasive versus non-invasive treatment in patients with non-STelevation acute coronary syndrome (FRISC-II): 15 year follow-up of a prospective, randomised, multicentre study. Lancet 2016;388:1903–11. https://doi.org/10.1016/S01406736(16)31276-4; PMID: 27585757 Boden W, O’Rourke A, Teo K, 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. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. https://doi. org/10.1056/NEJMoa1008232; PMID:20961243. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical

15.

16.

17.

18.

19.

20.

aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. https://doi.org/10.1056/ NEJMoa1514616; PMID: 27040324. Adams DH, Popma JJ, Reardon MJ. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790–8. https://doi.org/10.1056/NEJMoa1400590; PMID:24678937. Rodés-Cabau J, Dumont E, Boone RH, et al. Cerebral embolism following transcatheter aortic valve implantation: comparison of transfemoral and transapical approaches. J Am Coll Cardiol 2011;57:18–28. https://doi.org/10.1016/j. jacc.2010.07.036; PMID: 21185496. Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: a propensity score analysis. Lancet. 2016;387:2218–25 https://doi.org/10.1016/S01406736(16)30073-3. PMID: 27053442. Haussig S, Mangner N, Dwyer MG, et al. Effect of a cerebral protection device on brain lesions following transcatheter aortic valve implantation in patients with severe aortic stenosis: the CLEAN-TAVI randomized clinical trial. JAMA 2016;316:592–601. doi: 10.1001/jama.2016.10302. https://doi. org/10.1001/jama.2016.10302 PMID: 27532914. Yates JD, Kirsh MM, Sodeman TM, et al. Coronary ostial stenosis: a complication of aortic valve replacement. Circulation 1974;49:530–4. https://doi.org/10.1161/01. CIR.49.3.530; PMID: 4544298. Pillai JB, Pillay TM, Ahmad J. Coronary ostial stenosis after aortic valve replacement, revisited. Ann Thorac Surg 2004;78:2169–71. https://doi.org/10.1016/S00034975(03)01536-4; PMID: 15561065.

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Structural

Abstract Bicuspid aortic valve is the most common congenital cardiac malformation. Aortic valve replacement is often required in older patients but the surgical risk is often extremely high. As Transcatheter aortic valve implantation (TAVI) is an established therapy for intermediate and high surgical risk patients with symptomatic severe aortic valve stenosis (AS). Advances in technology and knowledge have led to TAVI being used for other pathologies and populations such as bicuspid AS. Recently, the diagnosis and classification of bicuspid aortic valve based on multidetector computed tomography (MDCT) assessment has been proposed, which may have an impact of outcomes after TAVI. This review article describes the advancements in diagnosis and outcomes of bicuspid AS.

Keywords Aortic stenosis, bicuspid aortic valve, transcatheter aortic valve implantation Disclosure: RS has served as a proctor for Edwards Lifesciences. RM has received grants from Edwards Lifesciences and personal fees from St. Jude Medical and Medtronic. All other authors have no relevant conflicts of interests to declare. Received: 28 March 2018 Accepted: 1 May 2018 Citation: Interventional Cardiology Review 2018;13(2):62–5. DOI: https://doi.org/10.15420/icr.2018:8:2 Correspondence: Raj Makkar, Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA 90048, USA. E: Raj.Makkar@cshs.org

Bicuspid aortic valve is the most common congenital cardiac malformation, affecting 1.3 % of the population, and responsible for a significant proportion of aortic valve replacement in adults.1-3 Clinical presentation varies from severe valve disease in infancy to asymptomatic valve in old age, but symptoms typically develop in adulthood. Surgical aortic valve replacement is generally required at an earlier age than surgeries for degenerative tricuspid aortic disease.3 However, in some patients, bicuspid aortic valve disease progresses in their 80s, but surgical risk is often extremely high due to age and multiple comorbidities. Transcatheter aortic valve implantation (TAVI) is a safe and effective therapy for intermediate- and high-risk surgical patients with symptomatic severe aortic stenosis (AS), and more than 250,000 patients have been treated with this technology.4-9 Landmark randomised trials showed TAVI is a safe and effective standard treatment in patients classed as inoperable and is a reasonable option in patients at increased surgical risk, but these trials excluded congenital bicuspid AS due to its unique morphological features.4,5,8-10 Nevertheless, growing experience, accumulated knowledge, and advances in transcatheter heart valves have led to an expanded use of TAVI in lower risk surgical populations and in other pathologies such as bicuspid AS. Initally, the use of TAVI in bicuspid AS was limited to small series.11–15 Previous registries showed that the proportion of patients with bicuspid AS treated with TAVI may reach 2–6 %.16,17 Considering the worldwide shift of treating younger and lower surgical-risk patients with TAVI and higher prevalence of bicuspid AS in younger populations, the clinical outcomes of TAVI in bicuspid AS warrants special attention.9,18,19 Furthermore, although diagnosis of bicuspid AS has been traditionally

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based on pathological findings, integration of multidetector computed tomography (MDCT) into pre-procedural assessment for TAVI is providing new insight. This review article described outcomes of TAVI in bicuspid AS and advances in diagnosis of bicuspid AS.

Outcomes of TAVI in Bicuspid Aortic Stenosis The first use of TAVI in bicuspid AS was reported by Wijesinghe et al.20 Sapien valves (Edwards Lifesciences) were implanted successfully in 11 patients, resulting in significant haemodynamic improvement, a reduction of mean aortic valve gradient from 41 mmHg to 13 mmHg and an increase of aortic valve area from 0.7 cm2 to 1.5 cm2. However, 2 patients (18.2 %) had moderate paravalvular leak. Hayashida et al. reported the outcomes of 21 patients with bicuspid AS and compared the outcomes between bicuspid and tricuspid AS.21 Despite limited sample size, they reported comparable outcomes of TAVI between bicuspid AS and tricuspid AS. CoreValve (Medtronic) was used more frequently in the bicuspid AS group (47.6 % versus 16.3 %; p=0.002). There was no significant difference in aortic regurgitation ≥ grade 2 (19.0 % versus 14.9 %; p=0.54), 30-day mortality (4.8 % versus 8.2 %; p=1.00) and device success rate (100 % versus 92.8 %; p=0.37). Mylotte et al. showed the feasibility of TAVI in a large cohort (n=139) of bicuspid aortic valve stenosis using the first-generation balloonexpandable valves (Sapien [Edwards]; n=48) or self-expanding valves (CoreValve [Medtronic]; n=91).11 Mean age was 78.0 ± 8.9, and 56.1 % of patients were male with a mean Society of Thoracic Surgeons (STS) score of 4.9 ± 3.4, indicating intermediate surgical risk. The type of bicuspid aortic valve was available in 120 patients; type 0 in 26.7 %, type 1 in 68.3 %, and type 2 in 5.0 %. Paravalvular leak ≥

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TAVI in Bicuspid Aortic Valve Stenosis grade 2 occurred in 28.4 % of patients (19.6 % Sapien versus 32.2 % CoreValve; p=0.11). A new pacemaker was implanted in 23.2 % of patients (16.7 % Sapien versus 26.7 % CoreValve; p=0.21). One-year mortality was 17.5 %, without significant difference between the valves (20.8 % Sapien versus 12.5 % CoreValve; p=0.12). As in patients with degenerated tricuspid AS, the use of pre-procedural MDCT for device sizing was associated with a lower rate of significant paravalvular leak (OR 0.19; 95 % CI [0.08–0.45]; p<0.001). Major vascular complication was identified as a significant predictor of 1-year all-cause mortality (OR 5.66; 95 % CI [1.21–26.42]; p=0.03), which was consistently observed in tricuspid AS population. Interestingly, paravalvular leak ≥ grade 2 was not associated with 1-year all-cause mortality (OR 1.55; 95 % CI [0.56–4.32]; p=0.40). This work showed the safety and efficacy of TAVI in selected patients with bicuspid AS, but the high rate of significant paravalvular leak with these devices was alarming.

Figure 1: Transcatheter Aortic Valve Implantation With Early- and New-generation Devices in Bicuspid Aortic Valve Stenosis

Newer devices designed to overcome these limitations showed superior procedural outcomes in tricuspid AS compared to the early devices. Accordingly, these devices were used in bicuspid AS, with the expectation that they would overcome the procedural challenges resulting from the unique anatomic features of bicuspid AS. Perlman et al. reported improved outcomes using a new-generation balloon-expandable valve (Sapien 3, Edwards Lifesciences).12 Among 51 patients with bicuspid AS treated with the Sapien 3, none had second valve implantation or paravalvular leak ≥ moderate. New permanent pacemakers were implanted in 23.5 % of patients, a relatively higher rate than in tricuspid AS. The low implantation of the transcatheter valves was associated with more frequent new permanent pacemaker implantation, which was also observed in tricuspid AS patients. Less oversized devices (area oversizing < 10 %) tended to have more frequent paravalvular leak >mild compared to those with more oversized devices (area oversizing ≥10 %; 48 % versus 26.9 %; p=0.10). Given that no moderate or greater paravalvular leak was observed in this study, and the fact that using more oversizing devices may carry the risk of annulus rupture or aortic injury, the selection of less oversized devices may be a reasonable option. Post-procedural echocardiography at 30 days showed a slightly smaller aortic valve area in patients who received the less oversized devices (1.56 ± 0.27 cm2 versus 1.78 ± 0.33 cm2; p=0.01), which could be a potential cause of future deterioration in valve function. Future studies are awaited to clarify the association of valve haemodynamics and selection of device size. The Bicuspid AS TAVI registry included 301 patients with bicuspid AS from 20 centres in Europe, North America and Asia-Pacific.13 The mean age was 77.0 ± 9.2 with mean STS score of 4.7 ± 5.2 % (intermediate surgical risk). Early-generation devices were used in 199 patients (Sapien XT: n=87; CoreValve: n=112) and new-generation devices in 102 patients (Sapien 3: n=91; Lotus [Boston Scientific]: n=11). Pre-procedural MDCT was performed in 86.0 % of patients with a significantly higher rate in the new-generation device group (100.0 % versus 78.9 %; p<0.001), reflecting preprocedural MDCT assessment as a gold standard. Transfemoral access was used more frequently in the new-generation device group (95.1 % versus 78.4 %; p<0.001). Procedure-related death, conversion to surgery and coronary obstruction occurred in 1.3 %, 2.9 %, and 1.0 % of patients overall, with no significant differences between the groups. New-generation devices were associated with less frequent second valve implantation (1.0 % versus 6.5 %; p=0.04) and moderate or greater paravalvular leak (0.0 % versus 8.5 %; p=0.002), which resulted in higher device

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Top: In comparing clinical outcomes of the early- and new-generation devices, moderate or greater paravalvular leak was less frequent and device success rate was higher with new-generation devices. However, there were no significant differences in new permanent pacemaker implantation, 30-day mortality, and early safety endpoint between groups. Bottom: Procedural outcomes improved with device advancement. Compared to the early-generation devices, the new-generation devices were associated with less frequent paravalvular leak; specific new-generation devices improved on rates of annulus rupture and second valve implantation as shown. Source: Yoon et al., 2016,17 reprinted with permission from Elsevier.

success rate (92.2 % versus 80.9 %; p=0.01) (Figure 1). Annulus rupture occurred more frequently with the Sapien XT than the CoreValve (4.6 % versus 0.0 %; p=0.04). Second valve implantation was more frequent with the CoreValve compared to the Sapien XT (10.7 % versus 1.1 %; p=0.007) and the Sapien 3 (10.7 % versus 1.1 %; p=0.005). There were no significant differences in new permanent pacemaker insertions between devices, although there was a trend towards a higher rate with the Sapien 3 compared to the Sapien XT (17.6 % versus 9.2 %; p=0.10). Device success was higher with the Sapien 3 compared to the Sapien XT (94.5 % versus 85.1 %; p=0.04) and the CoreValve (94.5 % versus 77.7 %; p=0.001). There were no significant differences in major 30-day endpoints between the early- and new-generation device groups (all-cause 30-day mortality: 4.5 % versus 3.9 %; p>0.99; stroke: 2.5 % versus 2.0 %; p>0.99; life-threatening bleeding: 3.5 % versus 2.9 %; p>0.99; major vascular complications: 4.5 % versus 2.9 %; p=0.76; stage 2 or 3 acute kidney injury: 15.1 % versus 10.8 %; p=0.30). The higher rate of annulus rupture with the Sapien XT may be attributable to the nature of balloon-expandable heart valves and the need for selection of oversized valves to prevent paravalvular leak and device embolisation. The Sapien 3 has an external skirt, so the selection of extremely oversized valves may be no longer required.

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Structural Figure 2: Transcatheter Aortic Valve Implantation for Bicuspid Versus Tricuspid Aortic Valve Stenosis

Top: Schematic presentations of bicuspid and tricuspid aortic valves. Type 0 and 1 indicate bicuspid aortic valve with no raphe, and 1 raphe, respectively. Bottom: Cumulative all-cause mortality rates in patients with bicuspid aortic valve stenosis (AS) (orange) and tricuspid AS (blue) in a propensity score matched cohort. Event rates were compared using the win ratio test. Source: Yoon et al., 2017,23 reprinted with permission from Elsevier.

For patients with challenging anatomy, such as heavily calcified leaflet and raphe, less oversized balloon-expandable devices can be selected. The early generation self-expanding CoreValve was associated with more frequent paravalvular leak. Due to the complex anatomy of bicuspid aortic valve, annulus measurement with MDCT may not be accurate in patients with bicuspid AS, and supra-annular structure may have a potential role in anchoring the transcatheter valves, particularly self-expanding valves. Liu et al. performed sequential balloon aortic valvuloplasty before TAVI with self-expanding valves.22 In 12 patients, 11 (91.7 %) received smaller devices according to the sequential balloon sizing compared to the annulus measurement with MDCT without any significant complications, including moderate or severe paravalvular leak. This suggests the potential role of balloon sizing, but the subsequent risk of adverse events such as aortic injury or stroke should be considered. In terms of intermediate- and long-term survival data in bicuspid AS, studies were limited by the clear differences in age and comorbidities favouring the bicuspid AS population compared with tricuspid AS population. Given that patients with bicuspid AS are younger and have fewer coexisting comorbidities compared with tricuspid AS, there is a potential risk that clinical outcomes of TAVI for bicuspid AS could differ from those for tricuspid AS with equivalent surgical risk. A recent study compared the outcomes of TAVI between the bicuspid and tricuspid AS populations using propensity-score matching.23 A total of 576 patients with bicuspid AS from 33 centres and 5,900 patients with tricuspid AS were included in this analysis, and 546 pairs of patients with bicuspid and tricuspid AS were created. In the unadjusted cohort, patients with bicuspid AS were younger and more likely to be male, whereas patients with tricuspid AS were more likely to have multiple comorbidities. Accordingly, patients with bicuspid AS had a lower Logistic European

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System for Cardiac Operative Risk Evaluation (EuroSCORE) (14.8 ± 12.3 % versus 16.7 % versus 11.8 %; p=0.003) and STS score (5.0 ± 5.1 % versus 6.5 ± 8.8 %; p<0.001). After performing propensity score matching, both groups were well matched, with no significant differences in baseline characteristics. In the propensity score-matched cohort, patients with bicuspid AS had more frequent conversion to surgery compared to those with tricuspid AS (2.0 % versus 0.2 %; OR 11.00; 95 % CI [1.42–85.20]; p=0.006) and second valve implantation (4.8 % versus 1.5 %; OR 3.71; 95 % CI [1.61–8.56]; p=0.002), and moderate or severe paravalvular leak (10.4 % versus 6.8 %; OR 1.61; 95 % CI [1.04–2.48]; p=0.04), leading to lower device success rate (85.3 % versus 91.4 %; OR 0.54; 95 % CI [0.37–0.80]). When using the early-generation devices, the more frequent adverse events in bicuspid AS compared to tricuspid AS were consistently observed (conversion to surgery: 2.5 % versus 0.3 %; p=0.02; second valve implantation: 7.2 % versus 2.2 %; p=0.003; moderate or severe paravalvular leak: 15.9 % versus 10.3 %; p=0.03; device success, 78.4 % versus. 86.9 %; p=0.005). In contrast, there were no significant differences between groups in procedural complications with the new-generation devices (conversion to surgery: 1.3 % versus 0.0 %; p=0.25; second valve implantation: 1.3 % versus 0.4 %; p=0.62; moderate or severe paravalvular leak: 2.7 % versus 1.8 %; p=0.53; device success: 95.1 % versus 97.8 %; p=0.13; new pacemaker implantation: 16.4 % versus 17.8 %; p=0.69). In terms of midterm mortality, the cumulative all-cause mortality rates at 2-year follow-up were comparable between the bicuspid and tricuspid AS groups (17.2 % versus 19.4 %; p=0.28) (Figure 2). Furthermore, there were no significant differences in 1-year all-cause mortality rates between the groups stratified according to the earlyand new-generation devices (early-generation devices: 14.5 % versus 13.7 %; p=0.80; new-generation devices: 4.5 % versus 7.4 %; p=0.64). Compared to tricuspid AS, TAVI in bicuspid AS was associated with lower device success rate due to challenging anatomy, but 1-year mortality rates were similar. Procedural differences were observed in patients treated with the early-generation devices, whereas no differences were observed with the new-generation devices. Nevertheless, the unique anatomic features of bicuspid AS – including eccentric distribution of calcification and calcified raphe – may hinder the expansion of transcatheter heart valves. This raises the concerns about long-term valve durability in bicuspid AS population. Given higher prevalence of bicuspid AS in younger population, the expanding use of TAVI to younger and less comorbid populations warrants longterm durability data in the bicuspid AS population.

CT for Diagnosis of Bicuspid Aortic Valve Pre-procedural MDCT assessment of aortic valve has become standardised in the TAVI era, and pre-procedural diagnosis of bicuspid AS with MDCT has gained considerable attention. With accumulation of experience in MDCT assessments of aortic valves, the great variety of bicuspid AS morphology has been observed, leading Jilaihawi et al. to propose a more simplified, TAVI-directed classification of bicuspid aortic valve.15 Bicuspid aortic valves were classified according to the numbers of raphe and commissures with high-resolution MDCT images (Figure 3). This classification specified three bicuspid aortic valve morphologies as tricommissural (one commissure completely fused between two cusps, often referred to as functional or acquired bicuspid aortic valve); bicommissural raphe type (two cusps are fused by a fibrous or calcified ridge of various

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TAVI in Bicuspid Aortic Valve Stenosis heights which does not reach the height of the commissure); and bicommissural non-raphe type (two cusps completely fused from their basal origin with no visible seam). Among 21 patients with tricommissural bicuspid aortic valves and 70 patients with bicommissural bicuspid aortic valves, there were no significant differences in annulus dimensions (mean maximum diameter: 27.6 ± 2.9 mm versus 27.6 ± 3.3 mm; p=0.96; mean minimum diameter: 22.2 ± 2.2 mm versus 22.3 ± 2.8 mm; p=0.82; annulus area: 472.5 mm2 versus 486.4 mm2; p=0.57; annulus perimeter: 78.2 mm versus 79.4 mm; p=0.52) except larger intercommissural distance and ascending aorta in bicommissural group (intercommissural distance: 28.7 mm versus 24.3 mm; p<0.001; ascending aorta: 40.9 mm Sapien 3 36.0 mm; p<0.001). When comparing bicommissural non-raphe type (n=19) and bicommissural raphe type (n=50), bicommissural raphe type had larger annulus dimensions (annulus area 505.0 mm2 versus 434.4 mm2; p=0.015; annulus perimeter 80.9 mm versus 75.0 mm; p=0.016), but the diameter of ascending aorta was similar between the two groups (40.5 mm versus 42.5 mm; p=0.25). Interestingly, intercommissural distance was associated with paravalvular leak in bicommissural but not tricommissural bicuspid AS. Further studies are needed to evaluate the impact of this parameter in treating patients with bicuspid AS. This classification may clarify the difference between functional/acquired bicuspid aortic valves and bicuspid aortic valves with one raphe (Sievers’ type 1) on the basis of MDCT images.

Figure 3: Classification of Bicuspid Aortic Valve

Top: Leaflet morphology is classified on the basis of number of commissures (2 or 3) and, in the presence of 2 commissures, the presence or absence of a raphe. This classification yields tricommissural, bicommissural raphe type, and bicommissural non-raphe types. Bottom: Leaflet orientation is classified on the basis of cusp fusion, which is either coronary cusp fusion or mixed non-coronary–coronary cusp fusion. Take off of the right coronary artery is indicated by the red line; take off of the left coronary artery is indicated by the blue line. Values are overall frequency of bicuspid aortic valve treated with TAVI relative to overall TAVI cases. Source: Jilaihawi et al., 2016,15 reprinted with permission from Elsevier.

versus 2.8 %; p=0.005), and tended to have more frequent aortic root injury (4.2 % versus 0.7 %; p=0.056), whereas all-cause mortality rates were similar at 30 days (4.9 % versus 3.5 %; p=0.55) and 1 year (18.2 % versus 19.8 %; p=0.74). This study provided a comprehensive overview of the various spectra of bicuspid aortic valve morphologies. Given that bicuspid AS is associated with procedural challenges, the proper identification and classification of bicuspid AS phenotypes is essential.

Based on this classification, Kim et al. performed a systematic review pre-procedural MDCT images in a large contemporary TAVI cohorts to accurately determine the prevalence of bicuspid aortic valve and to compare clinical outcomes with patients with tricuspid aortic valve stenosis.24 MDCT images of 1,996 patients were retrospectively

Conclusion

reviewed by two experienced readers for the presence of bicuspid AS. After exclusion of undetermined cases (n=20) or tricuspid with acquired fusion (n=60), bicuspid AS was confirmed in 144 patients (7.3 %). After adjustment for baseline differences with propensity matching, comparing to patients with tricuspid AS, those with bicuspid AS had more frequent paravalvular regurgitation ≥ grade 2 (11.1 %

TAVI has led to changes in the diagnosis and classification of bicuspid aortic valve. Due to unfavourable anatomic features of bicuspid aortic valves, the outcomes of TAVI in bicuspid AS were suboptimal, particularly when using early generation devices. However, new generation devices improved the outcomes of TAVI in bicuspid AS comparable to those of tricuspid AS. n

asso C, Boschello M, Perrone C, et al. An echocardiographic B survey of primary school children for bicuspid aortic valve. Am J Cardiol 2004;93:661–3. DOI: 10.1016/j.amjcard.2003.11.031; PMID: 14996606. Nistri S, Basso C, Marzari C, et al. Frequency of bicuspid aortic valve in young male conscripts by echocardiogram. Am J Cardiol 2005;96:718–21. DOI: 10.1016/j.amjcard.2005.04.051; PMID: 16125502. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation 2005;111:920–5. DOI: 10.1161/01.CIR.0000155623.48408.C5; PMID: 15710758. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. DOI: 10.1056/ NEJMoa1008232; PMID: 20961243. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. DOI: 10.1056/NEJMoa1103510; PMID: 21639811. Gilard M, Eltchaninoff H, Iung B, et al. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med 2012; 366:1705–15. DOI: 10.1056/NEJMoa1114705; PMID: 22551129. Reinöhl J, Kaier K, Reinecke H, et al. Effect of availability of transcatheter aortic-valve replacement on clinical practice. N Engl J Med 2015;373:2438–47. DOI: 10.1056/NEJMoa1500893; PMID: 26672846. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aorticvalve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790–8. DOI: 10.1056/NEJMoa1400590; PMID: 24678937.

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10.

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L eon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. DOI: 10.1056/NEJMoa1514616; PMID: 27040324. Thyregod HG, Steinbrüchel DA, Ihlemann N, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis. J Am Coll Cardiol 2015;65:2184–94. DOI: 10.1016/j.jacc.2015.03.014; PMID: 25787196. Mylotte D, Lefevre T, Sondergaard L, et al. Transcatheter aortic valve replacement in bicuspid aortic valve disease. J Am Coll Cardiol 2014;64:2330–9. DOI: 10.1016/j.jacc.2014.09.039; PMID: 25465419. Perlman GY, Blanke P, Dvir D, et al. Bicuspid aortic valve stenosis. JACC Cardiovasc Interv 2016;9:817–24. DOI: 10.1016/j. jcin.2016.01.002; PMID: 27101906. Yoon SH, Lefèvre T, Ahn JM, et al. Transcatheter aortic valve replacement with early- and new-generation devices in bicuspid aortic valve stenosis. J Am Coll Cardiol 2016;68:1195– 205. DOI: 10.1016/j.jacc.2016.06.041; PMID: 27609682. Yousef A, Simard T, Webb J, et al. Transcatheter aortic valve implantation in patients with bicuspid aortic valve. Int J Cardiol 2015;189:282–8. DOI: 10.1016/j.ijcard.2015.04.066; PMID: 25910593. Jilaihawi H, Chen M, Webb J, et al. A bicuspid aortic valve imaging classification for the TAVR era. JACC Cardiovasc Imaging 2016;9:1145–58. DOI: 10.1016/j.jcmg.2015.12.022; PMID: 27372022. Mack MJ, Brennan JM, Brindis R, et al. Outcomes following transcatheter aortic valve replacement in the United States. JAMA 2013;310:2069–77. DOI: 10.1001/jama.2013.282043; PMID: 24240934.

17. Y oon SH, Ahn JM, Hayashida K, et al. Clinical outcomes following transcatheter aortic valve replacement in Asian population. JACC Cardiovasc Interv 2016;9:926–33. DOI: 10.1016/j. jcin.2016.01.047; PMID: 27151607. 18. Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg 2007;133:1226–33. DOI: 10.1016/j. jtcvs.2007.01.039; PMID: 17467434. 19. Sabet HY, Edwards WD, Tazelaar HD, Daly RC. Congenitally bicuspid aortic valves. Mayo Clin Proc 1999;74:14–26. DOI: 10.4065/74.1.14; PMID: 9987528. 20. Wijesinghe N, Ye J, Rodés-Cabau J, et al. Transcatheter aortic valve implantation in patients with bicuspid aortic valve stenosis. JACC Cardiovasc Interv 2010;3:1122–5. DOI: 10.1016/j. jcin.2010.08.016; PMID: 21087746. 21. Hayashida K, Bouvier E, Lefèvre T, et al. Transcatheter aortic valve implantation for patients with severe bicuspid aortic valve stenosis. Circ Cardiovasc Interv 2013;6:284–91. DOI: 10.1161/CIRCINTERVENTIONS.112.000084; PMID: 23756698. 22. Liu X, He Y, Zhu Q, et al. Supra-annular structure assessment for self-expanding transcatheter heart valve size selection in patients with bicuspid aortic valve. Catheter Cardiovasc Interv 2018;91:986–94. DOI: 10.1002/ccd.27467; PMID: 29399947. 23. Yoon SH, Bleiziffer S, De Backer O, et al. Outcomes in transcatheter aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. J Am Coll Cardiol 2017;69:2579– 89. DOI: 10.1016/j.jacc.2017.03.017; PMID: 28330793. 24. Kim WK, Gaede L, Husser O, et al. Computed tomography for diagnosis and classification of bicuspid aortic valve disease in transcatheter aortic valve replacement. JACC Cardiovasc Imaging 2018. DOI: 10.1016/j.jcmg.2017.12.010; PMID: 29454778; epub ahead of press.

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Structural

Transcatheter Aortic Valve Implantation in Small Anatomy: Patient Selection and Technical Challenges Makoto Nakashima and Yusuke Watanabe Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan

Abstract Transcatheter aortic valve implantation (TAVI) has become a standard treatment for severe aortic stenosis. Although this technique has reached relative maturity, further optimisation of patient selection and device implantation is essential to improve prognosis. Smaller body size is a predictor of a challenging TAVI procedure due to specific anatomical difficulty and adverse events including annulus rupture, acute coronary obstruction and vascular complications. A newer generation, lower profile TAVI system is useful for patients with smaller anatomy. Moreover, TAVI is superior to surgical aortic valve replacement in patients with a narrowing annulus because this treatement has a low incidence of prosthesis–patient mismatch.

Keywords Acute coronary obstruction, prosthesis–patient mismatch, small body size, transcatheter aortic valve implantation, vascular complication Disclosure: YW is a proctor for TF-TAVI for Edwards SAPIEN and Medtronic. Received: 30 September 2017 Accepted: 2 January 2018 Citation: Interventional Cardiology Review 2018;13(2):66–8. DOI: https://doi.org/10.15420/icr.2017:28:1 Correspondence: Yusuke Watanabe, Department of Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-0003, Japan. E: yusuke0831@gmail.com

Transcatheter aortic valve implantation (TAVI) has become a commonly used and minimally invasive approach for patients with severe aortic stenosis (AS).1,2 In the latest guidelines from the 2017 European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) for the management of valvular heart disease, the following clinical characteristics favour TAVI: Society of Thoracic Surgeons (STS)/ EuroSCORE II ≥4 % (logistic EuroSCORE I ≥10 %); presence of severe comorbidity; age ≥75 years; and presence of frailty or restricted mobility and conditions that may affect the rehabilitation process after the procedure.3 Accumulated data from randomised controlled trials and large registries of elderly patients show that TAVI is superior to medical therapy in terms of mortality in extreme-risk patients4, noninferior or superior to surgery in high-risk patients,5–8 and non-inferior to surgery and even superior when transfemoral access is possible in intermediate-risk patients.9–12 The second-generation self-expanding transcatheter heart valve (THV) also showed substantial efficacy with a low rate of vascular complications compared with older devices.13 It is expected that more patients will be candidates for TAVI in the future. Although this technique has reached relative maturity, further optimisation of patient selection and device implantation is essential to improve prognosis. Pre-procedural assessment of imaging techniques, specifically, multidetector computed tomography (MDCT), has been recommended for TAVI optimisation.14 Asian populations have smaller body size (BSA=1.41±0.15 m2), aortic annulus size, and vascular access size than European populations (BSA=1.72±0.18 m2);15 this is a potential risk for annulus rupture, residual aortic valve stenosis, or vascular complications.16,17 Women with severe AS had smaller aortic root dimensions, even after correcting for their

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smaller body size and height, reflecting a sex-specific difference.18 This review includes a discussion of issues related to a small aortic complex and small access arteries. These issues are illustrated in a short case study provided in Figure 1.

Small Aortic Annulus MDCT is useful to decide on the TAVI strategy in relation to access site, valve type and valve size. The incidence of annulus rupture or perforation is as low as 0–1.1 %; however, this is a catastrophic complication associated with a high risk of death.19,20 Aggressive device oversizing and large calcifications in the epicardial fat area of the annulus/left ventricular outflow tract have been reported as risk factors for annulus rupture.19,21,22 A smaller annulus calculated by MDCT (e.g. annulus area <300 cm2) may increase the risk of annulus rupture due to relative valve oversizing.21 A previous report showed a trend towards higher incidence of annulus rupture in patients with a small body size (BSA <1.75 m2) compared with patients with a larger body size (BSA ≥1.75 m2) (2.3 % versus 0.5 %; p=0.11).23

Prosthesis–patient Mismatch Prosthesis–patient mismatch (PPM), defined by an indexed effective orifice area <0.85 cm2/m2 using echocardiography, is a major concern after aortic valve replacement. The risk factors for PPM are small annulus diameter and larger BSA.24 PPM is common (20–70 %) after surgical aortic valve replacement (SAVR), and has a negative impact on short- and long-term outcomes.25 Head et al. reported that moderate and severe PPM are associated with a 1.2- and 1.8-fold increase in the risk of all-cause mortality, respectively.26 Some studies have reported that PPM is associated with less regression of left ventricular hypertrophy, less improvement in patient functional status and increased mortality after TAVI,27,28 whereas other studies found no significant impact of PPM on

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TAVI in Small Anatomies outcomes.29 Pibarot et al. reported that PPM is more frequent and often more severe after SAVR than after TAVI, and that TAVI may be preferable to SAVR in patients with a small aortic annulus who are susceptible to PPM, to avoid the adverse impact on left ventricular mass regression and survival.30 Distention of the aortic annulus due to systematic oversizing and the absence of a sewing ring may have been potential mechanisms accounting for the superior haemodynamic profile associated with TAVI compared with standard surgical valves.31

Figure 1: Small Aortic Complex in an 84-year-old Woman with a Body Surface Area of 1.23 m 2 A

Aortic annulus

Sino-tubular junction

Sinus of valsalva

Acute Coronary Obstruction The coronary height from the aortic annulus plane to the coronary ostium is also a matter of great concern for TAVI in patients with a small body size. Acute coronary obstruction (ACO) is thought to be caused by native-valve leaflet involvement in the coronary ostium among patients undergoing TAVI.32 A previous study showed the distance between the left coronary ostium and the aortic annulus plane was shorter in the small-body group.23 Rebeiro et al. reported on data from a multicentre registry that showed that both coronary height <12 mm and sinus of Valsalva <30 mm were powerful predictors of ACO.33 Yamamoto et al. reported females were more prevalent in the coronary protection (CP) group than in the non-CP group (89.4 % versus 67.3 %), resulting in a smaller body height and body surface area in the CP group in the Japanese population. They also reported ACO occurred in 70 % of patients with bulky calcification, 50 % of patients with leaflet length exceeding target coronary height, and 20 % of patients with flow limitation during valvuloplasty with simultaneous aortic root injection. Although the complication of ACO was difficult to predict, a preparatory CP strategy, such as guidewire insertion with or without a therapeutic balloon, is safe and feasible for the management of ACO during TAVI.34

Min. diameter Max. diameter Area Perimeter

16.4 mm 22.6 mm 289.8 mm2 62.2 mm

RCC diameter LCC diameter NCC diameter

25.3 mm 25.0 mm 25.7 mm

Min. diameter Max. diameter

22.4 mm 23.8 mm

Small aortic complex.

B Right coronary height 11.3 mm

Left coronary height 11.4 mm

Left and right coronary ostium heights were <12 mm.

Right iliac

Left iliac

Small Femoral Artery Asian populations, including Japanese, have a smaller femoral artery diameter compared with Europeans.15 Vascular complications are relatively frequent and serious in transfemoral TAVI, and previous reports have shown that vascular complications are associated with significantly increased patient morbidity and mortality.35,36 The ratio of the sheath outer diameter (in millimetres) to the minimal femoral artery diameter (in millimetres) >1.05 is a predictor of vascular complications.35 In previous reports, newer TAVI technology with a lower-profile sheath system, SAPIEN 3 (Edwards Lifesciences), reduced bleeding and vascular complications by reducing sheath size using 14Fr or 16Fr Edwards eSheath (minimum artery diameter 5.5 mm). Arai et al. reported that SAPIEN 3 had a lower incidence of vascular complications (3 %) than those of SAPIEN XT (Edwards Lifesciences) implantation (12 %) via the femoral artery. 37 The second-generation self-expanding transcatheter heart valve (THV) EvolutTM R (Medtronic) also showed substantial efficacy, with a low rate of vascular complications by reducing sheath size using 14Fr-equivalent system with InLineTM (minimum artery diameter 5.0 mm), which is adaptable to smaller access arteries compared with SAPIEN 3.13 Subclavian access with EvolutTM R was not significantly different from transfemoral access and may represent the safest non-femoral access route for TAVI.38

Iliac arteries were small and tortuous. Calcification was mild.

Insertion of Evolut™ R 23 mm. Left: Angiography shows severe tortuosity of the right iliac artery. Right: Right iliac artery was extended by lunderquist® super stiff guide wire (Cook Medical) and the InLine™ sheath of Evolut™ R was passed through successfully.

Summary Small body size is more common in Asians and women and is associated with small aortic annulus size, low coronary height and smaller femoral artery size. Patients with small body size have a potential risk for annulus rupture, ACO, PPM and vascular complications

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Successful implantation of Evolut™ R 23 mm. Left: Aortography shows proper location of Evolut™ R implantation. Right: Iliac aortography shows no arterial dissection nor rupture.

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Structural during a TAVI procedure. The surgical approach to a patient with a small annulus has a risk of PPM, and TAVI is superior to SAVR, especially in terms of PPM, so we should consider TAVI for patients with a small annulus. Selection of THV in a patient with a small annulus is the next consideration. The area of the SAPIEN 3 THV is smaller than that of the SAPIEN XT when opened with the same nominal pressure and same size valve due to an outer skirt attachment. Therefore, the S3 20 mm THV may have potential risk of PPM.39 The EvolutTM R is designed for a supra-annular position to increase the effective orifice area, and may

10.

11.

12.

13.

14.

ilard M, Eltchaninoff H, Iung B, et al. Registry of G transcatheter aortic-valve implantation in high-risk patients. New Engl J Med 2012;366:1705–15. DOI: 10.1056/ NEJMoa1114705; PMID: 22551129 Mylotte D, Osnabrugge RL, Windecker S, et al. Transcatheter aortic valve replacement in Europe: adoption trends and factors influencing device utilization. J Am Coll Cardiol 2013;62:210–9. DOI: 10.1016/j.jacc.2013.03.074; PMID: 23684674 Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease: The Task Force for the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2017;38:2739–91. DOI: 10.1093/eurheartj/ehx391; PMID: 28886619 Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. New Engl J Med 2010; 363:1597–607. DOI: 10.1056/NEJMoa1008232; PMID: 20961243 Mack MJ, Leon MB, Smith CR, et al. 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;385:2477–84. DOI: 10.1016/S0140-6736(15)60308-7; PMID: 25788234 Deeb GM, Reardon MJ, Chetcuti S, et al. 3-Year outcomes in high-risk patients who underwent surgical or transcatheter aortic valve replacement. J Am Coll Cardiol 2016;67:2565–74. DOI: 10.1016/j.jacc.2016.03.506; PMID: 27050187 Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. New Engl J Med 2011;364:2187–98. DOI: 10.1056/NEJMoa1103510; PMID: 21639811 Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aorticvalve replacement with a self-expanding prosthesis. New Engl J Med 2014;370:1790–8. DOI: 10.1056/NEJMoa1400590; PMID: 24678937 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;65:2184–94. DOI: 10.1016/j.jacc.2015.03.014; PMID: 25787196 Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: A propensity score analysis. Lancet 2016;387:2218–25. DOI: 10.1016/S0140-6736(16)30073-3; PMID: 27053442 Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. New Engl J Med 2016;374:1609–20. DOI: 10.1056/NEJMoa1514616; PMID: 27040324 Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediate-risk patients. New Engl J Med 2017;376:1321–31. DOI: 10.1056/ NEJMoa1700456; PMID: 28304219 Kalra SS, Firoozi S, Yeh J, et al. Initial experience of a secondgeneration self-expanding transcatheter aortic valve: The UK & Ireland Evolut R Implanters’ Registry. JACC Cardiovasc Interv 2017;10:276–82. DOI: 10.1016/j.jcin.2016.11.025; PMID: 28183467 Achenbach S, Delgado V, Hausleiter J, et al. SCCT expert consensus document on computed tomography imaging before transcatheter aortic valve implantation (TAVI)/

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15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

be suitable in patients with a small annulus. Pre-procedural planning with CT scan is quite important to determine the selection of THV and avoid complications.

Conclusion Small body size is a predictor of a challenging TAVI procedure. TAVI with new generation devices is superior to SAVR and has a lower incidence of PPM. A self-expanding supra-annular THV would be favourable in a patient with a small annulus. n

transcatheter aortic valve replacement (TAVR). J Cardiovasc Comput Tomogr 2012;6:366–80. DOI: 10.1016/j.jcct.2012.11.002; PMID: 23217460 Watanabe Y, Hayashida K, Takayama M, et al. First direct comparison of clinical outcomes between European and Asian cohorts in transcatheter aortic valve implantation: the Massy study group vs. the PREVAIL JAPAN trial. J Cardiol 2015;65:112–6. DOI: 10.1016/j.jjcc.2014.05.001; PMID: 24927855 Nara Y, Watanabe Y, Kozuma K, et al. Incidence, predictors, and mid-term outcomes of percutaneous closure failure after transfemoral aortic valve implantation using an expandable sheath (from the Optimized Transcatheter Valvular Intervention [OCEAN-TAVI] Registry). Am J Cardiol 2017;119:611–7. DOI: 10.1016/j.amjcard.2016.11.009; PMID: 27939382 Yoon SH, Ohno Y, Araki M, et al. Comparison of aortic root anatomy and calcification distribution between Asian and Caucasian patients who underwent transcatheter aortic valve implantation. Am J Cardiol 2015;116:1566–73. DOI: 10.1016/j. amjcard.2015.08.021; PMID: 26428022 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;11:87–96. DOI: 10.1016/j.jcct.2017.01.006; PMID: 28139364 Hayashida K, Bouvier E, Lefevre T, et al. Potential mechanism of annulus rupture during transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2013;82:E742–6. DOI: 10.1002/ccd.24524; PMID: 22718400 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. DOI: 10.1161/CIRCINTERVENTIONS.111.967315; PMID: 22589295 Blanke P, Reinohl 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;5:540–8. DOI: 10.1161/ CIRCINTERVENTIONS.111.967349; PMID: 22872051 Barbanti M, Yang TH, Rodes 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. DOI: 10.1161/ circulationaha.113.002947; PMID: 23748467 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. DOI: 10.1002/ccd.24970; PMID: 23613222 Bax JJ, Delgado V, Bapat V, et al. Open issues in transcatheter aortic valve implantation. Part 2: procedural issues and outcomes after transcatheter aortic valve implantation. Euro Heart J 2014;35:2639–54. DOI: 10.1093/eurheartj/ehu257; PMID: 25062953 Dumesnil JG, Pibarot P. Prosthesis–patient mismatch: An update. Curr Cardiol Rep 2011;13:250–7. DOI: 10.1007/s11886011-0172-7; PMID: 21350829 Head SJ, Mokhles MM, Osnabrugge RL, et al. The impact of prosthesis–patient mismatch on long-term survival after aortic valve replacement: A systematic review and metaanalysis of 34 observational studies comprising 27 186 patients with 133 141 patient-years. Euro Heart J 2012;33:1518–29. DOI: 10.1093/eurheartj/ehs003; PMID: 22408037

27. E we SH, Muratori M, Delgado V, et al. Hemodynamic and clinical impact of prosthesis–patient mismatch after transcatheter aortic valve implantation. J Am Coll Cardiol 2011;58:1910–8. DOI: 10.1016/j.jacc.2011.08.027; PMID: 21982276 28. Kukucka M, Pasic M, Dreysse S, et al. Patient–prosthesis mismatch after transapical aortic valve implantation: Incidence and impact on survival. J Thorac Cardiovasc Surg 2013;145:391–7. DOI: 10.1016/j.jtcvs.2012.01.043; PMID: 22329976 29. Tzikas A, Piazza N, Geleijnse ML, et al. Prosthesis–patient mismatch after transcatheter aortic valve implantation with the Medtronic CoreValve system in patients with aortic stenosis. Am J Cardiol 2010;106:255–60. DOI: 10.1016/j. amjcard.2010.02.036; PMID: 20599012 30. Pibarot P, Weissman NJ, Stewart WJ, et al. Incidence and sequelae of prosthesis–patient mismatch in transcatheter versus surgical valve replacement in high-risk patients with severe aortic stenosis: A PARTNER trial cohort – a analysis. J Am Coll Cardiol 2014;64:1323–34. DOI: 10.1016/j. jacc.2014.06.1195; PMID: 25257633 31. Clavel MA, Webb JG, Pibarot P, et al. Comparison of the hemodynamic performance of percutaneous and surgical bioprostheses for the treatment of severe aortic stenosis. J Am Coll Cardiol 2009;53:1883–91. DOI: 10.1016/j. jacc.2009.01.060; PMID: 19442889 32. Bagur R, Dumont E, Doyle D, et al. Coronary ostia stenosis after transcatheter aortic valve implantation. JACC Cardiovasc Interv 2010;3:253–5. DOI: 10.1016/j.jcin.2009.11.016; PMID: 20170886 33. 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. DOI: 10.1016/j.jacc.2013.07.040; PMID: 23954337 34. Yamamoto M, Shimura T, Kano S, et al. Impact of preparatory coronary protection in patients at high anatomical risk of acute coronary obstruction during transcatheter aortic valve implantation. Int J Cardiol 2016;217:58–63. DOI: 10.1016/j. ijcard.2016.04.185; PMID: 27179209 35. Hayashida K, Lefevre T, Chevalier B, et al. Transfemoral aortic valve implantation new criteria to predict vascular complications. JACC Cardiovasc Interv 2011;4:851–8. DOI: 10.1016/j.jcin.2011.03.019; PMID: 21851897 36. Steinvil A, Leshem-Rubinow E, Halkin A, et al. Vascular complications after transcatheter aortic valve implantation and their association with mortality reevaluated by the valve academic research consortium definitions. Am J Cardiol 2015;115:100–6. DOI: 10.1016/j.amjcard.2014.09.047; PMID: 25456874 37. Arai T, Lefevre T, Hovasse T, et al. Comparison of Edwards SAPIEN 3 versus SAPIEN XT in transfemoral transcatheter aortic valve implantation: Difference of valve selection in the real world. J Cardiol 2017;69:565–9. DOI: 10.1016/j. jjcc.2016.04.012; PMID: 27288330 38. Frohlich GM, Baxter PD, Malkin CJ, et al. Comparative survival after transapical, direct aortic, and subclavian transcatheter aortic valve implantation (data from the UK TAVI registry). Am J Cardiol 2015;116:1555–9. DOI: 10.1016/j.amjcard.2015.08.035; PMID: 26409640 39. Nakashima M, Watanabe Y, Hioki H, et al. Efficacy and safety of transcatheter aortic valve implantation with Edwards SAPIEN 3 and XT in smaller Asian anatomy. Cardiovasc Interv Ther 2017. DOI: 10.1007/s12928-017-0502-9; PMID: 29185181

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Structural

Coronary Revascularisation in Transcatheter Aortic Valve Implantation Candidates: Why, Who, When? Davide Cao, Mauro Chiarito, Paolo Pagnotta, Bernhard Reimers and Giulio G Stefanini Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy; Cardio Center, Humanitas Research Hospital, Rozzano-Milan, Italy

Abstract Coronary artery disease (CAD) and aortic stenosis (AS) frequently coexist. The presence of CAD has been consistently associated with an impaired prognosis in patients undergoing surgical aortic valve replacement during short- and long-term follow-up. Accordingly, current guidelines recommend coronary revascularisation of all significant stenoses in patients undergoing surgical aortic valve replacement. Conversely, the management of concomitant CAD in patients with severe AS undergoing transcatheter aortic valve implantation (TAVI) is still a matter of debate. The aim of this review article is to provide an overview on the role of coronary revascularisation in TAVI patients.

Keywords Concomitant PCI, coronary artery disease, percutaneous coronary intervention, severe aortic stenosis, staged PCI, Syntax Score, transcatheter aortic valve implantation Disclosure: GGS has received an institutional research grant from Boston Scientific, and speaker or consultant fees from B.Braun, Biosensors, and Boston Scientific. Received: 9 January 2018 Accepted: 12 March 2018 Citation: Interventional Cardiology Review 2018;13(2):69–76. DOI: https://doi.org/10.15420/icr.2018:2:2 Correspondence: Giulio G Stefanini, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy. E: giulio.stefanini@hunimed.eu

The prevalence of concomitant coronary artery disease (CAD) in patients with severe aortic stenosis (AS) varies widely among different reports. This depends primarily on the definition used to assess CAD as well as study design and patient selection, therefore making a uniform estimate difficult. Major trials investigating transcatheter aortic valve implantation (TAVI) highlighted a substantial majority of high- and intermediate-risk patients (63–75 %) with concomitant CAD.1–4 Contemporary multicentre TAVI registries of real-world patients reported a slightly lower but still considerable incidence of CAD (Table 1).5–13 The large Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) registry revealed that only 37 % of patients undergoing TAVI in the USA are free from significant CAD.14 However, it should be noted that CAD prevalence is often reported according to either angiographic evidence of epicardial coronary stenosis, or based on history of previous myocardial infarction or revascularisation, thereby entailing a risk of overestimation in those previously fully revascularised. Elderly patients with severe AS complaining of angina frequently exhibit concomitant CAD.15,16 Whether myocardial ischaemia is determined by insufficient oxygen supply due to the underlying valvular disease or due to the presence of CAD is a matter of debate.17 Interestingly, recent studies showed that coronary blood flow and vasodilator reserve are immediately improved after TAVI, with consequent symptom relief.18–21 Of note, due to the mutual worsening of myocardial ischaemia by concomitant CAD and severe AS, clinical manifestations of the two conditions may overlap, rendering the ischaemic relevance of each condition difficult to interpret. Therefore, combined percutaneous coronary intervention (PCI) and TAVI require careful evaluation of the prognostic impact of both CAD and AS. According to most recent European guidelines, PCI should be considered in patients with significant stenosis of major epicardial

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vessels undergoing TAVI.22 The objective of the present review is to provide an overview of available evidence on the role of PCI in TAVI patients, focusing on rationale for treatment, patient selection and optimal timing of intervention.

Why Treat: Impact of Coronary Artery Disease on Clinical Outcomes after TAVI Initial studies exploring the influence of concomitant CAD in patients with severe AS undergoing TAVI reported conflicting results.23–26 This lack of consensus was likely to be a result of several issues such as limited experience with first-generation bioprosthesis, heterogeneity of the study population, small sample size and the absence of a standardised definition of CAD. More recently, different contemporary large-scale registries investigating outcomes in a broad TAVI population found the presence of concomitant CAD to be related to adverse clinical outcomes and impaired survival (Table 1). In an analysis from the German TAVI registry, patients with CAD presented higher crude rate of in-hospital mortality and lower unadjusted 30-day survival compared with those without CAD. However, this difference was no longer significant after adjusting for confounders, suggesting that outcomes could be largely explained by comorbidities.27 Similar findings were reported within the SOURCE XT registry. Although not quite statistically significance on multivariate analysis (HR 1.22; 95 % CI [1.00–1.49], p=0.0552), the presence of CAD at baseline was associated with a higher risk of 1-year mortality.9 Along this line, data from the Bern University Hospital PCI and TAVI registries were extrapolated to analyse three age- and gendermatched cohorts of 248 subjects each. A significantly increased rate of major adverse cardiovascular and cerebrovascular events (MACCE) at 1 year was observed in patients undergoing TAVI with concomitant CAD (16.8 %) compared with TAVI without CAD (9.8 %), and stable CAD undergoing PCI without AS (9.5 %), primarily due to a higher risk of cardiovascular death. Moreover, the first cohort presented more

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Structural Table 1: Large Multicentre Studies on Prevalence and Impact of CAD in TAVI

Study

Year

Pts (n) CAD (%)

History (%)

Findings

Prior MI Prior CABG Prior PCI Randomised clinical trials PARTNER 1A1

2011

348

74.9†

26.8

42.6

34.0

COREVALVE2

2014

390

75.4

25.4

29.5

34.1

PARTNER 2A3

2016

1011

69.2

18.3

23.6

27.1

SURTAVI

2017

864

62.6

14.5

16.0

21.3

22.7

25.0

Major real-world multicentre registries SOURCE5

2011

1,038

51.7

2012

3,195

47.9

16.4

18.2

2012

1,382

62.2

15.8

18.4

35.1

CAD associated to higher crude rate of in-hospital mortality (OR 1.90; p<0.01) and lower survival at 30 days (91.6 % vs. 94.7 %, p=0.04). No longer significant after adjusting for confounders (OR 1.41; p=0.18)

Italian CoreValve26

2013

659

38*

21.7

15.8

28.5

CAD not associated with procedural outcomes, MACCE (HR 0.76; p=0.353) or survival (HR 0.74; p=0.331) at 1 year

ADVANCE7

2014

1,015

57.8

16.4

21.5

31.5

CAD, history of MI, PCI or CABG did not predict mortality at 1 year

GARY8

2014

3,875

54.5

16.6

21.2

29.1

SOURCE XT9

2015

2,688

44.2

15.1

16.0

30.5

1-year mortality associated to CAD (HR 1.39; p=0.0002) and prior MI (HR 1.40; p=0.0026) CAD not an independent predictor of mortality on multivariate analysis (HR 1.22; p=0.0552) Previous PCI and CABG not associated with mortality at 1 year

UK TAVI, Ludman10

2015

3,980

45.2

22.5

21.2

CAD independent predictor of mortality at 2 years on univariate (HR 1.23; p=0.003) and multivariate (HR 1.08; p=0.036) analysis CAD did not predict 30-day mortality

UK TAVI, Snow11

2015

2,588

45.2

22.7

STS/ACC TVT14

2016

26,414

25.3

Singh

2016

22,344

66.9

13.0

2017

1,947

51.5

11.7

FRANCE 26 German TAVI

SOURCE 313

CAD associated to 1-year mortality on univariable (HR 1.45; p=0.02) but not on multivariate analysis CAD associated to higher rate of transapical TAVI

CAD not associated with early (30-days, p=0.36) or late (4 years, p=0.10) survival on multivariate analysis 31.4

35.6 Higher rates of mortality (10.7 % vs 4.6 %), vascular (8.2 % vs 4.2 %), cardiac (25.4 % vs 18.6 %), respiratory (24.6 % vs 16.1 %), and infectious (10.7 % vs 3.3 %) complications (p<0.001 % for all) in TAVI + PCI group vs TAVI alone

11.4

33.8

CABG = coronary artery bypass grafting; CAD = coronary artery disease; MACCE = major adverse cardiovascular and cerebrovascular events; MI = myocardial infarction; PCI = percutaneous coronary intervention; pts = patients; TAVI = transcatheter aortic valve implantation. †Patients requiring revascularisation were excluded; *CAD defined as history of prior PCI or CABG.

frequently with diabetes mellitus, peripheral artery disease, chronic renal failure and a greater extent and complexity of coronary lesions compared with patients with stable CAD without AS.28 Conversely, results from the UK TAVI registry outlined that CAD, albeit associated with greater comorbid conditions, predicted neither shortnor long-term survival.11 Similarly, in the ADVANCE study, neither CAD, nor history of MI or prior revascularisation were found to be predictors of mortality at 12 months.7 Several small studies showed the feasibility of PCI in TAVI patients (Table 2). A recent meta-analysis by Kotronias and colleagues included 3,858 patients who did or did not undergo PCI prior to or concomitant with TAVI.29 Interestingly, coronary revascularisation was associated with an increased risk of major vascular complications and higher 30-day mortality. However, this association was no longer present at 1 year, suggesting that early adverse outcomes could be ascribed to a worse preoperative risk profile of the PCI group. Indeed, PCI negative impact vanished when outcomes were compared only among studies with 100 % prevalence of CAD in both revascularised and nonrevascularised groups. Furthermore, no difference between the two

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cohorts was observed with respect to 30-day cardiovascular mortality, myocardial infarction and acute kidney injury. Of note, CAD is a complex and heterogeneous disease, not only due to its frequent association with various comorbidities, but also in terms of extent of myocardium at risk, which may explain the discrepancy between different reports. For this purpose, stratifying patients according to disease severity – i.e. by means of Syntax score – may allow assessment of the prognostic implications of CAD on clinical outcomes after TAVI with greater accuracy (Table 3). In a retrospective analysis of 445 patients from the Bern TAVI registry, severity of CAD was associated with impaired clinical outcomes at 1 year after TAVI. Specifically, this study showed that patients with a Syntax score >22 received less complete revascularisation and had a higher risk of cardiovascular death, stroke or MI than patients without CAD or with a lower Syntax score.30 These findings were confirmed by a recent multicentre study of 1,270 TAVI patients that identified the same threshold of Syntax score >22 as an independent predictor of all-cause mortality (HR 2.09; p=0.017).31 In another observational study, Khawaja and colleagues found a residual Syntax score of 9 to be independently associated with mortality (HR 1.95;

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Coronary Revascularisation in TAVI

Year

Pts (n)

CAD (%)

% PCI (in CAD pts)

Timing of PCI

Table 2: Studies on Safety and Feasibility of PCI in TAVI Patients Study 44 (100)

Before (81.9 %), during (12.7 %) or after (5.4 %) TAVI

100 % combined after transapical TAVI

Mean of 56.6 ± 29.4 days before TAVI

Mean of 32 ± 10 days before TAVI

Before or during TAVI

Median of 27 days before TAVI

12.8 (24.7)

24.5 (42.4)

66.5 (66.5)

23.5 (100)

20.4 (34.5)

125

128 pairs with 1:1 case-control matching

51.9

57.8

100

23.5

59.2

2012

593

249

275

153

191

Abdel-Wahab44

2016

2015

2014

2013

Before or combined with TAVI (median of 10 days before)

Gasparetto43

Codner58

Ussia26

Abramowitz59

Penkalla60

Chakravarty61

204 TAVI + LM PCI 1188 TAVI alone

No adverse events with PCI

No difference between CAD and no CAD in 30-day and 1-year in allcause mortality and other adverse events

No difference in 30-day VARC combined (11 % vs 13 %, p=0.74) and individual endpoints

Additional findings

Outcomes

12.9 ± 9.5 months

Increased baseline creatinine (HR 1.55; p=0.049) predicted allcause mortality

Follow-up

Up to 2 years (mean: 454 days)

No difference in 2-year mortality between PCI + TAVI and TAVI alone (p=0.67)

Higher incidence of MI in pts without any revascularization (p=0.050)

Stent type (%)

Up to 1 year

Similar 1-year MACCE (p=0.594) and mortality (p=0.807) between complete, incomplete and no revascularization

No difference between groups in long-term survival (p=0.68)

Up to 3 years

Up to 3 years (mean: 17 months)

No difference in 30-day mortality and VARC endpoints between CAD and no CAD pts, and between PCI and no PCI group among CAD pts

DES: 71 BMS: 24 DES + BMS: 5

Up to 5 years

No difference in 30-day mortality (p=0.609) and 3-year survival between transapical TAVI without CAD, with CAD and no PCI, and with PCI

Trend towards increased 3-year mortality in pts with CAD due to higher pre-operative risk and comorbidities PCI + TAVI associated to higher amount of contrast but not to renal injury Up to 1 year

No difference in 30-day mortality (2 % vs 6 %, p=0.27) and long-term survival (p=0.36) between PCI + TAVI and isolated TAVI

BMS: 56.4

DES: 86.9 BMS: 11.5 DES + BMS: 1.6

BMS: 14.2 DES: 73.0 DES + BMS: 1.0

Similar 30-day (p=0.67) and 1-year mortality (p=0.83) between the TAVI + LM PCI pts and matched controls undergoing TAVI alone

Similar outcomes in unprotected vs protected, ostial vs nonostial, and with LM PCI less vs more than 3 months before TAVI Higher mortality in unplanned vs planned LM PCI

BMS = bare metal stent; CAD = coronary artery disease; DES = drug eluting stent; LM = left main; MACCE = major adverse cardiovascular and cerebrovascular events; MI = myocardial infarction; PCI = percutaneous coronary intervention; pts = patients; TAVI = transcatheter aortic valve implantation; VARC = Valve Academic Research Consortium.

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Structural Table 3: Studies on TAVI Outcomes According to CAD Severity and Revascularisation Extent Study

Year

Pts (n) Assessment of relevant

Prevalence

% PCI (in

Completeness of

of CAD (%)

CAD pts)

revascularization

Follow-up

Outcomes

Conclusions

among CAD pts

CAD Van Mieghem34

2013

263

Coronary 47 stenosis >50 % SYNTAX Score in pts without prior CABG

14.8 (31.5)

20.2 % bSS 9, rSS 5

Median of 16 months

Complete revascularization (p=0.85) and rSS threshold of 8 (p=0.71) did not impact on 1-year survival

Revascularization status not associated to outcomes

Stefanini30

2014

445

SYNTAX Score: low SS 0-22, high SS >22

31.2 (48.4)

Low SS: bSS 10.1, rSS 4.0 High SS: bSS 33.2, rSS 21.2

Up to 1 year

bSS >22 associated with 2-fold increased risk of 1-year cardiovascular mortality (p=0.029) Higher rSS associated with increased ischemic outcomes

Severity of CAD and less complete revascularization associated with impaired 1-year outcomes Higher bSS received less complete revascularization

Khawaja32

2015

271

QCA: coronary 34.3 stenosis ≥70 % (or ≥50 % if left main or vein graft) SYNTAX Score

9.2 (26.9)

Median of 683 days

SS threshold of 9 independently predicted mortality (HR 1.95, p=0.006) High SS (>33) associated with mortality (p= 0.007), conversely CAD per se was not (p=0.805)

No effect of CAD (p=0.805) and PCI among CAD pts (p=0.918) on mortality at 30 days and 1 year

Witberg31

2017

1270

SYNTAX Score: moderate CAD (SS 0-22), severe CAD (SS >22)

35.7 SS 0-22: 26.1 SS >22: 9.6

32.3 (90.2) SS 0-22: 88.6 SS >22: 94.3

Median of 1.9 years

SS >22 (HR 2.09; p=0.017) and rSS >8 (HR 1.72; p=0.031) independently predicted mortality

More complete revascularization may lower the impact of severe CAD on mortality Survival with moderate CAD and reasonable incomplete (rSS <8) revascularization was comparable to prognosis without CAD

Shamekhi39

2017

666

SYNTAX Score: low SS 0-24, high SS >24 SYNTAX Score II

65.6

24.3 (37.1)

Low SS: bSS 7.0, rSS 2 High SS: bSS 38.5, rSS 11

Median of 593 days

Higher bSS (p=0.001), rSS (p=0.01), and SS-II (p<0.001) associated with increased 3-year mortality bSS, rSS and SS-II did not independently predict mortality

Severity of CAD at baseline and after PCI associated with survival after TAVI

Paradis57

2017

377

QCA-derived SYNTAX Score: low SS 1-22, intermediate SS 23-32, high SS ≥33

78.2

42.2 (53.6)

Low SS: bSS 11.5, rSS 6.4 Intermediate SS: bSS 27.7, rSS 16.4 High SS: bSS 45.9, rSS 33.8

Median of 452 days

CAD presence, bSS, rSS threshold of 8, and CABG-SS did not impact on 30-day and 1-year outcomes

Neither severity of CAD, nor completeness of revascularization after PCI or CABG were associated with worse clinical outcomes

65.5 SS 0-22: 46.5 SS >22: 18

bSS = baseline SYNTAX Score; CAD = coronary artery disease; CABG = coronary artery bypass grafting; MACCE = major adverse cardiovascular and cerebrovascular events; MI = myocardial infarction; PCI = percutaneous coronary intervention; pts = patients; QCA = quantitative coronary angiography; rSS = residual SYNTAX Score; SS = SYNTAX Score; TAVI = transcatheter aortic valve implantation.

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Coronary Revascularisation in TAVI Table 4: Studies on Timing of PCI in TAVI Patients Study

Year

Pts (n) % PCI (in

Timing of

CAD pts)

PCI

Stent type (%) Follow-up

Outcomes

Conclusions

Additional findings

Before and concomitant Wenaweser45

2011

256

23.0 (35.3)

34 ± 26 days before TAVI (39 %) Concomitant with TAVI (61 %)

DES: staged 52.5, concomitant 88.4

Up to 2 years

No difference in 30-day mortality (5.6 % vs 10.2 %, p=0.24) and VARC endpoints between isolated TAVI and PCI + TAVI

Staged and concomitant PCI safe and feasible

Completeness of revascularization did not impact on long-term survival (p=0.16)

Conradi46

2011

100 (100)

14.3 ± 9.6 days before TAVI (75 %) Concomitant prior to TAVI (25 %)

BMS: 69.5 DES: 34.1

30 days

In-hospital and 30-day mortality rate of 7.1 % (2/28 deaths all in the PCI concomitant to TAVI group)

Staged and concomitant PCI safe and feasible

No periprocedural MI or stroke Higher risk of renal failure with concomitant strategy

Griese51

2014

411

15.8

Before (74 %) or concomitant (26 %) with TAVI

BMS: 71

Median of 16 months

PCI + TAVI associated to increased rate of 30-day MI (6 % vs 1 %; p=0.01) and mortality (15 % vs 5 %; p=0.01), and worse 2-year survival (p=0.03)

Similar 2-year survival between staged and concomitant PCI (p=0.65)

PCI associated to an elevated risk of MI and death regardless of synchronous or staged strategy

2015

100

<30 days (50 %) ≥30 days (50 %)

DES: 44 <30 days: 40 ≥30 days: 48

Up to 3 years

3-year mortality not Shortly or associated to timing of remotely staged staged PCI (p=0.363) PCI before TAVI yields comparable results

Higher rates of minor bleeding (p=0.011) and vascular injury (p=0.016) with PCI <30 days

Pasic47

2012

419

11.0

Same session after transapical TAVI

Up to 3 year

4.3 % mortality rate at 30 day 87.1 % survival rate at 1 year, 69.7 % at 2 and 3 years

PCI immediately after transapical TAVI safe and feasible

100 % technical procedural success

Blumenstein54

2015

100

Any time after TAVI (232.8 ± 158.4 days)

Procedural success of PCI

Coronary cannulation failed in 9/15 cases with valve covering coronary ostia

Supracoronary devices and high valve implantation may impair PCI success after TAVI

Coronary cannulation was feasible with all devices in subcoronary position

Allali55

2016

100

Any time after DES: 86.2 TAVI (median of 17.7 months)

In-hospital

Successful coronary cannulation in 95.8 % of procedures

PCI safe and 1 procedural failure feasible after self- and consequent expandable TAVI death in emergency setting

Before Van Rosendal50

After

BMS = bare metal stent; CAD = coronary artery disease; DES = drug eluting stent; MI = myocardial infarction; PCI = percutaneous coronary intervention; pts = patients; TAVI = transcatheter aortic valve implantation.

p=0.006).32 Consistently, a meta-analysis of 979 patients showed that a low extent of CAD, estimated as baseline or residual Syntax Score ≤10, did not negatively affect outcomes at 30 days and 1 year.33 Moreover, Van Mieghem and colleagues observed no impact on TAVI outcomes according to revascularisation status (complete or incomplete), nor by a residual Syntax score threshold of 8.34 Based on these observations, the authors concluded that only a carefully selective PCI of major proximal epicardial vessels subtending large areas of myocardium at risk is likely to confer a clinical benefit. Taken together, these findings suggest that severe CAD, often encountered in association with a wide range of comorbid conditions, may negatively affect survival of patients with AS undergoing

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TAVI. Therefore, reducing myocardial ischaemic burden through PCI appears a legitimate option to improve clinical outcomes after TAVI.

Who to Treat: Assessment of Relevant Coronary Artery Disease Non-invasive Assessment Assessment of myocardial ischaemia due to concomitant CAD in the presence of severe AS can be challenging because of the overt difficulties in interpreting symptoms when both diseases coexist. In patients with suspected CAD, exercise or pharmacological stress examination is essential in determining inducible ischaemia, which may benefit from coronary revascularisation. However, these tests are usually contraindicated in patients with severe AS. Nonetheless,

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Structural dobutamine echocardiography is accepted in cases of low-gradient AS to assess disease severity and guide treatment. Moreover, stress echocardiography is a prognostic tool for risk stratification by appraising contractile reserve in patients with severe AS and impaired left ventricular function. Studies investigating safety and diagnostic accuracy of non-invasive testing with vasodilator stressor in severe AS demonstrated an overall feasibility due to absence of major adverse cardiac events related to the test, although specificity of results might be lower than in the absence of AS.35 In fact, dipyridamole echocardiography on patients with severe AS and normal coronary artery may elicit an ischaemic susceptibility arising only from the aortic valve disease, which is possibly reversible after treatment of AS.36

Coronary Angiography Angiographic screening of coronary anatomy is recommended prior to any aortic valve intervention. Indication and survival benefit attributed to coronary artery bypass grafting (CABG) of ≥50 % coronary stenosis in subjects who are candidates for surgical aortic valve replacement has been established for decades.37,38 Given the importance of assessing CAD severity to properly evaluate its clinical significance, coronary angiography allows quantification of the disease extent and complexity. For this purpose, the Syntax score represents an attractive tool for decision making also in patients with AS. Available evidence indicates that CAD in patients without a high ischaemic burden may bear a neutral effect on outcomes after TAVI. Indeed, as summarised above, several studies showed that survival of patients with moderate CAD and reasonably incomplete revascularisation was comparable with the prognosis of patients without CAD (Table 3).30,31,39 Owing to its high negative predictive value in the detection of CAD, computed tomography angiography, regularly performed preoperatively to evaluate vascular access, annular and aortic root measurements, might also be useful for CAD assessment in TAVI patients. Indeed, Chieffo and colleagues reported that only 22 % of patients required additional coronary angiography after first-line CAD screening with coronary computed tomography angiography in a single centre registry.40

independent iFR as screening tool, while sparing the assessment of borderline lesions by means of FFR only after TAVI.42

When to Treat: Timing of Percutaneous Coronary Intervention Available data seem to suggest that PCI both before and along with TAVI are feasible and do not impact on early survival, but there are a few caveats.43–47 However, there is very limited evidence in support of staging PCI after TAVI (Table 4).

Before Transcatheter Aortic Valve Implantation PCI can be safely performed in patients with severe AS, although low ejection fraction and high STS score determine a higher risk of shortterm mortality.48 Patients with stable CAD at high bleeding risk undergoing coronary stent implantation require dual antiplatelet therapy for a minimum of 3 months, yet a 1 month duration may also be considered.49 Performing early staged TAVI after PCI may result in an additional periprocedural haemorrhagic risk due to the ongoing antithrombotic therapy. Conversely, postponing TAVI until antithrombotic therapy cessation raises concerns about the delay of definitive treatment for severe symptomatic AS. Moreover, a delayed approach would further prolong patient exposure to dual antiplatelet therapy for 3–6 months immediately after TAVI, as suggested by current guidelines.22 A study investigating optimal timing of PCI prior to TAVI stratified 96 patients in one group undergoing PCI ≥30 days before TAVI and another group undergoing PCI within 30 days before TAVI. Interestingly, the shortly staged PCI (<30 days) cohort was at higher risk of minor bleeding events and vascular injury after TAVI, although the lower haemoglobin level and higher incidence of atrial fibrillation at baseline in this group might have contributed to these findings.50 Along the same lines, it appears reasonable to postpone TAVI until vascular access healing has occurred and enough time has passed since antiplatelet loading dose administration. Finally, hypotension from rapid ventricular pacing has often been considered to potentially worsen myocardial ischaemia, therefore revascularisation before TAVI would allow mitigation of a patient’s procedural risk.

Invasive Functional Assessment Functional assessment of coronary lesions by means of fractional flow reserve (FFR) has been shown to accurately guide coronary revascularisation, determining clinical, rather than anatomical, relevance of flow-limiting stenosis. FFR evaluation is based on pressure-flow measurements during adenosine-induced maximal hyperaemia. As well as safety concerns related to vasodilator administration in AS, diagnostic accuracy of FFR has been arguable due to potential underestimation of functionally relevant intermediate stenosis secondary to haemodynamic changes derived from aortic valve disease.35 Although apparently clinically feasible, a series of minor coronary flow variations were observed with FFR after TAVI, suggesting that borderline coronary lesions could become significant following the procedure.41 Alternatively, avoiding induced hyperaemia through instantaneous wave-free ratio (iFR) may be advantageous, increasing safety and reliability of functional evaluation of critical CAD in TAVI patients. Some authors also advocated a hybrid approach, opting for adenosine-

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Concomitant with Transcatheter Aortic Valve Implantation Beyond reducing costs of intervention and rehospitalisation, another potential advantage of single-staged PCI and TAVI is the use of the same transartierial access for both procedures, with a lower consequent risk of vascular and bleeding complications. Although higher rates of periprocedural mortality, vascular complications and myocardial infarction have been reported in patients undergoing combined TAVI and PCI, no significant difference between staged and concomitant procedures was observed.29,51 However, a trend towards a reduced incidence of bleeding and vascular complications was noted in patients undergoing PCI and TAVI in the same session.45,51 Nevertheless, it must be acknowledged that studies are heterogeneous and no uniform information regarding ongoing therapy and time interval between the two procedures was provided.29 There is also legitimate apprehension of concomitant PCI because of nephrotoxicity due to a prolonged intervention. Indeed, patients

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Coronary Revascularisation in TAVI Figure 1: Flow Chart of Suggested Strategies for Coronary Artery Disease Management in Transcatheter Aortic Valve Implantation Candidates

Large area of myocardium at risk (proximal epicardial vessel, multivessel) Obstructive CAD Small area of myocardium at risk (distal lesion, small vessel, CTO)

Pre-TAVI coronary angiography screening

No obstructive CAD

Severe CAD (coronary stenosis >75 %, >50 % if LM)

Staged upfront or concomitant PCI and TAVI

Moderate CAD (coronary stenosis 50–75 %)

Consider TAVI first, then CAD functional assessment

Consider TAVI first, then ischemia-driven revascularization

TAVI alone

CAD = coronary artery disease; CTO = chronic total occlusion; LM =left main; PCI = percutaneous coronary intervention; TAVI = transcatheter aortic valve implantation.

undergoing simultaneous PCI and TAVI may receive a higher amount of contrast agent, therefore being more exposed to renal injury.46,52 However, correlation between contrast volume and acute kidney injury is weak in TAVI patients and many studies failed to show its predictive value.53

After Transcatheter Aortic Valve Implantation Since TAVI has been shown to improve coronary perfusion and anginal symptom relief, evaluation of CAD after valve intervention may allow a more physiological and accurate assessment of myocardium at risk of ischaemia, especially in the presence of borderline coronary lesions. However, this strategy entails a series of technical challenges. Coronary cannulation and catheter manipulation may be hampered later after valve deployment, especially with self-expandable prosthesis due to the bulgy stented frame placed over coronary ostia. Malpositioning of the valve, mainly in the case of high implantation and consequent aortic root distortion, are essential factors raising this risk.54 More importantly, compromised cannulation of coronaries could be ominous in an emergency situation.55 Notwithstanding, a recent study reported technical success in all 46 cases of PCI performed right after balloonexpandable TAVI within the same operative session, without additional procedural complexity.47 This suggests that in the presence of extensive CAD and the possibility of future need for PCI, valve selection – i.e., favouring bioprosthesis with subcoronary implantation – may be crucial to allow coronary accessibility after TAVI.

Conclusion CAD is frequent among TAVI patients and PCI is commonly performed in this setting. However, assessment of relevant CAD in the presence

mith CR, Leon MB, Mack MJ, et al. Transcatheter versus S surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. DOI: 10.1056/NEJMoa1103510; PMID: 21639811. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790–8. DOI: 10.1056/NEJMoa1400590; PMID: 24678937. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. DOI: 10.1056/NEJMoa1514616; PMID: 27040324. Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediaterisk patients. N Engl J Med 2017;376:1321–31. DOI: 10.1056/ NEJMoa1700456; PMID: 28304219. Thomas M, Schymik G, Walther T, et al. One-year outcomes of cohort 1 in the Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) Registry: The European Registry

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of severe AS can be difficult and symptoms potentially misleading. Available evidence in support of different revascularisation strategies is mostly based on retrospective, single-centre studies reporting unadjusted and discordant outcomes. The ongoing percutaneous coronary intervention prior to transcatheter aortic valve implantation (ACTIVATION) study is the first randomised controlled trial designed to evaluate non-inferiority of PCI compared with not treating such coronary lesions before TAVI.56 While awaiting further data to provide solid recommendations, the decision to pursue coronary revascularisation in TAVI patients should be tailored case-by-case and based on clinical and anatomical variables, appraised by multi-disciplinary consensus within the local Heart Team. For this purpose, Syntax score may help stratify CAD severity to guide selection of patients who will benefit the most from concomitant PCI. At this point, it is reasonable to foster selective revascularisation strategies of proximal epicardial coronary arteries in subjects with signs of high ischaemic burden (Figure 1). Finally, staging PCI either before or concomitant with TAVI appears feasible. Optimal timing should be decided on an individual basis, taking into consideration patients and procedural characteristics. Overall, current management of CAD in TAVI patients is largely based on observational evidence. Given the broad expansion of TAVI indication in lower risk patients, large and well-designed randomised trials investigating strategies for the optimal management of CAD in TAVI patients are needed. n

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46.

47.

48.

49.

50.

51.

52.

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54.

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intervention on outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation. EuroIntervention 2011;7:541–8. DOI: 10.4244/EIJV7I5A89; PMID: 21930453. Conradi L, Seiffert M, Franzen O, et al. First experience with transcatheter aortic valve implantation and concomitant percutaneous coronary intervention. Clin Res Cardiol 2011;100:311–6. DOI: 10.1007/s00392-010-0243-6; PMID: 20959999. Pasic M, Dreysse S, Unbehaun A, et al. Combined elective percutaneous coronary intervention and transapical transcatheter aortic valve implantation. Interact Cardiovasc Thorac Surg 2012;14:463–8. DOI: 10.1093/icvts/ivr144; PMID: 22232234. Goel SS, Agarwal S, Tuzcu EM, et al. Percutaneous coronary intervention in patients with severe aortic stenosis: implications for transcatheter aortic valve replacement. Circulation 2012;125:1005–13. DOI: 10.1161/ CIRCULATIONAHA.111.039180; PMID: 22282327. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur J Cardiothoracic Surg 2018;53:34–78. DOI: 10.1093/ejcts/ezx334; PMID: 29045581. van Rosendael PJ, van der Kley F, Kamperidis V, et al. Timing of staged percutaneous coronary intervention before transcatheter aortic valve implantation. Am J Cardiol 2015;115:1726–32. DOI: 10.1016/j.amjcard.2015.03.019; PMID: 25890631. Griese DP, Reents W, Tóth A, et al. Concomitant coronary intervention is associated with poorer early and late clinical outcomes in selected elderly patients receiving transcatheter aortic valve implantation. Eur J Cardiothoracic Surg 2014;46:e1–7. DOI: 10.1093/ejcts/ezu187; PMID: 24819362. Bajaj A, Pancholy S, Sethi A, et al. Safety and feasibility of PCI in patients undergoing TAVR: a systematic review and meta-analysis. Heart Lung 2017;46:92–9. DOI: 10.1016/j. hrtlng.2016.12.003; PMID: 28088437. Najjar M, Salna M, George I. Acute kidney injury after aortic valve replacement: incidence, risk factors and outcomes. Expert Rev Cardiovasc Ther 2015;13:301–16. DOI: 10.1586/14779072.2015.1002467; PMID: 25592763. Blumenstein J, Kim W-K, Liebetrau C, et al. Challenges of coronary angiography and intervention in patients previously treated by TAVI. Clin Res Cardiol 2015;104:632–9. DOI: 10.1007/ s00392-015-0824-5; PMID: 25720330. Allali A, El-Mawardy M, Schwarz B, et al. Incidence, feasibility and outcome of percutaneous coronary intervention after transcatheter aortic valve implantation with a self-expanding prosthesis. Results from a single center experience. Cardiovasc Revasc Med 2016;17:391–8. DOI: 10.1016/j.carrev.2016.05.010; PMID: 27396607. Khawaja MZ, Wang D, Pocock S, et al. The percutaneous coronary intervention prior to transcatheter aortic valve implantation (ACTIVATION) trial: study protocol for a randomized controlled trial. Trials 2014;15:300. DOI: 10.1186/1745-6215-15-300; PMID: 25059340. Paradis J, White JM, Généreux P, et al. Impact of coronary artery disease severity assessed with the SYNTAX score on outcomes following transcatheter aortic valve replacement. J Am Heart Assoc 2017;6:e005070. DOI: 10.1161/ JAHA.116.005070; PMID: 28219920. Codner P, Assali A, Dvir D, et al. Two-year outcomes for patients with severe symptomatic aortic stenosis treated with transcatheter aortic valve implantation. Am J Cardiol 2013;111:1330–6. DOI: 10.1016/j.amjcard.2013.01.275; PMID: 23415022. Abramowitz Y, Banai S, Katz G, et al. Comparison of early and late outcomes of TAVI alone compared to TAVI plus PCI in aortic stenosis patients with and without coronary artery disease. Catheter Cardiovasc Interv 2014;83:649–54. DOI: 10.1002/ ccd.25233; PMID: 24532332. Penkalla A, Pasic M, Drews T, et al. Transcatheter aortic valve implantation combined with elective coronary artery stenting: a simultaneous approach†. Eur J Cardio-Thoracic Surg 2015;47:1083–9. DOI: 10.1093/ejcts/ezu339. Chakravarty T, Sharma R, Abramowitz Y, et al. Outcomes in patients with transcatheter aortic valve replacement and left main stenting. J Am Coll Cardiol 2016;67:951–60. DOI: 10.1016/j. jacc.2015.10.103; PMID: 26916485.

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Transseptal Transcatheter Mitral Valve Replacement for Post-Surgical Mitral Failures Marvin H Eng and Dee Dee Wang Center for Structural Heart Disease, Henry Ford Hospital, Detroit, MI, USA

Abstract Post-surgical deterioration of mitral valve repairs or replacements may present a clinical dilemma due to the high-risk nature of repeat surgery. Recent advances in transcatheter techniques and surgery have enabled the implantation of balloon-expandable valves in the mitral position when surgical rings and valves are present. Valves may be implanted either via transseptal or transapical access, with a reported success rate between 88–100 %.

Keywords Mitral regurgitation, mitral stenosis, valve-in-ring, valve-in-valve, transseptal Disclosure: The authors have no conflicts of interest to declare. Received: 13 June 2017 Accepted: 13 April 2018 Citation: Interventional Cardiology Review 2018;13(2):77–80. DOI: https://doi.org/10.15420/icr.2017:16:3 Correspondence: Marvin H Eng, Director of Research for the Center of Structural Heart Disease, Structural Heart Disease Fellowship Director, Henry Ford Hospital, 2799 W. Grand Blvd, Detroit, MI 48202, USA. E: meng1@hfhs.org

Approximately 1.8 % of the US population has mitral valve disease,1 and an estimated 106,000 surgeries per year are for the treatment of valvular heart disease.2 A total of 210,529 mitral surgeries were performed from 2000 to 2007, averaging approximately 30,000 mitral valve surgeries yearly in the US, accounting for both combined and isolated mitral procedures, with approximately 60 % of surgeries using a bioprosthetic valve.3 Unfortunately, the durability of surgical mitral valve repairs and replacement are limited. There is a 25 % rate of significant mitral regurgitation recurrence in surgical repairs at 2 years and 44 % rate of primary valvular failure at 15 years,4 leaving the patient with either symptomatic mitral regurgitation, stenosis or both.5 Elderly patients with significant prosthetic mitral valve disease are often non-ideal candidates for cardiac surgery as advanced age, multiple comorbidities and prior sternotomies can elevate the risk of mitral valve replacement to 7.4–15.1 % mortality.6–8 In fact, in a multivariable analysis, independent predictors of in-hospital mortality, including New York Heart Association III and IV symptoms (OR 3.19; p=0.012) as well as more than re-operation (OR 2.59; p=0.058).7 In another retrospective analysis of elderly patients with mitral valve surgery, previous mitral valve replacement increased the 30-day mortality rate nine-fold (p=0.013). Moreover, 30-day mortality was compounded by chronic renal failure (OR 8.041; p=0.022), peripheral vascular disease (OR 5.976; p=0.025) and increasing age (OR 1.077; p=0.013), all of which frequently complicate the clinical course of elderly patients.6 Degenerative changes in surgically repaired mitral valves or valve replacements can result in severe regurgitation or stenosis-causing symptomatic heart failure. Degeneration of such surgical repairs may present with up to 25 % moderate–severe mitral regurgitation within 3–4 years post-repair and most bioprosthetic mitral prostheses sustain 10–15 years usage before degenerating.5,9,10 Furthermore, repeat cardiac surgery can be high-risk due to advanced age and

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the accumulated comorbidities associated with the elderly.11 Evolving transcatheter heart technology has expanded the options of treating degenerated post-surgical valves to using transcatheter heart valve (THV) implantation for the mitral position.12–26 State-of-the-art transcatheter therapy in failed mitral valve surgeries use balloon-expandable THVs, mostly from the Edwards Lifesciences’ family of valves (SAPIEN, SAPIEN XT, SAPIEN 3). In general, the first step in the implantation process is identifying the correct prosthesis size for the intended location of implantation. For patients with failed surgical valves, identifying the manufacturer and model of valve are essential. Once the internal dimensions have been identified, a valve may be chosen and the options are readily available in the form of a mobile app.27 Alternatively, a gated CT scan can be used to approximate the internal dimensions and a valve can be selected appropriately. While the selection of new prosthesis for degenerated surgical valves is relatively simple, selection of valves for degenerated repairs and mitral rings is more nuanced. Some rings are complete and some are incomplete and there is not a consensus as to whether or not to size a ring to the broadest dimension, the commissure-to-commissure distance, or to size according to the area within the ring similar to the way aortic valves are sized to an annulus. In general, we suggest sizing the valve to circumscribed area within the confines of the ring with the understanding that the ring is usually oval or ‘D’ shaped. The prosthesis usually conforms to the ring but must fill out the commissure-to-commissure distance to avoid a perivalvular leak. If there is concern that the commissure-to-commissure distance is very broad (e.g. area of 390 mm but a commissure-to-commissure distance of 30 mm), we would choose a larger valve (26 mm Sapien 3). Sizing of mitral rings continues to be a work in progress in attempts to optimise effective orifice area and minimise perivalvular leak. Of note,

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Structural Figure 1: Stereotypical Transcatheter Mitral Valve Implantation for a Failed Mitral Valve Repair.

A) Transseptal access has already been achieved and a stiff, pre-shaped wire is placed in the left ventricle (Confida, Medtronic). A 14 mm balloon is being inflated in the interatrial septum to facilitate passage of a transcatheter heart valve through the septum. B) A 29 mm SAPIEN 3 (Edwards Lifesciences) has been appropriately prepped and oriented antegrade on the delivery system. In this case, the valve has been advanced so that the centre marker of the balloon is just past the ventricular side of the ring. C) With rapid pacing, the valve is slowly inflated and minor adjustments can be made mid-inflation to accommodate any shifting of the valve. D) After implantation, the balloon was advanced towards the ventricle more in order to flare the stent and attempt to give it a more trapezoidal shape.

the last challenge is when the mitral annular ring is too large for the off-label use of an Edwards SAPIEN 3. To date, we are aware of only the Tiaraâ&#x201E;˘ valve (Neovasc) being used for the treatment of valve-in-ring degenerated repairs. In addition to determining the size of prosthesis, the possibility of left ventricular outflow tract (LVOT) obstruction must be thoroughly evaluated using CT, and, as of yet, protocols using advanced 3D modelling tools are still in development for evaluating LVOT obstruction. 28 As this remains a significant vulnerability in transcatheter mitral valve therapies, clinicians have been prompted to develop techniques to avoid LVOT obstruction, either by alcohol septal ablation or intentional percutaneous laceration of the anterior mitral leaflet.29,30 For the procedural technique, transapical access uses a standard thoracotomy similar to what is used for transapical transcatheter aortic valve replacement access. Once the apex of the heart is exposed, pledgeted sutures are placed and an 18 gauge needle is used to access the apex. Once a wire is passed from the left ventricular (LV) apex to the left atrium, a balloon-tipped catheter can be used to ensure that no chordal entrapment occurred with passing the wire. Next, exchange

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for a large, dedicated delivery sheath is performed over a stiff wire and the valve is prepped and deployed. Transapical access has the advantage of providing co-axial delivery of a prosthesis in the mitral space and makes deployment simple. The balloon inflation is still performed with a run of rapid pacing similar to the implantation of a balloon-expandable valve. For transseptal delivery of a balloon-expandable valve prosthesis, transoesophageal imaging plays a larger role. Transseptal access with a mid-posterior bias is helpful in establishing a favourable trajectory for the valve. Subsequently, balloon septostomy is performed using a 12â&#x20AC;&#x201C;14 mm peripheral balloon to enable smooth crossing of the valve. The majority of cases are performed with transseptal access only because of the narrow delivery profile of the SAPIEN 3 delivery system. In the past, small sheaths have been placed at the ventricular apex to facilitate transseptal crossing by externalisation of the wire through the apex and providing countertraction to the delivery catheter. After the delivery sheath is in place, the valve is mounted on the balloon catheter in an orientation that allows blood to flow from the left atrium to the LV. After the valve is mounted on the balloon and crosses the atrial septum, it is deployed with a slow gradual inflation and simultaneous rapid pacing (Figure 1).

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Transseptal Mitral Valve Therapy The largest published cohort of mitral valve-in-valve is comprised of 33 patients with median follow up of 723 days.12 Patients had a mean age of 81 ± 6 years and a mean Society of Thoracic Surgeons score of 12.2 ± 6.9 %. The mode of THV delivery was transapical in all patients, with most patients being extubated in the operating room (87 %). Valve implantation resulted in a significant decrease of mitral regurgitation and the mean gradient decreased from a mean of 11.1 mmHg to 6.9 mmHg post-procedure. Mortality was found to be 9.6 % and there was a 26.1 % rate of Valve Academic Research Consortium (VARC)-2 defined major bleeding observed in the cohort. Subsequent analysis from the same institution with median follow up of 4.4 years showed a survival of <40 %, primarily attributed to the elderly nature of the population and the multiple associated comorbidities.31 Notably, this series found a 6.5 % rate of valve thrombosis. Other transcatheter valve-in-valve series have been described using a transseptal approach, either with an apical rail or without.32–34 One series describes the procedural success of nine patients, using the same technique as described in this manuscript, with an apical access used as an external rail to facilitate Melody™ valve (Medtronic) implantation. In their series, two of the nine patients required thoracotomy for haemothorax and their occluder device of choice was the Amplatzer™ vascular plug (St. Jude Medical). Two other series, a 17- and 4-patient clinical series demonstrated the feasibility of performing transcatheter mitral valve replacement (TMVR) without the apical access and via transseptal access alone. In the 17-patient series, they describe an 82 % rate of procedural success with one procedural death for a patient in cardiogenic shock, a valve migration and one patient with moderate paravalvular leak.34 Ultimately, it appears that TMVR for failed surgical prostheses or surgical repairs is technically feasible and achieves acceptable immediate results. The latest series of transcatheter valve implantation describes the outcomes of 48 patients in a single-centre experience that encompasses implantation in not only degenerated mitral bioprostheses and annuloplasty repairs but also mitral stenosis due to annular calcification.35 In this cohort, the authors emphasise a procedural modification where use of pre-shaped nitinol wires improved the safety of the mitral valve-invalve/ring delivery. With new variation, they report 100 % success (19/19 cases), shorter procedure time (pre-modification 114 ± 28 minutes versus post-modification 86 ± 30 minutes; p<0.05) and numerically lower numbers of major bleeding, ventricular perforation and death. The mean gradient at 30-day follow up was 7.0 mmHg. This single-centre series illustrates that the early experience does include some major

komo VT, Gardin JM, Skelton TN, et al. Burden N of valvular heart diseases: a populationbased study. Lancet 2006;368:1005–11. https://doi.org/10.1016/S0140-6736(06)69208-8; PMID: 16980116. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation 2015;131:e29–322. https://doi.org/10.1161/CIR.0000000000000152; PMID: 25520374. Gammie JS, Sheng S, Griffith BP, et al. Trends in mitral valve surgery in the United States: results from the Society of Thoracic Surgeons Adult Cardiac Surgery Database. Ann Thorac Surg 2009;87:1431–7. https://doi.org/10.1016/j.athoracsur.2009.01.064; PMID: 19379881. Mauri L, Foster E, Glower DD, et al. 4-year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation. J Am Coll Cardiol 2013;62:317–28. https://doi.org/10.1016/j.jacc.2013.04.030;

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Table 1: Complications from a 48-patient Single-centre Registry of Transcatheter Mitral Valve-in-valve, Valve-inring and Valve-in-native Procedures Procedural and 30-day Event Rates

Patients (n)

Procedural Complications Left ventricular perforation

3 (6 %)

Valve embolisation

3 (6 %)

Emergency cardiac surgery

4 (8 %)

Major bleeding

4 (8 %)

Major vascular complication

Stroke

Myocardial infarction

Left ventricular pseudoaneurysm

1 (2 %)

Death

3 (6 %)

30-day Events Prosthetic valve thrombosis

1 (2 %)

Left ventricular outflow obstruction

2 (4 %)

Stroke

Elective cardiac surgery

1 (2 %)

Death

4 (8 %)

complications including ventricular perforation and valve embolisation, however, for patients without surgical options the mortality remains relatively low at 30 days (Table 1). The 30-day mortality rate for redo-mitral valve replacement was 10.1 % and the mortality for the percutaneous cohort is 8 %, illustrating the burden of comorbidities of the patient population.6,35 While this singlecentre series encompasses most of the major complications, the prospect of late migration with subsequent embolisation remains a concern.36 To address this issue, operators have advocated implanting the THV on the ventricular side of the prosthesis or ring and flare this side to prevent migration.

Conclusion Transcatheter mitral valve implantation for post-surgical failures is a feasible alternative to repeat surgery. Transapical and transseptal delivery routes are both feasible, with the latter associated with a relatively low rate of morbidity. Key elements to success include rigorous anatomic evaluation for prosthesis size and possibility of LVOT obstruction. We are currently seeing a number of dedicated transcatheter mitral valves for treating native mitral pathology delivered transapically, and transseptal delivery may possibly grow. n

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valve replacement in patients aged 50 to 69 years. JAMA 2015;313:1435–42. https://doi.org/10.1001/jama.2015.3164; PMID: 25871669. 9. Ciarka A, Braun J, Delgado V, et al. Predictors of mitral regurgitation recurrence in patients with heart failure undergoing mitral valve annuloplasty. Am J Cardiol 2010;106:395–401. https://doi.org/10.1016/j.amjcard.2010.03.042; PMID: 20643253. 10. Crabtree TD, Bailey MS, Moon MR, et al. Recurrent mitral regurgitation and risk factors for early and late mortality after mitral valve repair for functional ischemic mitral regurgitation. Ann Thorac Surg 2008;85:1537-42. https://doi.org/10.1016/j.athoracsur.2008.01.079; PMID: 18442534. 11. Maganti M, Rao V, Armstrong S, et al. Redo valvular surgery in elderly patients. Ann Thorac Surg 2009;87:521–5. https://doi.org/10.1016/j.athoracsur.2008.09.030; PMID: 19161771. 12. Cheung A, Webb JG, Barbanti M, et al. 5-year experience with

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tract obstruction induced by transcatheter mitral valve replacement. Catheter Cardiovasc Interv 2016;88:e191–97. https://doi.org/10.1002/ccd.26649; PMID: 27377756. Khan JM, Rogers T, Schenke WH, et al. Intentional laceration of the anterior mitral valve leaflet to prevent left ventricular outflow tract obstruction during transcatheter mitral valve replacement. JACC Cardiovasc Interv 2016;9:1835–43. https://doi.org/10.1016/j.jcin.2016.06.020. Ye J, Cheung A, Yamashita M, et al. Transcatheter aortic and mitral valve-in-valve implantation for failed surgical bioprosthetic valves: an 8-year single-center experience. JACC Cardiovasc Interv 2015;8:1735–44. https://doi.org/10.1016/j.jcin.2015.08.012; PMID: 26476608. Coylewright M, Cabalka AK, Malouf JA, et al. Percutaneous mitral valve replacement using a transvenous, transseptal approach: transvenous mitral valve replacement. JACC Cardiovasc Interv 2015;8:850–7. https://doi.org/10.1016/j.jcin.2015.01.028; PMID: 25999110. Cullen MW, Cabalka AK, Alli OO, et al. Transvenous, antegrade Melody valve-in-valve implantation for bioprosthetic mitral and tricuspid valve dysfunction: a case series in children and adults. JACC Cardiovasc Interv 2013;6:598–605. https://doi.org/10.1016/j.jcin.2013.02.010; PMID: 23683739. Bouleti C, Fassa AA, Himbert D, et al. Transfemoral implantation of transcatheter heart valves after deterioration of mitral bioprosthesis or previous ring annuloplasty. JACC Cardiovasc Interv 2015;8:83–91. https://doi.org/10.1016/j.jcin.2014.07.026; PMID: 25616821. Eleid MF, Cabalka AK, Williams MR, et al. Percutaneous transvenous transseptal transcatheter valve implantation in failed bioprosthetic mitral valves, ring annuloplasty, and severe mitral annular calcification. JACC Cardiovasc Interv 2016;9:1161–74. https://doi.org/10.1016/j.jcin.2016.02.041; PMID: 27085576. Bapat VV, Khaliel F, Ihleberg L. Delayed migration of Sapien valve following a transcatheter mitral valve-invalve implantation. Catheter Cardiovasc Interv 2014;83:e150–4. https://doi.org/10.1002/ccd.25076; PMID: 23784983.

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Coronary

Expert Opinion ‘Combat’ Approach to Cardiogenic Shock Alexander G Truesdell, 1,2 Behnam Tehrani, 2 Ramesh Singh, 2 Shashank Desai, 2 Patricia Saulino, 2 Scott Barnett, 2 Stephen Lavanier 2 and Charles Murphy 2 1. Virginia Heart, Falls Church, VA, USA; 2. INOVA Heart and Vascular Institute, Falls Church, VA, USA

Abstract The incidence of cardiogenic shock is rising, patient complexity is increasing and patient survival has plateaued. Mirroring organisational innovations of elite military units, our multidisciplinary medical specialists at the INOVA Heart and Vascular Institute aim to combine the adaptability, agility and cohesion of small teams across our large healthcare system. We advocate for widespread adoption of our ‘combat’ methodology focused on: increased disease awareness, early multidisciplinary shock team activation, group decision-making, rapid initiation of mechanical circulatory support (as appropriate), haemodynamic-guided management, strict protocol adherence, complete data capture and regular after action reviews, with a goal of ending preventable death from cardiogenic shock.

Keywords Cardiogenic shock, mechanical circulatory support, multidisciplinary care Disclosure: AGT has received consultant fees from Abiomed. The other authors have no conflicts of interest to declare. Received: 26 December 2017 Accepted: 14 March 2018 Citation: Interventional Cardiology Review 2018;13(2):81–6. DOI: https://doi.org/10.15420/icr.2017:35:3 Correspondence: Alexander G Truesdell, Virginia Heart, INOVA Heart and Vascular Institute, 2901 Telestar Court, Falls Church, VA, 22042, USA. E: agtruesdell@gmail.com

Considering the unacceptably high mortality rate of patients with cardiogenic shock (CS) and the absence of widespread improvements in survival over recent decades, the time has arrived for the cardiovascular community to embrace a ‘combat’ approach to CS.1 In the past 20 years we have witnessed a revolution in the management of combat polytrauma towards a goal of zero preventable battlefield death. Specialists from diverse disciplines challenged assumptions, collected and analysed data, conducted actionable research, made incremental care changes, measured outcomes and then repeated this cycle over and over again. In the end, new products were fielded, new techniques refined and organisational innovations realised. Several thousand lives were saved and combat casualty care was rapidly modernised.2–5 Our multidisciplinary team at the INOVA Heart and Vascular Institute aims for similar success defeating our own enemy: CS.

Cardiogenic Shock CS, ‘the rude unhinging of the machinery of life’, is a state of endorgan dysfunction, often complicated by a systemic inflammatory response syndrome, secondary to insufficient cardiac output despite adequate preload, as a result of left ventricular (LV), right ventricular (RV), or biventricular (BiV) dysfunction.6–9 This complex and often multifactorial pathophysiological process is defined by haemodynamic parameters – systolic blood pressure <90 mmHg, cardiac index <1.8 litre/min/m2 without pharmacological support (or >2.2 litre/ min/m2 with support), LV end-diastolic pressure >18 mmHg or RV end-diastolic pressure >10–15 mmHg or pulmonary capillary wedge pressure (PCWP) >15 mmHg – and clinical signs and symptoms of hypoperfusion, such as cool extremities, decreased urine output, and altered mental status.9,10

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Following the uniform adoption of early revascularisation for acute MI (AMI), mortality rates for AMI CS decreased from near 90 % to <50 %.11–14 In the decades since, in-hospital survival rates have plateaued while the incidence of AMI CS and acute decompensated heart failure (ADHF) CS has increased despite improvements in door-to-balloon times (the cardiovascular specialist’s version of the surgeon’s ‘Golden Hour’) and adjunctive pharmacotherapy.15–28 Early survivors also suffer unacceptably high rates of post-discharge heart failure, rehospitalisation and death.29–32 Revascularisation is necessary but not sufficient for survival in AMI CS. Contemporary meta-analyses suggest no survival benefit to an immediate multivessel percutaneous coronary intervention (PCI) strategy compared with culprit vessel revascularisation in CS.33,34 Most recently, the randomised CULPRIT-SHOCK trial demonstrated a 7.3 % reduction in all-cause mortality rate at 30 days with a culprit-lesion-only PCI strategy versus immediate multivessel PCI in patients presenting with CS found to have multivessel coronary artery disease on angiography.25

Paradigm Shift The fragility of critically ill patients with CS and multisystem organ dysfunction leaves little margin for error. The short-term stabilising effects of inotrope and vasopressor therapy are offset by adverse effects on afterload, oxygen demand, impaired tissue microcirculation, and arrhythmogenicity – translating into cardiotoxicity, end-organ dysfunction and higher mortality rates.35–40 The advent of rapidly deployable, user-friendly percutaneous mechanical circulatory support (MCS) devices may drive a paradigm shift in the treatment of CS: administration of circulatory and ventricular support to restore stable

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Coronary Figure 1: Cardiogenic Shock Pathophysiology and Management Considerations

haemodynamics, minimise myocardial ischaemia, reduce native heart workload and maintain vital organ perfusion (Figure 1).

Cardiogenic shock pathophysiology and management

Previous preclinical investigations demonstrated haemodynamic benefits to early LV unloading and initiation of ventricular and circulatory support for ADHF CS and AMI CS.36,41–49 More recent studies suggest LV unloading may reduce reperfusion injury, myocyte loss and myocardial infarct size, and activate cardioprotective mechanisms preventing adverse remodelling.50–53 This approach – similar to the ‘damage control’ strategies employed by combat trauma surgeons – prioritises normal physiology over normal anatomy to prevent cardiovascular collapse and lethal multiorgan dysfunction.5

Acute myocardial infarction/ decompensated heart failure

Left ventricular systolic/ diastolic dysfunction • Elevated LVEDP • Decreased cardiac output • Decreased coronary perfusion

Goals • Timely recognition • Invasive hemodynamics • Minimise inotropes/ vasopressors • Coronary reperfusion • Ventricular support • Circulatory support • Recovery

Systemic hypoperfusion • Compensatory vasoconstriction • Systemic inflammatory response • Progressive myocardial dysfunction • Multi-organ failure

Death MCS support considerations • Need for support • Timing of support • Right, left, biventricular support • Degree of support • Respiratory support • Institutional availability/expertise • Continuous clinical reassessment • Weaning and escalation protocols • Futility

The current clinical evidence in favour of MCS employment to combat CS consists only of observational data, meta-analyses and small feasibility trials. While these investigations demonstrate superior haemodynamics and improved organ perfusion with percutaneous MCS employment in AMI CS, they do not demonstrate any survival benefit with this strategy.54–59

LVEDP = left ventricular end-diastolic pressure; MCS = mechanical circulatory support. Reproduced and modified with permission from Abiomed.

More recently, small single-centre studies (most notably the Detroit Cardiogenic Shock Initiative), international registry data and our own local experience lend some support to the immediate haemodynamic and potential short-term clinical survival benefits of initiation of percutaneous axial flow LV to aorta support as soon as possible after the onset of shock.36,56,60–66 Other investigations, such as the recent

Figure 2: INOVA Cardiogenic Shock Diagnosis, Team Activation and Treatment Algorithm/Protocol

IMPella versus IABP Reduces mortality in STEMI patients treated with primary PCI (IMPRESS) trial, suggest that the benefits of percutaneous MCS devices are time-dependent and unlikely to impact outcomes if employed late, once overt multiorgan dysfunction has occurred.67

Team Building

Cardiogenic shock algorithm Clinical goals • Rapid identification • Early mechanical circulatory support (LV and RV) • Right heart catheterisation • Minimise inotropes/ vasopressors • Heart recovery Shock criteria • SBP<90 mmHg (for 30 min) or use of vasopressors/ inotropes • CI<2.2 l/min/ m2 • PCWP>18 mmHg • CPO<0.6 W • Lactate>2 mmol/l

• CPO = MAP x CO/451 • PAPi = (sPAP-dPAP)/RA

Identify shock • Vitals signs, ECG, labs • +/– Right heart catheterisation, Echo • See “shock criteria” • Activate cath lab/CICU/MCCS • Consider shock team activation

Non-ACS

ACS

Right heart catheterisation Diagnostic angiography Echo Right heart catheterisation Assess vascular access Prepare PMCS Percutaneous mechanical circulatory support Reassess hemodynamics Assess for RV support (CPO, PAPi) Coronary revascularisation Reassess hemodynamics Assess for RV support (CPO, PAPi) Cardiac intensive care unit • Assess for myocardial recovery • Wean inotropes/vasopressors

ACS = acute coronary syndrome; CI = cardiac index; CICU = cardiac intensive care unit; CO = cardiac output; CPO = cardiac power output; dPAP = diastolic pulmonary artery pressure; ECG = electrocardiogram; LV = left ventricle; MAP = mean arterial pressure; MCCS = medical critical care service; PAPi = pulmonary artery pulsatility index; PCWP = pulmonary capillary wedge pressure; PMCS = percutaneous mechanical circulatory support; RA = right atrium; RV = right ventricle; SBP = systolic blood pressure; sPAP = systolic pulmonary artery pressure.

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The INOVA Heart and Vascular Institute Cardiogenic Shock Initiative began in mid-2016 with the assembly of a diverse task force of clinical and administrative stakeholders across multiple disciplines to assess the current state of affairs, establish priorities of effort and assign ownership for these priorities.68–71 A detailed care pathway was proposed based on available scientific evidence. Graphics of our management algorithm (Figure 2) were posted in key work locations and laminated pocket cards distributed to hospital staff. Simultaneously, a 6-monthlong training process focused on individual and team CS management skills, haemodynamic expertise, percutaneous MCS device insertion and management, team communication and dedicated protocol training. At the conclusion of our training and rehearsals, on 1 January 2017, the INOVA Cardiogenic Shock Team went live.

The INOVA Pathway Our team selected five key areas of focus: rapid identification of shock (with early activation of our multi-specialty Shock Team and rapid collaborative decision making), early right heart catheterisation (to facilitate invasive haemodynamic-tailored therapy), expedited initiation of percutaneous MCS as appropriate (followed by early escalation as necessary), minimisation of vasopressor and inotrope use, and most importantly, meaningful patient recovery and survival. The initial task of our team is the rapid identification of the shock state and assessment of its clinical severity via integrated clinical, laboratory, haemodynamic and imaging data.7,9,72 Immediate bedside echocardiography is used to assess cardiac function and identify potential causes of CS.73–77 While the indiscriminate use of right heart

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Cardiogenic Shock catheterisation in all-comers in the intensive care unit has proven ineffective, such detailed invasive haemodynamic data are essential for optimal management of CS, particularly when percutaneous MCS devices are used.78–84 In addition to typically measured parameters such as right atrial (RA) pressure, PCWP, systemic vascular resistance and cardiac output/cardiac index, our INOVA protocol further emphasises measurement of cardiac power output (CPO), RA:PCWP ratio and pulmonary artery pulsatility index (PAPi), all of which have recognised diagnostic and prognosticative power in the CS population.85–89

Protocol Implementation Since initiating our INOVA cardiogenic shock programme in January 2017, there have been 161 team activations for AMI CS, ADHF CS and suspected or undifferentiated CS. Team activation occurs 24 hours per day, 7 days per week via a one-call process to a central operator at our Heart and Vascular Institute who gathers our five-person multidisciplinary team via either in-person or virtual (telephonic) bedside consultation. A consensus plan of care based on our protocol and established care priorities is developed and tailored to the specific clinical scenario. In the cardiac catheterisation laboratory, we focus our institutional priorities on provision of axial flow percutaneous circulatory support and ventricular unloading prior to coronary reperfusion. For non-AMI aetiologies of CS, patients may instead require extracorporeal life support or urgent cardiac surgery. Decisions regarding sufficiency of support, need for escalation of support, and addition of right-sided or oxygenation support are made based on mandatory echocardiography and invasive haemodynamic reassessment prior to departing the bedside, angiography suite or operating room. Although our protocol prioritises axial flow LV aortic assist devices, extracorporeal membrane oxygenation (ECMO) is also commonly used at our centre in cardiac arrest, respiratory arrest and severe BiV shock requiring higher levels of circulatory support – usually with concomitant LV unloading to mitigate the deleterious effects of increased afterload.90–93 Not infrequently, patients may require various

Figure 3: INOVA Mechanical Circulatory Support Escalation and Weaning Algorithm/Protocol Cardiogenic shock algorithm Refractory shock • ↓ CO • ↓ CPO • ↓ UOP • ↑ Lactate • ↑ Inotropes RV dysfunction • CI<2.2 l/min/m2 • CVP>15 mmHg • CPO<0.6 W • PAPi<1.5 • CVP/PCWP or LAP ratio>0.63 • RV dysfunction on TTE (TAPSE<14 mm)

Refractory cardiogenic shock post-PMCS

CPO>0.6

CPO<0.6

No RV dysfunction

RV dysfunction

No RV dysfunction

Consider RV support No hypoxemia

• CPO = MAP x CO/451 • PAPi = (sPAP-dPAP)/RA

Hypoxemia

No hypoxemia

Consider ECLS

Reassess for PMCS weaning versus escalation

CI = cardiac index; CO = cardiac output; CPO = cardiac power output; CVP = central venous pressure; dPAP = diastolic pulmonary artery pressure; ECLS = extracorporeal life support; LAP = left atrial pressure; PAPi = pulmonary artery pulsatility index; PCWP = pulmonary capillary wedge pressure; PMCS = percutaneous mechanical circulatory support; RV = right ventricle; sPAP = systolic pulmonary artery pressure; TAPSE = tricuspid annular plane systolic excursion; TTE = transthoracic echocardiogram; UOP = urine output.

Figure 4: INOVA After Action Case Review Form Date of Review: Patient MRN: Date of Admission: Clinical History: Diagnostic Studies:

ECG:

‘plug-and-play’ combinations of device support – such as Bi-Pella (combined left- and right-sided Impella® axial flow catheter support) or EC-Pella (combined ECMO and left-sided Impella support) to overcome the limitations inherent to each device.93–99

Laboratory Studies: Echocardiography: Invasive Hemodynamics:

In the cardiac or cardiothoracic surgery intensive care unit, patients are co-managed by a co-attending team of an intensivist and a cardiologist or a cardiac surgeon providing collaborative 24-hour care.100 Joint rounds are conducted daily in conjunction with other multispecialty consultants. Serial physical exams are performed; lactate levels, organ function markers and urine output are repeatedly measured; bedside echocardiography is performed and invasive haemodynamics are regularly assessed. This continuous tracking of standard haemodynamic parameters as well as CPO and PAPi facilitates our team’s decisions regarding MCS escalation, addition of right-sided cardiac support and device weaning (Figure 3). This pattern of assessment, adjustment, reassessment and readjustment mirrors the ‘unblinking eye’ of continuous cyclic battlefield intelligence collection, analysis and dissemination.68,101 Between 1 January 2017 and 28 February 2018, our team managed 161 patients with CS: 41 % (n=66) AMI CS and 59 % (n=95) ADHF CS. Average patient age was 61 years (64 years for AMI and 59 years for

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Coronary Angiography:

Plan of Care: Indications for MCS: Outcome: Care Metrics: Did the care plan meet the standard of care? Opportunities for improvement? Follow-up:

Committee Member:

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Coronary Figure 5: INOVA ‘Spoke and Hub’ Cardiogenic Shock Hospital Network

H Stone Springs Hospital Center

H Inova Loudoun Hospital

H Inova Alexandria Hospital

H HCA Reston Hospital Center

H Inova Fair Oaks Hospital

H Virginia Hospital Center

H Inova Mount Vernon Hospital

Inova Fairfax Hospital

H Novant Haymarket Medical Center H Fauquier Hospital

H Sentara Northern Virginia Medical Center

H Novant Health Prince William Medical Center

ADHF). A total of 70 % of patients were male (n=112) and 30 % were female (n=49). Our initiatives to date have resulted in progressively improving outcomes for AMI CS and ADHF CS with in an increase in all-comer survival rates at our institution from 47 % (n=110) in 2016, to 61 % (n=140) in 2017, and 81 % (n=21) in the first 2 months of 2018.102 These data support our hypothesis that team-based multidisciplinary care, haemodynamic guidance and early consideration of MCS improve survival in patients with AMI or ADHF CS.103 Our single-centre 18-month results (to include outcomes by shock aetiology, patient age, initial haemodynamics and time to treatment) will be reported in late 2018. Even when successful, these aggressive team interventions are costly and labour-intensive and may not be suited to facilities without 24-hour on-site multidisciplinary cardiac, surgical and critical care services and advanced heart failure therapies, such as permanent ventricular assist device and cardiac transplantation. Such hospitals are therefore better served partnering with larger institutions as part of a ‘spoke and hub’ model.104–108

After Action Reviews Our cardiogenic shock team conducts novel cross-discipline meetings with clinical and non-clinical staff and leaders with 100 % case

1. 2.

6. 7.

Truesdell AG. War on shock. J Invasive Cardiol 2017;29:E14–5. PMID: 28045675. Kotwal RS, Montgomery HR, Miles EA, et al. Leadership and a casualty response system for eliminating preventable death. J Trauma Acute Care Surg 2017;82:S9–5. DOI: 10.1097/ TA.0000000000001428; PMID: 28333833. Kotwal RS, Montgomery HR, Kotwal BM, et al. Eliminating preventable death on the battlefield. Arch Surg 2011; 146:1350–8. DOI: 10.1001/archsurg.2011.213; PMID: 21844425. Remick KN. Leveraging trauma lessons from war to win in a complex global environment. US Army Med Dep J 2016; 2–16:106–13. PMID: 27215876. Holcomb JB. Major scientific lessons learned in the trauma field over the last two decades. PLoS Med 2017;14:e1002339. DOI: 10.1371/journal.pmed.1002339; PMID: 28678788. Gross SG. A System of Surgery: Pathological, Diagnostic, Therapeutic and Operative. Philadelphia, PA: Lea and Febiger, 1872. Hochman JS, Buller CE, Sleeper LA, et al. Cardiogenic shock complicating acute myocardial infarction--etiologies, management and outcome: a report from the SHOCK trial registry. Should we emergently revascularize occluded coronaries for cardiogenic shock? J Am Coll Cardiol 2000;36(3

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10.

11. 12.

13.

review. Data related to each shock patient (i.e. clinical presentation, objective data, hospital course, clinical outcomes) are collected and reviewed every 2 weeks. We modified the validated military after action review model, which was designed to critique training and combat events and answer four questions: What was planned? What really happened? Why did it happen? What can we do better next time? (Figure 4).109 Our roundtable process assesses compliance to our protocols, determines the effectiveness of our interventions and facilitates regular incremental changes in our care pathways as part of a continuous process improvement programme.

Future Perspective Looking forward, in our region and across the US, new networks of partnered multidisciplinary care ought to emerge on a large scale to establish linked regional systems of community hospitals and large centralised centres of excellence emphasising rapid triage, immediate transport and expedited door-to-support for patients with CS, emulating the highly successful military and civilian trauma systems and the cardiovascular communities historical successes in early revascularisation for acute ST-elevation MI.1,104–108 Locally, having focused on our ‘hub’ medical centre (Figure 5) in 2017, we are currently expanding our protocol and process to our linked ‘spoke’ hospitals (both internal and external to our health system) in 2018. Due to the heterogeneous patient population and multifactorial aetiologies of death in CS, demonstrating a survival benefit will be challenging. However, ongoing treatment analyses (and hopefully rigorously performed randomised controlled trials) may continue to improve our understanding of modes of death in CS, identify ongoing areas for performance improvement and inform future guideline development.66,103,110–114

Conclusion Although hampered by small sample sizes and lack of long-term outcomes data, current registries and single-centre reports, to include our own preliminary experience to date, suggest that team-based multidisciplinary care, early initiation of MCS, and haemodynamicguided therapy may form the next leap forward in CS care to interrupt the vicious triad of ischaemia, hypotension and myocardial dysfunction and allow for myocardial salvage and meaningful patient recovery. In our first year, our INOVA team has worked to develop a heightened awareness of CS and an organisational commitment to building a comprehensive system of CS care, research and innovation, focused on our combat medicine inspired goal of zero preventable death from CS. We hope other institutions will do the same. n

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Drakos SG, Kfoury AG, Selzman CH, et al. Left ventricular assist device unloading effects on myocardial structure and function: current status of the field and call for action. Curr Opin Cardiol 2011;26:245–55. DOI: 10.1097/ HCO.0b013e328345af13; PMID: 21451407. 49. Burkhoff D, Sayer G, Doshi D, et al. Hemodynamics of mechanical circulatory support. J Am Coll Cardiol 2015; 66:2663–74. DOI: 10.1016/j.jacc.2015.10.017; PMID: 26670067. 50. Sjauw KD, Remmelink M, Baan J, et al. Left ventricular unloading in acute ST-segment elevation myocardial infarction patients is safe and feasible and provides acute and sustained left ventricular recovery. J Am Coll Cardiol 2008;51:1044–6. DOI: 10.1016/j.jacc.2007.10.050; PMID: 18325447. 51. Kapur NK, Paruchuri V, Urbano-Morales JA, et al. Mechanically unloading the left ventricle before coronary reperfusion reduces left ventricular wall stress and myocardial infarct size. Circulation 2013;128:328–36. DOI: 10.1161/ CIRCULATIONAHA.112.000029; PMID: 23766351. 52. Kapur NK, Qiao X, Paruchuri V, et al. Mechanical preconditioning with acute circulatory support before reperfusion limits infarct size in acute myocardial infarction. JACC Heart Fail 2015;3:873–82. DOI: 10.1016/j.jchf.2015.06.010; PMID: 26541785. 53. Kloner RA, Schwartz Longacre L. State of the science of cardioprotection: challenges and opportunities--proceedings of the 2010 NHLBI workshop on cardioprotection. J Cardiovasc Pharmacol Ther 2011;16:223–32. DOI: 10.1177/1074248411402501; PMID: 21821520. 54. Seyfarth M, Sibbing D, Bauer I, et al. A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction. J Am Coll Cardiol 2008;52:1584–8. DOI: 10.1016/j. jacc.2008.05.065; PMID: 19007597. 55. Lauten A, Engstrom AE, Jung C, et al. Percutaneous leftventricular support with the Impella 2.5 assist device in acute cardiogenic shock: results of the Impella-EUROSHOCK registry. Circ Heart Fail 2013;6:23–30. DOI: 10.1161/ CIRCHEARTFAILURE.112.967224; PMID: 23212552. 56. O’Neill WW, Schreiber T, Wohns DHW, et al. The current use of Impella 2.5 in acute myocardial infarction complicated by cardiogenic shock: results from the USpella Registry. J Interv Cardiol 2014;27:1–11. DOI: 10.1111/joic.12080; PMID: 24329756. 57. Thiele H, Sick P, Boudriot E, et al. Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 2005;26:1276–83. PMID: 15734771. 58. Kapur NK, Paruchuri V, Jagannathan A, et al. Mechanical Circulatory Support for Right Ventricular Failure. JACC Heart Fail 2013;1:127–34. DOI: 10.1016/j.jchf.2013.01.007; PMID: 24621838. 59. Anderson MB, Goldstein J, Milano C, et al. Benefits of a novel percutaneous ventricular assist device for right heart failure: the prospective RECOVER RIGHT study of the Impella RP device. J Heart Lung Transplant 2015;34:1549–60. DOI: 10.1016/j. healun.2015.08.018; PMID: 26681124. 60. Schroeter MR, Köhler H, Wachter A, et al. Use of the Impella device for acute coronary syndrome complicated by cardiogenic shock - experience from a single heart center with analysis of long-term mortality. J Invasive Cardiol 2016;28:467–72. PMID: 27529657.

61. M eraj PM, Doshi R, Schreiber T, et al. Impella 2.5 initiated prior to unprotected left main PCI in acute myocardial infarction complicated by cardiogenic shock improves early survival. J Interv Cardiol 2017;30:256–63. DOI: 10.1111/joic.12377; PMID: 28419573. 62. O’Neill W, Basir M, Dixon S, et al. Feasibility of early mechanical support during mechanical reperfusion of acute myocardial infarct cardiogenic shock. JACC Cardiovasc Interv 2017;10:624–5. DOI: 10.1016/j.jcin.2017.01.014; PMID: 28335901. 63. Lazkani M, Murarka S, Kobayashi A, et al. A retrospective analysis of Impella use in all-comers: 1-year outcomes. J Interv Cardiol 2017;30:577–83. DOI: 10.1111/joic.12409; PMID: 28736903. 64. Flaherty MP, Khan AR, O’Neill WW. Early initiation of Impella in acute myocardial infarction complicated by cardiogenic shock improves survival: a meta-analysis. JACC Cardiovasc Interv 2017;10:1805–6. DOI: 10.1016/j.jcin.2017.06.027; PMID: 28882288. 65. Basir MB, Schreiber T, Dixon S, et al. Feasibility of early mechanical circulatory support in acute myocardial infarction complicated by cardiogenic shock: the Detroit cardiogenic shock initiative. Catheter Cardiovasc Interv 2018;91:454–61. DOI: 10.1002/ccd.27427; PMID: 29266676. 66. Detroit Cardiogenic Shock Initiative (D-CSI). Available at: https://henryford.com/cardiogenicshock (accessed 26 March 2018). 67. Ouweneel DM, Eriksen E, Sjauw KD, et al. Percutaneous mechanical circulatory support versus intra-aortic balloon pump in cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 2017;69:278–87. DOI: 10.1016/j. jacc.2016.10.022. PMID: 27810347. 68. McChrystal G, Collins T, Silverman D, et al. Team of teams: new rules of engagement for a complex world. New York: Penguin Publishing Group, 2015. 69. Doll JA, Ohman EM, Patel MR, et al. A team-based approach to patients in cardiogenic shock. Catheter Cardiovasc Interv 2016;88:424–33. DOI: 10.1002/ccd.26297; PMID: 26526563. 70. Morrow DA, Fang JC, Fintel DJ, et al. Evolution of critical care cardiology: transformation of the cardiovascular intensive care unit and the emerging need for new medical staffing and training models: a scientific statement from the American Heart Association. Circulation 2012;126:1408–28. PMID: 22893607. 71. Burzotta F, Trani C, Doshi SN, et al. Impella ventricular support in clinical practice: collaborative viewpoint from a European expert user group. Int J Cardiol 2015;201:684–91. DOI: 10.1016/j. ijcard.2015.07.065; PMID: 26363632. 72. Forrester JS, Diamond G, Chatterjee K, et al. Medical therapy of acute myocardial infarction by application of hemodynamic subsets. N Engl J Med 1976;295:1356–62. PMID: 790191. 73. McLean AS. Echocardiography in shock management. Crit Care 2016;20:275. DOI: 10.1186/s13054-016-1401-7; PMID: 27543137. 74. Oh JK. Echocardiography as a noninvasive Swan-Ganz catheter. Circulation 2015;111:3192–4. PMID: 15967860. 75. Lancellotti P, Price S, Edvardsen T, et al. The use of echocardiography in acute cardiovascular care: recommendations of the European Association of Cardiovascular Imaging and the Acute Cardiovascular Care Assocaition. Eur Heart J 2015;4:3–5. DOI: 10.1177/2048872614568073; PMID: 25635106. 76. Picard MH, Davidoff R, Sleeper LA, et al. Echocardiographic predictors of survival and response to early revascularization in cardiogenic shock. Circulation 2003;107:279–84. DOI: 10.1161/01.CR.0000045667.11911.F6; PMID: 12538428. 77. Kaul S, Stratienko AA, Pollock SG, et al. Value of two dimensional echocardiography for determining the basis of hemodynamic compromise in critically ill patients: a prospective study. J Am Soc Echocardogr 1994;7:598–606. PMID: 7840987. 78. Hadian M, Pinsky MR. Evidence-based review of the use of the pulmonary artery catheter: impact data and complications. Crit Care 2006;10:S8. DOI: 10.1186/cc4834; PMID: 17164020. 79. Cohen MG, Kelly RV, Kong DF, et al. Pulmonary artery catheterization in acute coronary syndromes: insights from the GUSTO IIb and GUSTO III trials. Am J Med 2005;118:482–8. PMID: 15866250. 80. Sotomi Y, Sato N, Kajimoto K, et al. Impact of pulmonary artery catheter on outcome in patients with acute heart failure syndromes with hypotension or receiving inotropes: from the ATTEND registry. Int J Cardiol 2014;172:165–72. DOI: 10.1016/j. ijcard.2013.12.174; PMID: 24447746. 81. Rossello X, Vila M, Rivas-Lasarte M, et al. Impact of pulmonary artery catheter use on short- and long-term mortality in patients with cardiogenic shock. Cardiology 2017;136:61–9. PMID: 27553044. 82. Sorajja P, Borlaug BA, Dimas VV, et al. SCAI/HFSA clinical expert consensus document on the use of invasive hemodynamics for the diagnosis and management of cardiovascular disease. Catheter Cardiovasc Interv 2017; 89:E233–47. DOI: 10.1002/ccd.26888; PMID: 28489331. 83. Atkinson TM, Ohman EM, O’Neill WW, et al. Interventional scientific council of the American College of Cardiology. A practical approach to mechanical circulatory support in patients undergoing percutaneous coronary intervention: an interventional perspective. JACC Cardiovasc Interv 2016;9:871–83. DOI: 10.1016/j.jcin.2016.02.046; PMID: 27151604. 84. Teuteberg J, O’Neill W. Association between the use of invasive hemodynamic monitoring and outcomes

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with percutaneous left ventricular support: a call for standardization? J Heart Lung Transplant 2017;36:S59. DOI: 10.1016/j.healun.2017.01.142. Torgersen C, Schmittinger CA, Wagner S, et al. Hemodynamic variables and mortality in cardiogenic shock: a retrospective cohort study. Crit Care 2009;13:R157. DOI: 10.1186/cc8114; PMID: 19799772. Morine KJ, Kiernan MS, Pham DT, et al. Pulmonary artery pulsatility index is associated with right ventricular failure after left ventricular assist device surgery. J Card Fail 2016;22:110–6. DOI: 10.1016/j.cardfail.2015.10.019; PMID: 26564619. Fincke R, Hochman JS, Lowe AM, et al. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 2004;44:340–8. PMID: 15261929. Korabathina R, Heffernan KS, Paruchuri V, et al. The pulmonary artery pulsatility index identifies severe right ventricular dysfunction in acute inferior myocardial infarction. Catheter Cardiovasc Interv 2012;80:593–600. DOI: 10.1002/ccd.23309; PMID: 21954053. Mendoza DD, Cooper HA, Panza JA. Cardiac power output predicts mortality across a broad spectrum of patients with acute cardiac disease. Am Heart J 2007;153:366–70. DOI: 10.1016/j.ahj.2006.11.014; PMID: 17307413. Napp LC, Kuhn C, Bauersachs. ECMO in cardiac arrest and cardiogenic shock. Herz 2017;42:27–44. DOI: 10.1007/s00059016-4523-4; PMID: 28127638. Mourad M, Gaudard P, De La Arena P, et al. Circulatory support with extracorporeal membrance oxygenation and/or Impella for cardiogenic shock during myocardial infarction. ASAIO J 2017; DOI: 10.1097/MAT.0000000000000704; PMID: 29240628. Abrams D, Reshad Garan A, Abdelbary A, et al. Position paper for the organization of ECMO programs for cardiac failure in adults. Intensive Care Med 2018; DOI: 10.1007/s00134-018-50645; PMID: 29450594. den Uil CA, Jewbali LS, Heeren MJ, et al. Isolated left ventricular failure is a predictor of poor outcome in patients receiving veno-arterial extracorporeal membrane oxygenation. Eur J Heart Fail 2017;19:104–9. DOI: 10.1002/ ejhf.853; PMID: 28470918. Kuchibhotla S, Esposito ML, Breton C, et al. Acute

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biventricular mechanical circulatory support for cardiogenic shock. J Am Heart Assoc 2017;6:e006670. DOI: 10.1161/ JAHA.117.006670; PMID: 29054842. 95. Pappalardo F, Schulte C, Pieri M, et al. Concomitant implantation of Impella on top of veno-arterial extracorporeal membrane oxygenation may improve survival of patients with cardiogenic shock. Eur J Heart Fail 2017;19:404–12. DOI: 10.1002/ejhf.668; PMID: 27709750. 96. Lim HS, Howell N, Ranasinghe A. Extracorporeal life support: physiological concepts and clinical outcomes. J Card Fail 2017;23:181–96. DOI: 10.1016/j.cardfail.2016.10.012; PMID: 27989868. 97. Patel S, Lipinski J, Al-Kindi SG, et al. Simultaneous venoarterial extracorporeal membrane oxygenation and percutaneous left ventricular decompression therapy with Impella is associated with improved outcomes in refractory cardiogenic shock. ASAIO Journal 2018; DOI: 10.1097/MAT.0000000000000767; PMID: 29489461. 98. Engstrom AE, Cocchieri R, Driessen AH, et al. The Impella 2.5 and 5.0 devices for ST-elevation myocardial infarction patients presenting with severe and profound cardiogenic shock: the Academic Medical Center intensive care unit experience. Crit Care Med 2011;39:2072–9. DOI: 10.1097/ CCM.0b013e31821e89b5; PMID: 21602670. 99. Truby LK, Takeda K, Mauro C, et al. Incidence and implications of left ventricular distention during venoarterial extracorporeal membrance oxygenation support. ASAIO J 2017;63:257–65. DOI: 10.1097/MAT.0000000000000553; PMID: 28422817. 100. Na SJ, Park TK, Lee GY, et al. Impact of a cardiac intensivist on mortality in patients with cardiogenic shock. Int J Cardiol 2017;244:220–5. DOI: 10.1016/j.ijcard.2017.06.082; PMID: 28666601. 101. Headquarters Department of the Army. The targeting process. Fort Leavenworth, KS: Training Management Directorate, 2010. 102. Truesdell AG. “Combat” approach to cardiogenic shock. Presented at Cardiovascular Research Technologies, Washington, DC, USA, 3–6 March 2018. 103. INOVA Cardiogenic Shock Registry (INOVA-SHOCK). Available at: https://clinicaltrials.gov/ct2/show/NCT03378739 (accessed

26 March 2018). 104. Graham KJ, Strauss CE, Boland LL, et al. Has the time come for a national cardiovascular emergency care system? Circulation 2012;125:2035–44. DOI: 10.1161/ CIRCULATIONAHA.111.084509; PMID: 22529065. 105. Nathens AB, Brunet FP, Maier RV. Development of trauma systems and effect on outcomes after injury. Lancet 2004;363:1794–801. PMID: 15172780. 106. Tchantchaleishvili V, Hallinan W, Massey HT. Call for organized statewide networks for management of acute myocardial infarction-related cardiogenic shock. JAMA Surg 2015;150:1025–6. DOI: 10.1001/jamasurg.2015.2412; PMID:26375168. 107. van Diepen S, Katz JN, Albert NM, et al. Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association. Circulation 2017;136:e232–68. DOI: 10.1161/CIR.0000000000000525; PMID: 28923988. 108. Shaefi S, O’Gara B, Kociol RD, et al. Effect of cardiogenic shock hospital volume on mortality in patients with cardiogenic shock. J Am Heart Assoc 2015;4:e001462. DOI: 10.1161/ JAHA.114.001462; PMID: 25559014. 109. Headquarters Department of the Army. A leader’s guide to afteraction reviews. Fort Leavenworth, KS: Training Management Directorate, 2003. 110. French observatory on the management of cardiogenic shock in 2016 (FRENSHOCK). Available at: https://clinicaltrials.gov/ ct2/show/NCT02703038 (accessed 26 March 2018). 111. Danish cardiogenic shock trial (DANSHOCK). Available at: https://clinicaltrials.gov/ct2/show/NCT1633502 (accessed 26 March 2018). 112. Delmas C, Leurent G, Lamblin N, et al. Cardiogenic shock management: still a challenge and a need for large-registry data. Arch Cardiovasc Dis 2017;110:433–8. DOI: 10.1016/j. acvd.2017.03.002; PMID: 28479041. 113. Harjola V-P, Lassus J, Sionis A, et al. Clinical picture and risk prediction of short-term mortality in cardiogenic shock. Eur J Heart Fail 2015;17:501–9. DOI: 10.1002/ejhf.260; PMID: 25820680. 114. Pöss J, Köster J, Fuernau G, et al. Risk stratification for patients in cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 2017;69:1913–20. DOI: 10.1016/j.jacc.2017.02.027; PMID: 28408020.

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Anticoagulant Therapy for Acute Coronary Syndromes Eunice NC Onwordi, 1 Amr Gamal 2 and Azfar Zaman 2 1. Portsmouth Hospitals NHS Trust, Portsmouth, UK; 2. Freeman Hospital and Newcastle University and Newcastle Upon Tyne Hospitals NHS Trust, Newcastle, UK

Abstract Anticoagulation in conjunction with antiplatelet therapy is central to the management of acute coronary syndromes (ACS). When used effectively it is associated with a reduction in recurrent ischaemic events including myocardial infarction and stent thrombosis as well as a reduction in death. Effective ischaemic risk reduction whilst balancing bleeding risk remains a clinical challenge. This article reviews the current available evidence for anticoagulantion in ACS and recommendations from the European Society of Cardiology.

Keywords Acute coronary syndrome, anticoagulation, bleeding, thrombogenesis, heparin, bivalirudin, fondaparinux Disclosure: The authors have no conflicts of interest to declare. Received: 27 July 2017 Accepted: 27 March 2018 Citation: Interventional Cardiology Review 2018;13(2):87–92. DOI: https://doi.org/10.15420/icr.2017:26:1 Correspondence: Azfar Zaman, Royal Victoria Infirmary, Queen Victoria Rd, Newcastle upon Tyne NE1 4LP, UK. E: azfar.zaman@newcastle.ac.uk

Acute coronary syndromes (ACS) are a major cause of morbidity and mortality. Despite the use of optimal medical therapy and revascularisation there remains a significant risk of vascular events. Registry data indicates a persistent risk even in patients who are event free in the first year following ACS, with as many as 1 in 5 patients suffering a vascular event in the subsequent 3 years.1

Early mechanical and chemical reperfusion with percutaneous coronary intervention (PCI) and the use of antithrombotic agents respectively form the basis of ACS treatment and have been proven to reduce the frequency of both early and late cardiovascular events.7–13 Increased use of PCI further necessitates adequate antithrombotic therapy to reduce the risk of device-related complications.

The central process underlying ACS is the development of a thrombus overlying a ruptured or eroded plaque, leading to various degrees of acute vessel occlusion and myocardial ischaemia.2 A thrombus that originates following plaque rupture consists largely of platelets; in addition, coagulation pathways are also triggered by plaque rupture and platelet aggregation.3

Individual patient assessment is required to balance the need for thrombosis inhibition against a subsequently increased bleeding risk, which itself is an independent adverse prognostic marker in postPCI patients.10,14

Therapies that modify thrombogenesis form the foundation for the management of ACS and prevention of recurrent ischaemic events. The net clinical benefit of antithrombotic therapies must be weighed against the inevitable increased risk of bleeding. This article will review the pathophysiology of thrombosis and evidence for the use of anticoagulants in ACS, including recommendations from the current European Society of Cardiology (ESC) guidelines.4

Pathophysiology of Thrombogenesis Vascular damage triggers a cascade of pathways designed to maintain the integrity of the coronary circulation and to achieve haemostasis. Under normal conditions, controlled regulation of these pathways achieves the right balance between adequate coronary flow and appropriate vessel repair. Disruption of this homeostasis in the coronary circulation may result in life-threatening thrombosis. Acute coronary syndromes are characterised by vascular inflammation, subsequent endothelial dysfunction and platelet activation, followed by thrombus formation.5 In the most extreme circumstances, uncontrolled thrombosis can culminate in complete vascular occlusion and ST-segment elevation MI (STEMI).6

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Mechanisms of Thrombus Formation Activation of coagulation pathways is crucial for thrombus formation. Fibroblasts and smooth muscle cells express the membrane protein tissue factor, which is also present in blood. At sites of vascular damage, platelets express disulphide isomerase, which cleaves tissue factor into its active form. Activated tissue factor can then bind factor VIIa and the resulting complex activates factors VII, IX and X. Factors Xa and V complex together promoting thrombin generation. The presence of thrombin activates factors V and VII promoting prothrombin conversion to thrombin by the more active complex Xa–Va. Fibrin generation from fibrinogen is triggered early in the coagulation cascade resulting in thrombus formation (Figure 1).15,16

Anticoagulation Therapies The combination of anticoagulation with antiplatelet agents is more effective in reducing recurrent thrombotic events in non-ST elevation ACS (NSTE-ACS) than use of antiplatelets alone. This is due to the inhibition of thrombin production and activity.17

Unfractionated Heparin Unfractionated heparin (UFH) is a sulphate-polysaccharide that is endogenously secreted. Its pentasaccharide component has a high affinity for antithrombin III (AT). Binding causes unfolding of

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Coronary Figure 1: Main Mechanisms of Thrombogenesis Aspirin

Ticlopidine Clopidogrel Prasugrel Ticagrelor Cangrelor

ATP Histamine Serotonin

TXA

ADP

Abciximab Tirofiban Eptifibatide

TPα TPβ

r YI2

n do

GPIIbIIIa

D gr ens an e ule s

P2Y

12r

GPIIbIIIa

Fibrinogen

1 PAR

Ib GPIV

Bivalirudin Dabigatran

IIa

Thrombin

Apixaban Rivaroxaban Otamixaban LMWH

vWF Va-Xa

UFH LMWH

Collagen Fibrin

Xa Fibrin

AT-III

Fibrin

Prothrombin TF-VIIa

Fondaparinux

Circulating TF Vit. K γ-glutamill-carboxylase

VKA

IXa

VII TF-VIIa

II, VII, IX, X IX

VIIa

AT = antithrombin; COX = cyclo-oxygenase; GP = glycoprotein; LMWH = low molecular weight heparin; TF = tissue factor; TXA2 = thromboxane A2; UFH = unfractionated heparin; VKA = vitamin K antagonist; vWF = von Willebrand factor. Source: Pesarini, et al., 2014.16 By permission of Radcliffe Cardiology.

antithrombin III exposing its active site more efficiently. The result is a dramatic increase in AT ability to inactivate thrombin and factor Xa.18 The narrow therapeutic window of UFH and its significant pharmacokinetic variability between patients requires administration to be closely monitored. Its anticoagulant effect can be monitored using either the activated clotting time (ACT) in the cardiac catheterisation laboratory or the activated partial thromboplastin time (aPTT) in other areas. The efficacy of UFH in ACS has been validated in various randomised controlled trials.8,19–21 In summary, all trials consistently revealed a significant reduction in the frequency of recurrent ischaemic events. The Fondaparinux with Unfractionated Heparin During Revascularization in Acute Coronary Syndromes (FUTURA/OASIS8) trial compared a low dose of UFH (50 IU/kg) against standard dosing (85 IU/kg) in patients with NSTE-ACS, and showed that dose adjustment had no significant effect on rates of major peri-PCI bleeding or vascular access-site complications.22 Intravenous UFH dosing is weight dependent, with current ESC guidelines recommending an initial bolus of 60–70 IU/kg up to a maximum of 5000 IU, followed by an infusion of 12–15 IU/kg/h up to

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a maximum of 1000 IU/h.4 During PCI, ACT-guided IV UFH boluses can be used, aiming for a range of 200–250 seconds if a glycoprotein IIb/ IIIa (GPIIb/IIIa) inhibitor is given and 250–350 seconds in all other cases. Alternatively, weight-adjusted UFH at 50–70 IU/kg in combination with a GPIIb/IIIa inhibitor or 70–100 IU/kg (in the absence of GPIIb/IIIa) can be administered.4 If there are no other indications for UFH, it should be stopped following revascularisation. The ESC recommends use of additional parenteral anticoagulation both before and after fibrinolysis in ST-elevation ACS (STE-ACS) with anticoagulation, and this should be used until planned definitive revascularisation is performed.23 Medically managed patients should be anticoagulated for at least 48 hours. The use of UFH in patients with primary PCI (PPCI) has not been evaluated in placebo-controlled trials. It is, however, routinely recommended in patients not receiving bivalirudin or enoxaparin. An initial bolus of 70–100 U/kg is recommended when no GP IIb/IIIa inhibitor is planned. A dose of 50–60 U/kg should be administered when the use of GP IIb/IIIa inhibitors is expected.23 There is no clear evidence supporting ACT monitoring of UFH in the context of PPCI and doing so should not delay revascularisation.

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Anticoagulant Therapy for ACS The use of UFH poses a greater bleeding risk when compared with other anticoagulation strategies. Despite this, it remains popular, in part due to its efficacy in combination with low cost, short half-life and easy reversibility with protamine.24

Low Molecular Weight Heparin Low molecular weight heparins (LMWHs) are 2–10 Kda derivatives of heparin that are well absorbed subcutaneously and have a longer half-life compared with UFH. They are less likely to bind to plasma proteins, thereby making the pharmacokinetics of LMWH more predictable than that of UFH, and reducing the likelihood of side effects such as bleeding and heparin-induced thrombocytopaenia (HIT).25–27 Enoxaparin is the most studied and utilised LMWH. Non-inferiority compared with UFH in patients with NSTE-ACS managed with aspirin and tirofiban was demonstrated in the A to Z trial.28 Enoxaparin was found to be non-inferior with respect to a composite end-point of death and non-fatal MI at 30 days in patients presenting with high-risk NSTEACS managed with an early invasive strategy in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/ IIIa Inhibitors (SYNERGY) trial.29 A significant increase in the rate of TIMI major bleeding was noted in the enoxaparin arm compared with the UFH arm. However, in the Acute Myocardial Infarction Treated with Primary Angioplasty and Intravenous Enoxaparin or Unfractionated Heparin to Lower Ischemic and Bleeding Events at Short- and Long-term Follow-up (ATOLL) trial, rates of death, recurrent ACS and urgent revascularisation were significantly reduced in patients treated with enoxaparin (30 % versus 52 %; p=0.015), with no significant increase in bleeding rates.30

Several non-randomised studies have also shown a clear benefit of enoxaparin over UFH in PPCI.24,36,37 In the ATOLL trial, enoxaparin (0.5 mg/kg IV followed by SC treatment) was compared with UFH.30 There was no significant reduction in the primary composite endpoint of death, MI, procedural failure and major bleeding at 30 days. However, reductions were noted in secondary composite endpoint of death, recurrent MI or urgent revascularisation, and in other secondary composite endpoints such as death, or resuscitated cardiac arrest and death, or complication of myocardial infarction were seen. Unlike previous studies, enoxaparin use was not associated with increased bleeding risk compared with UFH use in the PPCI setting.30 Subcutaneous enoxaparin at a dose of 1 mg/kg twice daily is the most frequently used anticoagulant in NSTE-ACS, as recommended by the ESC if fondaparinux is not available.4 It is contraindicated in patients with a glomerular filtration rate (GFR) <15 ml/min/1.73 m2, but the dose can be reduced to 1 mg/kg once daily for patients with a GFR of 15–29 ml/min/1.73 m2. In the latter case, it is advisable to monitor anti-Xa activity, which should also be done in patients whose body weight exceeds 100 kg. If the last enoxaparin dose was given ≥8 hours prior to PCI, a further 0.3 mg/kg IV bolus should be administered at the time of PCI.38,39 It is not advisable to change anticoagulant at the time of PCI.40 The ESC recommends that anticoagulation with enoxaparin may be used in preference over UFH peri-procedurally in patients with STEACS due to undergo PPCI.23,41–43

Fondaparinux Enoxaparin is marginally favoured in a meta-analysis of all trials comparing the combined endpoint of death and MI at 30 days in patients with ACS receiving either enoxaparin or UFH (10 % versus 11 %; OR 0.90; 95 % CI [0.810–0.996]; p=0.043).31 At 7 days, no significant between-group difference in major bleeding rates was noted (6.3 % with enoxaparin versus 5.4 % with UFH; OR 1.13; 95 % CI [0.84–1.54]). Another meta-analysis of 23 trials involving 30,966 patients suggested superiority of enoxaparin in reduction in the rates of a composite of death and MI, complications of MI and bleeding when compared with UFH.24

Fondaparinux is a selective Xa inhibitor with a half-life of 17 hours administered subcutaneously and once daily in patients with NSTACS. It prevents the formation of thrombin by reversibly binding to antithrombin. Similarly to enoxaparin, fondaparinux rarely binds plasma proteins resulting in a more predictable anticoagulant effect, and no monitoring is required as it is fully bioavailable. Although there is no risk of HIT, fondaparinux is renally excreted and is not recommended if estimated GFR is <20 ml/min/1.73 m2. In a dosing study, patients with ACS who were randomised to enoxaparin or varying doses of fondaparinux showed no relation of clinical endpoints with different fondaparinux dosing regimens leading to the establishment of the lowest dose – 2.5 mg.44

In patients presenting with STE-ACS, the Assessment of the Safety and Efficacy of a New Thrombolytic 3 (ASSENT 3) trial compared outcomes of 6095 patients thrombolysed with tenecteplase receiving empirical enoxaparin versus UFH.32 Despite increased bleeding rates, the net clinical benefit favoured enoxaparin as rates of in-hospital recurrent ischaemic events were significantly lower in patients receiving enoxaparin up to a maximum of 7 days. Pre-hospital use of the same dose of enoxaparin in the ASSENT-3 PLUS trial was associated with a significant increase in rates of intracranial bleeding in elderly patients.33

In the Arixtra Study in Percutaneous Coronary Intervention: a Randomized Evaluation (ASPIRE) trial, 350 patients undergoing PCI were randomised to receive either fondaparinux (2.5 mg or 5 mg) or UFH.45 There was no significant difference in rates of bleeding between the two groups (6.4 % versus 7.7 %; p=0.61), but significantly fewer bleeding events were noted when the lower dose (2.5 mg) of fondaparinux was used.

In the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction Study 25 (ExTRACT–TIMI 25) trial lower doses of enoxaparin (0.75 mg/kg twice daily) in patients aged >75 years and those with significant renal impairment demonstrated lower rates of MI and death at 30 days compared with UFH (intravenous bolus of 60 U/kg of body weight followed by an infusion of 12 U/kg/h). Although rates of non-intracranial bleeding were significantly increased with enoxaparin, the net benefit favoured enoxaparin.34,35

An analysis of 20,078 patients demonstrated non-inferiority of fondaparinux compared with enoxaparin with respect to ischaemic events in NSTE-ACS in the fifth Organization to Assess Strategies in Acute Ischaemic Syndromes (OASIS-5) study.46 The use of fondaparinux in this trial resulted in a substantial reduction in 30-day and 6-month mortality rates. In-hospital major bleeding rate was approximately half of that of the enoxaparin arm. The rate of major bleeding events at 9 days in patients who had PCI was significantly lower in those treated with fondaparinux compared with enoxaparin.47. This was independent

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Coronary of the timing of the intervention in relation to the last dose of anticoagulation administered. Catheter-related thrombosis occurred more frequently in patients pre-treated with fondaparinux leading to a recommendation to give a bolus of UFH at the time of PCI. The findings from the OASIS trial were replicated in a real-world Scandinavian registry analysing 40,616 patients and showing reduced rates of bleeding and in-hospital death in patients treated with fondaparinux for NSTE-ACS when compared with LMWH.48 The use of fondaparinux in the context of primary PCI was associated with potential harm in the OASIS 6 trial and is therefore not recommended.23,49 In this trial, STEMI patients receiving streptokinase, rates of recurrent MI and death were significantly reduced in patients receiving fondaparinux compared with those treated with UFH or placebo.49,50 Due to its efficacy and safety profile, the ESC recommends the use of subcutaneous fondaparinux at a dose of 2.5 mg once daily in patients presenting with NSTE-ACS regardless of the planned management strategy unless coronary angiography is imminent.4,48 In patients managed for NSTE-ACS with fondaparinux a bolus of UFH is recommended at the time of PCI to reduce the risk of catheter-related thrombosis.22,51

Bivalirudin Bivalirudin is a synthetic congener of naturally occurring hirudine, with a high affinity for thrombin in its clot-adherent and circulating form, thereby preventing the conversion of fibrinogen to fibrin. The bivalirudin–thrombin bonds can be gradually cleaved by thrombin itself making bivalirudin’s actions reversible. It has a short half-life of 25 minutes. Bivalirudin’s anticoagulant effect is predictable as it does not bind plasma proteins and monitoring can be done using APTT or ACT measurements. No association between bivalirudin and HIT has been found. Outcomes for bivalirudin (0.75 mg/kg followed by 1.75 mg/kg/h during the intervention) plus GPIIb/IIIa was compared with UFH plus GPIIb/IIIa inhibitor in patients undergoing elective or urgent PCI in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events 2 (REPLACE-2) trial. 52 Although there were no differences in the overall primary composite endpoint of death, MI, urgent repeat revascularisation and in-hospital major bleeding at 30 days, analysis of the individual components revealed a significant reduction in the rates of in-hospital major and minor bleeding in the bivalirudin arm. The use of bivalirudin was tested in 13,819 patients presenting with moderate-to high-risk NSTE-ACS planned for an invasive strategy in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial.53 Patients were randomised to receive one of three treatments: UFH or LMWH plus GPIIb/IIIa inhibitor, bivalirudin plus GPIIb/IIIa inhibitor or bivalirudin with bailout use of GPIIb/IIIa inhibitor. Those receiving bivalirudin were given a dose of 0.1 mg/kg IV bolus, followed by an infusion of 0.25 mg/kg/h. If patients underwent PCI, a further IV bolus of 0.5 mg/kg bivalirudin was given and the infusion dose was increased to 1.75 mg/kg/h prior to PCI and stopped at the end of the procedure. There was no significant difference in the rates of the composite endpoint of death, MI or unplanned revascularisation for ischaemia at 30 days between the two groups. The use of bivalirudin with GPIIb/IIIa inhibitor as a bailout strategy was also shown to be noninferior compared with the combination of UFH/LMWH and a GPIIb/IIIa

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inhibitor. However, ischaemic events were significantly more common in bivalirudin-treated patients if they had not received pre-treatment with clopidogrel.54,55 A sub-study of the ACUITY trial assessed outcomes when patients were switched from UFH or LMWH to bivalirudin monotherapy at the time of PCI against those who received consistent UFH or LMWH.56 Death, MI and unplanned revascularisation rates were similar between the two groups, but there was significantly less major bleeding (2.8 % vs. 5.8 %, p<0.01) and an improvement in the net clinical benefit (defined as major adverse cardiovascular events plus bleeding) in patients who switched to bivalirudin. Qualitatively, similar observations were made in the Intracoronary Stenting and Anti-thrombotic Regimen– Rapid Early Action for Coronary Treatment (ISAR-REACT) 4 study. In patients presenting with NSTE-ACS undergoing PCI a significant reduction in bleeding was seen in patients treated with bivalirudin versus abciximab and UFH without a significant difference in death, recurrent MI or urgent target vessel revascularisation.57 A direct comparison of bivalirudin versus UFH in stable coronary artery disease was carried out in the ISAR-REACT 3 study.58 In 4,750 patients undergoing PCI for biomarker-negative NSTE-ACS, rates of death, MI and revascularisation at 30 days were similar between the two groups. A significant reduction in the rate of bleeding events was noted in the bivalirudin arm. The ESC recommends bivalirudin as an alternative to UFH plus GPIIb/ IIIa inhibitors in patients presenting with NSTE-ACS undergoing early invasive revascularisation, particularly if bleeding risks are high.4 Bivalirudin use following streptokinase has been demonstrated to significantly reduce rates of recurrent MI, but had no impact on mortality rates compared with UFH.59 An increase in bleeding rates was noted in the bivalirudin arm, but this was not significant. In the Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) trial, 7,213 patients presenting with an ACS and planned for PCI were randomly assigned to receive either a bivalirudin infusion post PCI or UFH.60 Major adverse cardiac event and net adverse clinical events rates were not significantly different between the groups. In the How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT-PPCI) trial, 1,812 patients presenting with STE-ACS either received bivalirudin of heparin following randomisation.61 Rates of major adverse ischaemic events in the setting of PPCI were significantly lower in the heparin group without an increase in bleeding rates. In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, 3,602 patients presenting within 12 hours of STE-ACS onset were randomised to receive either UFH plus GPIIb/IIIa inhibitor or bivalirudin. 62 Rates of major bleeding, death and all-cause death were significantly reduced in patients receiving bivalirudin. An increase in rates of acute stent thrombosis was noted in the bivalirudin group, but this effect disappeared by 30 days. ESC guidelines for STEMI recommend bivalirudin with bailout GPIIb/IIIa inhibitors over UFH plus GPIIb/IIIa inhibitors.23 An antithrombin agent

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Anticoagulant Therapy for ACS should be given to patients presenting within 12 hours of symptom onset that have not been given reperfusion therapy.

therapy, was associated with a dose-dependent increase in bleeding events and significantly reduced coagulation activity in patients with a recent MI.

New anticoagulant agents Newer anticoagulants in the setting of ACS mostly target secondary prevention rather than the initial phase of the disease. These include anti-Xa therapies (apixaban, rivaroxaban, otamixaban) and the direct thrombin inhibitor dabigatran. Phase III trials with anti-Xa drugs (apixaban and rivaroxaban) have shown a dose-related increase in the rate of bleeding when added to standard dual antiplatelet therapy. There was a trend towards a reduction in ischaemic events seen in patients treated with aspirin only. The Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2 trial) was stopped prematurely due to excessive bleeding with the apixaban regimen.63 Significantly lower rates of cardiovascular death were seen in patients with ACS established on aspirin and clopidogrel who were given low-dose rivaroxaban over placebo in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) study.64 This has led to the recommendation that the use of rivaroxaban 2.5 mg twice daily might be considered in combination with aspirin and clopidogrel if ticagrelor and prasugrel are not available for patients with NSTEMI who have high ischaemic and low bleeding risks. Dabigatran was investigated in a Phase II dose-finding trial (Randomized Dabigatran Etexilate Dose Finding Study In Patients with Acute Coronary Syndromes Post Index Event With Additional Risk Factors For Cardiovascular Complications Also Receiving Aspirin And Clopidogrel [RE-DEEM]).65 Dabigatran, in addition to dual antiplatelet

J ernberg T, Hasvold P, Henriksson M, et al. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J 2015;36:1163–70. DOI: 10.1093/eurheartj/ehu505; PMID: 25586123. 2. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992;326:310–8. DOI: 10.1056/NEJM199201303260506; PMID: 1728735. 3. De Caterina R, Goto S. Targeting thrombin long-term after an acute coronary syndrome: opportunities and challenges. Vasc Pharmacol 2016 81:1–14. DOI: 10.1016/j.vph.2016.03.003; PMID: 26994821. 4. Roffi M, Patrono C, Collet JP, Mueller C, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267–315. DOI: 10.1093/eurheartj/ehv320; PMID: 26320110. 5. Arbustini E, Dal Bello P, Morbini P, et al. Plaque erosion is a major substrate for coronary thrombosis in acute myocardial infarction. Heart 1999;82:269–72. DOI: 10.1136/hrt.82.3.269; PMID: 10455073. 6. Davies MJ. The pathophysiology of acute coronary syndromes. Heart 2000;83:361–6. DOI: 10.1136/heart.83.3.361; PMID: 10677422. 7. Lewis HD, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Engl J Med 1983;309:396–403. DOI: 10.1056/NEJM198308183090703; PMID: 6135989. 8. Théroux P, Ouimet H, McCans J, et al. Aspirin, heparin or both to treat unstable angina. N Engl J Med 1988;319:1105–11. DOI: 10.1056/NEJM198810273191701; PMID: 3050522. 9. Cohen M, Demers C, Gurfinkel EP, et al. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. A comparison of low-molecularweight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447–52. DOI: 10.1056/NEJM199708143370702; PMID: 9250846. 10. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in

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A Phase III trial of the intravenous anti-Xa drug otamixaban did not reduce ischaemic event rates, but significantly increased bleeding rates when compared with UFH plus eptifibatide.66 These findings did not support the use of otamixaban for patients with NSTE-ACS undergoing planned early PCI.

Conclusion The use of anticoagulant therapy is an essential adjunct to antiplatelet therapy in the acute treatment of ACS, and is limited to treatment during initial hospitalisation and revascularisation. Large, randomised clinical trials have shown the benefit of fondaparinux as a safer (with similar efficacy) alternative to either LMWH or UFH and it is the anticoagulant of choice on admission. Once a decision is made for invasive management then either UFH or LMWH must be given during catheterisation to prevent formation of thrombus during the procedure. The role of bivalirudin in ACS has been controversial. It is an effective, but expensive drug with a short half-life; however, recent data showing an increase in acute stent thrombosis have largely negated the reduction seen in major bleeding rates. A patient-centred approach is required to balance ischaemic and bleeding risk and it would appear that this can be successfully achieved with a choice of antiplatelet agents of differing potency and anticoagulants limited to fondaparinux and low dose heparins. At the time of writing, the newer direct anti-Xa and direct thrombin inhibitors lack the data to recommend routine use in ACS patients but may have a role in ACS patients presenting with persistent atrial fibrillation. n

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65.

66.

blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–63. DOI: 10.1001/jama.289.7.853; PMID: 12588269. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203–16. DOI: 10.1056/NEJMoa062437; PMID: 17124018. Stone GW, White HD, Ohman EM, et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial. Lancet 2007;369:907–19. DOI: 10.1016/S0140-6736(07)60450-4; PMID: 17368152. Stone GW, Ware JH, Bertrand ME, et al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial. JAMA 2007;298:2497–506. DOI: 10.1001/jama.298.21.2497; PMID: 18056903. White HD, Chew DP, Hoekstra JW, et al. Safety and efficacy of switching from either unfractionated heparin or enoxaparin to bivalirudin in patients with non-ST-segment elevation acute coronary syndromes managed with an invasive strategy: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol 2008;51:1734–41. DOI: 10.1016/j.jacc.2007.12.052; PMID: 18452778. Kastrati A, Neumann FJ, Schulz S, et al. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med 2011;365:1980–9. DOI: 10.1056/NEJMoa1109596; PMID: 22077909. Kastrati A, Neumann FJ, Mehilli J, et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008;359:688–96. DOI: 10.1056/NEJMoa0802944; PMID: 18703471. White H. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet 2001;358:1855–63. DOI: 10.1016/S0140-6736(01)06887-8; PMID: 11741625. Valgimigli M, Frigoli E, Leonardi S, et al. Bivalirudin or unfractionated heparin in acute coronary syndromes. N Engl J Med 2015;373:997–1009. DOI: 10.1056/NEJMoa1507854; PMID: 26324049. Shahzad A, Kemp E, Mars C, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014;384:1849–58. DOI: 10.1016/S0140-6736(14)60924-7; PMID: 25002178. Stone G, Clayton T, Deliargyris E, et al. Reduction in cardiac mortality with bivalirudin in patients with and without major bleeding: The HORIZONS-AMI Trial (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction). J Am Coll Cardiol 2014;63:15–20. DOI: 10.1016/j.jacc.2013.09.027. PMID: 24140664. Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699–708. DOI: 10.1056/NEJMoa1105819; PMID: 21780946. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9–19. DOI: 10.1056/NEJMoa1112277; PMID: 22077192. Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011;32:2781–9. DOI: 10.1093/eurheartj/ehr113; PMID: 21551462. Steg PG, Mehta SR, Pollack CV Jr, et al. Anticoagulation with otamixaban and ischemic events in non-ST-segment elevation acute coronary syndromes: the TAO randomized clinical trial. JAMA 2013;310:1145–55. DOI: 10.1001/jama.2013.277165; PMID: 23995608.

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Coronary

Non-vitamin K Antagonist Oral Anticoagulant After Acute Coronary Syndrome: Is There a Role? Paul Guedeney, 1,2 Birgit Vogel 1 and Roxana Mehran 1 1. Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USA; 2. Department of Cardiology, Sorbonne University, ACTION Study Group, INSERM UMRS 1166, Cardiology Institute, Pitie-Salpetriere Hospital, Paris, France

Abstract Despite dual antiplatelet therapy (DAPT) including potent P2Y12 inhibitors, recurrent ischaemic events occur in a significant number of patients after acute coronary syndrome (ACS), warranting new antithrombotic strategies. Combinations of non-vitamin K antagonist oral anticoagulant (NOAC) with antiplatelet therapy have been tested in several large phases II and III randomised trials. Overall, current evidence suggests that the use of NOACs on top of DAPT after ACS reduces the rate of recurrent ischaemic events, albeit at the price of increased risk for major bleeding. In the particular field of patients with ACS and atrial fibrillation, NOACs may be associated with reduced bleeding complications compared with vitamin K antagonist. Further randomised trials evaluating low-dose NOAC combined with single antiplatelet therapy are warranted.

Keywords Acute coronary syndrome, anticoagulation, apixaban, dabigatran, NOACs, rivaroxaban, vitamin K antagonist Disclosure: RM declare fees for serving on a data and safety monitoring board from Watermark Research Partners, fees for serving on executive committees from Janssen Pharmaceuticals and Osprey Medical, consulting fees from AstraZeneca, the Medicines Company, Medscape, Boston Scientific, Merck & Company, Cardiovascular Systems, Inc. (CSI), Sanofi, and Shanghai BraccoSine Pharmaceutical Corporation, and grant support to her institution from Eli Lilly/ Daiichi-Sankyo, Bristol-Myers Squibb, AstraZeneca, the Medicines Company, OrbusNeich, Bayer, CSL Behring, Abbott Laboratories, Watermark Research Partners, Novartis Pharmaceuticals, Medtronic, and AUM Cardiovascular. GP and BV have no conflicts of interest to declare. Received: 16 March 2018 Accepted: 19 April 2018 Citation: Interventional Cardiology Review 2018;13(2):93–8. DOI: https://doi.org/10.15420/icr.2018:5:2 Correspondence: Roxana Mehran, MD, The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1030, New York, NY 10029, USA. E: Roxana.Mehran@mountsinai.org

Dual antiplatelet therapy (DAPT) including aspirin and a P2Y12 inhibitor is the current gold standard for the treatment and mid-term secondary prevention of acute coronary syndrome (ACS).1–4 However, despite the use of potent P2Y12 inhibitors such as ticagrelor or prasugrel, patients remain at high ischaemic risk after ACS. More specifically, in the prasugrel treatment arm of the TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel – Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38 trial,5 the rate of the combined endpoint of cardiovascular (CV) death, non-fatal MI or urgent target-vessel revascularisation was 9.9 % within 15 months. In the PLATelet Inhibition and Patient Outcomes (PLATO) trial,6 the rate of the composite of CV death, MI, stroke, severe or not recurrent ischaemia, transient ischaemic attack or other arterial thrombotic events in the ticagrelor arm was 14.6 % within 12 months. Hence, there is clearly room for improvement and reduction of ischaemic events after ACS.

Rationale for Adding an Oral Anticoagulant to Post-ACS Treatment The underlying mechanism of an acute ischaemic event is mostly intracoronary thrombus formation on the basis of an atherosclerotic plaque, leading to a more-or-less complete obstruction of the coronary vessel and resulting in myocardial cell injury or death.7 The rupture or erosion8–10 of the fibrous cap of an atherosclerotic coronary plaque exposes the highly thrombotic necrotic core to the circulating blood triggering pathways, leading to activation of platelets and

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the coagulation cascade.11,12 Hence, both antiplatelet agents and anticoagulants are effective and recommended in the acute treatment of ACS until revascularisation is achieved.1–3 However, coagulation may remain activated even after the acute phase, resulting in adverse outcomes.13 Therefore, administration of anticoagulants in addition to antiplatelet agents may be an attractive strategy to further reduce recurrent ischaemic events on a long-term basis.

Treatment Strategies Including a Vitamin K Antagonist Early studies investigated the safety and efficacy of an anticoagulant strategy with a vitamin K antagonist (VKA) and aspirin compared with an antiplatelet-only strategy in the setting of secondary prevention after ACS. In a randomised control trial (RCT) including 257 patients after successful coronary stenting, Schömig et al. demonstrated that DAPT (then with ticlopidin and aspirin) was associated with a reduced rate of haemorrhagic and vascular complications within 30 days of successful stenting compared with aspirin and VKA.14 In keeping with these findings, another RCT showed a lower rate of stent thrombosis associated with DAPT compared with aspirin plus warfarin after stent placement.15 More recently, a meta-analysis of 25,307 patients from 14 randomised trials compared VKA plus aspirin with aspirin alone in patients after ST-segment elevation MI (STEMI) or non-ST segment elevation (NSTE)-ACS. Overall, risk of major bleeding was increased with VKA plus aspirin (OR 1.77; 95 % CI [1.47–2.13]; p<0.001) without significant difference in ischaemic events.16

Access at: www.ICRjournal.com

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Coronary Table 1: Pharmacological Characteristic of Commercially Approved NOACs Compared with Warfarin Drug

Target

Prodrug

Bioavailability (%)

Dosing

Half-life

Elimination

Interaction

(hours)

Biological

Antidote

monitoring required

Vitamin K-antagonist Warfarin

Synthesis of factor II, VII, IX and X and protein S and C

100

Once daily

35–45

Hepatic metabolism

CYP450 isozymes: CYP2C9, 2C19, 2C8, 2C18, 1A2, 3A4; antibiotics and antifungals; botanical products and food

Yes

Commercially available: vitamin K; prothrombin complex concentrate

Dabigatran

Thrombin

Yes

3–7

Twice daily

12–17

80 % of kidney excretion

P-glycoprotein inhibitor or inducers

Commercially available: Idarucizumab

Rivaroxaban

Factor Xa

66–100

Once or twice daily

7–11

33 % of kidney excretion

P-glycoprotein inhibitor or inducers

Apixaban

Factor Xa

Twice daily

27 % of renal excretion

P-glycoprotein inhibitor or inducers

Edoxaban

Factor Xa

Twice daily

9–11

27 % of renal excretion

P-glycoprotein inhibitor or inducers

NOAC

No antidote commercially available

NOAC = non-vitamin K antagonist oral anticoagulant.

Treatment Strategies Including Non-vitamin K Oral Anticoagulants Non-vitamin K oral anticoagulants (NOACs) are direct anticoagulant agents with more favourable pharmacological properties than VKA,17 as detailed in Table 1. One of the main limitation of the use of NOACs may be the limited access to an antidote for effect reversal, compared with VKA. A antibody fragment, idarucizumab, recently received US Food and Drug Administration approval to reverse the anticoagulant effect of dabigatran, a thrombin inhibitor, in cases of life-threatening bleeding or urgent surgical procedure.18 There is currently no commercially available antidote for direct factor-Xa inhibitors, such as apixaban, rivaroxaban or edoxaban. Andexanet alfa, a recombinant modified human factor Xa decoy, was recently tested in a small phase III study and will require further investigations.19 Notwithstanding this limitation, in randomised trials and real-world registries, NOACs demonstrated an overall safer profile than VKA, with reduced rates of major bleeding and/or intracranial haemorrhage when used to prevent thromboembolic complication of AF.20–24 Recent phase II and III trials have investigated the potential benefits of NOACs in combination with single or dual antiplatelet therapy in patients after ACS (Table 2).

Dabigatran The RandomizEd Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel: Multi-centre, Prospective, Placebo Controlled, Cohort Dose Escalation Study (RE-DEEM) trial was a phase II trial that investigated dabigatran in the setting of ACS.25 In this study, 1,878 high-risk patients were randomised within 14 days after an ACS to receive either dabigatran (50 mg, 75 mg, 110 mg or 150 mg twice daily) or placebo as

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well as DAPT with aspirin and clopidogrel. The primary endpoint was the composite of major or clinically relevant minor bleeding at 6 months after randomisation. There was a dose-dependent increase in the rate of the primary outcome, with a hazard ratio (HR) of 1.77 (95 % CI [0.7–4.5]) for 50 mg twice daily; HR 2.17 (95 % CI [0.88–5.31]) for 75 mg twice daily; HR 3.92 (95 % CI [1.72–8.95]) for 110 mg twice daily and HR 4.27 (95 % CI [1.86–9.81]) for 150 mg twice daily. The rates of cardiovascular death, MI and stroke were lower in patients receiving the two higher doses (110 mg and 150 mg) compared with patients receiving the two lower dabigatran doses (50 mg and 75 mg).

Apixaban The APixaban for Prevention of Acute Ischaemic Events (APPRAISE) trial was a phase II randomised, placebo-controlled study evaluating apixaban at different dosages (2.5 mg twice daily, 10 mg once daily, 10 mg twice daily or 20 mg once daily) among 1,715 high-risk patients enrolled within 7 days of an ACS. All patients received aspirin and 76 % received additional clopidogrel.26 A dose-dependent increase in International Society of Thrombosis and Haemostasis (ISTH) major bleeding or clinically relevant non-major bleeding was observed within 6 months with apixaban 2.5 mg twice daily (5.7 %; 95 % CI [3.4–8.9]) and 10 mg once daily (7.9 %; 95 % CI [5.2–11.5]) compared with placebo (3.0 %; 95 % CI [1.8–4.7]). Of note, enrolment was prematurely interrupted for the two highest doses (10 mg twice daily and 20 mg once daily) due to high rates of relevant bleeding. The composite efficacy endpoint of CV death, MI, severe recurrent ischaemia and stroke was lower with apixaban 2.5 mg twice daily and apixaban 10 mg once daily compared with placebo. Following these results, the APPRAISE-2 phase III randomised, placebocontrolled trial was performed to investigate apixaban 5 mg twice daily in addition to DAPT among high-risk patients enrolled within 7 days of

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NOACs After ACS: Is There a Role? Table 2: Main Randomised Trials Evaluating NOAC After ACS in Patient without Chronic Indication for Oral Anticoagulation Trial

NOAC

Study

Dosage

phase

Number of patients

Population main

% of DAPT

% of STEMI/

characteristics

prescription

NSTEMI/UA

(% of the

Follow-up

Impact of main safety outcome HR (95 % CI)

population) RE-DEEM25

Dabigatran

50 mg/75 mg/ 110 mg/150 mg twice daily

1,861 patients 60 % /40 %/none

44.1 % with age ≥ 65 years 31.3 % with diabetes mellitus Severe stroke within 6 months was an exclusion criterion

99.2 %

6 months

50 mg: 1.77 (0.7–4.5) 75 mg: 2.17 (0.88–5.31) 110 mg: 3.92 (1.72–8.95) 150 mg: 4.27 (1.86–9.81)

APPRAISE 126

Apixaban

2.5 mg or 10 mg twice daily or 10 mg or 20 mg once daily

1,715 patients 62.4 %/29.4 %/8 %

12.4 % with age ≥75 years 22.5 % with diabetes mellitus 4.3 % with prior cerebrovascular disease 30.4 % with CKD

75.9 %

6 months

2.5 mg: 1.78 (0.91–3.48) 10 mg once daily: 2.45 (1.31–4.61) Premature interruption of other dosages for safety issue

APPRAISE 227

III

5 mg twice daily

7,392 patients 39.6 %/41.6 %/18.8 %

58.9 % with age ≥ 65 years 47.8 % with diabetes mellitus 10 % with prior cerebrovascular disease 28.9 % with prior CKD

81 %

15 months

2.59 (1.5–4.46)

ATLAS ACSTIMI 4628

5 mg or 10 mg or 15 mg or 20 mg once daily or same total twice daily

3,491 patients 52.2 %/29.8 %/18 %

Mean age around 57.4 years 19.3 % with diabetes mellitus

Stratum 1: none Stratum 2: 100 %

6 months

5 mg: 2.1 (1.25–3.91) 10 mg: 3.35 (2.31–4.87) 15 mg: 3.6 (2.32–5.58) 20 mg: 5.06 (3.45–7.42)

III

2.5 mg or 5 mg twice daily

15526 patients 50.4 %/25.6 %/24 %

36.5 % with age ≥ 65 years 9 % with age ≥ 75 years 32 % with diabetes mellitus Prior stroke within 6 months was an exclusion criterion

Thienopyridine prescribed with 92.8 % of the patients

13 months

2.5 mg: 3.46 (2.08–5.77) 5 mg: 4.47 (2.71–7.36)

2.5 mg twice daily

3037 patients 49 %/40 %/11 %

42 % with age ≥ 65 years 30 % with diabetes mellitus

No DAPT prescription in the rivaroxaban arm

12 months

1.09 (0.8–1.5)

ATLAS ACS 2-TIMI 5129

Rivaroxaban

GEMINI30

ACS = acute coronary syndrome; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; HR = hazard ratio; NOAC = non-vitamin K antagonist oral anticoagulant; NSTEMI = non-ST-segment elevation MI; STEMI = ST-segment elevation MI; UA = unstable angina.

an ACS.27 After recruitment of 7,392 patients out of the 10,800 initially planned, the trial was stopped prematurely because of a significant increase in the rate of thrombolysis in myocardial infarction (TIMI) major bleeding with apixaban compared with placebo (HR 2.59; 95 % CI [1.5–4.46]; p=0.001) without significant differences in the rates of CV death, MI or stroke.

Rivaroxaban Rivaroxaban was investigated in the setting of ACS within the phase II Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard

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Therapy in Subjects with Acute Coronary Syndromes – Thrombolysis In Myocardial Infarction (ATLAS ACS-TIMI) 46 trial.28 In total, 3,491 patients were enrolled within 7 days of an ACS and stratified into the aspirin only (stratum 1, n=761 patients) or DAPT (stratum 2, n=2,730) groups. In a second step, patients were randomised to receive either placebo or rivaroxaban (5 mg, 10 mg, 15 mg or 20 mg once daily). The risk of clinically significant bleeding associated with rivaroxaban compared with placebo increased in a dose-dependent manner (HR 2.21, 95 % CI [1.25–3.91] for 5 mg; HR 3.35, 95 % CI [2.31–4.87] for 10 mg; HR 3.6, 95 % CI [2.32–5.58] for 15 mg; and HR 5.06, 95 % CI [3.45–7.42] for 20 mg

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Coronary Figure 1: Summary of Benefits and Limitations of the Different Antithrombotic Regimen including NOACs after ACS

Without concomitant Atrial fibrillation

ACUTE CORONARY SYNDROME

NOACs full-dose + DAPT

Dabigatran: RE-DEEM Apixaban: APPRAISE 1-2 Rivaroxaban: ATLAS 1

Increase of bleeding risk Possible reduction of ischemic events*

NOACs low-dose + DAPT

Dabigatran: RE-DEEM Apixaban: APPRAISE 1-2 Rivaroxaban: ATLAS 1-2

Increase of bleeding risk Possible reduction of ischemic events*

NOACs low-dose + SAPT

Rivaroxaban: GEMINI 1

No increase in bleeding risk Effect on ischemic event to be determined

NOACs low-dose + DAPT

Rivaroxaban: PIONEER†

Reduction of bleeding risk No difference on ischemic event

NOACs low-dose + SAPT

Dabigatran: RE-DUAL‡ Rivaroxaban: PIONEER†

Reduction of bleeding risk No difference on ischemic event

With concomitant Atrial fibrillation

ACS = acute coronary syndrome; DAPT = dual antiplatelet therapy; NOACs = non-vitamin K antagonist oral anticoagulants; SAPT = single antiplatelet therapy. *With rivaroxaban in the ATLAS trials. †51.6 % of the randomised population presented an acute coronary syndrome as index event. ‡50.5 % of the randomised population presented an acute coronary syndrome as index event.

doses; p<0.001). With regard to ischaemic events, rivaroxaban reduced the risk for the main secondary efficacy endpoint (a composite of death, MI and stroke) compared with placebo (3.9 % versus 5.5 %; HR 0.69, 95 % CI [0.5–0.96], p=0.027). These encouraging results led to the initiation of the ATLAS-ACS 2-TIMI 51 trial, a phase III study, that enrolled 15,526 patients with recent ACS, randomising them to either rivaroxaban (2.5 mg or 5 mg twice daily) or placebo.29 In ~93 % of patients, background therapy included a thienopyridine in addition to aspirin. After a mean treatment period of 13.1 months, rivaroxaban (both doses combined) significantly reduced the rate of the composite of CV death, MI and stroke compared with placebo (8.9 % versus 10.7 %; HR 0.84, 95 % CI [0.74–0.96], p=0.008). While the twice-daily 2.5 mg dose of rivaroxaban reduced the rates of CV death (2.7 % versus 4.1 %, p=0.002) and all-cause death (2.9 % versus 4.5 %, p=0.002), rivaroxaban 5 mg twice daily did not show any survival benefit compared with placebo. Rates of major bleeding were increased with 2.1 % versus 0.6 % for rivaroxaban compared with placebo (p<0.001). While the rate of intracranial haemorrhage was increased (0.6 % versus 0.2 %, p=0.009), there was no significant difference with regard to fatal bleeding (0.3 % versus 0.2 %, p=0.66). The discrepancy between the results of the APPRAISE-2 and ATLAS 2-TIMI 51 trials may be explained by a higher-risk profile of patients enrolled in the former compared with the latter (Table 2). Indeed, patients from the APPRAISE-2 trial were older and had more frequent diabetes or chronic kidney disease. In ATLAS ACS 2-TIMI 51, prior stroke was an exclusion criterion in patients on DAPT, while approximately 10 % of the APPRAISE-2 study population had a history of cerebrovascular disease. Finally, the dose of apixaban tested in APPRAISE-2 was the same as the one used for thromboembolic prevention of AF, while in ATLAS 2-TIMI 51, relatively lower doses of rivaroxaban were tested. A lower dose of rivaroxaban in combination with a single antiplatelet therapy was also used in the Study to Compare the Safety of Rivaroxaban

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Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome (GEMINI-ACS) 1 trial.30 In this phase II study, 3,037 patients with recent ACS were randomised to receive either rivaroxaban 2.5 mg twice daily or aspirin 100 mg once daily. The randomisation was stratified by the background therapy of either clopidogrel (43.9 % of the patients) or ticagrelor (56.1 % of the patients), which was at the discretion of the treating physician. At a median treatment duration of 291 (range 239–354) days, there was no difference in terms of TIMI clinically significant bleeding between the rivaroxaban and the aspirin group (HR 1.09; 95 % CI [0.8–1.5], p=0.584). The GEMINI-ACS trial demonstrated that the association of NOAC and single antiplatelet therapy was safe after ACS. However, this trial was not powered to show any meaningful differences in ischaemic events between treatment groups. The results of the GEMINI trial were confirmed by a recent meta-analysis of seven randomised trials including 31,574 patients, which showed that the addition of NOACs to a single antiplatelet therapy did not increase the rate of clinically significant bleeding.31 Of note, there was no significant reduction of ischaemic events with this combination. Another meta-analysis looked at the effect of NOAC plus antiplatelet therapy in accordance to baseline clinical presentation in patients with ACS.32 While this treatment strategy was not associated with any benefit in NSTE-ACS patients, it was associated in STEMI patients with a decreased risk of ischaemic events. This analysis suggests that a combination of NOACs plus antiplatelet therapy is an attractive option only in patients with high thrombotic risk, in line with the recent results of the Cardiovascular OutcoMes for People Using Anticoagulation StrategieS (COMPASS) trial on high-risk patients with stable atherosclerotic vascular disease.33 Of note, bleeding risk was increased with adding NOACs to antiplatelet therapy compared with antiplatelet therapy alone in both NSTE-ACS and STEMI patients.

NOACs After ACS Among Patients with Atrial Fibrillation AF has been reported to occur in up to 21 % of ACS patients.34–36 This particular population constitutes a challenge in terms of prevention

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NOACs After ACS: Is There a Role? of ischaemic events. While DAPT is superior to VKA with respect to the prevention of coronary thrombosis,14,15 VKAs are superior to DAPT regarding the prevention of thromboembolic complications associated with AF.37 Hence, these patients are frequently treated with a triple therapy, including an oral anticoagulant and DAPT,38 which is associated with increased rates of major haemorrhage.39,40 Combinations including NOACs and antiplatelets may reduce the risk of bleeding compared with triple therapy including a VKA. In the Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) trial, triple therapy with DAPT plus VKA was compared with two other regimens: rivaroxaban 2.5 mg twice daily plus DAPT for 1 to 12 months; or rivaroxaban 15 mg once daily plus a P2Y12 inhibitor for 12 months.41 The initial presentation was ACS in 51.6 % of patients. At 12 months, rates of clinically significant bleeding were significantly lower in the two groups receiving rivaroxaban compared with standard therapy, with similar rates of ischaemic events. A similar concept was tested with dabigatran in the Randomised Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (RE-DUAL PCI) trial.42 The gold standard association of DAPT and VKA was compared with the association of a P2Y12 inhibitor (overwhelmingly clopidogrel) and dabigatran, either 110 mg or 150 mg twice daily. With an ACS for index event for 50.5 % of the population and after a mean follow-up of 14 months, both doses of dabigatran were associated with an improvement in term of ISTH major or clinically

indecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS W 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. 2. 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;37:267–315. https://doi.org/10.1093/eurheartj/ehv320; PMID: 26320110. 3. Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the Management of Acute Myocardial Infarction in Patients Presenting with ST-segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–77. https://doi.org/10.1093/eurheartj/ehx393; PMID: 28886621. 4. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082–115. https://doi.org/10.1016/j.jacc.2016.03.513; PMID: 27036918. 5. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–15. https://doi.org/10.1056/ NEJMoa0706482; PMID: 17982182. 6. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. https://doi.org/10.1056/ NEJMoa0904327; PMID: 19717846. 7. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013;368:2004–13. https://doi.org/10.1056/NEJMra1216063; PMID: 23697515. 8. Fuster V, Moreno PR, Fayad ZA, et al. Atherothrombosis and high-risk plaque: part I: evolving concepts. J Am Coll Cardiol 2005;46:937–54. https://doi.org/10.1016/j.jacc.2005.03.074; PMID: 16168274. 9. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–95. https://doi. org/10.1056/NEJMra043430; PMID: 15843671. 10. Lippi G, Franchini M, Targher G. Arterial thrombus formation in

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11.

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20.

21.

relevant bleeding (for 110 mg twice daily HR 0.52, 95 % CI [0.42–0.63], p<0.001; for 150 mg twice daily HR 0.72, 95 % CI [0.58–0.88], p=0.002). The criteria of non-inferiority regarding thromboembolic events, death or unplanned revascularisation was met (HR 1.04, 95 % [CI 0.84–1.29], p=0.005 for non-inferiority for the combined dose of dabigatran). Similar trials are being performed to evaluate other NOACs agent in the setting of ACS or PCI and AF. The EdoxabaN TReatment versUS Vitamin K Antagonist in PaTients with Atrial Fibrillation undergoing Percutaneous Coronary Intervention (ENTRUST-AF-PCI) trial is testing apixaban 2.5 or 5 mg twice daily (NCT02415400) while the Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis (Blood Clots) Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart (AUGUSTUS-AF-ACS) trial is testing edoxaban 30 or 60 mg once daily (NCT02866175).

NOACs After ACS: Is There a Role? While higher doses of NOACs in combination with DAPT have been shown to be associated with decreased ischaemic events, the bleeding risk was markedly increased with these regimens compared with antiplatelet therapy alone in patients after ACS (Figure 1). Conversely, there is evidence that a strategy including lower doses of NOACs in combination with a single antiplatelet therapy may be safe. A significant reduction of ischaemic events associated with this strategy has yet to be proven. Further studies are needed to evaluate the role of NOACs after ACS and to identify the patient population that may benefit the most of such treatment. n

cardiovascular disease. Nat Rev Cardiol 2011;8:502–12. https:// doi.org/10.1038/nrcardio.2011.91; PMID: 21727917. Silvain J, Collet J-P, Nagaswami C, et al. Composition of coronary thrombus in acute myocardial infarction. J Am Coll Cardiol 2011;57:1359–67. https://doi.org/10.1016/ j.jacc.2010.09.077; PMID: 21414532. De Caterina R, Husted S, Wallentin L, et al. General mechanisms of coagulation and targets of anticoagulants (Section I). Position Paper of the ESC Working Group on Thrombosis – Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013;109:569–79. https://doi.org/10.1160/ TH12-10-0772; PMID: 23447024. Ardissino D, Merlini PA, Bauer KA, et al. Coagulation activation and long-term outcome in acute coronary syndromes. Blood 2003;102:2731–5. https://doi.org/10.1182/blood-2002-03-0954; PMID: 12843003. Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084–9. https://doi.org/10.1056/ NEJM199604253341702; PMID: 8598866. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665–71. https://doi.org/10.1056/ NEJM199812033392303; PMID: 9834303. Andreotti F, Testa L, Biondi-Zoccai GGL, et al. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur Heart J 2006;27:519–26. https://doi. org/10.1093/eurheartj/ehi485; PMID: 16143706. De Caterina R, Husted S, Wallentin L, et al. Oral anticoagulants in coronary heart disease (Section IV). Position paper of the ESC Working Group on Thrombosis – Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2016;115:685–711. https://doi. org/10.1160/TH15-09-0703; PMID: 26952877. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511–20. https://doi. org/10.1056/NEJMoa1502000; PMID: 26095746. Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016;375:1131–41. https://doi.org/10.1056/ NEJMoa1607887; PMID: 27573206. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. https://doi.org/10.1056/NEJMoa0905561; PMID: 19717844. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. https://doi.org/10.1056/NEJMoa1107039;

PMID: 21870978. 22. P atel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. https://doi.org/10.1056/NEJMoa1009638; PMID: 21830957. 23. Beyer-Westendorf J, Förster K, Pannach S, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014;124:955–62. https://doi.org/10.1182/blood-2014-03563577; PMID: 24859362. 24. Larsen TB, Skjøth F, Nielsen PB, et al. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2016;353:i3189. https://doi.org/10.1136/bmj.i3189 PMID: 27312796. 25. Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011;32:2781–9. https://doi.org/10.1093/eurheartj/ ehr113; PMID: 21551462.. 26. APPRAISE Steering Committee and Investigators, Alexander JH, Becker RC, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009;119:2877–85. https://doi.org/10.1161/ CIRCULATIONAHA.108.832139; PMID: 19470889. 27. Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699–708. https://doi.org/10.1056/ NEJMoa1105819; PMID: 21780946. 28. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29–38. https://doi.org/10.1016/S01406736(09)60738-8; PMID: 19539361. 29. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9–19. https://doi.org/10.1056/NEJMoa1112277 PMID: 22077192. 30. Ohman EM, Roe MT, Steg PG, et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet 2017;389:1799–808. https://doi.org/10.1016/S01406736(17)30751-1; PMID: 28325638. 31. Khan SU, Arshad A, Riaz IB, et al. Meta-analysis of the safety and efficacy of the oral anticoagulant agents (apixaban, rivaroxaban, dabigatran) in patients with acute

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39. V andvik PO, Lincoff AM, Gore JM, et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e637S–68S. https://doi.org/10.1378/chest.112306; PMID: 22315274. 40. Rubboli A, Faxon DP, Juhani Airaksinen KE, et al. The optimal management of patients on oral anticoagulation undergoing coronary artery stenting. The 10th anniversary overview. Thromb Haemost 2014;112:1080–7. https://doi.org/10.1160/ TH14-08-0681; PMID: 25298351. 41. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375:2423–34. https://doi.org/10.1056/NEJMoa1611594; PMID: 27959713. 42. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017;377:1513–24. https://doi.org/10.1056/ NEJMc1715183; PMID: 29385366.

INTERVENTIONAL CARDIOLOGY REVIEW

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Erratum

Erratum to: Minimally Invasive Surgical Mitral Valve Repair: State of the Art Review Karel M Van Praet, 1 Christof Stamm, 1 Simon H Sündermann, 1,2 Alexander Meyer, 1,2,3 Axel Unbehaun, 1 Matteo Montagner, 1 Timo Z Nazari Shafti, 1,2,3 Stephan Jacobs, 1 Volkmar Falk 1,2,3,4 and Jörg Kempfert 1 1. German Heart Center Berlin, Germany; 2. DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Germany; 3. Berlin Institute of Health (BIH), Germany; 4. Charité – Universitätsmedizin Berlin, Germany

Citation: Interventional Cardiology Review 2018;13(2):99. DOI: https://doi.org/10.15420/icr.2018.13.2.ER1

For the paper entitled ‘Minimally Invasive Surgical Mitral Valve Repair: State of the Art Review’, which appeared in Interventional Cardiology Review 2018;13(1):14–9, the source for Tables 1–2 and Figure 1 is shown as: ‘Courtesy of Professor Volkmar Falk; adapted from Baumgartner, et al., 2017’. The statement of source should be: ‘Baumgartner H, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017;38(36):2739–91. By permission of Oxford University Press on behalf of the European Society of Cardiology.’ The reference to the source work, and the nature of permission, were incomplete. Interventional Cardiology Review apologises for the error.

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First-in-man study of dedicated bifurcation cobalt-chromium sirolimus-eluting stent BiOSS LIM CÂŽ

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