ICR 12.2 by Radcliffe Cardiology

Interventional Cardiology Review Volume 12 • Issue 2 • Autumn 2017

Volume 12 • Issue 2 • Autumn 2017

www.ICRjournal.com

Unprotected Left Main Coronary Artery Disease: Management in the Post NOBLE and EXCEL Era Nyal Borges, Samir R Kapadia and Stephen G Ellis

Optimising Stent Deployment in Contemporary Practice: The Role of Intracoronary Imaging and Non-compliant Balloons Ashok Seth, Sajal Gupta, Vivudh Pratap Singh and Vijay Kumar

Predilatation Prior to Transcatheter Aortic Valve Implantation: Is it Still a Prerequisite? Matteo Pagnesi, Luca Baldetti, Paolo Del Sole, Antonio Mangieri, Marco B. Ancona, Damiano Regazzoli, Nicola Buzzatti, Francesco Giannini, Antonio Colombo and Azeem Latib A

Will PARTNER 2 Change My Practice? Fadi J Sawaya and Lars Søndergaard

ISSN: 1756-1477

Coronary angiogram demonstrates a severe distal SVG lesion

Positioning of FFR wire with the pressure sensor (arrow) directly distal to the second lesion

Significant malapposition of the proximal part of the stent in the left main stem

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Volume 12 • Issue 2 • Autumn 2017

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

Sameer Gafoor CardioVascular Center, Frankfurt

Gennaro Sardella 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

Mount Sinai Hospital, New York

Rigshospitalet - Copenhagen University Hospital, Copenhagen

Thomas Modine

Gregg Stone Columbia University Medical Center and New York-Presbyterian 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

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

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 Genevieve Walton • Production Jennifer Lucy • Senior Designer Tatiana Losinska Sales & Marketing Executive William Cadden • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director David Bradbury •

Editorial Contact Genevieve Walton gen.walton@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

Cover image 3D illustration of Heart, medical concept. © yodiyim | stock.adobe.com

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use 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 © 2017 All rights reserved

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ISSN: 1756–1477 • eISSN: 1756–1485

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Established: June 2006 Frequency: Bi-annual Current issue: Autumn 2017

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 bi-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, Genevieve Walton gen.walton@radcliffecardiology.com

Reprints All articles included in Interventional Cardiology Review are available as reprints. Please contact the Publishing Director, Liam O’Neill liam.oneill@radcliffecardiology.com

Editorial Expertise

Distribution and Readership

Interventional Cardiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by Section Editors and an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities in their respective fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

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

Peer Review

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

• 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.

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.

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Lisbon, Portugal

September 22-26

CIRSE 2018 featuring

SAVE THE DATE www.cirse.org

Cardiovascular and Interventional Radiological Society of Europe

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Contents

Foreword

Simon Kennon Editor-in-Chief, ICR

Coronary

Optimising Stent Deployment in Contemporary Practice: The Role of Intracoronary Imaging and Non-compliant Balloons Ashok Seth, Sajal Gupta, Vivudh Pratap Singh and Vijay Kumar

Current State of the Art in Approaches to Saphenous Vein Graft Interventions

Unprotected Left Main Coronary Artery Disease: Management in the Post NOBLE and EXCEL Era

Michael Lee and Jeremy Kong

Nyal Borges, Samir R Kapadia and Stephen G Ellis

Performing and Interpreting Fractional Flow Reserve Measurements in Clinical Practice: An Expert Consensus Document Stephan Achenbach, Tanja Rudolph, Johannes Rieber, Holger Eggebrecht, Gert Richardt, Thomas Schmitz, Nikos Werner, Florian Boenner and Helge Möllmann

110

The Proximal Optimisation Technique for Intervention of Coronary Bifurcations Angela Hoye

Structural

116

126

Will PARTNER 2 Change My Practice?

128

Safety and Efficacy of Protected Cardiac Intervention: Clinical Evidence for Sentinel Cerebral Embolic Protection

Fadi J Sawaya and Lars Søndergaard

Ulrich Schäfer

133

Guidelines for the Management of Patients with Aortic Stenosis Undergoing Noncardiac Surgery: Out of Date and Overly Prescriptive Simon Kennon and Andrew Archbold

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Foreword

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

n this issue of Interventional Cardiology Review there are three papers that demonstrate how the steady accumulation of data, not exclusively randomised data, can lead to the development of a consensus regarding particular aspects of interventional cardiology. Vein graft interventions, stent optimisation and predilation prior to TAVI are longstanding issues of concern to all cardiologists undertaking coronary and structural interventions. Michael Lee and Jeremy Kong, Ashok Seth’s group, and Matteo Pagnesi’s group, respectively, have provided excellent papers summarising the available data that has informed their approach to these issues. The treatment of left main stem disease is another frequently encountered clinical scenario that coronary interventionists have to face and Nyal Borges, Samir R Kapadia and Stephen G Ellis have usefully documented their approach to left main stem revascularisation, based on data from recent randomised controlled trials. Stephan Achenbach’s group have written a paper that comprehensively details how fractional flow reserve measurements can be reliably performed and, importantly, interpreted: a useful practical guide with tips and tricks for the use of pressure wires to assess coronary lesions. Angela Hoye completes the coronary section with an excellent paper on the why and how to perform the proximal optimisation technique. Fadi J Sawaya and Lars Søndergaard tell us how the results of the PARTNER 2 trial have affected practice in a department that has contributed to many of the seminal randomised controlled trials in the field of transcatheter aortic valve implantation. There is also now a substantial body of research assessing the value of the Sentinel cerebral protection device and Professor Schafer from the University Hospital Eppendorf, Hamburg along with Peyton Willert from Claret Medical have concisely summarised this data. Finally, Andrew Archbold and I have provided a commentary on the most recent guidelines relating to the management of patients with severe aortic stenosis who require non-cardiac surgery, and how we think the next set of guidelines should differ. n

Access at: www.ICRjournal.com

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Coronary

Expert Opinion Optimising Stent Deployment in Contemporary Practice: The Role of Intracoronary Imaging and Non-compliant Balloons Ashok Seth, Sajal Gupta, Vivudh Pratap Singh and Vijay Kumar Fortis Escorts Heart Institute, New Delhi, India

Abstract Final stent dimensions remain an important predictor of restenosis, target vessel revascularisation (TVR) and subacute stent thrombosis (ST), even in the drug-eluting stent (DES) era. Stent balloons are usually semi-compliant and thus even high-pressure inflation may not achieve uniform or optimal stent expansion. Post-dilatation with non-compliant (NC) balloons after stent deployment has been shown to enhance stent expansion and could reduce TVR and ST. Based on supporting evidence and in the absence of large prospective randomised outcome-based trials, post-dilatation with an NC balloon to achieve optimal stent expansion and maximal luminal area is a logical technical recommendation, particularly in complex lesion subsets.

Keywords post-dilatation, coronary angioplasty, stents, non-compliant balloon Disclosure: The authors have no conflicts of interest to declare. Received: 13 April 2017 Accepted: 14 June 2017 Citation: Interventional Cardiology Review 2017;12(2):81–4. DOI: 10.15420/icr.2017:12:1 Correspondence: Ashok Seth, Fortis Escorts Heart Institute, Okhla Road, New Delhi 110025, India. E: ashok.seth@fortishealthcare.com

In 1995, stent implantation became the second revolution in interventional cardiology when Colombo et al. demonstrated that intravascular ultrasound (IVUS)-guided post-dilatation of stents to achieve optimal expansion and larger lumens led to reduced restenosis and stent thrombosis (ST).1 This ‘bigger is better’ hypothesis became the technical cornerstone of all stent implantation in the bare metal stent (BMS) era. Despite numerous smaller randomised studies demonstrating superiority of IVUS over angiography in diagnosing suboptimal stent expansion and thereby resulting in improved outcomes,2 most operators – in the absence of IVUS guidance – made it a uniform practice to post-dilate stents to achieve an angiographic ‘step up and step down’ appearance. The initial hype of dramatic reduction in restenosis and target lesion revascularisation (TLR) with drug-eluting stents (DES) led to a false belief that the ‘bigger is better’ hypothesis was redundant and that post-dilatation was an unnecessary for DES. However, it was soon realised through IVUS-guided studies that one of the strongest predictors of restenosis, target vessel revascularisation (TVR) and ST – even with DES – was suboptimal stent expansion and minimal stent area (MSA).3,4 While it is clear that post-dilation with a non-compliant (NC) balloon can optimise stent expansion and achieve larger stent areas, there are no major randomised studies to prove that this translates into improved hard endpoints of major adverse cardiac events. Postdilatation could also possess inherent disadvantages and cause complications, which may outweigh its benefits. Furthermore, the current generation of stent delivery balloons are less compliant, allowing higher-pressure implantations. Hence, post-dilatation in the present DES era is variable and has been left to operator experience and discretion. Many operators deploy the stent with the implantation

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balloon to moderate pressures of 12–16 atmospheres and occasionally to higher pressures of 16–20 atmospheres. Others prefer to postdilate after moderate pressure implantation with an optimal size or quarter size larger NC balloon to 16–20 atmospheres based on angiographic guidance. A minority do this post-dilation selectively under intracoronary imaging guidance.

The Need for Post-dilatation Twenty to thirty per cent of stents are found to be under expanded on IVUS in various studies of both BMS5,6 and DES7 after standard deployment with stent balloons. Costa et al. studied second-generation BMS and found that in vivo only 3.8 % of stents achieved >90 % of the nominal stent diameters as per recommended charts and that 70 % of stents were <80 % of the nominal diameter.5 The same was also true for DES.8 Suboptimal stent implantation is the result of an interplay of multiple factors in isolation or combination. These may include stent under sizing, compliance of the balloon and deployment pressures (the compliance charts from the manufacturer are in-vitro measurements that differ from what occurs in an atherosclerosed rigid coronary artery) and plaque vessel compliance (large plaque burden, calcium or fibrosis). Suboptimal stent deployment may occur because of under sizing of the stent delivery balloon related to the target vessel. In this case even higher pressures on the semi-compliant balloon may not compensate for under sizing inside the vessel. Furthermore, pressures may not build up uniformly throughout the balloon length, especially when more outward force is needed at the area of maximal stenosis

Access at: www.ICRjournal.com

13/09/2017 23:13

Coronary Figure 1: Angiographic Image of Mid LAD Lesion Treated with a 25 × 28 mm A-BVS Showing Similar Angiographic Appearance Before and After High-pressure Post-Dilation

safer polymers, and better antiplatelet agents have all led to improved outcomes with present generation DES. Nevertheless, the target vessel failure and ST rates are not insignificant. It is possible that the current generation of advanced thin-strut DES may possess lesser radial strength and thus excessive recoil, especially in complex lesions, thereby predisposing to smaller CSAs. It is therefore likely that the need for post-dilation with an NC balloon may be even more important in the present thin strut DES era.15

Rationale for Using NC Balloons for Post-dilatation

Mid LAD total occlusion

Post 2.5 x 28 mm A-BVS deployment at 14 atm (2.89 mm final size)

Reference vessel diameter 2.54 mm by OCT, pre-dilatation with a non-compliant 2.5 x 15 mm balloon at 20 atm

Post high-pressure dilatation with 2.75 mm NC balloon at 22 atm (2.93 mm final size)

A-BVS = AbsorbTM bioresorbable vascular scaffold; LAD = left anterior descending; NC = noncompliant; OCT = optical coherence tomography. Source: Seth et al.29. Reproduced with the permission of Europa Digital & Publishing, © 2015.

where there is the largest and most resistant plaque bulk. The semicompliant stent balloon – especially in large plaque burden, calcific or fibrotic lesions – does not achieve focused force at the lesion site, and at higher pressures results in ‘dog boning’ leading to underexpansion.

Romagnoli et al.15 demonstrated the advantage of achieving better stent expansion using NC balloon post dilatation over semi compliant stent balloons despite achieving the same final balloon size (based on manufacturer’s balloon compliance charts). The NC balloons not only have a linear relationship between the changes in applied pressure and the changes in observed volume (∆V/∆P, the definition of compliance) but also tolerate 50 % greater inflation pressures. These combined properties allow greater forces to be applied focally without overstretching other parts of the diseased segment.16 Atherosclerotic coronary artery distensibility by balloon inflation is a linear function of pressure at low inflation pressures only and primarily in arteries with concentric lesions.17 At higher pressures, of relevance for percutaneous coronary intervention (PCI), distensibility is unpredictable. De Ribamar Costa Jr et al.5 showed that stent balloon compliance charts overestimate the final stent dimensions, as these measurements are typically made in vitro without the vessel constraint that limits balloon expansion. When the stent is deployed at high pressures with the semi-compliant stent balloon, it may cause stent edge dissection, coronary perforation and intimal injury leading to an increased inflammatory response and higher restenosis rate.18 Hence, using an NC balloon for high-pressure post-dilatation stent optimisation is not just physiologically appropriate but technically safer than going up to higher pressures with a compliant balloon.

Disadvantages of NC High-pressure Post-dilation In the Stent Optimization (STOP) study, only 21 % of DES achieved optimal deployment at 16 atmospheres, which increased to 54 % after routine post-dilatation with an NC balloon to 20 atmospheres. Further IVUS-guided optimization achieved optimal deployment in 81 % of the stents finally.9 The Postdilatation Clinical Comparative Study (POSTIT)10 demonstrated that high-pressure stent deployment alone reaches only 55 % of the achievable luminal gain, whereas adjunctive NC balloon post-dilatation can double the frequency of optimal stent expansion. In a study of first-generation DES, follow up demonstrated that under-deployed stents with a cross-sectional area (CSA) <5–5.5 mm² was one of two procedural factors associated with restenosis, while a smaller area of 4.2–4.65 mm² was associated with ST.3, 11–13 DES with a larger CSA also have a more complete neointimal coverage.14 However, despite achieving optimal stent expansion and large CSA by IVUS guidance, many post-dilation studies have failed to demonstrate clear long-term benefits in outcomes.15 One important reason for this could be that the outcome benefits could be more demonstrable in high-risk subgroups such as calcified vessels, long lesions, fibrotic lesions, bifurcation lesions or ostial lesions, but these studies were underpowered to look at these subgroups.

While it has been clearly demonstrated that high-pressure postdilatation with the NC balloon helps optimise stent expansion and achieve a large lumen, disadvantages to the approach may also exist. Aggressive post-dilatation might result in more intimal hyperplasia compared with a less aggressive approach,19 or lead to edge dissections, geographic miss20 or even coronary perforation.21 These complications may require additional stenting and influence TLR adversely. Another possible complication of repeated recrossing of partially deployed stents with NC balloons is the risk of damaging the stent and causing longitudinal stent deformation, especially with newer generation thin-strut stents.22 High-pressure NC balloon postdilation may be associated with greater side branch occlusions and myocardial injury23 and may also be a risk factor for stent fracture and restenosis.24 During angioplasty in acute myocardial infarction, there is a thrombotic milieu and aggressive post-dilatation may lead to distal embolisation25,26 and ‘slow flow’ due to microvascular plugging and worsening myocardial damage.24 We should also not forget that post-dilatation adds to the cost of the procedure, which is an important consideration for many centres and countries across the world.

We should also keep in mind that target vessel failure and ST are multi factorial. Refinements in stent materials and design, thinner struts,

In The Real-World Endeavor Resolute Versus Xience V Drug-Eluting Stent Study in Twente (TWENTE) trial, post-dilatation was performed

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Expert Opinion in 82 % of stents. This may have contributed to a higher incidence of peri-procedural myocardial infarction (4.1 %), although the 12-month clinical TLR rates were lower (2.1 %) compared with historic controls.27 In an analysis of more than 90,000 stent implantations from the Swedish Coronary Angiography and Angioplasty Registry from 2008 to 2012, Fröbert et al.28 looked at outcomes related to different implantation pressure and found that the risk of ST and restenosis appeared to be high with low (<15 atmospheres) and with very high (>20 atmospheres) pressure group.

Figure 2: OCT Images of the Same Mid LAD Lesion Showing Inadequate Deployment of A-BVS, which is Optimised by High-pressure NC Balloon Post-Dilation Despite Achieving Similar Final Balloon Diameters Post 2.5 x 28 mm A-BVS deployment at 14 atm (2.89 mm final size)

Post high-pressure dilatation with 2.75 mm NC balloon at 22 atm (2.93 mm final size)

Post-dilation in Bioresorbable Vascular Scaffolds Bioresorbable vascular scaffolds (BVS) are thick-strut (156 µm) devices compared with current-generation DES, and in many ways similar to the first generation of metallic thin strut DES (65-85 µm). Over the last 3 years, the technique for optimal implantation of BVS has evolved to mandate the need for high-pressure post-dilation with a NC balloon. This achieves large MSA and also embeds the struts.29 The earlier studies of BVS, (Absorb II30 and Absorb III31), did not utilise high-pressure post-dilation with the NC balloon and deployed the scaffold at low to moderate pressures with scaffold balloon, which may have accounted for higher scaffold thrombosis rates at follow up. Registries and single-centre experiences using high-pressure NC balloon post-dilatation demonstrate outcomes as good as the bestin-class DES with extremely low scaffold thrombosis rates, although a randomised trial is still awaited on the impact of optimal implantation technique on the outcomes of BVS. However, through observations and experience, IVUS- or optical coherence tomography (OCT)-guided data from experienced centres it is now mandatory that for safe and effective implantation of BVS, the lesion should be prepared well, the BVS should be sized appropriate to the vessel and post-dilatation with a 0.25–0.5 mm larger NC balloon at 18-20 atmospheres keeping within the limits of scaffold expansion should be used. This help achieves the best outcomes.32 We have demonstrated by OCT that – despite adequate and aggressive pre-dilatation of the lesion and subsequent deployment of BVS to achieve a good angiographic result – a high-pressure post-dilatation with an NC balloon 0.25 mm larger (while achieving the same final size as the BVS implant balloon as per pressure compliance data chart) still corrects underexpansion, apposes struts, achieves better luminal enlargement and even embeds the thick struts into the vessel wall. All of this could help decrease ST and improve outcomes (see Figure 1 and Figure 2).29

well as optimally apposes the double layer of stents. so that struts are properly apposed to wall in double layer of stents. Ostial lesions are usually fibrotic and resilient, and there is expert consensus to post-dilate the stents with a NC balloon to enable optimal expansion.

Conclusion

Bifurcation lesion treatment is associated with a high incidence of non-uniform stent expansion especially in the side branch, resulting in a higher TVR rate.33 Several studies have demonstrated that when both branches are stented, final post-dilatation with a kissing balloon is associated with more favourable long-term outcomes.34–36. and is therefore mandatory.

Advancements in science, technology and drugs have improved outcomes of stent implantation. At the same time more complex patient and lesion population are being increasingly treated. Thus, improving on target lesion failure rates and ST remains an important focus. Even the current generation of DES need a perfect final result and technique continues to play an important role. With multiple tools at our disposal, lesion evaluation and result optimization by IVUS or OCT, vascular bed preparation and plaque modification with scoring/ cutting balloons or rotational atherectomy, achieving end-to-end lesion coverage and avoiding geographical miss are important for long-term outcomes. Finally, post-dilation continues to play an important role for achieving maximal luminal gains.

In long lesions, the Randomised Trial of Endoluminal Reconstruction Comparing the NIR Stent and Wallstent in Angioplasty of Long Segment Coronary Disease (RENEWAL) and Multicenter Ultrasound Stenting in Coronaries (MUSIC) studies showed that high restenosis rates with long stents could be related to suboptimal stent deployment.37 Thus, for long or overlapping stents, high pressure NC balloon post dilatation especially at the overlapping zone achieves maximal luminal gain as

It is highly unlikely that any large randomized trial will be performed to test the concept of high-pressure post-dilatation of DES in current era and frankly we don’t believe such trials are needed. Achieving complete stent apposition and maximal luminal gain still remains the ultimate goal and is associated with the best long-term outcomes. Not all lesions in our PCI practice require post-dilation with NC balloons. Type-A denovo lesions, lesions in large vessels >3.5 mm

Specific Conditions

INTERVENTIONAL CARDIOLOGY REVIEW

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Coronary or softer lesions could achieve a large CSA even with the current generation of semi-compliant stent implantation balloons. However, more than 60–70 % of the lesions we treat in real-world practice include bifurcation lesions, ostial lesions, left main lesions, calcified or fibrotic vessels, small vessels, in-stent restenosis, overlapping stents or

10.

11.

12.

13.

olombo A, Hall P, Nakamura S, et al. Intracoronary stenting C without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995;91:1676–88. DOI: 10.1161/01.CIR.91.6.1676; PMID: 7882474 Parise H, Maehara A, Stone GW, et al. Meta-analysis of randomized studies comparing intravascular ultrasound versus angiographic guidance of percutaneous coronary intervention in pre-drug-eluting stent era. Am J Cardiol 2011;107:374–82. DOI: 10.1016/j.amjcard.2010.09.030; PMID: 21257001 Fujii K, Carlier SG, Mintz GS, et al. Stent under expansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: an intravascular ultrasound study. J Am Coll Cardiol 2005;45:995–8. DOI: 10.1016/j.jacc.2004.12.066; PMID: 15808753 Iakovou 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. PMID: 15870416; PMID: 15870416 de Ribamar Costa Jr J, Mintz GS, Carlier SG, et al. Intravascular ultrasonic assessment of stent diameters derived from manufacturer’s compliance charts. Am J Cardiol 2005;96:74–8. DOI: 10.1016/j.amjcard.2005.02.049; PMID: 15979438 Johansson B, Olsson H, Wennerblom B. Angiographyguided routine coronary stent implantation results in suboptimal dilatation. Angiology 2002;53:69–75. DOI: 10.1177/000331970205300109; PMID: 11863311 Javaid A, Chu WW, Cheneau E, et al. Comparison of paclitaxel-eluting stent and sirolimus-eluting stent expansion at incremental delivery pressures. Cardiovasc Revasc Med 2006;7:208–11. DOI: 10.1016/j.carrev.2006.09.002; PMID: 17174865 de Ribamar Costa Jr J, Mintz GS, Carlier SG, et al. Intravascular ultrasound assessment of drug-eluting stent expansion. Am Heart J 2007;153:297–303. DOI: 10.1016/j.ahj.2006.08.026; PMID: 17239693 Rana O, Shah NC, Wilson S, et al. The impact of routine and intravascular ultrasound-guided high-pressure postdilatation after drug-eluting stent deployment: The STent OPtimization (STOP) Study. J Invasive Cardiol 2014;26:640–6. PMID: 25480993 Brodie BR, Cooper C, Jones M, et al. Is adjunctive balloon postdilatation necessary after coronary stent deployment? Final results from the POSTIT trial. Catheter Cardiovasc Interv 2003;59:184–92. DOI: 10.1002/ccd.10474; PMID: 12772236 Hong MK, Mintz GS, Lee CW, et al. Intravascular ultrasound predictors of angiographic restenosis after sirolimus-eluting stent implantation. Eur Heart J 2006;27:1305–10. DOI: 10.1093/ eurheartj/ehi882; PMID: 16682378 Okabe T, Mintz GS, Buch AN, et al. Intravascular ultrasound parameters associated with stent thrombosis after drugeluting stent deployment. Am J Cardiol 2007;100:615–20. DOI: 10.1016/j.amjcard.2007.03.072; PMID: 17697816 Rogacka R, Latib A, Colombo A. IVUS-guided stent implantation to improve outcome: a promise waiting

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25.

tapering vessels. These lesions have higher thrombosis and restenosis rates and follow up. High-pressure post-dilatation of DES in these complex lesions should be considered standard practice preferably with intracoronary imaging to achieve the best outcomes in the short and long term. n

to be fulfilled. Curr Cardiol Rev 2009;5:78–86. DOI: 10.2174/157340309788166697; PMID: 20436848 Sera F, Awata M, Uematsu M, et al. Optimal stent-sizing with intravascular ultrasound contributes to complete neointimal coverage after sirolimus-eluting stent implantation assessed by angioscopy. JACC Cardiovasc Interv 2009;2:989–94. DOI: 10.1016/j.jcin.2009.07.006; PMID: 19850260 Romagnoli E, Sangiorgi GM, Cosgrave J, et al. Drug-eluting stenting: The case for post-dilation. JACC Cardiovascular Interv 2008;1:22–31. DOI: 10.1016/j.jcin.2007.10.005; PMID: 19393140 Abele JE. Balloon catheters and transluminal dilatation: technical considerations. AJR Am J Roentgenol 1980;135:901–6. DOI: 10.2214/ajr.135.5.901; PMID: 6778167 Frøbert O, Schiønning J, Gregersen H, et al. Impaired human coronary artery distensibility by atherosclerotic lesions: a mechanical and histological investigation. Int J Exp Path 1997;78: 421–8. DOI: 10.1046/j.1365-2613.1997.470374.x; PMID: 9516874 Brasselet C, Garnotel R, Perotin S, et al. Percutaneous coronary intervention-induced variations in systemic parameters of inflammation: relationship with the mode of stenting. Clin Chem Lab Med 2007;45:526–30. DOI: 10.1515/ CCLM.2007.088; PMID: 17439332 Hoffmann R, Guagliumi G, Musumeci G, et al. Vascular response to sirolimus-eluting stents delivered with a nonaggressive implantation technique: comparison of intravascular ultrasound results from the multicenter, randomized E-SIRIUS, and SIRIUS trials. Catheter Cardiovasc Interv 2005;66:499–506. DOI: 10.1002/ccd.20542; PMID: 16273564 Tahara S, Bezerra HG, Kyono H, et al. Impact of acute gain on clinical outcomes of patients treated with sirolimuseluting stent - A sub-analysis study from the STLLR trial. Circ J 2011;75:2113–19. DOI: 10.1253/circj.CJ-10-0647; PMID: 21757826 Karabulut A, Topcu K. Coronary perforation due to sirolimuseluting stent’s strut rupture with post-dilatation. Kardiol Pol 2011;69:183–6. PMID: 21332068 Williams PD, Mamas MA, Morgan KP, et al. Longitudinal stent deformation: a retrospective analysis of frequency and mechanisms. EuroIntervention 2012;8:267–74. DOI: 10.4244/ EIJV8I2A41; PMID: 22052084 Brodie BR, Cooper C, Jones M, et al. Is adjunctive balloon postdilatation necessary after coronary stent deployment? Final results from the POSTIT trial. Catheter Cardiovasc Interv 2003;59:184–92. DOI: 10.1002/ccd.10474; PMID: 12772236 Kan J, Ge Z, Zhang JJ, et al. Incidence and clinical outcomes of stent fractures on the basis of 6,555 patients and 16,482 drug-eluting stents from 4 centers. JACC Cardiovasc Interv 2016;9:1115–23. DOI: 10.1016/j.jcin.2016.02.025; PMID: 27009464 Stone GW, Webb J, Cox DA, et al. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction: a randomized controlled trial. JAMA 2005;293:1063–72. DOI: 10.1001/jama.293.9.1063; PMID: 15741528

26. L imbruno U, De Carlo M, Pistolesi S, et al. Distal embolization during primary angioplasty: histopathologic features and predictability. Am Heart J 2005;150:102–8. DOI: 10.1016/j. ahj.2005.01.016; PMID: 16084155 27. Von Birgelen C, Basalus MW, Tandjung K, et al. A randomized controlled trial in second-generation zotarolimus-eluting Resolute stents versus everolimus-eluting Xience V stents in real-world patients: the TWENTE trial. J Am Coll Cardiol 2012;59:1350–61. DOI: 10.1016/j.jacc.2012.01.008; PMID: 22341737 28. Fröbert O, Sarno G, James SK, et al. Effect of stent inflation pressure and post-dilatation on the outcome of coronary artery intervention. A report of more than 90 000 stent implantations. PLoS One 2013;8:e56348. DOI: 10.1371/journal. pone.0056348; PMID: 23418560 29. Seth A, Kumar V, Rastogi V. BRS in complex lesions: massaging (and messaging) the right pressure points. EuroIntervention 2015;11:131–5. DOI: 10.4244/EIJV11I2A25; PMID: 26093835 30. Serruys PW, Chevalier B, Sotomi Y, et al. Comparison of an everolimus-eluting bioresorbable scaffold with an everolimuseluting metallic stent for the treatment of coronary artery stenosis (ABSORB II): a 3 year, randomised, controlled, singleblind, multicentre clinical trial. Lancet 2016;388:2479–91. DOI: 10.1016/S0140-6736(16)32050-5; PMID: 27806897 31. Ellis SG, Kereiakes DJ, Metzger, DC, et al. Everolimus-eluting bioresorbable scaffolds for coronary artery disease. N Engl J Med 2015;373:1905–15. DOI: 10.1056/NEJMoa1509038; PMID: 26457558 32. Seth A. Bioresorbable scaffold use in the “real world” – mantras from the East. AsiaIntervention 2016;2:78–9. 33. Colombo A, Moses JW, Morice MC, et al: Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004;109:1244–9. DOI: 10.1161/01.CIR.0000118474.71662.E3; PMID: 14981005 34. Costa RA, Mintz GS, Carlier SG, et al. Bifurcation coronary lesions treated with the “crush” technique: an intravascular ultrasound analysis. J Am Coll Cardiol 2005;46:599–605. DOI: 10.1016/j.jacc.2005.05.034; PMID: 16098422 35. Ge L, Airoldi F, Iakovou I, et al. Clinical and angiographic outcome after implantation of drug-eluting stents in bifurcation lesions with the crush stent technique: importance of final kissing balloon post-dilatation. J Am Coll Cardiol 2005;46:613–20. DOI: 10.1016/j.jacc.2005.05.032; PMID: 16098424 36. Di Mario C, Morici N, Godino C, et al. Predictors of restenosis after treatment of bifurcational lesions with paclitaxel eluting stents: a multicenter prospective registry of 150 consecutive patients. Catheter Cardiovasc Interv 2007;69:416–24. DOI: 10.1002/ ccd.20951; PMID: 17191238 37. Nageh T, de Belder AJ, Thomas MR, et al. A randomised trial of endoluminal reconstruction comparing the NIR stent and the Wallstent in angioplasty of long segment coronary disease: results of the RENEWAL Study. Am Heart J 2001;141: 971–6. DOI: 10.1067/mhj.2001.115301; PMID: 11376312

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Coronary

Current State of the Art in Approaches to Saphenous Vein Graft Interventions Michael Lee and Jeremy Kong UCLA Medical Center, Los Angeles, CA, USA

Abstract Saphenous vein grafts (SVGs), used during coronary artery bypass graft surgery for severe coronary artery disease, are prone to degeneration and occlusion, leading to poor long-term patency compared with arterial grafts. Interventions used to treat SVG disease are susceptible to high rates of periprocedural MI and no-reflow. To minimise complications seen with these interventions, proper stents, embolic protection devices (EPDs) and pharmacological selection are crucial. Regarding stent selection, evidence has demonstrated superiority of drug-eluting stents over bare-metal stents in SVG intervention. The ACCF/AHA/SCA American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions guidelines recommend the use of EPDs during SVG intervention to decrease the risk of periprocedural MI, distal embolisation and no-reflow. The optimal pharmacological treatment for slow or no-reflow remains unclear, but various vasodilators show promise.

Keywords Saphenous vein graft, percutaneous coronary intervention, drug-eluting stent, distal embolisation, no-reflow phenomenon Disclosure: The authors have no conflicts of interest to declare. Received: 19 February 2017 Accepted: 20 June 2017 Citation: Interventional Cardiology Review 2017;12(2):85–91. DOI: 10.15420/icr.2017:4:2 Correspondence: Michael S Lee, Division of Cardiology, UCLA Medical Center, 100 UCLA Medical Plaza, Suite 630, Los Angeles, CA 90095, USA. E: MSLee@mednet.ucla.edu

Saphenous vein grafts (SVGs) are commonly used during coronary artery bypass graft surgery (CABG) for severe coronary artery disease. However, SVGs are prone to both degeneration and occlusion, leading to poor long-term patency compared with arterial grafts. Previous reports suggest rates of SVG failure in the first 12–18 months may be as high as 25 %.1–4 SVG neointimal hyperplasia and accelerated atherosclerosis diminish the long-term benefits of CABG, while subsequent SVG interventions are plagued by plaque embolisation and no-reflow phenomenon. Percutaneous coronary intervention (PCI) of SVGs is associated with worse clinical outcomes compared with native coronary artery PCI,5,6 but certain strategies may help mitigate complications. In this review, we discuss risk factors for SVG intervention and the optimal approaches for treating this challenging subset of patients.

Atheroembolic debris liberated during SVG intervention becomes lodged in distal capillaries, while the release of neurohormonal factors such as serotonin can induce vasospasm. Slow or no-reflow phenomena may subsequently follow, which are associated with both periprocedural angina and ischaemic ST-segment changes.19 The exact mechanism of no-reflow remains unclear, but it has been hypothesised that endothelial swelling, neutrophil infiltration and platelet aggregation induce microvasculature spasm and obstruction.20,21 SVG intervention is thus associated with higher rates of in-stent restenosis, target vessel revascularisation (TVR), periprocedural MI and in-hospital mortality compared with PCI for native coronary circulation. The severity of these potential consequences makes proper patient selection and optimal technique essential during invasive SVG revascularisation.

Pathophysiology of Saphenous Vein Graft Complications

Predictors of Adverse Outcomes

Various factors contribute to SVG deterioration and occlusion, which may ultimately require revascularisation. Approximately 10–15 % of SVGs occlude within 1 year and 50 % fail by 10 years.7 Platelet aggregation, growth factor secretion, endothelial dysfunction, inflammation, luminal foam cell accumulation, decreased local fibrinolytic potential from plasminogen activator inhibitor-1 upregulation and marked intimal hyperplasia contribute to SVG occlusion within the first 12–18 months post-CABG.8–14 Occlusions after 12–18 months occur following lipid deposition within intimal hyperplasia, eventually forming atherosclerotic plaque.14 Increased pressure load from vein graft arterialisation induces this development of neointimal growth and atherosclerosis.7 Deteriorating SVG lesions also possess thinner, more friable fibrous caps compared with native coronary artery lesions.15,16 this increases the incidence of plaque embolisation and platelet aggregation,17,18 especially during SVG interventions.

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The strongest predictors of SVG intervention 30-day major adverse cardiac events (MACE) are angiographic estimations of SVG degeneration and plaque volume.22,23 Another study analysing patients undergoing SVG intervention with distal embolic protection reported that lesion length has the strongest correlation with short-term adverse events.24 A graded increase in MACE was observed with increasing lesion lengths, perhaps correlating to the increase in SVG plaque burden. The data on the impact of gender have provided mixed results. One study suggested that male patients were more inclined to have worse outcomes,25 but another study reported that female patients had a higher 30-day cumulative mortality rate (4.4 % versus 1.9 %, P=0.02).26 Female patients also had significantly higher rates of vascular complications (12 % versus 7.3 %; P=0.006) and post-procedural acute renal failure (8.1 % versus 4 %; P=0.02) compared with male patients.

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Coronary Chronic renal insufficiency (serum creatinine ≥1.5 mg/dl) was a significant predictor of 1-year MACE in patients who underwent SVG intervention with drug-eluting stents (DES) (hazard ratio [HR] 2.2; 95 % CI [1.1–4.3]; P=0.03).27 There was also a trend toward higher rates of TVR in the renal insufficiency group (21.8 % versus 10.3 %; HR 2.42; 95 % CI [0.94–6.24]; P=0.059). Another study reported that patients with renal insufficiency had higher mortality rates following SVG PCI.28

Percutaneous revascularisation is not recommended in patients with chronic total SVG occlusion. A study of 34 patients with chronic total SVG occlusions reported that successful recanalisation with stent implantation was low (68 %).36 Rates of TVR and in-stent restenosis at 18-month follow-up were very high (61 % and 68 %, respectively) in patients who underwent successful stenting.

Intervention Technique Patients commonly experienced elevations in levels of creatine kinasemyocardial band (CK-MB) following SVG intervention.17 Approximately 15 % of patients who underwent SVG intervention were found to have CK-MB levels >5x the upper limit of normal (ULN), which increased the 1-year mortality rate in patients with normal CK-MB from 4.8 % to 11.7 % (P<0.05 analysis of variance [ANOVA]). Even minor elevations in CK-MB levels (>1x to <5x ULN) were associated with an increased 1-year mortality rate (6.5 %; P<0.05 ANOVA).17

Lesion Evaluation and Patient Selection Lesion Evaluation The decision to perform SVG revascularisation should predominantly be based on patient symptoms and evidence of myocardial ischaemia in regions supplied by the SVG. Fractional flow reserve (FFR) is used to determine the significance of native coronary vessel stenosis, but has not been well studied in SVG lesions. Limited studies show that FFR has low sensitivity, but an acceptable specificity and negative predictive value compared with stress myocardial perfusion imaging in assessing the significance of SVG lesions.29 Myocardial perfusion imaging has good specificity for detecting ischaemia after CABG, but variable sensitivity in detecting angiographically significant graft stenosis.30 Intravascular ultrasound (IVUS) may play a role in SVG disease evaluation, as positive remodelling on IVUS is a strong predictor of post-intervention no-reflow.31 However, IVUS has not been adequately evaluated in prospective SVG intervention trials to support intervention based on IVUS findings alone. Multidetector computed tomography (MDCT) provides adequate visualisation of SVGs given their reduced motion and large lumens.32 Although it provides a sensitivity of 96 % and a specificity of 95 % in evaluating graft patency,33 it is limited in its ability to visualise distal anastomosis sites. Further advancements in this technique are needed to match the gold standard of coronary angiography.

Patient Selection Prophylactic stenting of intermediate SVG lesions has been advocated given that the progression of SVG disease can be rapid. In the Moderate Vein Graft Lesion Stenting With the Taxus Stent and Intravascular Ultrasound (VELETI) trial, 57 patients with moderate (30–60 %) SVG stenosis were randomised to medical therapy alone or revascularisation with DES.34 Both minimal luminal diameter and percent stenosis were decreased in the DES group. The MACE rates at 1 and 3 years were lower in the DES group compared with the medical therapy group (At 1 year: 3 % versus 19 %, P=0.09; at 3 years: 3 % versus 26 %, P=0.02).35,36 The VELETI trial was underpowered for clinical endpoints. The larger 450-patient VELETI II trial randomised patients with intermediate SVG lesions to either SVG intervention with paclitaxeleluting stents or medical therapy alone.37 This study was terminated prematurely due to slow patient enrolment.

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Preparation Given inferior long-term outcomes of SVG intervention compared with native vessel PCI,38,39 revascularisation of the bypassed native vessel should be considered only if the indication is clear. Knowledge of the CABG operative report details, including graft locations, number of grafts and complications encountered during the surgery, is helpful. Previous angiography can provide additional benefit in guiding angiography and revascularisation. Optimal guiding-catheter support is imperative to the procedural success of SVG intervention. The size of the aorta combined with the position and angle of the SVG determines the type and size of catheter best suited for engagement. The multipurpose catheter is often used for right coronary graft interventions, especially if the graft take-off is steep and inferior. The Judkins right (JR) catheter or Amplatz left (AL) catheter may be used if the angle of the origin of the SVG to the right coronary artery is more horizontal. The JR catheter can engage left coronary artery grafts as well, especially those with a horizontal takeoff from the aorta. Other available catheters include the AL, left bypass and hockey stick catheters.

Pre-dilation Versus Direct Stenting Although pre-dilation with balloon angioplasty is often employed in native vessel PCI to optimise lesions, this strategy may not be suitable for SVG interventions. Direct stenting provides the potential benefit of trapping debris and decreasing distal embolisation that can occur with pre-dilatation. Patients who underwent direct stenting were associated with nearly a 50 % reduction in CK-MB level elevations >4x normal (13.6 % versus 23 %; P<0.12), overall lower maximum CK-MB release (9.5 versus 19.6 IU/L; P<0.001) and reduction in non-Q-wave MI (10.7 % versus 18.4 %; P<0.02) compared with angioplasty first without distal protection.40 However, one retrospective study of patients undergoing direct stenting without distal protection versus angioplasty followed by stenting with distal protection reported that the rate of increase in CK-MB levels >2x ULN and rates of MACE were no different in-hospital or at 30 days.41 Prospective randomised trials are needed to confirm whether direct stenting versus pre-dilation is most effective in reducing distal embolisation.

Stent Selection Stent Sizing Proper stent sizing is crucial to ensuring long-term stent longevity and vessel patency. One study explored the concept of undersized stenting to reduce distal embolisation. Hong et al. analysed outcomes of SVG intervention with DES in three groups according to the ratio of stent diameter to average IVUS reference lumen diameter (group I: <0.89 mm, group II: 0.9 to 1.0 mm, group III: >1.0 mm).42 Incidence of CK-MB level elevation >3x normal was 6 %, 9 % and 19 %, respectively (P=0.03) without an increase in clinical events at 1 year. The hypothesised reduction in distal embolisation and periprocedural MI with undersized stenting must be weighed against the conceivable risk of increased stent restenosis and thrombosis.

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Saphenous Vein Graft Interventions Table 1: DES Versus BMS in Randomised Saphenous Vein Graft Trials

RRISC SOS ISAR-CABG

N=75

N=988 N=610

SES

PES

BMS

P-value BMS

DES

P-value

MACE rates, % 1 year

29.7* 15.8* 0.15 49 37 0.20 22.1 15.4 0.03

3 years

41 58 0.13 77 54 0.49 NA NA NA

MI rates, % 1 year

2.6*

0.99

0.10

6.0

4.2

0.27

3 years

0.15

0.01

TLR rates, % 1 year

21.6* 5.3* 0.05 28 5 0.003 13.1 7.2 0.02

3 years

30 24 0.55 41 10 0.004 NA NA NA

Death rates, % 1 year

2.6*

0.99

0.27

4.7

5.2

0.82

3 years

<0.001

0.19

Source: Adapted from Lee, et al., 2011. BMS = bare-metal stent(s); DES = drug-eluting stent(s); ISAR-CABG = Is Drug-eluting Stenting Associated With Improved Results in Coronary Artery Bypass Grafting; MACE = major adverse cardiac event(s); NA = not available; RRISC = Reduction of Restenosis in Saphenous Vein Grafts With Cypher Sirolimus-Eluting Stent; SOS = Stenting of Saphenous Vein Grafts; TLR = target lesion revascularisation. *6 months.

Bare-metal Stents The Saphenous Vein De Novo (SAVED) trial reported that bare-metal stents (BMS) were associated with higher procedural success rates compared with balloon angioplasty (47 % versus 36 %; P=0.11) with a lower MACE rate throughout 240 days (26 % versus 38 %; P=0.04).43

Covered Stents Covered stents comprised of polytetrafluoroethylene (PTFE) membranes were developed to act as local filters that would trap plaque debris extruding between stent struts. A multicentre registry suggested favourable results with their use in SVG intervention.44 However, randomised trials failed to show superiority over BMS.45–48 The Stents in Grafts (STING) trial reported no differences in MI, target lesion revascularization (TLR) or death with PTFE-covered stents compared with conventional stents.45 The Randomized Evaluation of Polytetrafluoroethylene Covered Stent in Saphenous Vein Grafts (RECOVERS) trial also reported similar clinical outcomes between PTFE-covered stents and BMS with higher rates of non-fatal MI with PTFE-covered stents.46 These findings were confirmed in the Symbiot III trial, which found PTFE-covered stents to have similar clinical outcomes and rates of restenosis as BMS.47 Finally, the Barrier Approach to Restenosis: Restrict Intima to Curtail Adverse Events (BARRICADE) trial reported more long-term target vessel failure in patients with covered stents compared with BMS.48 There remain two covered stents that show potential benefit in treating degenerated SVGs, although they lack long-term head-to-head comparison data with BMS. The SESAME first-in-human trial reported that patients treated with a nanosynthesised, membrane-covered self-expanding, super-elastic, all-metal endoprosthesis stent (SESAME stent, Advanced Bioprosthetic Surfaces Ltd) had 0 % 30-day and 14 % 9-month MACE rates.49 The other stent under study is the MGuard stent (InspireMD), with preliminary evaluation in one study demonstrating an excellent performance with no angiographic/procedural complications or adverse events in 30-day follow-up.50

Drug-eluting Stents The Is Drug-eluting Stenting Associated With Improved Results in CABG (ISAR-CABG) trial, which randomised 610 patients with diseased SVG to

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DES or BMS, reported that DES were associated with lower rates of TVR (7.2 % versus 13.1 %; P=0.02) and met the primary endpoint of 1-year MACE (15.4 % versus 22.1 %; P=0.03) (see Table 1).51 The Stenting of Saphenous Vein Grafts (SOS) trial also demonstrated a significant reduction in MACE rates with paclitaxel-eluting stents (Taxus, Boston Scientific Corp.) compared with BMS,52 which was driven by lower TLR rates without increased MI or death through nearly 3-year follow-up.53 Sirolimus-eluting stents (SES; Cordis) were studied in the Reduction of Restenosis In Saphenous Vein Grafts With Cypher Sirolimus-eluting Stent (RRISC) trial, which demonstrated a reduction in TLR, TVR, binary restenosis rate and late stent loss in the DES group compared with the BMS group at 6 months.54 Conversely, the DELAYED RRISC study found the TVR benefit was lost at 3-year follow-up,55 and that the DES group had increased mortality rates. However, the study was not statistically powered for clinical outcomes such as mortality. Multiple meta-analyses (including non-randomised studies) comparing DES with BMS in SVG intervention support the superiority of DES demonstrated in the randomised trials discussed above.15,56–63 One meta-analysis reported that 39,213 DES patients had lower rates of MACE (odds ratio [OR] 0.63; 95 % CI [0.54–0.74]; P<0.001), TVR (OR 0.70; 95 % CI [0.57–0.86]; P<0.001) and TLR (OR 0.64; 95 % CI [0.50–0.84]; P<0.01), with no difference in stent thrombosis (OR 0.90; 95 % CI [0.61–1.32]; P=0.58) compared with 26,461 BMS patients.15 These benefits persisted at 36-month follow-up. Lee et al. compared SES and paclitaxel-eluting stents head to head in a multicentre analysis of 172 real-world patients undergoing SVG intervention and found nonsignificant differences in survival (HR 1.28; 95 % CI [0.39–4.25; P=0.69) and TVR (HR 2.54; 95 % CI [0.84–7.72; P=0.09).64 A 2014 study compared first-generation DES with secondgeneration everolimus-eluting stents (EES) in SVG PCI, reporting that EES showed no significant differences in MI, TVR or cardiac death following risk adjustment during 4-year follow-up. 65 In summary, although there is no specified class recommendation for DES in SVG PCI, the 2011 American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) guidelines do note a ‘preference’ for their use over BMS.66

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Coronary Figure 1: Saphenous Vein Graft (SVG) Intervention of a 20-year-old SVG to the Left Anterior Descending Artery

guidewire selection cannot be tailored to procedural requirements and relatively disease-free distal landing zones are required.

The PercuSurge GuardWire became the first FDA-approved EPD following the results of the Saphenous vein graft Angioplasty Free of Emboli Randomized (SAFER) trial, which randomised 801 patients with SVG stenosis to stent placement over the GuardWire device shaft or a conventional angioplasty guidewire.69 EPDs significantly reduced the frequency of no-reflow (3 % versus 9 %; P=0.02), MI (8.6 % versus 14.7 %; P=0.008) and 30-day MACE (9.6 % versus 16.5 %; P=0.004). The TriActiv system was later FDA approved in the Protection During Saphenous Vein Graft Intervention to Prevent Distal Embolization (PRIDE) trial, which compared the TriActiv with both the GuardWire and the FilterWire EX™ (Boston Scientific) systems.70 TriActiv was non-inferior to the other devices in terms of 30-day MACE (11.2 % versus 10.1 %; P=0.65 [P=0.02 for non-inferiority]), but was associated with more vascular complications (10.9 % versus 5.4 %; P=0.01) and required more blood transfusions (7.7 % versus 3.5 %; P=0.02). These complications could be due to the larger calibre (8F) guiding catheters that were used in the TriActiv study arm.

A: Coronary Angiogram Demonstrates a Severe Distal SVG Lesion. B: Final Angiography Demonstrated Excellent Results After Stenting.

Table 2: Strengths and Weaknesses of Embolic Protection Devices

Proximal Distal Occlusion Occlusion

Distal Filter

Maintenance of antegrade blood flow during intervention

Limited contrast opacification

Unlimited debris capture

Distal Embolic Filters

Capture of debris <100 μm

Capture of soluble mediators

Shunting of debris into proximal side branches

Ease of use

Complex

Simple

Manoeuverability

Good

Reduced

Crossing profile

Low (2.7 Fr)*

High (3.2 Fr)**

Distal embolic filters use filter bags with 100–110 μm-sized pores attached to the distal portion of a 0.014-inch guidewire with a delivery sheath. The filter bag is deployed distal to the target lesion to trap debris that embolises during the intervention and is later retrieved with its retained contents via a retrieval catheter. Advantages include the ability to maintain contrast opacification and perfusion during the procedure, along with ease of use. Disadvantages include the potential risk of distal embolisation during the wiring and device-crossing phases, debris embolisation during filter retrieval, inability to completely contain microparticles and soluble vasoreactive substances, large-diameter delivery sheath requirement and inability to deploy filters without a distal landing zone. Such devices include the FilterWire, Spider FXTM (Medtronic), Interceptor® PLUS Coronary Filter

NA = not available. * PercuSurge GuardWire (Medtronic). ** FilterWire EZ (Boston Scientific).

Bioresorbable vascular scaffolds have not been adequately studied in SVG intervention and therefore cannot be recommended at this time. However, given the large diameter of the SVG, it can be considered in select situations (see Figure 1).

System (Medtronic Vascular) and CardioShield (MedNova).

Embolic Protection Devices Embolic protection devices (EPD) were designed to capture and retrieve plaque particles that embolise during SVG intervention (see Table 2). In fact, MACE rates have been shown to double in SVG intervention compared with that of native coronary vessels.67 Despite the ACCF/AHA/SCAI class I indication for the use of EPDs during SVG intervention to decrease the risk of periprocedural MI, distal embolisation and no-reflow,66 they remain underutilized.68 EPDs can be categorised into distal occlusion aspiration devices, distal embolic filters and proximal occlusion aspiration devices.

Distal Occlusion Aspiration Devices Distal occlusion aspiration devices use an interventional guidewire with an occlusion balloon that is inflated distal to the SVG lesion. Inflation obstructs antegrade flow, trapping plaque debris that is subsequently removed via an aspiration catheter. Such devices include the PercuSurge GuardWire (6F; Medtronic) and TriActiv® system (7F or 8F; Kensey Nash). The TriActiv includes a flush catheter for infusing heparinised saline during the procedure, which is absent in the GuardWire. Advantages of these EPDs include a low crossing profile and unlimited debris capture of particles <100 μm and soluble vasoactive mediators. Disadvantages include risk of embolisation during the wiring and device-crossing phase, ischaemia during balloon occlusion, limited contrast opacification and the risk of shunting debris into proximal side branches. Furthermore,

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The FilterWire EX became the first FDA-approved filter after completion of the FilterWire EX Randomized Evaluation (FIRE) trial, which compared the FilterWire EX with the GuardWire in 651 patients who received SVG PCI.71 The 30-day composite endpoint of MI, TVR or death was equivalent in both the FilterWire EX and GuardWire groups (9.9 % versus 11.6 %; superiority P=0.53, non-inferiority P<0.001), as were the 6-month MACE rates (19.3 % versus 21.9 %; P=0.44).72 The second-generation FilterWire EZ was then introduced with a lower crossing profile (3.2F versus 3.9F), smaller pore size (100 μm versus 110 μm) and overall improved delivery system compared with its predecessor. The Embolic Protection Transluminally with the FilterWire EZ Device in Saphenous Vein Grafts (BLAZE) registry reported that the success rate of this device was 97.8 %, and 30-day MACE rate was 6.7 % due entirely to non-Q-wave MI.73 The Spider Rx filtration device is also FDA approved for SVG intervention and was non-inferior to the FilterWire and GuardWire (MACE: 9.1 % versus 8.4 %; P=0.001 for non-inferiority) in the Saphenous Vein Graft protection In a Distal Embolic Protection Randomized Trial (SPIDER) trial.74 The Interceptor PLUS device was also non-inferior to the Filterwire and GuardWire in the (Assessment of the Medtronic AVE Interceptor Saphenous Vein Graft Filter System) AMEthyst trial.75 A multicentre, randomised clinical trial evaluating the CardioShield, a third-generation EPD, found the 30-day MACE primary endpoint occurred in 11.4 % with

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Saphenous Vein Graft Interventions CardioShield versus 9.1 % with GuardWire (P=0.37), whereas intentionto-treat analysis demonstrated a strong trend for CardioShield noninferiority (P=0.57).76 A secondary modified intention-to-treat analysis including only patients receiving treatment device without protocol deviation also supported non-inferiority of CardioShield (P=0.022).76

to those of the control group.80 Post hoc analysis of the FIRE trial showed a trend toward improved procedural success when GP IIb/IIIa inhibitors were used with filter-based embolic protection (P=0.058), but 30-day MACE rates were unchanged.83 Its potential benefit must be balanced by the potential risk of bleeding during SVG intervention.

Proximal Occlusion Aspiration Devices

Anticoagulants

The Proxis™ (7F; St. Jude Medical), which is no longer commercially available, is a proximal occlusion aspiration device that uses a guiding catheter with an inflatable balloon tip deployed proximal to the SVG lesion. This temporary suspension of antegrade flow generates a column of stagnant blood containing debris that is later aspirated via the guiding catheter. The balloon is deflated to restore antegrade perfusion following the intervention. Its advantages include use in lesions without a distal landing zone, retrieval of both atheromatous debris and vasoactive substances, protection from emboli prior to lesion crossing, protection of proximal side branches and the ability to tailor guidewire selection to procedural requirements. Notable disadvantages include limited contrast opacification and ischaemia during balloon occlusion. The Proximal Protection During Saphenous Vein Graft Intervention (PROXIMAL) trial evaluated the Proxis system in 594 patients undergoing stenting in 639 SVG lesions.77 The Proxis study arm was non-inferior to the control arm with distal EPDs (FilterWire or GuardWire) in the primary composite endpoint of MI, TVR or death at 30 days (10.0 % versus 9.2 %; P=0.0061).77

Dual antiplatelet therapy recommendations for optimal treatment of SVG disease prior to hospitalisation are similar to that in native coronary vessel PCI.66,84 However, the ideal anticoagulants for SVG intervention have not been specifically established. A single-centre, retrospective, observational study reported that bivalirudin was associated with a significant reduction in major CK-MB level elevation compared with unfractionated heparin.85 Net clinical endpoints and rates of ischaemic bleeding were similar with bivalirudin monotherapy, bivalirudin plus a GP IIb/IIIa inhibitor and heparin plus a GP IIb/IIIa inhibitor in a subset of patients undergoing SVG intervention in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial.86 Bivalirudin alone had fewer minor bleeding complications compared with heparin plus a GP IIb/IIIa inhibitor (26 % versus 38 %; P=0.05). Heparin remains a popular choice for all forms of PCI, as the current ACCF/AHA/SCAI guidelines recommend a class I indication for its use in this setting.66

Recommendations The trial data demonstrate the efficacy of all three EPD classes in minimising ischaemic complications. Its use must account for the degree of distal embolisation risk and the complexity of the coronary anatomy itself, especially when certain EPDs require distal landing zones. As indicated in the ACCF/AHA/SCAI guidelines, EPDs should ultimately be used during SVG intervention whenever feasible.66 Although these devices have proven effective during SVG intervention, they remain remarkably underutilised. An evaluation of 19,546 SVG PCI procedures in the American College of Cardiology-National Cardiovascular Data Registry found that EPDs were used in only 22 % of cases, despite being independently associated with a lower incidence of no-reflow (OR 0.68; P=0.032).78 One potential reason for this underutilisation could be that the delivery sheath heft makes distal filter deployment challenging. A recent study by Kaliyadan et al. highlighted the use of adjunct delivery techniques to optimize filter delivery in SVG procedures.79 Deployment failure in this study was reduced from 21.9 % initially to 7.6 % after using adjunct delivery techniques (P<0.01).79 Such techniques that facilitate device delivery success could potentially improve clinical outcomes and promote more frequent use of distal protection.

Adjunctive Pharmacology Various pharmacological strategies can be used to decrease ischaemic complications during SVG intervention.

Glycoprotein IIb/IIIa Inhibitors Adjunctive use of glycoprotein (GP) IIb/IIIa antagonists does not provide significant benefit in SVG intervention.80–82 The ACCF/AHA/SCAI guidelines recommend a class III (no benefit) indication for use of these agents in SVG lesions.66 The Evaluation of IIb/IIIa platelet receptor antagonist 7E3 in Preventing Ischemic Complications (EPIC) trial reported a reduction in the rate of distal embolisation in patients treated with GP IIb/IIIa inhibitors, but 30-day and 6-month clinical endpoints were comparable

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Vasodilators Intragraft administration of vasodilators targets microvasculature to combat slow and no-reflow phenomena. Microcatheters can maximise pharmacotherapy delivery to these vessels. Pretreatment with intracoronary adenosine, a potent dilator of arteries and arterioles, decreases MI incidence after elective PCI,87,88 while it improves myocardial flow89,90 and lowers the incidence of no-reflow in the setting of acute MI.89,91 Adenosine may help reverse slow and no-reflow phenomena in patients undergoing SVG intervention.92,93 High doses of intragraft adenosine (at least five boluses of 24 μg each) significantly improved final Thrombolysis In Myocardial Infarction (TIMI) flow grade compared with low doses (less than five boluses) of adenosine (2.7 ± 0.6 versus 2.0 ± 0.8; P=0.04) and led to more slow and no-reflow reversal (91 % versus 33 %; P=0.02).93 Intragraft verapamil was effective in reducing no-reflow in SVG PCI.94–96 Intragraft verapamil (100–500 μg) improved flow in all 32 episodes of no-flow (TIMI flow grade 1.4 ± 0.8 pre- to 2.8 ± 0.5 post-intragraft verapamil; P<0.001) and re-established TIMI flow grade 3 in 88 % of cases.94 Prophylactic intragraft verapamil prior to SVG intervention mitigated occurrence of no-reflow compared with placebo (0 % versus 33.3 %; P=0.10) and increased TIMI frame count (53.3 ± 22.4 % faster versus 11.5 ± 38.9 %; P=0.016).96 Prophylactic intragraft nicardipine without the use of a distal protection device followed by direct stenting for degenerated SVG was shown to be safe and effective with low rates of slow-/no-reflow (2.4 %) and in-hospital MACE (4.4 %).97 Despite the lack of a control group for direct comparison, nicardipine appeared clinically beneficial compared with historical control data of SVG PCI procedures performed without nicardipine or distal protection devices.98,99 Nicardipine is not only used prophylactically during PCI, but is also safe and highly efficacious in reversing no-reflow, as demonstrated by Huang et al.100 Nitroprusside promotes nitric oxide production to induce vasodilation. One case-control study of patients who underwent SVG intervention pretreatment with nitroprusside (50–300 µg) reported significant

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Coronary reduction in periprocedural elevation of CK-MB levels >3x and >5x ULN, but no reduction in slow or no-reflow.101 However, another study found that nitroprusside (median dose 200 μg) injected into a diseased SVG led to highly significant and rapid improvement in both angiographic flow (P<0.01 compared with pretreatment angiogram) and blood flow velocity (P<0.01 compared with pretreatment angiogram) in SVG interventions complicated by either impaired flow or no-reflow.102

Conclusion SVG conduit degeneration, restenosis and friable lesions with high embolic potential attenuate long-term CABG survival, while SVG intervention

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53. B rilakis ES, Lichtenwalter C, Abdel-Karim AR, et al. Continued benefit from paclitaxel-eluting compared to bare-metal stent implantation in saphenous vein graft lesions during long-term follow-up of the SOS (Stenting of Saphenous Vein Grafts) trial. J Am Coll Cardiol Interv 2011;4:176–82. DOI: 10.1016/ j.jacc.2008.11.029; PMID: 19281920. 54. Vermeersch P, Agostoni P, Verheye S, et al. Randomized double-blind comparison of sirolimus-eluting stent versus bare-metal stent implantation in diseased saphenous vein grafts: six-month angiographic, intravascular ultrasound, and clinical follow-up of the RRISC Trial. J Am Coll Cardiol 2006;48:2423–31. DOI: 10.1016/j.jacc.2006.09.021; PMID: 17174178. 55. Vermeersch P, Agostoni P, Verheye S; DELAYED RRISC Investigators, et al. Increased late mortality after sirolimuseluting stents versus bare-metal stents in diseased saphenous vein grafts: results from the randomized DELAYED RRISC Trial. J Am Coll Cardiol 2007;50:261–7. DOI: 10.1016/ j.jacc.2007.05.010; PMID: 17631219. 56. Wiisanen ME, Abdel-Latif A, Mukherjee D, Ziada KM. Drugeluting stents versus bare-metal stents in saphenous vein graft interventions: a systematic review and meta-analysis. J Am Coll Cardiol Interv 2010;3:1262–73. DOI: 10.1016/j. jcin.2010.08.019; PMID: 21232720. 57. Lee MS, Yang T, Kandzari DE, et al. Comparison by metaanalysis of drug-eluting stents and bare metal stents for saphenous vein graft intervention. Am J Cardiol 2010;105:1076– 82. DOI: 10.1016/j.amjcard.2009.12.006; PMID: 2038165. 58. Meier P, Brilakis ES, Corti R, et al. Drug-eluting versus bare-metal stent for treatment of saphenous vein grafts: a meta-analysis. PLoS One 2010;5:e11040. DOI: 10.1371/journal. pone.0011040; PMID: 20548794. 59. Joyal D, Filion KB, Eisenberg MJ. Effectiveness and safety of drug-eluting stents in vein grafts: a meta-analysis. Am Heart J 2010;159:159–69.e4. DOI: 10.1016/j.ahj.2009.11.021; PMID: 20152212. 60. Sanchez-Recalde A, Jimenez Valero SJ, Moreno R, et al. Safety and efficacy of drug-eluting stents in saphenous vein grafts lesions: a meta-analysis. EuroIntervention 2010;6:149–60. DOI: 10.4244/; PMID: 20542811. 61. Testa L, Agostoni P, Vermeersch P, et al. Drug eluting stent versus bare metal stent in the treatment of saphenous vein graft disease: a systematic review and meta-analysis. EuroIntervention 2010;6:527–36. DOI: 10.4244/EIJ30V6I4A87; PMID: 20884442. 62. J.-M. Paradis, P. Bélisle, L. Joseph, et al. Drug-eluting or bare metal stents for the treatment of saphenous vein graft disease: a Bayesian meta-analysis. Circ Cardiovasc Interv 2010;3:565–76. DOI: 10.1161/CIRCINTERVENTIONS.110.949735; PMID: 21098743. 63. Hakeem A, Helmy T, Munsif S, et al. Safety and efficacy of drug eluting stents compared with bare metal stents for saphenous vein graft interventions: a comprehensive meta-analysis of randomized trials and observational studies comprising 7,994 patients. Catheter Cardiovasc Interv 2011;77:343–55. DOI: 10.1002/ccd.22720; PMID: 21328679. 64. Lee MS, Hu PP, Aragon J, et al. Comparison of sirolimuseluting stents with paclitaxel-eluting stents in saphenous vein graft intervention (from a multicenter Southern California Registry). Am J Cardiol 2010;106:337–41. DOI: 10.1016/ j.amjcard.2010.03.030; PMID: 20643242. 65. Taniwaki M, Räber L, Magro M, et al. Long-term comparison of everolimus-eluting stents with sirolimus- and paclitaxeleluting stents for percutaneous coronary intervention of saphenous vein grafts. EuroIntervention 2014;9:1432–40. DOI: 10.4244/EIJV9I12A241; PMID: 24064377. 66. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/ SCAI Guideline for Percutaneous Coronary Intervention: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv 2012;79:453–95. DOI: 10.1002/ccd.23438; PMID: 22328235. 67. Stone GW, Rogers C, Hermiller J, et al. Randomized comparison of distal protection with a filter-based catheter and a balloon occlusion and aspiration system during percutaneous intervention of diseased saphenous vein aorto-coronary bypass grafts. Circulation 2003;108:548–53. DOI: 10.1161/01.CIR.0000080894.51311.0A; PMID: 12874191. 68. Mauri L, Rogers C, Baim DS. Devices for distal protection during percutaneous coronary revascularization. Circulation 2006;113:2651–6. DOI: 10.1161/CIRCULATIONAHA.105.551770; PMID: 16754813.

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69. B aim DS, Wahr D, George B, et al. Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts. Circulation 2002;105:1285–90. PMID: 11901037. 70. Carrozza JP Jr, Mumma M, Breall JA, et al. Randomized evaluation of the TriActiv balloon-protection flush and extraction system for the treatment of saphenous vein graft disease. J Am Coll Cardiol 2005;46:1677–83. DOI: 10.1016/ j.jacc.2005.06.073; PMID: 16256868. 71. Stone GW, Rogers C, Hermiller J, et al. Randomized comparison of distal protection with a filter-based catheter and a balloon occlusion and aspiration system during percutaneous intervention of diseased saphenous vein aorto-coronary bypass grafts. Circulation 2003;108:548–53. DOI: 10.1161/01.CIR.0000080894.51311.0A; PMID: 12874191. 72. Halkin A, Masud Z, Rogers C, et al. Six-month outcomes after percutaneous intervention for lesions in aortocoronary saphenous vein grafts using distal protection devices: results from the FIRE trial. Am Heart J 2006;151:915.e1–7. DOI: 10.1016/j.ahj.2005.09.018; PMID: 16569562. 73. Vermeersch P, Agostoni P, Verheye S, et al. Increased late mortality after sirolimus-eluting stents versus bare-metal stents in diseased saphenous vein grafts: results from the randomized DELAYED RRISC Trial. J Am Coll Cardiol. 2007; 50(3):261–7. 74. Dixon SR. Saphenous vein graft protection in a distal embolic protection randomized trial. Presented at: Transcatheter Cardiovascular Therapeutics 2005,; Washington, DC, USA, 18 October 2005. 75. Kereiakes DJ, Turco MA, Breall J, et al. A novel filterbased distal embolic protection device for percutaneous intervention of saphenous vein graft lesions: results of the AMEthyst randomized controlled trial. JACC Cardiovasc Interv 2008;1:248–57. DOI: 10.1016/j.jcin.2008.03.009; PMID: 19463308. 76. Holmes DR, Coolong A, O’Shaughnessy C, et al. Comparison of the CardioShield filter with the GuardWire balloon in the prevention of embolisation during vein graft intervention: results from the CAPTIVE randomised trial. EuroIntervention 2006;2:161–8. PMID: 19755255. 77. Mauri L, Cox D, Hermiller J, et al. The PROXIMAL trial: proximal protection during saphenous vein graft intervention using the Proxis Embolic Protection System: a randomized, prospective, multicenter clinical trial. J Am Coll Cardiol 2007;50:1442–9. DOI: 10.1016/j.jacc.2007.06.039; PMID: 17919563. 78. Mehta SK, Frutkin AD, Milford-Beland S, et al. Utilization of distal embolic protection in saphenous vein graft interventions (an analysis of 19,546 patients in the American College of Cardiology-National Cardiovascular Data Registry). Am J Cardiol 2007;100:1114–8. DOI: 10.1016/j. amjcard.2007.04.058; PMID: 17884373. 79. Kaliyadan AG, Chawla H, Fischman DL, et al. Importance of adjunct delivery techniques to optimize deployment success of distal protection filters during vein graft intervention. J Invasive Cardiol 2017;29:54–58. PMID: 27974668. 80. Mak KH, Challapalli R, Eisenberg MJ, et al. Effect of platelet glycoprotein IIb/IIIa receptor inhibition on distal embolization during percutaneous revascularization of aortocoronary saphenous vein grafts: EPIC Investigators. Evaluation of IIb/ IIIa platelet receptor antagonist 7E3 in Preventing Ischemic Complications. Am J Cardiol 1997;80:985–8. PMID: 9352964. 81. Roffi M, Mukherjee D, Chew DP, et al. Lack of benefit from intravenous platelet glycoprotein IIb/IIIa receptor inhibition as adjunctive treatment for percutaneous interventions of aortocoronary bypass grafts: a pooled analysis of five randomized clinical trials. Circulation 2002;106:3063–7. PMID: 12473552. 82. Ellis SG, Lincoff AM, Miller D. Reduction in complications of angioplasty with abciximab occurs largely independently of baseline lesion morphology: EPIC and EPILOG investigators. Evaluation of 7E3 for the Prevention of Ischemic Complications. Evaluation of PTCA to Improve Long-Term Outcome With Abciximab GPIIb/IIIa Receptor Blockade. J Am Coll Cardiol 1998;32:1619–23. PMID: 9822087. 83. Jonas M, Stone GW, Mehran R, et al. Platelet glycoprotein IIb/IIIa receptor inhibition as adjunctive treatment during saphenous vein graft stenting: differential effects after randomization to occlusion or filter-based embolic protection. Eur Heart J 2006;27:920–8. DOI: 10.1093/eurheartj/ehi736; PMID: 16415300. 84. Harskamp RE, Beijk MA, Damman P, et al. Prehospitalization antiplatelet therapy and outcomes after saphenous vein graft intervention. Am J Cardiol 2013;111:153–8. DOI: 10.1016/ j.amjcard.2012.09.010; PMID: 23102882.

85. R ha SW, Kuchulakanti PK, Pakala R, et al. Bivalirudin versus heparin as an antithrombotic agent in patients who undergo percutaneous saphenous vein graft intervention with a distal protection device. Am J Cardiol 2005;96:67–70. DOI: 10.1016/ j.amjcard.2005.02.047; PMID: 15979436. 86. Kumar D, Dangas G, Mehran R. Comparison of bivalirudin versus bivalirudin plus glycoprotein IIb/IIIa inhibitor versus heparin plus glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes having percutaneous intervention for narrowed saphenous vein aorto-coronary grafts (the ACUITY Trial Investigators). Am J Cardiol 2010;106:941–5. DOI: 10.1016/j.amjcard.2010.06.003; PMID: 20854954. 87. Lee CH, Low A, Tai BC, et al. Pretreatment with intracoronary adenosine reduces the incidence of myonecrosis after nonurgent percutaneous coronary intervention: a prospective randomized study. Eur Heart J 2007;28:19–25. DOI: 10.1093/ eurheartj/ehl411; PMID: 17132650. 88. Desmet WJ, Dens J, Coussement P, Van de Werf F. Does adenosine prevent myocardial micronecrosis following percutaneous coronary intervention? The ADELINE pilot trial. ADEnosine LImit myocardial Necrosis. Heart 2002;88:293–5. PMID: 12181228. 89. Marzilli M, Orsini E, Marraccini P, Testa R. Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction. Circulation 2000;101:2154–9. PMID: 10801755. 90. Stoel MG, Marques KM, de Cock CC, et al. High dose adenosine for suboptimal myocardial perfusion ater primary PCI: a randomized placebo-controlled pilot study. Catheter Cardiovasc Interv 2008;71:283–9. DOI: 10.1002/ccd.21334; PMID: 17985384. 91. Assali AR, Sdringola S, Ghani M, et al. Intracoronary adenosine administered during percutaneous intervention in acute myocardial infarction and reduction in the incidence of “no reflow” phenomenon. Catheter Cardiovasc Interv 2000;51:27–32. PMID: 10973014. 92. Fischell TA, Carter AJ, Foster MT, et al. Reversal of “no reflow” during vein graft stenting using high velocity boluses of intracoronary adenosine. Cathet Cardiovasc Diagn 1998;45:360–5. PMID: 9863736. 93. Sdringola S, Assali A, Ghani M, et al. Adenosine use during aortocoronary vein graft interventions reverses but does not prevent the slow-no reflow phenomenon. Catheter Cardiovasc Interv 2000;51:394–9. PMID: 11108667. 94. Kaplan BM, Benzuly KH, Kinn JW, et al. Treatment of no-reflow in degenerate saphenous vein graft interventions: comparison of intracoronary verapamil and nitroglycerin. Cathet Cardiovasc Diagn 1996;39:113–8. DOI: 10.1002/(SICI) 1097-0304(199610)39:2<113::AID-CCD1>3.0.CO;2-I; PMID: 8922307. 95. Piana RN, Paik GY, Mosucci M, et al. Incidence and treatment of ‘no-reflow’ after percutaneous coronary intervention. Circulation 1994;89:2514–8. PMID: 8205658. 96. Michaels AD, Appleby M, Otten MH, et al. Pretreatment with intragraft verapamil prior to percutaneous coronary intervention of saphenous vein graft lesions: results of the randomized, controlled vasodilator prevention on no-reflow (VAPOR) trial. J Invasive Cardiol 2002;14:299–302. PMID: 12042618. 97. Fischell TA, Subraya RG, Ashraf K, et al. “Pharmacologic” distal protection using prophylactic, intragraft nicardipine to prevent no-reflow and non-Q wave myocardial infarction during elective saphenous vein graft intervention. J Invasive Cardiol 2007;19:58–62. PMID: 17268038. 98. Resnic FS, Wainstein M, Lee MK, et al. No-reflow is an independent predictor of death and myocardial infarction after percutaneous coronary intervention. Am Heart J 2003;145:42–6. DOI: 10.1067/mhj.2003.36; PMID: 12514653. 99. Abbo KM, Dooris M, Glazier S, et al. Features and outcome of no-reflow after percutaneous coronary intervention. Am J Cardiol 1995;75:778–82. PMID: 7717278. 100. Huang R, Patel P, Walinsky P, et al. Efficacy of intracoronary nicardipine in the treatment of no-reflow during percutaneous coronary intervention. Catheter Cardiovasc Interv 2006;68:671–6. DOI: 10.1002/ccd.20885; PMID: 17034064. 101. Zoghbi GJ, Goyal M, Hage F, et al. Pretreatment with nitroprusside for microcirculatory protection in saphenous vein graft interventions. J Invasive Cardiol 2009;21:34–9. PMID: 19182287. 102. Hillegass WB, Dean NA, Liao L, et al. Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience. J Am Coll Cardiol 2001;37:1335–43. PMID: 11300444.

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Coronary

Unprotected Left Main Coronary Artery Disease: Management in the Post NOBLE and EXCEL Era Nyal Borges, Samir R Kapadia and Stephen G Ellis Division of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA

Abstract The optimal management of unprotected left main coronary artery (ULMCA) disease is currently a debated topic. Percutaneous coronary intervention (PCI) has seen an increased adoption for the management of ULMCA disease after numerous small-scale randomised trials and cohort studies showed equipoise with coronary artery bypass grafting (CABG) for low complexity lesions. The recently published NOBLE and EXCEL trials are two of the largest international randomised clinical trials comparing PCI and CABG in patients with ULMCA disease. In lieu of all the available evidence, PCI appears to be equivalent to CABG in regard to mortality in patients with ULMCA disease. In non-diabetic patients with low complexity coronary disease (SYNTAX score ≤32), PCI appears to be a reasonable alternative to CABG, especially for ostial and midshaft left main coronary lesions. CABG is preferable in the presence of diabetes, multivessel coronary disease in addition to ULMCA or complex coronary lesions (SYNTAX score >33) including distal left main lesions.

Keywords Left main coronary artery, percutaneous coronary intervention, coronary artery bypass graft, SYNTAX score, NOBLE, EXCEL Disclosure: The authors have no conflicts of interest to declare. Received: 29 June 2017 Accepted: 4 August 2017 Citation: Interventional Cardiology Review 2017;12(2):92–6. DOI: 10.15420/icr.2017:18:2 Correspondence: Nyal Borges, Division of Cardiovascular Medicine, Cleveland Clinic Foundation, J3-129, 9500 Euclid Avenue, Cleveland, OH 44195, USA. E: borgesn@ccf.org

Obstructive unprotected left main coronary artery (ULMCA) disease has been recognised as a high-risk condition since the 1960s owing to the large quantum of myocardium supplied by this system (see Figure 1). In that era, medical therapy was the only available management and 5-year mortality rates exceeded 60 %.1 With the introduction of coronary artery bypass grafting (CABG) it became clear that surgical management of these patients conferred a significant mortality benefit over medical therapy alone.2,3 For several decades CABG was accepted as the first line management option for ULMCA disease while techniques for the percutaneous management of coronary atherosclerosis were in the early stages of development. While percutaneous transluminal coronary angioplasty was deemed too high risk in this setting, the introduction of bare-metal stents (BMS) in 1986 marked the beginning of the era of percutaneous management of ULMCA disease.4 Early results of BMS use were mixed with intraprocedural mortality rates as high as 10 % for ULMCA interventions and 3-year survival rates of 30 %.4 In-stent restenosis was also identified as a significant barrier to the adoption of BMS in this patient population, with mortality rates as high as 40 % reported. Drugeluting stents (DES) were developed primarily to tackle the high rates of in-stent restenosis being observed, and numerous studies confirmed the overall safety and long-term patency of DES. Advances in technique and stent design combined with newer antiproliferative drugs led to the increasing adoption of percutaneous coronary intervention (PCI) in the management of ULMCA disease in the mid-2000s. In the context of increasing adoption of PCI to treat ULMCA disease, the need for robust clinical trials comparing PCI to CABG arose. The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) trial sought to determine the optimal

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revascularisation strategy for patients with multivessel coronary artery disease or ULMCA disease with randomisation to either CABG or PCI with paclitaxel-eluting (TAXUS, Boston Scientific) stents.5 The SYNTAX trial was a prospective, multicentre, randomised clinical trial that successfully randomised 1800 patients to CABG or PCI groups and enrolled 1275 patients in nested registries for PCI or CABG, as they were not suitable candidates for both procedures. The trial was designed to test the non-inferiority of PCI compared to CABG. The primary endpoint was a composite of death (all cause), stroke, MI or repeat revascularisation. Over a period of 12 months the primary endpoint occurred in 17.8 % of patients in the PCI group versus 12.4 % in the CABG group, which failed the prespecified non-inferiority margin. The observed difference in primary endpoint was primarily driven by a higher repeat revascularisation rate in the PCI group (13.5 % versus 5.9 %) and no difference was seen in all-cause death rate or the combined endpoint of all-cause death, MI and stroke. Thus, PCI was deemed to be inferior to CABG in the SYNTAX trial for management of multivessel coronary artery disease. Subgroup analysis of the ULMCA group (n=705), while considered strictly hypothesis generating given the failure of the primary outcome, painted a more nuanced picture.6 No difference was observed for the primary composite endpoint between the CABG and PCI groups (13.7 % and 15.8 %, p=0.44) in this population. PCI appeared numerically favorable in regard to major adverse cardiac and cerebrovascular events (MACCE) in isolated ULMCA disease (7.1 % versus 8.5 %), left main plus concomitant single vessel disease (7.5 % versus 13.2 %) and those with low or intermediate SYNTAX scores (≤32). CABG was favored in those with two or three vessel disease in regard to MACCE. Overall, PCI MACCE rates were driven

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Unprotected Left Main Coronary Artery Disease largely by increased repeat revascularisation (6.5 % versus 11.8 %; 95 % CI [1.0–9.6], p=0.02), while the stroke rate in the CABG group was considerably higher at 1-year follow-up (2.7 % versus 0.3 %; Δ−2.4 %; 95 % CI [−4.2–−0.1], p=0.009). Thus, the SYNTAX trial suggested that in patients with ULMCA disease, especially those with low complexity lesions as identified by SYNTAX scores ≤32, PCI could be a reasonable alternative to CABG with the benefit of fewer strokes at 12 months being balanced by higher rates of repeat revascularisation. The final results of the left main subgroup within the SYNTAX trial were reported at 5-year follow-up and confirmed the 1-year outcomes with no difference in MACCE between the PCI and CABG groups (36.9 % versus 31.0 %, p=0.12) in the ULMCA disease subgroup.7 When analysed by SYNTAX score, MACCE in the high-risk group (≥33) was significantly higher with PCI (46.5 % versus 29.7 %, p=0.003) and repeat revascularisation rates remained higher in the PCI group irrespective of SYNTAX score (26.7 % versus 15.5 %, p<0.01). While mortality was no different in the two groups at 5 years, the benefit of PCI in regard to lower stroke incidence persisted at 5 years (1.5 % versus 4.3 %, p=0.03). These findings were largely confirmed by smaller scale randomised Left Main Coronary Artery Stenting (LE MANS) and Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-eluting Stent in Patients with Left Main Coronary Artery Disease (PRECOMBAT) trials as well as meta-analyses of high-quality studies completed at the time.8–11 In the background of the SYNTAX trial, non-randomised single-centre and registry-based studies were also underway, the largest of which was the Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization (MAIN COMPARE).12 This cohort study enrolled 2240 patients from 12 centres in Korea with a minimum follow-up of 3 years with patients undergoing CABG or PCI with BMS early on and subsequently first- and second-generation (sirolimus) DES. Overall, no difference was noted between the two groups in regard to death or a composite endpoint of death, MI or stroke. However, target vessel revascularisations were significantly higher in the PCI group (HR 4.55; 95 % CI [2.88–7.20], p<0.001). Target vessel revascularisation (TVR) emerged as a constant signal that was driving higher MACCE rates in ULMCA disease treated with PCI in both randomised trials and cohort studies. Further research into risk factors for TVR elucidated that age ≥75, acute coronary syndrome presentation and distal/bifurcation left main (LM) lesion were independently associated with TVR rates.13 TVR rates for ostial/shaft ULMCA PCI and single-stent distal LM disease have been reported to be <5 %. Two-stent technique for bifurcation lesions has been shown to confer higher TVR rates up to 25 % and the optimal technique (minicrush, T-stent, etc.) remains unknown. Nonetheless, it was expected that advances in stent design and introduction of newer DES would impact TVR rates based on results of meta-analyses showing progressive reduction in TVR rates with newer generation DES.14,15 Given the growing body of evidence supporting the non-inferiority of PCI compared to CABG in regard to mortality, guidelines from the American Heart Association and the European Society of Cardiology, which listed PCI for ULMCA as a Class III indication, were updated in 2011.16 PCI for ULMCA disease was assigned a Class IIb recommendation for patients with low to intermediate (≤32) SYNTAX score and bifurcation ULMCA disease, and a Class IIa recommendation

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Figure 1: Example of an Unprotected Distal Left Main Coronary Artery Stenosis

for those with low SYNTAX scores (<23) and ostial/shaft ULMCA disease. However, the evidence supporting these recommendations was considered to be imperfect given it was derived primarily from the ULMCA subgroup analysis of the SYNTAX trial, which was considered to be hypothesis generating only. Furthermore, the effect of latest generation DES on MI and TVR rates was not represented in any randomised clinical trial in this patient population. The Nordic–Baltic– British Left Main Revascularization (NOBLE) study and the Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trials were designed to address these shortcomings in the available evidence.17,18 The NOBLE trial was designed as a prospective, open-label noninferiority trial and successfully randomised 1201 patients in 36 centres in northern Europe in a 1:1 fashion to PCI or CABG. Five hundred and ninety-eight patients were assigned to PCI group with the majority (92 %) of patients receiving BIOLIMUS™-eluting stents (Biosensors International Ltd.). Ostial and midshaft lesions were treated with single-stent technique while bifurcation/distal LM lesions could be treated with the two-stent technique. Intravascular ultrasound was strongly recommended pre- and post-stent deployment. Six hundred and three patients were assigned to the CABG group and current standard of care practices were recommended, including left internal mammary grafting for revascularisation of the left anterior descending artery and saphenous vein or arterial grafts for other vessel revascularisation. The primary endpoint was a composite of MACCE (death from any cause, non-procedural MI, repeat revascularisation or stroke). Secondary endpoints included the individual components of the primary endpoint, definite stent thrombosis and symptomatic graft occlusion. In the PCI group, 580 of 595 patients underwent PCI and seven received CABG instead. Bifurcation stenting was performed in 88 % of patients, with two-stent technique in 35 % of those patients. In the CABG group, 567 of 592 received CABG and 23 crossed over to PCI arm. Follow-up was available for 90 % of randomised patients at 1 year; however, dropout rates were high with only 38 % and 35 % of patients with follow-up at 5 years in PCI and CABG groups, respectively. The primary outcome occurred in 28 % versus 15 % of patients in PCI versus CABG groups at 5 years (HR 1.51; 95 % CI [1.13–2.0]), which exceeded the prespecified non-inferiority margin (see Table 1). However, at 1 year no difference was noted between the two groups. Analysing the individual components of MACCE, at 5 years no differences were appreciated between the two groups in all-cause mortality or stroke. Repeat revascularisation rates were higher in PCI versus CABG group (15 % versus 10 %, p=0.03) as were non-

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Coronary Table 1: Summary of Major Clinical Trial Endpoints Evaluating PCI versus CABG for Management of Unprotected Left Main Coronary Artery Disease Study

30 day

All-cause Mortality (HR PCI vs. CABG, p value) 1 Year 3 year

5 year

EXCEL NOBLE PRECOMBAT SYNTAX (Left Main Sub group)

0.90 (NS) 0.28 (NS) NA NA

NA 0.53 (NS) 0.74 (NS) 1.04 (NS)

NA 1.08 (NS) 0.73 (NS) 0.88 (NS)

30 day

EXCEL NOBLE PRECOMBAT SYNTAX (Left Main Sub group)

0.63 (0.42–0.95, p=0.02) 1.19 (NS) NA NA

NA 1.38 (NS) 1.34 (NS) 1.05 (NS)

30 day

Revascularization (HR PCI vs. CABG, p value) 1 Year 3 year

5 year

EXCEL NOBLE PRECOMBAT SYNTAX (Left Main Sub group)

0.54 (NS) 0.70 (NS) NA NA

NA 1.35 (NS) 1.25 (NS) 1.8 (p=0.02)

NA 1.58 (1.04–2.17, p=0.03) 1.47 (NS) 1.82 (1.28–2.57, p<0.001)

30 day

Stroke (HR PCI vs. CABG, p value) 1 Year 3 year

5 year

EXCEL NOBLE PRECOMBAT SYNTAX (Left Main Sub group)

0.50 (NS) 0.25 (p=0.04) NA NA

NA 0.33 (NS) 0.20 (NS) 0.11 (p=0.009)

NA 2.2(NS) 0.99 (ITS) 0.3 (0.12–0.92, p=0.03)

30 day

MACCE (HR PCI vs. CABG, p value) 1 Year 3 year

5 year

EXCEL NOBLE PRECOMBAT SYNTAX (Left Main Sub group)

NA NA NA 1.16 (NS)

NA 1.00 (NS) 1.33 (NS ) 1.16 (NS)

NA 1.51 (1.13–2.00, p=0.004) 1.27 (NS) 1.23 (NS)

1.34 (NS) NA NA 0.86 (NS)

Myocardial Infarction (HR PCI vs. CABG, p value) 1 Year 3 year 5 year 0.93 (NS) NA NA 3.0 (1.4–5.89, p=0.004) 1.20 (NS) 1.20 (NS) 1.77 (NS) 1.67 (NS)

1.72 (1.27–2.33, p<0.01) NA 1.48 (NS) 1.7 (p=0.004)

0.77 (NS) NA 1.00 (NS) 0.3 (p=−0.02)

NA NA 1.29 (NS ) 1.2 (NS)

CABG = coronary artery bypass grafting; EXCEL = Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; HR = heart rate; NOBLE = Nordic–Baltic–British Left Main Revascularization; MACCE = major adverse cardiac and cerebrovascular events; PCI = percutaneous coronary intervention; PRECOMBAT = Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-eluting Stent in Patients with Left Main Coronary Artery Disease.

procedural MIs (6 % versus 2 %, p=0.004). Contrary to prior studies, the SYNTAX score was not associated with outcomes in the PCI group and CABG was favored over PCI in the low SYNTAX score group. At 30 days PCI was favorable to CABG in regard to re-operation for bleeding, transfusions and index hospitalisations. Both the increased rate of non-procedural MIs and the surprising finding that CABG was superior to PCI for low complexity coronary lesions can be explained by the high percentage of distal LM interventions (88 %) in the NOBLE trial. The 8 % BMS use in the PCI group along with higher strut thickness of BIOLIMUS-eluting stents (120 µm) compared to modern everolimus-eluting stents could have impacted the revascularisation, non-procedural MI and stent thrombosis rates given their association with increased thrombogenicity. From a trial design standpoint, critics of the NOBLE trial highlight the change in assessment of MACCE from 2 years to 5 years and ultimately 3 years due to low event rates as a major limitation of this study, which may have biased results. It is also important to note that most randomised trials of ULMCA management, including NOBLE, enrolled CABG patients who are at low surgical risk and, therefore, short- and long-term surgical outcomes may be better in these trials than what can be expected in routine clinical practice.19 Lastly, the generalizability of the results has to be considered given that BIOLIMUS-eluting stents are not currently available in the many nonEuropean countries, including the US. The EXCEL trial was undertaken to specifically test the hypothesis from the SYNTAX ULMCA subgroup analysis that patients with low or intermediate (≤32) SYNTAX scores randomised to PCI or CABG

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had equivocal outcomes. EXCEL was designed as an international, open-label, multicentre trial that randomised 1905 patients with unprotected ULMCA disease to PCI with XIENCE™ stents (Abbott Laboratories) versus CABG. In the PCI arm, unlike previous trials, complete revascularisation of all ischaemic territories was the expected standard and utilisation of intravascular ultrasound to assess lesion size and stent apposition was strongly recommended. Medical therapy in this arm also reflected current standard of care with dual antiplatelet therapy use mandatory and heparin or bivalirudin use during catheterisation. The management of CABG also reflected current standard of care practices including complete revascularisation, utilisation of arterial grafts for left anterior descending artery revascularisation and utilisation of appropriate antiplatelet therapy in the perioperative and postoperative periods. The primary outcome in the trial was a composite endpoint of death, stroke or MI at 3 years. Secondary outcomes included composite endpoint of all-cause mortality, stroke, MI or ischaemia-driven revascularisation at 3 years, stroke at 30 days, ischaemia-driven revascularisation at 3 years or health-related quality of life and treatment costs. Of the 1905 patients randomised in the trial, 942 of 948 in the PCI arm underwent complete revascularisation (mean 2.4 stents/patient) and 940 of 957 in the CABG group underwent complete surgical revascularisation (mean 2.6 grafts/patient). The mean duration of follow-up was 3 years in both groups. The primary endpoint occurred in 15.4 % of patients in PCI group versus 14.7 % of patients in CABG group at 3 years (HR 1.0; 95 % CI [0.79–1.26], p=0.02 for inferiority). However,

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Unprotected Left Main Coronary Artery Disease at 30 days PCI was favored for the same composite endpoint (HR 0.61; 95 % CI [0.42–0.88], p=0.008), driven primarily by fewer MIs in the PCI arm, with a late catch-up noted by landmark analysis in the PCI group. Consistent with previous studies, within 30 days of revascularisation PCI had fewer adverse events including arrhythmias, infections requiring antibiotics and blood transfusions, compared to CABG (8.1 % versus 23 %, p<0.001). However, ischaemia-driven revascularisation remained higher in the PCI group (12.6 % versus 7.5 %, p<0.001), though stent thrombosis rates with XIENCE stents were lower (0.7 %) than the incidence of symptomatic graft occlusion as well as the stent thrombosis rate observed in the SYNTAX trial with TAXUS stents, highlighting the reduced thrombogenicity of the newer generation DES. There are several important takeaway points from the EXCEL trial that must be highlighted. The EXCEL trial confirmed that PCI appears to be equivalent to CABG in regard to meaningful outcomes of mortality, stroke and MI at 3-year follow-up in patients with low or intermediate risk anatomy with SYNTAX score ≤32. It is important to note that the primary endpoints for the EXCEL and NOBLE trials were different: the NOBLE trial included repeat revascularisation in the composite primary endpoint, with increased revascularisation partly driving the difference between CABG and PCI groups in the primary endpoint; the SYNTAX trial demonstrated that increased revascularisation does not translate to increased rates of MI or death and so the validity of this primary outcome design has been questioned. Furthermore, while critics of this trial cite the apparent separation of the mortality curves at the 3-year follow-up mark, the significance of this trend is unknown based on available data and long-term follow-up at 5 years and beyond is needed to further explore this finding. In this lower-risk population PCI also had less morbidity in the periprocedural period. The importance of this finding cannot be overemphasised as it is likely to affect decision making by patients in regard to personalised treatment plans. Unlike the SYNTAX trial, the EXCEL trial reflects outcomes of PCI and CABG utilising the latest technology and standard of care medical therapies, making the results very applicable to current global practices given the wide scale availability of XIENCE stents.

Conclusion Taken together, the current body of evidence for the optimal management of ULMCA disease does not strongly support the use of either PCI or CABG exclusively for all patients (see Figure 2). Most importantly, there is no mortality difference between the two treatment strategies and a recent meta-analysis including the SYNTAX, PRECOMBAT, Buodriot et al., NOBLE and EXCEL trials shows no difference in safety endpoints.20 In patients with high-risk anatomy or multivessel coronary disease with left main stenosis, CABG is clearly the better management strategy with

ruschke AV, Proudfit WL, Sones FM. Progress study of 590 B consecutive nonsurgical cases of coronary disease followed 5–9 Years. Circulation 1973;47(6):1154–63. PMID: 4709535. Chaitman BR, Fisher LD, Bourassa MG, et al. Effect of coronary bypass surgery on survival patterns in subsets of patients with left main coronary artery disease. Report of the Collaborative Study in Coronary Artery Surgery (CASS). Am J Cardiol 1981;48(4):765–77. PMID: 7025604. Takaro T, Hultgren HN, Lipton MJ, Detre KM. The VA cooperative randomized study of surgery for coronary arterial occlusive disease II. Subgroup with significant left main lesions. Circulation 1976;54(6):III107–17. PMID: 791537. O’Keefe JH, Hartzler GO, Rutherford BD, et al. Left main coronary angioplasty: early and late results of 127 acute and elective procedures. Am J Cardiol 1989;64(3):144–7. PMID: 2525868. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360(10):961–72. DOI: 10.1056/NEJMoa0804626. PMID: 19228612.

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Figure 2: Management Algorithm for Unprotected Left Main Coronary Artery Disease Unprotected Left Main Coronary Artery Disease (>70 % angiographic lesion, FFR <0.80)

Candidate for CABG?

Consider PCI

Yes

Syntax score >32 or multivessel CAD or diabetes

Yes

Perform CABG

Ostial or Midshaft Lesion

Yes

Distal/Bifurcation Lesion

Yes

Either CABG or PCI reasonable If single stent adequate, then PCI or CABG reasonable If two stent technique required, then CABG preferred but PCI could be attempted

CABG = coronary artery bypass grafting; CAD = coronary artery disease; PCI = percutaneous coronary intervention.

superior long-term outcomes. For patients with low or intermediate risk anatomy as defined by a SYNTAX score ≤32, either PCI or CABG are reasonable with PCI being associated with less morbidity, shorter hospital stays and lower stroke rates in the periprocedural period than CABG, but also resulting in high rates of repeat revascularisation over time despite use of latest generation DES, procedural techniques and medical therapy. Results of very long-term follow-up of patients in these trials would be particularly useful to assess delayed benefits or shortcomings of either management strategy. Over time it is likely that advances in PCI techniques, including development and adoption of drug-eluting dedicated bifurcation stents for distal LM lesions could reduce revascularisation rates, thereby addressing the Achilles heel of this management strategy. At present, incorporating the results of the NOBLE and EXCEL trials, a personalised, patient-centred approach, should be adopted in the management of ULMCA disease. It is unlikely that additional large randomised trials will be performed comparing CABG and PCI for the management of ULMCA disease in the near future. Given the lack of mortality difference between these two management strategies, the focus should now shift to improving outcomes for both CABG and PCI in ULMCA management. n

orice MC, Serruys PW, Kappetein AP, et al. Outcomes M in patients with de novo left main disease treated with either percutaneous coronary intervention using paclitaxel-eluting stents or coronary artery bypass graft treatment in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial. Circulation 2010;121(24):2645–53. DOI: 10.1161/ CIRCULATIONAHA.109.899211. PMID: 20530001. Morice MC, Serruys PW, Kappetein AP, et al. Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery trial. Circulation 2014;129(23):2388–94. DOI: 10.1161/CIRCULATIONAHA.113.006689. PMID: 24700706 Buszman PE, Buszman PP, Kiesz RS, et al. Early and longterm results of unprotected left main coronary artery stenting: the LE MANS (Left Main Coronary Artery Stenting) registry. J Am Coll Cardiol 2009;54(16):1500–11. DOI: 10.1016/ j.jacc.2009.07.007. PMID: 19699048.

10.

11.

12.

13.

ark SJ, Kim YH, Park DW, et al. Randomized trial of stents P versus bypass surgery for left main coronary artery disease. N Engl J Med 2011;364(18):1718–27. DOI: 10.1056/ NEJMoa1100452. PMID: 21463149. Athappan G, Patvardhan E, Tuzcu ME, et al. Left main coronary artery stenosis: a meta-analysis of drug-eluting stents versus coronary artery bypass grafting. JACC Cardiovasc Interv 2013;6(12):1219–30. DOI: 10.1016/j.jcin.2013.07.008. PMID: 24355112. Boudriot E, Thiele H, Walther T, et al. Randomized comparison of percutaneous coronary intervention with sirolimus-eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis. J Am Coll Cardiol 2011;57(5):538–45. DOI: 10.1016/j.jacc.2010.09.038. PMID: 21272743. Seung KB, Park DW, Kim YH, et al. Stents versus coronaryartery bypass grafting for left main coronary artery disease. N Engl J Med 2008;358(17):1781–92. DOI: 10.1056/NEJMoa 0801441. PMID: 18378517. Min SY, Park DW, Yun SC, et al. Major predictors of long-term clinical outcomes after coronary revascularization in patients with unprotected left main coronary disease: analysis from

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Coronary the MAIN-COMPARE study. Circ Cardiovasc Interv 2010;3(2):127– 33. DOI: 10.1161/CIRCINTERVENTIONS.109.890053. PMID: 20407112. 14. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Clinical outcomes with bioabsorbable polymer- versus durable polymer-based drugeluting and bare-metal stents: evidence from a comprehensive network meta-analysis. J Am Coll Cardiol 2014;63(4):299–307. DOI: 10.1016/j.jacc.2013.09.061. PMID: 24211507. 15. Bangalore S, Kumar S, Fusaro M, et al. Short- and long-term outcomes with drug-eluting and bare-metal coronary stents: a mixed-treatment comparison analysis of 117 762 patient-years of follow-up from randomized trials. Circulation 2012;125(23):2873–91. DOI: 10.1161/ CIRCULATIONAHA.112.097014. PMID: 22586281.

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16. L evine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/ SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practise Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011;124(23):e574–651. DOI: 10.1161/CIR.0b013e31823ba622. PMID: 22064601. 17. Stone GW, Sabik JF, Serruys PW, et al. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med 2016;375(23):2223–35. DOI: 10.1056/ NEJMoa1610227. PMID: 27797291. 18. Mäkikallio T, Holm NR, Lindsay M, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE):

a prospective, randomised, open-label, non-inferiority trial. Lancet 2016;388(10061):2743–52. DOI: 10.1016/S01406736(16)32052-9. PMID: 27810312. 19. Agarwal S, Zaman T, Tuzcu EM, et al. Comparison of outcomes of unprotected left main versus multivessel coronary artery interventions. Am J Cardiol 2011;108(1): 15–20. DOI: 10.1016/j.amjcard.2011.03.002. PMID: 21529732. 20. Nerlekar N, Ha FJ, Verma KP, et al. Percutaneous coronary intervention using drug-eluting stents versus coronary artery bypass grafting for unprotected left main coronary artery stenosis: a meta-analysis of randomizes trails. Circ Cardiovasc Interv 2016;9(12):e004729. DOI: 10.1161/ CIRCINTERVENTIONS.116.004729. PMID: 27899408.

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Coronary

Performing and Interpreting Fractional Flow Reserve Measurements in Clinical Practice: An Expert Consensus Document Stephan Achenbach, 1 Tanja Rudolph, 2 Johannes Rieber, 3 Holger Eggebrecht, 4 Gert Richardt, 5 Thomas Schmitz, 6 Nikos Werner, 7 Florian Boenner 8 and Helge Möllmann 9 1. Department of Cardiology, Friedrich-Alexander University (FAU) Erlangen-Nuremberg, Germany; 2. Department of Internal Medicine 3, University Hospital, Cologne, Germany; 3. Heart Centre, Municipal Hospitals of Munich, Munich, Germany; 4. Cardio-Angiologic Centre Bethanien (CCB), Frankfurt, Germany; 5. Heart Centre Segeberg, Segeberg, Germany; 6. Contilia Heart and Vascular Centre, Essen, Germany; 7. Department of Internal Medicine 2, University Hospital, Bonn, Germany; 8. Department of Internal Medicine, University Hospital, Düsseldorf, Germany; 9. Department of Cardiology, St Johannes Hospital, Dortmund, Germany

Abstract Fractional flow reserve (FFR) measurements can determine the haemodynamic relevance of coronary artery stenoses. Current guidelines recommend their use in lesions in the absence of non-invasive proof of ischaemia. The prognostic impact of FFR has been evaluated in randomised trials, and it has been shown that revascularisation can be safely deferred if FFR is >0.80, while revascularisation of stenoses with FFR values ≤0.80 results in significantly lower event rates compared to medical treatment. Left main stenoses, aorto-ostial lesions, as well as patients with left ventricular hypertrophy and severely-impaired ejection fraction, have been excluded from large, randomised trials. While FFR measurements are relatively straightforward to perform, uncertainty about procedural logistics, as well as data acquisition and interpretation in specific situations, could explain why they are not widely used in clinical practice. We summarise the clinical data in support of FFR measurements, and provide recommendations for performing and interpreting the procedure.

Keywords Coronary artery stenosis, revascularisation, fractional flow reserve, coronary artery disease, angiography, adenosine, ischaemia Disclosure: Helge Möllmann (speaker and proctor honoraria, St Jude Medical), Gert Richardt (speaker honoraria, St Jude Medical), Johannes Rieber (speaker honoraria, St Jude Medical and Volcano Corp) and Thomas Schmitz (proctor honoraria, St Jude Medical). The other authors have no conflicts of interest to declare. Received: 15 March 2017 Accepted: 29 May 2017 Citation: Interventional Cardiology Review 2017;12(2):97–109. DOI: 10.15420/icr.2017:13:2 Correspondence: Stephan Achenbach, Department of Cardiology, Friedrich-Alexander Universität Erlangen, Ulmenweg 18, 91054 Erlangen, Germany. E: stephan.achenbach@uk-erlangen.de

The invasive measurement of fractional flow reserve (FFR) can determine the haemodynamic relevance of coronary artery stenoses. Determination of FFR is recommended in coronary artery stenoses with a luminal diameter narrowing between 50 % and 90 % if no non-invasive proof of ischaemia is available.1 To measure the FFR of a given coronary lesion, a wire or a microcatheter equipped with a miniaturised pressure sensor is inserted into the coronary artery. Under conditions of maximum hyperaemia, the relationship between the mean blood pressure distal to the stenosis (pd) and mean pressure in the aorta (pa) is determined. Generally, FFR values ≤0.80 are ance and associated prognostic relevance of the respective stenosis. Based on the results of several randomised, prospective clinical studies, in which the decision to perform revascularisation was based on FFR, the method carries high clinical relevance. In the absence of non-invasive proof of ischaemia, FFR performed in stenoses with a 50–90 % diameter reduction was given a “class I recommendation” and “level of evidence A” in the guidelines for coronary revascularisation published by the European Society of Cardiology in 2014. 2 The latest update of the American College of Cardiology/American Heart Association Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease states: “It has been suggested in several studies that a PCI (percutaneous coronary intervention) strategy

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guided by FFR may be superior to a strategy guided by angiography alone”.3 One large clinical registry demonstrated that performing FFR changed further management in 43 % of patients compared to the purely visual assessment of coronary artery stenoses by invasive angiography.4 Even when non-invasive proof of ischaemia is available, FFR measurements often change clinical judgement regarding the need to revascularise a given coronary artery stenosis.5 However, despite clear evidence and guidance, many interventional cardiologists continue to rely on the visual assessment of stenosis severity alone, rather than performing FFR.6 Potential reasons include the logistical effort of performing FFR, concerns regarding potential complications and uncertainty about optimal performance and interpretation of FFR measurements, particularly in complex situations, such as multivessel disease, left main stenoses, serial stenoses or in patients with aortocoronary bypass grafts. In addition, while performing FFR is not technically difficult per se, several relevant procedural aspects have to be taken into account in order to avoid incorrect measurements or misinterpretation of results. For this reason, the present study provides a summary of consensus recommendations regarding the indication, performance and interpretation of FFR measurements. Clear evidence from randomised studies is not available for all patient groups and clinical situations.

Access at: www.ICRjournal.com

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Coronary Figure 1: Design and Results of the Sentinel Studies on Fractional Flow Reserve (FFR): DEFER, FAME and FAME-2

DEFER

FAME

FAME-2

325 patients with intermediate stenoses

1,005 patients with intermediate stenoses, multivessel disease

1,202 patients with intermediate stenoses

FFR

RANDOMISED

FFR

PCI of all stenoses >50 % FFR ≤0.75

FFR of all stenoses >50 % FFR ≤0.80

FFR >0.75

FFR >0.80

FFR ≤0.80

RANDOMISED

PCI

Medical

COMPARISON

DEFER: Deferal of revascularisation of stenoses with FFR >0.75 is not inferior to PCI (Revascularisation performed with Bare Metal Stents)

RANDOMISED

PCI

Medical

COMPARISON

FAME: Revascularisation only of stenoses with FFR ≤0.80 is not inferior to revascularisation of all stenoses. (Multivessel disease, revasularisation with drug-eluting stents)

Medical

PCI

Medical

COMPARISON

FAME-2: Stenoses with FFR ≤0.80 benefit from revascularisation. (single-vessel or multivessel disease, revascularisation with drug-eluting stents)

DEFER = a multicentre, randomised study to compare deferral versus performance of PCI in non-ischaemia-producing stenoses; FAME = Fractional flow reserve versus Angiography for Multivessel Evaluation; PCI = percutaneous coronary intervention.

Therefore, this expert consensus is based on the most pertinent literature and the authors’ personal experience with the procedure. Particular emphasis is placed on the practical performance of FFR measurements, along with tips and tricks for everyday clinical practice.

Clinical Evidence Revascularisation guided by FFR in patients with coronary artery disease and stenoses >50 % leads to better outcomes than revascularisation based on a visual analysis of angiographic stenosis severity alone. This is the conclusion of three large, randomised trials: the DEFER (a multicentre, randomised study to compare deferral versus performance of PCI in non-ischaemia-producing stenoses) trial, the Fractional flow reserve versus Angiography for Multivessel Evaluation (FAME) trial and the FAME-2 trial (Figure 1), including long-term follow up of patients initially included in these studies. The DEFER trial, published in 2001, included patients with de novo stenoses of intermediate angiographic severity.7 If FFR was ≤0.75, percutaneous coronary intervention (PCI) was performed. Patients with FFR >0.75 were randomised to PCI (perform PCI group, n=91) or conservative therapy (defer group, n=90). Regarding the primary endpoint survival free of major adverse cardiac events (MACE), there was no difference between the two groups after 1 and 5 years (perform PCI versus defer group: 73 % versus 80 % after 5 years, p=0.052).8 The composite rate of cardiac death and acute myocardial infarction in the perform PCI group was 7.9 % compared to 2.2 % in the defer group (p=0.021). This leads to the conclusion that a stenosis of intermediate angiographic severity, and with an FFR value >0.75, can be treated with a conservative approach. The risk of myocardial infarction or cardiac death was less than 1 % per year in patients treated conservatively. Even follow up after 15 years (complete in 92 % of patients) demonstrated that there was no increased event rate in patients with deferred PCI. In fact, the defer group had a significant

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advantage in the incidence of myocardial infarction (2 % versus 10 %). Regarding mortality and the number of revascularisations, no significant differences were observed between the two groups.9 The FAME trial, published in 2009, randomised 1,005 patients with twoor three-vessel coronary artery disease to angiographically- (n=496) or FFR-guided revascularisation (n=509).10 In the angiographically-guided arm, all stenoses ≥50 % were revascularised, while in the FFR-guided arm, PCI was only performed when FFR was ≤0.80. The mean number of stents placed was 2.7±1.2 per patient in the angiographically-guided group, and the primary endpoint (a combination of death, myocardial infarction and revascularisation) occurred in 18.3 % of patients after 1 year. In patients randomised to FFR-guided treatment, a mean of 1.9±1.3 stents per patient were implanted, and the primary endpoint occurred in only 13.2 % of individuals (p=0.002). Mortality was not significantly different between the two groups. The rate of a combined endpoint composed of death and myocardial infarction, albeit not prespecified, was significantly lower in the FFR-guided group after 2 years of follow up (8.4 % versus 12.9 %, p=0.002).11 Five-year data confirmed the long-term safety of the FFR-guided PCI strategy in patients with multivessel disease.12 While the DEFER and FAME trials clarified that revascularisation could safely be deferred if FFR indicates the absence of haemodynamic relevance, the FAME-2 trial, published in 2012, investigated whether patients profit from revascularisation if FFR is pathological (here: ≤0.80).13 The FAME-2 trial included stable patients with one-, two- or three-vessel disease. All lesions >50 % were investigated by FFR. Patients with stenoses with an FFR value ≤0.80 were randomised to PCI versus purely conservative therapy. Patients with FFR values >0.80 in all vessels were included in a registry. After randomisation of 880 patients and the inclusion of 322 patients into the registry, the FAME-2 trial was terminated prematurely, as the primary

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Fractional Flow Reserve Expert Consensus endpoint (combination of death, myocardial infarction and urgent revascularisation) among patients with an FFR ≤0.80 occurred significantly less frequently in the PCI group compared to the group managed with medication (4.3 % versus 12.7 %, hazard ratio with PCI: 0.32, p<0.001). The difference was mainly driven by the endpoint “urgent revascularisation” (1.6 % versus 11.1 %, hazard ratio with PCI: 0.13, p<0.001).13 Two-year follow-up data showed that the advantage of FFR-guided PCI compared to drug therapy was sustained.14 Therefore, the DEFER and FAME trials demonstrated that, in patients with stable coronary artery disease, the conservative management of stenoses that could be angiographically severe, but are not haemodynamically relevant, is safe. The DEFER trial used a threshold of 0.75 to define haemodynamic relevance by FFR, but it mainly included patients with single-vessel disease, and bare metal stents were used for revascularisation (so that positive effects of revascularisation were less likely than with modern devices or in more severe disease). Patients randomised in the FAME trial had multivessel disease, PCI was performed with drug-eluting stents and the threshold value used for FFR was 0.80. The FAME-2 trial, in turn, demonstrated that patients with pathological FFR values (≤0.80) benefit from revascularisation with drug-eluting stents. Large meta-analyses have evaluated the safety of using an FFRguided strategy. One meta-analysis encompassed a total of 49,517 patients, and showed a significantly lower rate of revascularisation (14.8 % versus 20.4 %), as well as a reduction of MACE (22.5 % versus 34.8 %), myocardial infarction (4.2 % versus 8.1 %) and death (7.6 % versus 15.3 %) in FFR-guided versus purely angiographicallyguided revascularisation.15 A second meta-analysis showed that FFRguided decision-making reduced the number of revascularisations by 50 % and the incidence of MACE by 20 % over a period of 16 months.16 When interpreting FFR, the range between 0.75 and 0.80 is often called the “grey zone”. Data from a large, ongoing observational study with 1,459 patients showed that classifying lesions with FFR values between 0.75 and 0.80 as “haemodynamically relevant” is justified, because even in this range, the long-term event rate after revascularisation using modern methods was lower than with purely drug-based therapy.17

Clinical Application of Fractional Flow Reserve Even though the risk associated with measuring FFR is low, FFR measurement of a given stenosis should only be considered if revascularisation of that lesion with PCI or bypass surgery is possible in case of a positive result. Current guidelines recommend the use of FFR to determine the haemodynamic relevance of stenoses with an angiographic diameter reduction between 50 % and 90 %, for which no non-invasive proof of ischaemia exists.2 There could be indeterminate or contradictory findings of non-invasive ischaemia testing that can be clarified or resolved by the invasive measurement of FFR. If FFR demonstrates the absence of haemodynamic relevance, the risk of future events associated with a stenosis is low, and cannot be further reduced by PCI with modern stents. FFR measurements are of particular relevance in patients with multivessel disease. The anatomical and functional severity of individual lesions in such patients varies widely. The DEFER and FAME trials, as well as numerous other prospective investigations, showed that the FFR-guided revascularisation only of haemodynamically-relevant lesions is superior to the angiographicallyguided revascularisation of all lesions that appear as “severe” or “relevant” luminal stenoses (Table 1).

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Table 1: Key Points of Data and Clinical Use of Fractional Flow Reserve (FFR) Major randomised FFR trials • D EFER: Revascularisation of stenoses with FFR >0.75 can safely be deferred. Revascularisation was performed with bare metal stents. • FAME: Limiting revascularisation to stenoses with FFR ≤0.80 is not inferior to revascularisation of all stenoses >50 % diameter reduction. Multivessel disease, revascularisation with drug-eluting stents. • FAME-2: Stenoses with FFR ≤0.80 benefit from revascularisation. Singlevessel or multivessel disease, revascularisation with drug-eluting stents. Clinical application of FFR • FFR measurement is recommended in the case of: • Angiographically-uncertain haemodynamic relevance of a stenosis and absence of non-invasive proof of ischaemia, or in the case of inconclusive or contradictory results of non-invasive ischaemia testing. • FFR measurement is not recommended in the case of: • Unambiguous non-invasive proof of ischaemia in a localised, angiographically-high-grade stenosis. • Assessment of culprit lesions of patients with acute coronary syndromes in the presence of thrombus load. • Haemodynamically-unstable patients. • Absence of therapeutic relevance. • Vessels without a circumscript stenosis if there is no other clinical sign of ischaemia. DEFER = a multicentre, randomised study to compare deferral versus performance of PCI in non-ischaemia-producing stenoses; FAME = Fractional flow reserve versus Angiography for Multivessel Evaluation.

Performing Fractional Flow Reserve Measurements Consent and Patient Preparation Recommendations To ensure that FFR can be performed within the context of any diagnostic angiogram if the need arises, it is recommendable to routinely include informed consent for FFR measurements into the consent procedure for every diagnostic angiogram or coronary intervention. Patients should be informed about potential discomfort (shortness of breath, angina, palpitations, sensation of heat, diaphoresis), as well as potential risks of the procedure (coronary injury caused by the guiding catheter or intracoronary wire, as well as side-effects of medication used to induce hyperaemia). If intravenous application of medication to induce hyperaemia is planned, the patient should have a large venous access (either a sheath in the femoral vein or a venous cannula not further distally than the cubital vein). A more peripheral location could be acceptable if regadenoson is used. Sufficient flow via the venous access (e.g. by using parallel saline infusion) should be ensured in order to achieve rapid onset of medication. Because foreign material is being introduced into the coronary artery, we recommend anticoagulation and antithrombotic medication in the same way as for PCI when FFR measurements are performed.

Pitfalls, Tips and Tricks Because patients typically do not interrupt their regular medication for invasive coronary angiography, and in many centres fasting is no longer required for invasive coronary procedures, the influence of drugs and nutrition on FFR measurements is a relevant issue. According to Ozdemir et al., beta blockers do not influence FFR measurement results, and therefore, do not need to be interrupted.18 The situation regarding caffeine is less clear. While caffeine and adenosine have antagonistic effects on A2a receptors, which could influence FFR results with adenosine-mediated hyperaemia, the

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Coronary Figure 2: Typical Sequence of Fractional Flow Reserve (FFR) Measurement A

(A) Angiography showing two stenoses of moderate degree in the left anterior descending coronary artery (arrows). (B) Positioning of the FFR wire for pressure equalisation; pressure sensor (arrow) is positioned directly behind the guide catheter, which is used to measure the aortic pressure. Introducer must be removed for pressure equalisation, the haemostatic valve must be completely closed and contrast agent should be removed from the guide catheter because of its high viscosity. (C) Positioning of the FFR wire with the pressure sensor (arrow) directly distal to the second lesion. (D) FFR measurement with intracoronary administration of a bolus of 80 μg adenosine. FFR measurement in steady state yields a value of 0.73.

majority of clinical studies, even including intravenous caffeine (4 mg/kg, corresponding to 3–4 cups of coffee), failed to demonstrate any significant effect.19 Therefore, the overall influence of caffeine appears to be minimal, especially when consumed in small amounts and >1 hour prior to FFR measurements.20,21 In case of doubt, alternative drugs to adenosine (e.g. papaverine) could be used. Theophylline should be interrupted at least 12 hours prior to FFR measurements.

Catheter Selection and Positioning Recommendations Transfemoral and transradial catheterisation are equally suited for FFR. For patient safety, the use of diagnostic catheters is not recommended. They should be exchanged for guide catheters (at least 5F) for FFR measurements, as coronary dissection by FFR wire is a theoretical possibility that would require immediate intervention. Catheters should not have side holes, as they could impair intracoronary adenosine

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administration. In addition, they could influence pressure calibration and equalisation due to local turbulences at the catheter tip. The catheter shape should be carefully chosen for coaxial alignment at the coronary ostium.

Pitfalls, Tips and Tricks The catheter must not obstruct a narrow ostium or proximal stenosis (“wedge pressure”), as incorrectly low values could be measured for both pa and pd, which in turn would generate inaccurate FFR results. If in doubt, the catheter should be completely disengaged from the ostium for pressure calibration, equalisation and recording of pd/pa.

Calibration Recommendations As a first step, zeroing of the aortic pressure must be ascertained. For that purpose, the pressure transducer must be positioned at the

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Fractional Flow Reserve Expert Consensus level of the heart (1/3 versus 2/3 chest diameter), opened towards the atmosphere and zeroing of the pressure performed.

Figure 3: Typical Artefacts Caused by Mechanical Interaction of the Pressure Sensor with the Vessel Wall (Arrows)

Next, the FFR wire/microcatheter is to be prepared and connected to the respective measurement system by cable or wireless connection. The following should be noted with regard to the different models:

225 200 175 mmHg

• St Jude Aeris® wire: Lay the wire flat and flush the coil with saline solution. Then, keep wire stationary, press “connect wirelessly” on the recevier and activate the wire’s transmitter. The wire pressure sensor is zeroed automatically. • Volcano Verrata® wire: Flush the wire, then connect. Zeroing of the pressure sensor then takes place automatically. When doing this, the catheter must be lying flat and not be moved. • Acist Navvus® microcatheter: Flush the catheter, then connect.

250

150 125 100 75 50 25 0

The wire (St Jude/Volcano) or the microcatheter (Acist) is then advanced into the coronary artery until the pressure sensor is positioned precisely at the end of the guide catheter (Figure 2). The guide catheter should be flushed at this point (due to the viscosity of contrast agent), and if necessary, disengaged from the coronay artery ostium. Pressure equalisation between the wire and aortic pressure must then be performed. This constitutes a procedural step of major importance.

Pitfalls, Tips and Tricks For the equalisation of pressures between the pressure sensor and the aortic pressure, the introducer must be removed and the haemostatic valve completely closed. A second wire, in addition to the FFR wire, could result in artefacts due to mechanical interaction, and should therefore be avoided if possible. The pressure curves must be stable and free of artefacts for several heartbeats before zeroing is performed, because the mean pressure is generally averaged over three-to-five heartbeats. “Drift” describes a slow deviation from baseline in the values measured by the pressure sensor (pressure wires/microcatheters generally have a specification of a maximum baseline drift of 7 mmHg/h); “shift” describes a sudden deviation from the baseline value, and can generally be traced back to connection problems or wire defects.

Positioning of the Fractional Flow Reserve Wire Recommendations The pressure sensor of the wire/microcatheter must be positioned directly distal to the lesion that is to be investigated. It should be placed in the main vessel, and not in a side branch. In case of sequential stenoses within one artery, the pessure sensor should be placed downstream of the most distal lesion (Figure 2).

Pitfalls, Tips and Tricks The tip of the wire should be carefully shaped to an appropriate curve before introducing it (generally by no more than 45°). If disconnecting the wire to advance it into the coronary artery cannot be avoided, upon reconnection, artefact-free connection must be ensured. During measurement, it is important to be mindful of artefacts; the pressure sensor on the FFR wire could interact with the vessel wall, especially in cases of a small vessel caliber (Figure 3). Similarly, severely tortuous coronary segments can cause artefacts because

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10 11 12 13 14 15

Seconds

of mechanical interaction of the pressure sensor with the vessel wall. Therefore, placement of the sensor in segments with substantial tortuosity should be avoided. It should also be noted that the presence of viscous contrast agent in the coronary artery can affect the gradient pd/pa. In the case of a resting gradient ≤0.80, haemodynamic relevance is evident, and hyperaemia is no longer required to make a clinical decision. If the FFR wire remains in the coronary vessel during an intervention, it should be ensured that the FFR wire is not “jailed” by stent implantation.

Hyperaemia Recommendations Prior to advancing the pressure wire/FFR microcatheter, nitroglycerin should be adminstered (intracoronary, generally 0.2 μg), in order to prevent spasms and minimise resistance in the epicardial vessels. There are several pharmacological options and routes of administration to induce hyperaemia, as outlined below.

Intravenous Medication Adenosine The intravenous administration of adenosine is safe and simple, provided that contraindications are observed. Given the very short half-life of adenosine, care must be taken to ensure that the site of administration is as proximal as possible, and flow speed is sufficient, otherwise adenosine could be degraded before it reaches the coronary circulation. The standard dose for sustained maximum hyperaemia is 140 μg/kg/min. Some authors recommend that if adenosine is not administered via a central venous access, the dose should be increased (e.g. 160–180 μg/kg/min), particularly if the FFR value is in the grey zone.22 The administration of more than 180 μg/kg/min is not recommended, because this could reduce coronary perfusion. Adenosine is commercially available at various concentrations (e.g. 3 mg/ml, 5 mg/ml). Tables A1 and A2 in the Appendix list exemplary rates of infusion depending on adenosine concentration, body weight and desired delivery rate. Regadenoson Regadenoson is administered intravenously at a standard dose of 400 μg, without adjustment to body weight. The time until onset of

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Coronary Figure 4: Errors Could be Caused if the Guide Catheter Occludes the Artery (“Wedge Pressure”) Due to a Stenosis Near the Ostium A

(A) Stenosis of the right coronary artery near the ostium (arrow). Guide catheter (JR4 6F) is resting on the stenosis. (B) With the fractional flow reserve (FFR) wire advanced into the distal right coronary artery to measure the combined effect of all lesions, adenosine is injected intracoronary. Guide catheter initially rests on the stenosis causing wedge pressure. Following withdrawal of the guide catheter into the ascending aorta (arrow), the correct pressure values are measured (FFR=0.84).

effect is approximately 37 seconds (compared to 66 seconds for intravenous adenosine.23). The maximal hyperaemic effect lasts for 30 seconds; hyperaemia fades out therafter, with a total duration of approximately 10 minutes. Overall, regadenoson appears to have fewer side-effects than adenosine and is considered to be safer in patients with chronic obstructive pulmonary disease.24 However, it has not been evaluated as thoroughly as adenosine.

possible injection rate are limited to lower values, and might need to be reprogrammed by the manufacturer. Administration of a contrast agent to induce hyperaemia is currently not recommended. If coronary spasm due to the FFR wire is suspected, repeated injection of nitrates might be required.

Registration and Evaluation Recommendations

Intracoronary Medication Adenosine Adenosine doses for intracoronary administration vary from 40 µg to 200 μg, injected as a rapid bolus of, for example, 10 ml volume.25-27 As a general rule, lower doses should be used for the right than for the left coronary artery, as atrioventricular-block occurs more often. Doses of 80 μg for the left coronary artery and 40 μg for the right coronary artery yielded FFR results that correlated extremely closely to intravenous adenosine at 140 μg/kg/min (r=0.99).28 Table A3 in the online Appendix shows the options for creating a solution for injection dosing of intracoronary adenosine. Papaverine Papaverine (intracoronary 8 mg for the right coronary artery and 12 mg for the left coronary artery) is a possible alternative to adenosine. 29 The onset of effect occurs after approximately 16 seconds. The duration of maximum hyperaemia is approximately 50±10 seconds, and return to the resting value occurs after approximately 2 minutes. Due to the lack of studies and potentially higher rate of side-effects (risk of accumulation and triggering of ventricular arrhythmias), papaverine should not be used as the standard substance for inducing hyperaemia.30

Pitfalls, Tips and Tricks For the peripheral administration of adenosine, ready-to-use 50 ml vials for infusion in an undiluted fashion are available. Of note, injection pumps for the peripheral administration of adenosine must permit an injection rate >200 ml/min. Often, factory settings for the maximum

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In the case of intravenous administration of the hyperaemic agent, pd/pa should be recorded until a steady state is reached, but for no less than 2 minutes. The FFR value is then the lowest ratio registered during the steady state (with the exception of artefacts that are not to be taken into account). It should be noted that the mean pd and pa often show a minimum just before reaching the constant mean pressure, but this point in time does not constitute the FFR value. In the case of intracoronary administration, pd/pa should be continuously recorded until it returns to the baseline value. The FFR value is the lowest recorded ratio (apart from artefacts). When the FFR wire/microcatheter is withdrawn after completion of the measurement, maintenance of accurate calibration should always be verified when the pressure sensor reaches the guiding catheter. This is important to identify shift or drift of pressure readings, which would lead to erroneous FFR results. If this verification indicates a relevant deviation from the baseline value of 1.00, the measurement might need to be repeated.

Pitfalls, Tips and Tricks In order to obtain correct aortic pressure tracings (pa), care must be taken to remove the wire introducer during the registration and to completely close the haemostatic valve. During FFR registration, the guide catheter must not occlude the ostium or a stenosis close to the ostium. This would cause incorrectly low pressure values to be measured, which in turn results in false high FFR values (Figure 4). Outlier pd/pa values that are caused by artefacts or arrhythmia must be carefully observed, and not be taken into

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Fractional Flow Reserve Expert Consensus account. If the patient has ectopic beats, this can cause incorrectly low pd/pa values, which must be disregarded. Values measured under AV-block/bradycardia must also be classified as “not evaluable”. If AV-block occurs during intracoronary administration (especially in the right coronary artery), the measurement might need to be repeated with intravenous administration.

Documentation Ideally, FFR measurements should be archived as pressure curves or as individually-measured numeric datasets.

Interpretation and Clinical Consequences The FFR value indicates the extent of ischaemia. Generally, FFR values ≤0.80 indicate that the stenosis in question is haemodynamically relevant. Therefore, based on the data from the above-mentioned prospective clinical studies, revascularisation is recommended in the case of FFR values ≤0.80. If FFR values are >0.80, it is assumed that the lesion is not haemodynamically relevant, and as a general rule, there is no need for revascularisation.2 However, the results of FFR measurements must always be evaluated taking the clinical context and clinical information into account. If the results of the FFR measurement are in conflict with non-invasive proof of ischaemia or the patient’s symptoms, decisions regarding further management must be made on an individual basis. Ultimately, an FFR value of 0.80 does not represent a single, dichotomous threshold value to be used as the sole criterion to decide in favour of or against revascularisation (Tables 2 and 3).

Fractional Flow Reserve in Special Situations Aorto-ostial Stenoses In the presence of an aorto-ostial stenosis, the guide catheter must be removed from the ostium for equalisation of pressures and during hyperaemia. Intravenous administration of adenosine is preferable to intracoronary administration. Of note, the large, prospective, randomised studies on which the FFR recommendations are based excluded left main coronary artery stenoses and aorto-ostial stenoses. However, small, non-randomised studies suggest that the same threshold value (FFR ≤0.80) should be used for decision-making.31,32

Long Vessel Segments without Circumscipt Luminal Stenosis in Angiography FFR is only validated for stenoses with a degree of stenosis of at least 50 %. Lesion length is a significant predictor of a positive FFR.39,40 A pathological FFR value identifies ischaemia as a possible reason for symptoms, including vessels with long stenoses that do not appear to be relevant in the angiogram. Nevertheless, the therapeutic decision can be difficult. Careful pullback of the FFR wire/FFR microcatheter should be performed under continuous hyperaemia (or stepwise repeated measurements with intracoronary adenosine) in order to identify any localised pressure step-up. If such a pressure step-up is present, revascularisation should be considered, potentially in combination with intracoronary imaging. If no localised pressure stepup can be identified, revascularisation is generally not recommended.

Coronary Artery Bypass Grafts There are limited data on FFR measurements in stenotic bypass vessels. In a non-randomised study, FFR-guided PCI of intermediate bypass graft stenoses (visually assessed to be 40–70 %) resulted in a lower MACE rate compared to an angiographic-guided strategy.41 Stenoses of native vessels downstream of a bypass graft could be considered as native stenoses, and should be assessable by FFR.

Acute Coronary Syndrome In the case of ST-elevation myocardial infarction (STEMI), impaired microcirculation in the infarction region has been shown to influence FFR measurements in the culprit vessel for up to 6 months after the acute event.42 Despite data suggesting that FFR in the culprit vessel and its change over the first postinfarction days can predict functional recovery of the infarcted region,43 FFR measurements in culprit vessels are not currently recommended in STEMI patients. However, FFR has been used to guide revascularisation decisions in non-culprit vessels with a better outcome than angiographically-guided revascularisation.44

Serial Stenoses

In patients with non-STEMI (NSTEMI), some trials have demonstrated that acute determination of the FFR in non-culprit lesions is safe, accurate and reproducible,45,46 and that it correlates with non-invasive proof of ischaemia or repeated FFR measurements after the acute phase.48,49 In addition, prospective studies (or subanalyses of such studies) have demonstrated the clinical value of FFR-based revascularisation in patients with NSTEMI.49–51 However, one observational analysis compared 206 consecutive acute coronary syndrome patients (NSTEMI and unstable angina) with 262 intermediate lesions to 370 stable coronary artery disease patients with 528 lesions. In that study, revascularisation was deferred if the FFR was >0.75. Not surprisingly, MACE rates were significantly higher in acute coronary syndrome patients than in stable patients, even when the FFR was >0.75. The best cut-off to predict future MACE was 0.81 in stable patients, but 0.84 in acute coronary syndrome patients.52 Similarly, a meta-analysis published by Adjej et al. identified an FFR threshold of 0.83 as the optimal cut-off to predict MACE in acute coronary syndrome patients (compared to 0.81 in patients with stable coronary artery disease).17

Serial stenoses cannot be evaluated individually in any straightforward fashion. In the case of two successive stenoses, the distally-measured value represents the combined effect of both lesions. As a pragmatic approach, it is recommended to first revascularise the lesion causing the higher pressure step-up upon pullback or in sequential measurements. If the higher pressure step-up cannot be clearly identified, the distal lesion should generally be treated first. Subsequently, the remaining stenosis must be reassessed.36–38

Overall, it can be assumed that, in the absence of clear impairment of microcirculation and relevant thrombus load, FFR measurements performed during immediate angiography are useful to plan further revascularisation in patients with acute coronary syndrome and multivessel coronary artery disease. Decisions about deferral of revascularisation might need to be made somewhat more cautiously for these patients compared to stable patients.

Left Main Coronary Artery Stenosis The best way to evaluate left main coronary artery stenosis is to take FFR measurements in both downstream vessels, unless one of them is very small. If one of the downstream vessels has a relevant stenosis, measurements should only be taken in the other vessel. If both downstream vessels have relevant stenoses, FFR evaluation of the left main coronary artery is not possible.33,34 Positioning of the pressure sensor before the downstream stenoses will not allow the left main coronary artery to be correctly evaluated.35

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Coronary Table 2: Key Points of Performance of Fractional Flow Reserve (FFR) Measurements Patient preparation • • • • • •

Routinely obtain informed consent for FFR prior to every diagnostic coronary angiogram. Medication for FFR identical to PCI. Use a large calibre access in the femoral or cubital vein for peripheral adenosine application. Beta-blockers do not need to be interrupted. Caffeine >1 hour prior to FFR measurement has no clinically-relevant effect. Theophylline should be interrupted 12 hours prior to FFR.

Catheter selection and positioning • Use guiding catheters (at least 5F) without side holes. • Ascertain coaxial catheter position in the coronary ostium. • Disengage guiding catheter from ostium for pressure calibration, equalisation and recording of pd/pa if there are doubts about the catheter potentially obstructing the ostium. Calibration • • • • • •

Before starting FFR measurement, ensure proper zeroing of the aortic pressure. Flush the FFR wire, lay flat when connecting/calibrating and do not move. Before equalisation of pressures, advance the FFR wire into the coronary artery until the pressure sensor is positioned precisely at the end of the guide catheter. Before equalisation of pressures, flush the guide catheter in order to remove the viscous contrast agent. Before equalisation of pressures, remove the introducer and close the haemostatic valve. Pressure curves are typically averaged across three-to-five heartbeats. Therefore, pressure equalisation requires some time, and no artefacts should occur during that time.

Positioning of the FFR wire or microcatheter • • • • •

Pressure sensor should be positioned in the main vessel directly downstream the most distal leasion. A second wire, in addition to the pressure sensor, could result in artefacts, and should therefore be avoided. Be careful of artefacts: the sensor could interact with the vessel wall, especially in cases of a narrow vessel calibre or severe tortuosity. Viscous contrast agent in the coronary artery can affect the gradient pd/pa. In the case of a resting gradient <0.80, measurement under hyperaemia is not necessarily required in order to make a clinical decision.

Hyperaemia • Prior to advancement of the FFR wire/FFR microcatheter, administer intracoronary nitrates in order to prevent spasms in epicardial vessels • Medication for hyperaemia: • Intravenous: Adenosine 140 μg/kg/min Regadenoson 400 μg undiluted. • Intracoronary: Adenosine (e.g. 40 μg intracoronary for the right coronary artery and 80 μg intracoronary for the left coronary artery) Papaverine (e.g. 8 mg for the right coronary artery and 12 mg for the left coronary artery) • In the case of measurement results in the borderline area, an increased dose of adenosine is possible (while not supported by evidence). Intravenous doses >180 μg/kg/min can reduce coronary perfusion, and are therefore, not recommended. Registration and evaluation • FFR value is the lowest ratio pd/pa registered during the steady state. • In case of intravenous adenosine administrations, pressure values can fall to a minimum before reaching a steady state. These values should not be interpreted as FFR values. • Artefacts must be carefully observed and excluded. • Ectopic beats can cause false-low FFR values, which must be excluded. • Values measured under atrioventricular-block/bradycardia must be classified as “not evaluable”. pa = mean blood pressure distal to the stenosis; pd = mean pressure in the aorta.

Table 3: Key Points of Special Clinical Situations Aorto-ostial stenoses • Intravenous administration of adenosine is preferred. • Withdraw the guide catheter from the ostium for pressure equalisation and FFR measurement. Left main coronary artery stenosis • FFR measurement in downstream vessels without stenosis, optimally both in the left circumflex coronary artery and left anterior descending coronary artery. Serial stenoses • Can only be evaluated jointly. • Distally-measured value represents the combined effect of both lesions. • Values measured in between two stenoses are unreliable. Acute coronary syndromes • I n the case of STEMI, FFR measurement in the infarcted vessel is neither reasonable nor possible. In the case of NSTEMI, in the absence of a relevant thrombus load, lesions can be assessed using FFR. FFR during and after PCI • There is no established target value for FFR after PCI. • In the case of bifurcation lesion PCI, revascularisation of the side branch is not necessary if FFR is >0.80 in the side branch. FFR = fractional flow reserve; NSTEMI = non-ST-elevation myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST-elevation myocardial infarction.

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Fractional Flow Reserve Expert Consensus Myocardial Bridges The administration of adenosine is not suitable for the evaluation of the possible haemodynamic relevance of myocardial bridges.53 Theoretically, dobutamine stress echocardiography would be more appropriate for this purpose.54 However, FFR measurements have not been evaluated for therapeutic decision-making in the case of myocardial bridges, the relevance of which is controversial.55

Fractional Flow Reserve Following Percutaneous Coronary Intervention Assessing Revascularisation Success In registries, FFR values after PCI correlate with the outcome.17,56 The higher the FFR value, the lower the event rate during follow up. A recent study of 574 patients with 664 lesions and FFR performed post-PCI suggested a threshold of 0.86 as the optimal predictor of MACE during follow up after PCI.57 In patients with acute coronary syndrome, that threshold might be higher (0.91 according to one study58). However, repeated FFR measurements are currently not routinely required or recommended post-PCI if the angiogram shows interventional success. If measurements are repeated, care must be taken with regard to shift and drift, and correct zeroing must be ensured. In particular, if the FFR wire was used for PCI and the pressure sensor remained distal to the lesion during the procedure, post-PCI FFR measurements must be followed by a careful pullback of the pressure sensor to the guide catheter to verify that correct calibration has been maintained.

Side Branch in the Case of Bifurcation Percutaneous Coronary Intervention It is possible to assess the haemodynamic relevance of a side-branch stenosis caused by PCI using FFR. An FFR ≤0.80 in the side branch correlates with an increased rate of events during follow up. In the case of FFR >0.80, no side-branch intervention is required (Table 3).59-61

Instantaneous Wave-free Ratio and Pressure Distal to the Stenosis/Mean Pressure in the Aorta at Rest and without Hyperaemia The need to use vasodilator substances to induce hyperaemia could be perceived as a limiting factor for FFR measurements and could prevent adoption in clinical routine. Two alternative pressuremeasurement methods, which are not based on hyperaemia, have been described in the literature. First, evaluation of the pd/pa ratio without hyperaemia has been suggested. Second, the so-called “instantaneous wave-free ratio” (iFR) has been proposed. It represents the pd/pa ratio not during the entire cardiac cycle, but during a specific phase within diastole when resistance in the microvasculature is lowest. All commonly-used FFR systems enable resting pd/pa values to be recorded across the entire cardiac cycle. Determination of the iFR requires a special algorithm, and is currently only possible with specific software (Volcano Harvest®). The diagnostic accuracy of iFR compared to standard FFR measurements with induced hyperaemia was 91 % in the ADenosine Vasodilator Independent Stenosis Evaluation study, which included 157 stenoses,62 80 % in a multicentre study with 392 stenoses63 and only 60 % in a multicentre study in 206 consecutive patients.64 In a large multicentre study (RESOLVE: Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa with fractional flow reserve), pd/pa and iFR were compared to FFR in 1,768 patients.65 It was demonstrated that 0.90 was the optimum cut-off for the iFR to identify stenoses with an FFR <0.80. For pd/pa, the optimal threshold

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value was 0.92. There were no significant differences between the two methods of measurement at rest, and in both cases, with these thresholds, approximately 80 % of the lesions were classified correctly compared to FFR. Two recent, large multicentre trials evaluated the use of the iFR versus FFR for clinical decision-making in a randomised fashion. The ‘SWEDEHEART’ trial randomised 2,037 patients with an indication for the invasive assessment of haemodynamic relevance of a coronary lesion to use either the iFR (threshold: 0.89) or FFR (threshold: 0.80) for decision-making.66 The mean iFR was 0.91 and the mean FFR was 0.82. In the iFR arm, 53 % of all patients underwent revascularisation compared to 56.5 % in the FFR arm (p=0.11). The primary endpoint (death from any cause, myocardial infarction or unplannd revascularisation during 12 months of follow up) was not significantly different between the groups (6.7 % versus 6.1 %, p=0.53). Using the same thresholds for decision-making, another trial randomised 2,492 patients to decision-making based on iFR or FFR.67 Again, no difference in the primary endpoint was observed at the end of the 12 month follow-up period (6.8 % versus 7.0 %), but significantly fewer baseline revascularisations were performed in the iFR group (47.5 %) compared to the FFR group (53.4 %, p=0.003). Thus, in the authors’ opinion, vasodilation can cleary be avoided in the case of resting iFR or pd/pa values that are either near 1.0 or ≤0.80. Using non-vasodilation-dependent parameters with adapted thresholds for decision-making could be a justified alternative if there were a need to avoid adenosine.

Limitations of Fractional Flow Reserve Measurements The concept of diagnosing lesion-specific coronary ischaemia through FFR requires hyperaemia following maximum vasodilation of the coronary microvasculature through adenosine administration.68 Therefore, there is a possibility that in the presence of microvascular dysfunction, such as in the case of previous myocardial infarction,69 in the case of left ventricular hypertrophy or as a result of diabetic microangiopathy, the extent of achieved maximum hyperaemia will be less than in healthy individuals, meaning that the measured pd is incorrectly high, and potentially, FFR is false negative.70 In absolute terms, the changes in FFR in patients with microvascular perfusion impairment appear rather low (5 %, or in absolute values, 0.05).71 However, in the FFR borderline area (approximately 0.80), this can lead to misinterpretation of haemodynamic relevance, so that in patients with borderline FFR values and suspected impairment of microvascular function, particular care must be taken regarding the interpretation of measurement results. FFR measurements also yield incorrectly high values (and thus possibly a false-negative result) in patients with severe hypotension.72 Therefore, FFR cannot, for example, be used for revascularisation decisions in patients with cardiogenic shock. Seto et al. observed unstable (i.e. increasing) pd/pa measurements in the course of continuous intravenous adenosine administration in 22 of 68 patients.73 Under maximum hyperaemia, there was a disproportionately high increase of pd, and FFR on average increased by 0.08. In 28 % of the patients examined, this caused FFR to exceed the threshold value of 0.80. This variability means that there is a risk of false-negative FFR measurements during the long-term infusion of adenosine. While the cause of the phenomenon is unclear, it might make the assessment of multiple or serial stenoses in a coronary vessel using a pullback manoeuver during extended administration of adenosine more difficult.

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Coronary There are further limitations due to the fact that certain patient groups were not included or tested in the randomised FFR studies. In the FAME studies, the excluded patient groups comprised the following: patients with left main coronary artery stenosis, patients with a recent history of STEMI, patients with a history of bypass surgery, patients with impaired left ventricular (LV) systolic function (LV ejection fraction <30 %) and patients with left ventricular hypertrophy (>13 mm). For these patient groups, there are currently no randomised, controlled outcome studies to validate FFR. Even though these limitations are not widely considered in everyday practice (particularly impaired LV function and LV hypertrophy), they should be given particular attention in the case of borderline measurement results.

Clinical Perspective A substantial further increase in our knowledge about intracoronary pressure wire and FFR measurements can be expected in the next several years.72 Numerous ongoing, prospective studies in special patient populations will significantly increase the body of available data regarding the integration of FFR measurements into clinical decisionmaking. In addition, methodical work can be expected to further clarify the value of various drugs and routes of administration for inducing

ijls NH, De Bruyne B, Peels K, et al. Measurement of P fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334(26):1703–8. DOI: 10.1056/NEJM199606273342604; PMID: 8637515. 2. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35(37):2541–619. DOI: 10.1093/eurheartj/ehu278; PMID: 25173339. 3. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/ AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2014;130(19):1749–67. DOI: 10.1161/CIR.0000000000000095; PMID: 25070666. 4. Van Belle E, Rioufol G, Pouillot C, et al. Outcome impact of coronary revascularization strategy reclassification with fractional flow reserve at time of diagnostic angiography: insights from a large French multicenter fractional flow reserve registry. Circulation 2014; 129(2):173–85. DOI: 10.1161/ CIRCULATIONAHA.113.006646; PMID: 24255062. 5. Lachance P, Déry JP, Rodés-Cabau J, et al. Impact of fractional flow reserve measurement on the clinical management of patients with coronary artery disease evaluated with noninvasive stress tests prior to cardiac catheterization. Cardiovasc Revasc Med 2008;9(4):229–34. DOI: 10.1016/j. carrev.2008.02.002; PMID: 18928947. 6. Toth GG, Toth B, Johnson NP, et al. Revascularization decisions in patients with stable angina and intermediate lesions: results of the international survey on interventional strategy. Circ Cardiovasc Interv 2014;7(6):751–9. DOI: 10.1161/ CIRCINTERVENTIONS.115.002296; PMID: 25663323. 7. Bech GJ, De Bruyne B, Pijls NH, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation 2001;103(24):2928–34. PMID: 11413082. 8. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER study. J Am Coll Cardiol 2007;49(21):2105–11. DOI: 10.1016 /j.jacc.2007.01.087; PMID: 17531660. 9. Zimmermann FM, Ferrara A, Johnson NP, et al. Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year followup of the DEFER trial. Eur Heart J 2015;36:3182–8. DOI: 10.1093/ eurheartj/ehv452; PMID: 26400825. 10. Pijls NH, Fearon WF, Tonino PA, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360(3):213–24. DOI: 10.1016/

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hyperaemia, and provide further data regarding the clinical reliability of pd/pa measurements without inducing hyperaemia.73 Furthermore, several methods of non-invasive FFR measurement with computational fluid dynamics are currently being evaluated; for example, based on computed tomography (CT) data,75–77 3-dimensionally reconstructed coronary angiograms78–83 and optical coherence tomography.84 However, these methods are still in the development and validation phases, and are not yet ready for clinical use. Among the methods mentioned, CT-based FFR has the most available data. Overall, given the available data from prospective studies and the clear recommendations in all the relevant guidelines, FFR measurement should be a readily available as part of the diagnostic repertoire in all cardiac catheterisation laboratories, and physicians and support staff should be intimately familiar with the process and interpretation of FFR. Experience shows that barriers to the use of FFR are significantly reduced when all staff within a catheterisation facility are able to follow a clearly-defined routine workflow with the fewest possible number of steps to measure FFR, whether with the intravenous administration of adenosine, the intracoronary administration of adenosine or the administration of another drug. This in particular pertains to the preparation of the measuring devices and preparation of the medication to induce hyperaemia. n

j.jacc.2010.04.012; PMID: 20537493. 11. P ijls NH, Fearon WF, Tonino PA, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol 2010;56(3):177–84. DOI: 10.1016/ j.jacc.2010.04.012; PMID: 20537493. 12. van Nunen LX, Zimmermann FM, Tonino PA, et al. Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomised controlled trial. Lancet 2015;386(10006):1853–60 DOI: 10.1016/S0140-6736(15)00057-4; PMID: 26333474. 13. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367(11):991–1001. DOI: 10.1056/ NEJMoa1205361; PMID: 22924638. 14. De Bruyne D, Fearon WF, Pijls NH, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 2014;371(13):1208–17. DOI: 10.1056/NEJMoa1408758; PMID: 25176289. 15. Zhang D, Lv S, Song X, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention: a meta-analysis. Heart 2015;101(6):455–62. DOI: 10.1136/ heartjnl-2014-306578; PMID: 25637372. 16. Johnson NP, Tóth GG, Lai D, et al. Prognostic value of fractional flow reserve: linking physiologic severity to clinical outcomes. J Am Coll Cardiol 2014;64(16):1641–54. DOI: 10.1016/ j.jacc.2014.07.973; PMID: 25323250. 17. Adjedj J, De Bruyne B, Floré V, et al. Significance of intermediate values of fractional flow reserve in patients with coronary artery disease. Circulation 2016;133(5):502–8. DOI: 10.1161/CIRCULATIONAHA.115.018747; PMID: 26733607. 18. Ozdemir M, Yazici GE, Turkoglu S, et al. Metoprolol does not affect myocardial fractional flow reserve in patients with intermediate coronary stenoses. Int Heart J 2007;48(4):477–83. PMID: 17827819. 19. Aqel RA, Zoghbi GJ, Trimm JR, et al. Effect of caffeine administered intravenously on intracoronary-administered adenosine-induced coronary hemodynamics in patients with coronary artery disease. Am J Cardiol 2004;93(3):343–6. DOI: 10.1016/j.amjcard.2003.10.017; PMID: 14759387. 20. Hage FG, Iskandrian AE. The effect of caffeine on adenosine myocardial perfusion imaging: time to reassess? J Nucl Cardiol 2012;19(3):415–9. DOI: 10.1007/s12350-012-9519-8; PMID: 22297853. 21. Salcedo J, Kern MJ. Effects of caffeine and theophylline on coronary hyperemia induced by adenosine or dipyridamole. Catheter Cardiovasc Interv 2009;74(4):598–605. DOI: 10.1002/ ccd.22030; PMID: 19496111. 22. Lindstaedt M, Bojara W, Holland-Letz T, et al. Adenosineinduced maximal coronary hyperemia for myocardial fractional flow reserve measurements: comparison of administration by femoral venous versus antecubital venous access. Clin Res Cardiol 2009;98(11):717–23. DOI: 10.1007/ s00392-009-0056-7; PMID: 19685258. 23. Prasad A, Zareh M, Doherty R, et al. Use of regadenoson for measurement of fractional flow reserve. Catheter Cardiovasc

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36.

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69. M cClish JC, Ragosta M, Powers ER, et al. Effect of acute myocardial infarction on the utility of fractional flow reserve for the physiologic assessment of the severity of coronary artery narrowing. Am J Cardiol 2004;93(9):1102–6. PMID: 10627357. 70. Pijls NH, Kern MJ, Yock PG, De Bruyne B. Practice and potential pitfalls of coronary pressure measurement. Catheter Cardiovasc Interv 2000;49(1):1–16. PMID: 10627357. 71. Claeys MJ, Bosmans JM, Hendrix J, Vrints CJ. Reliability of fractional flow reserve measurements in patients with associated microvascular dysfunction: importance of flow on translesional pressure gradient. Catheter Cardiovasc Interv 2001;54(4):427–34. PMID: 11747174. 72. Verdier-Watts F, Rioufol G, Mewton N, et al. Influence of arterial hypotension on fractional flow reserve measurements. EuroIntervention 2015;11(4):416–20. DOI: 10.4244/EIJV11I4A82; PMID: 24694379. 73. Seto AH, Tehrani DM, Bharmal MI, Kern MJ. Variations of coronary hemodynamic responses to intravenous adenosine infusion: implications for fractional flow reserve measurements. Catheter Cardiovasc Interv 2014;84(3):416–25. DOI: 10.1002/ccd.25305; PMID: 24282074. 74. Berry C, Corcoran D, Hennigan B, et al. Fractional flow reserve-guided management in stable coronary disease and acute myocardial infarction: recent developments. Eur Heart J 2015;36(45):3155–64. DOI: 10.1093/eurheartj/ehv206; PMID: 26038588. 75. Min JK, Leipsic J, Pencina MJ, et al. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. JAMA 2012;308(12):1237–45. DOI: 10.1001/2012.jama.11274; PMID: 22922562. 76. Norgaard BL, Leipsic J, Gaur S, et al. Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). J Am Coll Cardiol 2014;63(12):1145–55. DOI: 10.1016/j.jacc.2013.11.043; PMID: 24486266. 77. Gaur S, Bezerra HG, Lassen JF, et al. Fractional flow reserve derived from coronary CT angiography: variation of repeated analyses. J Cardiovasc Comput Tomogr 2014;8(4):307–14. DOI: 10.1016/j.jcct.2014.07.002; PMID: 25151923. 78. Morris PD, van de Vosse FN, Lawford PV, et al. “Virtual” (computed) fractional flow reserve: current challenges and limitations. JACC Cardiovasc Interv 2015;8(8):1009–17. DOI: 10.1016/j.jcin.2015.04.006; PMID: 26117471. 79. Morris PD, Ryan D, Morton AC, et al. Virtual fractional flow reserve from coronary angiography: modeling the significance of coronary lesions: results from the VIRTU-1 (VIRTUal Fractional Flow Reserve From Coronary Angiography) study. JACC Cardiovasc Interv 2013;6(2):149–57. DOI: 10.1016/ j.jcin.2012.08.024; PMID: 23428006. 80. Papafaklis MI, Muramatsu T, Ishibashi Y, et al. Fast virtual functional assessment of intermediate coronary lesions using routine angiographic data and blood flow simulation in humans: comparison with pressure wire – fractional flow reserve. EuroIntervention 2014;10(5):574–83. DOI: 10.4244/ EIJY14M07_01; PMID: 24988003. 81. Tu S, Barbato E, Köszegi Z, et al. Fractional flow reserve calculation from 3-dimensional quantitative coronary angiography and TIMI frame count: a fast computer model to quantify the functional significance of moderately obstructed coronary arteries. JACC Cardiovasc Interv 2014;7(7):768–77. DOI: 10.1016/j.jcin.2014.03.004; PMID: 25060020. 82. Tröbs M, Achenbach S, Röther J, et al. Comparison of fractional flow reserve based on computational fluid dynamics modeling using coronary angiographic vessel morphology versus invasively measured fractional flow reserve. Am J Cardiol 2016;117:29–35. DOI: 10.1016/ j.amjcard.2015.10.008; PMID: 26596195. 83. Tu S, Westra J, Yang J, et al. Diagnostic accuracy of fast computational approaches to derive fractional flow reserve from diagnostic coronary angiography: the international multicenter FAVOR pilot study. JACC Cardiovasc Interv 2016;9(19):2024–35. DOI: 10.1016/j.jcin.2016.07.013; PMID: 27712739. 84. Zafar H, Ullah I, Dinneen K, et al. Evaluation of hemodynamically severe coronary stenosis as determined by fractional flow reserve with frequency domain optical coherence tomography measured anatomical parameters. J Cardiol 2014;64(1):19–24, DOI: 10.1016/j.jjcc.2013.11.009; PMID: 24368093.

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Coronary Appendix 1 Table A1: Dosing regimen for periperal injection of adenosine (use of a solution with 3 mg adenosine/ml) a Desired application rate of

140 µg/kg/min

160 µg/kg/min

180 µg/kg/min

adenosine

ml/min ml/h

Body weight (kg) –

2.1 126

2.4 144

2.7 162

50–54

2.3 138

2.7 160

3.0 177

55–59

2.5 150

2.9 176

3.2 193

60–64

2.8 168

3.2 192

3.6 216

65–69

3.0 180

3.5 208

3.9 231

70–74

3.3 198

3.7 224

4.2 254

75–79

3.5 210

4.0 240

4.5 270

80–84

3.8 228

4.3 256

4.9 293

85–89

4.0 240

4.5 270

5.1 308

90–94

4.2 252

4.8 288

5.4 324

95–99

4.4 264

5.1 304

5.7 339

100–104

4.7 282

5.3 320

6.0 360

105–109

4.9 294

5.6 336

6.3 378

110–114

5.1 306

5.9 352

6.6 393

115–119

5.4 322

6.1 368

6.9 414

120–124

5.6 336

6.4 384

7.2 432

125–129

5.8 350

6.7 400

7.5 450

Can generally be drawn directly from respective vials or bottles and used undiluted. Usually, 30 ml of injection solution is sufficient for one examination.

Table A2: Dosing regimen for periperal injection of adenosine (use of a solution with 5 mg adenosine/ml) a Desired application rate of

140 µg/kg/min

160 µg/kg/min

180 µg/kg/min

adenosine

ml/min

ml/h

ml/min

ml/h

ml/min

ml/h

Body weight (kg) 45–49

1.3 78

1.4 84

1.6 96

50–54

1.4 84

1.6 96

13 108

55–59

1.5 90

1.8 108

2.0 120

60–64

1.7 102

1.9 114

2.2 132

65–69

1.8 108

2.1 126

2.3 138

70–74

2.0 120

2.2 132

2.5 150

75–79

2.1 126

2.4 144

2.7 162

80–84

2.2 132

2.6 156

2.9 174

85–89

2.4 144

2.7 162

3.1 186

90–94

2.5 150

2.9 174

33 192

95–99

2.7 162

3.0 180

33 204

100–104

23 168

3.2 192

3.6 216

105–109

2.9 174

3.4 204

33 228

110–114

3.1 186

3.5 210

4.0 240

115–119

3.2 192

3.7 222

4.1 246

120–124

33 204

33 228

4.3 258

125–129

3.5 210

4.0 240

4.5 270

Can generally be drawn directly from the respective vials or bottles and used undiluted.

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Table A3: Suggestion for preparation and dosing of adenosine for intracoronary administration 3 mg adenosine in 250 ml NaCl 0.9 % or 6 mg adenosine in 500 ml NaCl 0.9 % 10 ml

corresponds to

120 µg

9 ml

corresponds to

108 µg

8 ml

corresponds to

96 µg

7 ml

corresponds to

84 µg

6 ml

corresponds to

72 µg

5 ml

corresponds to

60 µg

4 ml

corresponds to

48 µg

3 ml

corresponds to

36 µg

2 ml

corresponds to

24 µg

1 ml

corresponds to

12 µg

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Possible doses for the left coronary artery

Possible doses for the right coronary artery

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Coronary

The Proximal Optimisation Technique for Intervention of Coronary Bifurcations Angela Hoye Department of Academic Cardiology, Hull York Medical School, Hull, UK

Abstract The proximal optimisation technique (POT) has been proposed as a strategy to improve the results of stent scaffolding of bifurcation lesions. It is a straightforward technique whereby a short, appropriately-sized balloon is inflated in the main vessel just proximal to the carina. The technique has several advantages: it reduces the risk of side branch compromise related to shifting of the carina, it improves stent apposition in the proximal main vessel, and it facilitates side branch access after main vessel stent implantation. When treating bifurcations, final kissing balloon dilation (KBD) has traditionally been used routinely to optimise angiographic results. However, recent clinical data have questioned this philosophy and bench models have demonstrated several shortcomings of KBD. Instead, the optimal strategy may centre on performing POT, followed by side branch dilation, and completed with a final (re)-POT. The following review article describes how to perform POT and presents the evidence to support its’ routine use.

Keywords Bench test, bifurcation, mal-apposition, optimisation, side branch, stent Disclosure: The author has no conflicts of interest to declare. Received: 11 May 2017 Accepted: 5 July 2017 Citation: Interventional Cardiology Review 2017;12(2):110–15. DOI: 10.15420/icr.2017:11:2 Correspondence: Angela Hoye, Department of Academic Cardiology, Hull York Medical School, Castle Hill Hospital, Castle Road, Hull HU16 5JQ, UK. E: angela.hoye@hyms.ac.uk

The coronary tree is comprised of arteries which divide into ever smaller branches to supply the myocardium. This means that the diameter of the vessel proximal to a bifurcation is always larger than the diameter of the main vessel distal to the bifurcation. The proximal optimisation technique (POT) was proposed by Dr Olivier Darremont as a technique to compensate for this difference in diameters when bifurcation lesions are stented. The technique is fully supported by the European Bifurcation Club and is a key part of the consensus statement produced by this group of experts.1 A short balloon is expanded in the proximal main vessel just up to the carina. This enables full expansion and complete apposition of the stent in the proximal main vessel. In addition, the POT also facilitates re-crossing into the side branch in order to optimise the final result if required. The following review article describes how to perform the technique and presents the evidence to support its routine use.

Murray’s Law The coronary tree is composed of vessels which branch into vessels of decreasing diameters. This follows Murray’s Law which states that the radii of daughter branches are related to the radius of the parent branch. Therefore, at each branch point within the coronary tree, the diameter of the vessels can be predicted. Professor Gérard Finet simplified Murray’s Law and showed that the proximal main vessel diameter closely approximates to the sum of the daughter vessel diameters (distal main plus side) multiplied by 0.67 (Figure 1). Therefore, for all bifurcations, the diameter of the distal main vessel will be consistently smaller than the diameter of the proximal main vessel. The greater the diameter of the side branch, the greater is the disparity between the diameter of the proximal main vessel and the vessel distal to the bifurcation. This difference in diameters is important when selecting a stent of appropriate diameter. If a stent is chosen based on the diameter of the proximal main vessel, this will

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be ‘over-sized’ for the distal main vessel. This may be associated with compromise of flow into the side branch as it can lead to shifting of the carina (Figure 2A). However, if the stent is chosen based on the diameter of the distal main vessel, the proximal part of the stent will be small relative to the vessel size (Figure 2B). This mal-apposition has implications particularly if a new guidewire is advanced through the stent as it may inadvertently pass behind the stent struts. Any further balloon dilatation will then crush the stent potentially leading to major complications including stent thrombosis.2 Importantly, this may not necessarily be evident to the operator on angiography or by ‘tactile feedback’ of the smoothness of wire passage.

Technique The aim of the POT is to fully appose the stent proximal to the bifurcation; in addition, POT expands the stent cells overlying the side branch ostium. A short balloon is taken and must be accurately positioned with the distal marker of the balloon placed at the carina, level with the side branch ostium (Figure 2C). This is best done by confirming a good position on orthogonal views. If positioned too distal, this could cause carinal shift, if too proximal then this will not appropriately expand the stent overlying the side branch ostium. If required, an additional balloon inflation is made more proximally to ensure that the inflow of the stent is fully apposed. To help accurately position the balloon, it is useful to use radiographic optimisation with techniques such as stent boost imaging. It is important to choose a correctly-sized balloon (non-compliant or semi-compliant) that will adequately expand the proximal part of the stent.

Evidence in Favour of POT from Bench Models Bench models have been key to developing the concept of the POT and demonstrate the associated excellent anatomical / scaffolding result.3–6 In 2011, Foin et al.3 evaluated the concept in a bench

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Proximal Optimisation of Bifurcations Figure 1: Finet’s formula of bifurcation vessel size

Figure 2: Bifurcation lesion

D1 = 0.67(D2 + D3)

A: Stent sized to the proximal main vessel

The proximal main vessel lumen diameter (D1) = 0.678 x (distal main vessel diameter (D2) + side branch diameter (D3)).

model of commercially available stents. They demonstrated that a final POT was able to significantly improve the anatomical result following single stent implantation for a bifurcation, confirming the reduction in mal-apposition of the stent in the proximal main vessel. Furthermore, they also showed the potential downside of final kissing balloon dilation (KBD) which has traditionally been recommended in clinical practice. KBD caused asymmetrical stent (over)expansion in the region where both balloons were expanded together, as well as development of mal-apposition of the proximal part of the main vessel stent (Figure 3). Computational simulations have been useful in assessing the negative impact of KBD. Studies have shown that in addition to creating elliptical deformation of the stent in the proximal main vessel, KBD also causes altered strut configuration, damage to the stent coating, as well as arterial injury to the side branch ostium.7–9 KBD results in higher

B: Stent sized to the distal main vessel

stresses in the arterial wall10 and stent ‘over-stretch’ has been shown to increase the inflammatory response to stent implantation. Otake et al. demonstrated, by Optical Coherence Tomography (OCT), that stent asymmetry was correlated with stent thrombosis and an increased rate of major adverse clinical events (MACE) in patients treated with drug-eluting stents.11 Foin and colleagues went on to carry out a further bench study and proposed a step-wise post-dilation strategy in preference to KBD.4 In this second study, following stent implantation, they performed POT followed by side branch balloon-inflation. The final step was either KBD or a final POT. As before, KBD was shown to have unfavourable features causing elliptical over-expansion of the stent proximal to the carina, as well as distortion of the proximal part of the main vessel stent with development of mal-apposition (even though POT had been done prior to the KBD). However, the step-wise approach (POT, side branch dilation, then re-POT) led to a more favourable result with significantly less strut mal-apposition at the proximal edge of the stent. In addition, POT expanded the stent cell overlying the side branch ostium. This is advantageous as it has the potential to make it easier to re-cross a guidewire into the side branch and may also facilitate ‘optimal re-cross’. When a provisional strategy is used, re-cross should ideally be performed through a distal stent cell.12 This ensures that balloon inflation will produce better clearance of struts from the side branch ostium.

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(A) The stent is sized to the proximal reference diameter of the main vessel. Stent deployment will displace the carina thereby compromising flow into the side branch. (B) The stent is sized to the distal reference diameter of the main vessel. Following stent deployment, the proximal part of the stent is mal-apposed. (C) Illustration of the proximal optimisation technique. A short balloon sized to the proximal main vessel diameter is positioned just up to the carina and inflated. (D) Following POT, there is good apposition of the stent throughout its length and without shifting of the carina. POT= Proximal Optimisation Technique

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Coronary Figure 3: Effect of kissing balloon dilation inflation on strut distribution during provisional bifurcation stenting and Impact of Proximal Optimisation Technique on stent apposition and side branch access

Table 1: Potential Benefits of the Proximal Optimisation Technique Reduce of strut mal-apposition especially in the main vessel proximal to the bifurcation Reduce the risk of inadvertent abluminal re-wiring of the main vessel stent Open the stent cells overlying the side branch ostium Facilitate re-wiring into the side branch Optimise the final stent geometry and flow dynamics

(A) Effect of kissing balloon dilation (KBD) inflation on strut distribution during provisional bifurcation stenting Strut mal-apposition and stent under-expansion during stenting of the main vessel (A.i) and dilation of the side branch (A.ii). Longitudinal and cross-sectional views show the asymmetrical distortion of the stent in the proximal main vessel after KBD (A.iii). Post-dilation of the proximal part of the main vessel (proximal optimisation technique) corrects the stent distortion while ensuring complete apposition of stent struts (A.iv). (B) Impact of proximal optimsation technique on stent apposition and side branch access. Comparison of the stent before (deployment) and after POT. View of the strut configuration from the side branch (right panel) shows how POT facilitates re-crossing by creating a ‘funnel effect’ through enlargement of the cells located in front of the side branch, reducing the number of possible cells available for crossing. Source: Foin et al. 20113 and Foin et al. 2013.13 Reproduced with permission from Europa Digital & Publishing, © 2011, 2013.

The studies by Foin have been subsequently supported by a further bench model study6 that evaluated six strategies: (i) KBD alone, (ii) POT then KBD, (iii) POT then asymmetrical KBD with the main vessel balloon inflated and maintained at 12 atm and the side branch balloon inflation reduced from 12 atm to 4 atm, (iv) POT then asymmetrical KBD with side branch balloon inflated and maintained at 12 atm and the main vessel balloon inflation reduced from 12 atm to 4 atm, (v) POT then side branch inflation (SBI), (vi) POT then SBI at 12 atm then re-POT.6 Each strategy was evaluated in two different stent designs. The results demonstrated that the best geometric result was obtained from POT – SBI –re-POT. Compared to techniques utilising KBD, the POT – SBI – re-POT strategy reduced the proximal area overstretch and restored circularity, reduced the side branch ostium stent-strut obstruction, and significantly reduced global strut mal-apposition (from 40 ± 6.2 % to 2.6 ± 1.4 %). This reduction in strut mal-apposition may have important clinical implications as strut mal-apposition disturbs blood flow causing high shear stress. This activates platelets and has been shown to delay neointimal coverage of struts, both potentially increasing thrombogenicity and the potential for late stent thrombosis.14,15 Furthermore, disturbed flow patterns caused by the geometrical complexity of bifurcation lesions may explain the relative increase in the risk of developing restenosis.16 Recently, Murasato et al.5 used a bench model to suggest that a compliant balloon may be preferable to the use of a non-compliant balloon to optimise strut apposition during POT. High pressure is not a pre-requisite as the balloon merely needs to dilate the unopposed stent; however, an adequately large balloon diameter is obligatory. For some larger vessels, the expansion range of non-compliant balloons will limit their ability to fully appose the struts whereas the greater expansion range of a semi-compliant balloon could be advantageous. For example, if a vessel is 4.9 mm diameter, a 4.5 mm non-compliant balloon may only reach a maximal diameter of 4.8 mm whereas a semi-compliant balloon will easily expand to 5.0 mm.

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All of these bench studies provide evidence to support the potential benefits of POT (Table 1) and emphasise the importance of always completing the procedure with a final POT. This can correct both the mal-apposition as well as improve the elliptical shape back to a circular lumen which will favourably influence the flow dynamics. This information forms the basis by which experts including the European Bifurcation Club have adopted and strongly support the routine use of POT.

Implications for single stent bifurcation strategy It is important to appreciate that the clinical trials evaluating various bifurcation strategies (e.g. one stent versus two-stent strategies) were performed prior to the widespread adoption of POT. However, there seems no reason why the important information obtained from bench model studies should not be incorporated into clinical practice. Randomised controlled studies have demonstrated that, for the majority of bifurcations, a single stent strategy is preferred over a twostent strategy; with recent data suggesting improved 5-year survival for the simpler technique.17 The recommendation from the EBC is that both vessels are wired, with pre-dilation of the main vessel if required.1 Pre-dilatation of the side branch is to be avoided if possible as, if this causes dissection, the side branch will be more difficult to re-wire once the main vessel has been stented. The main vessel is stented using a stent diameter based on the reference diameter of the main vessel distal to the bifurcation (Figure 4). The stent must be long enough to cover sufficient length of the proximal main vessel to allow POT to be performed, bearing in mind that the shortest available balloon may be 6 mm or 8 mm in length. After stenting, POT is performed to optimise stent expansion. In addition, this balloon dilatation will also open the stent cells overlying the side branch ostium and may partially scaffold the side branch ostium. In the majority of situations, the procedure can be terminated at this point. However, if there is concern regarding flow into the side branch, POT facilitates successful re-wiring of the side branch to enable further balloon dilatation +/- stent implantation. Based on information from the bench models, the procedure should always end with a final POT. Although there is a lack of robust clinical data to demonstrate the advantages of POT, there is evidence from a randomised study to show that that there is no benefit (or perhaps a disadvantage) to undertaking KBD routinely.18,19 The NORDIC III trial randomised 477 patients with bifurcation lesions to final KBD versus no KBD after main vessel stenting.19 At 6 months, there was no significant difference in the primary endpoint of cardiac death, non-procedural myocardial infarction, target lesion revascularisation (TLR) or stent thrombosis (2.1 % versus 2.5 %, p=1.0). However, the KBD procedures were longer and utilised higher contrast use. The 5-year clinical outcomes of this trial were presented in 2015.20 There were no differences in the rates of

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Proximal Optimisation of Bifurcations Figure 4: Case example of Proximal Optimisation Technique during provisional stenting in a 67-year-old patient admitted to hospital with an acute coronary syndrome

Figure 5: Case example of POT during a two-stent strategy in a 79-year-old patient with an acute coronary syndrome and on-going symptoms of chest discomfort

(A) There is a filling defect in the ostium of the left circumflex artery (LCx) extending back into the left main stem and compromising flow into the left anterior descending artery (LAD). There was no improvement in the angiographic appearances after pre-dilation so a 2-stent strategy was performed (Culotte technique). The first stent was implanted in the LCx back to the ostium of the LMS (B). POT was performed to fully appose the proximal part of the stent in the LMS (C) and facilitate re-wiring of the LAD. After further balloon dilation, the LAD was stented to cover the ostium of the LMS (D). The result was optimised with kissing balloon inflation (E) with a good angiographic result (F). LAD= left anterior descending artery; LCx=left circumflex artery; POT= Proximal Optimisation Technique There is a tight stenosis at the ostium of the left anterior descending artery seen on angiography (A) as well as by intravascular ultrasound (B). There was no significant plaque at the ostium of the left circumflex artery (C) so a single stent provisional strategy was chosen. The reference diameter of the left anterior descending artery was 3.0 mm (D) so the lesion was treated with a 3.0 x 23 mm Xience stent (Abbott Vascular) implanted at 16 atm. There is significant mal-apposition of the proximal part of the stent in the left main stem (E). A short 4.5 mm balloon was inflated in the left main stem to perform POT (F). Excellent final result both on angiography (G) as well as on intravascular ultrasound (H).

myocardial infarction, TLR or stent thrombosis. Interestingly however, cardiac mortality was significantly higher in the group treated with routine KBD (4.2 % versus 0.8 %, p=0.02). Though this may be a chance finding, it could also be hypothesized that in the absence of routine POT, some of the late events might be due to inadvertent abluminal wiring occurring in the pursuit of performing KBD.2 The efficacy of KBD from registry data is contradictory. The first COBIS registry21 evaluated 1,065 patients of which 736 (69 %) were treated with KBD. At 22 months’ follow-up, there was a significantly higher rate of MACE in those treated with KBD (10.0 % versus 4.9 %, p<0.05), driven by a higher rate of TLR in the KBD group (9.1 % versus 3.4 %, p<0.05). The subsequent COBIS II registry demonstrated quite the opposite and suggested that KBD might in fact be favourable.22 This study evaluated 1,901 patients with a bifurcation lesion treated by single drug-eluting stent implantation. KBD was performed at the discretion of the operator in 620 patients (32.6 %), notably a lower proportion than that seen in the first COBIS registry. At a median follow-up of 36 months, those treated with KBD had a significantly lower rate of MACE (adjusted hazard ratio [HR]: 0.68, 95 % CI: 0.46 to 0.99; p=0.048). This benefit remained apparent after propensity score matching (545 pairs, adjusted HR: 0.50, 95 % CI: 0.30 to 0.85; p=0.01); with a significantly lower rate of TLR in the KBD group. Ongoing in vivo work is being undertaken to evaluate POT in clinical practice and will potentially provide clinical evidence to back-up the evidence from bench studies. Studies have been designed that incorporate OCT imaging as a tool to identify stent strut mal-

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apposition, which is proposed as a surrogate marker for a higher risk of adverse clinical events.

Implications for a 2-stent strategy Whatever stenting technique is used, POT is an integral part of twostent strategies to appose the stent in the proximal main vessel as well as to open up the stent cells to facilitate easier guidewire crossing through the side of the stent. In contrast to a single stent strategy, there is strong evidence in favour of kissing balloon dilation for two-stent strategies. 23,24 Failure to perform successful KBD is associated with both a greater rate of stent thrombosis as well as a significantly higher rate of restenosis, TLR and MACE. Indeed, some of the best clinical results have been obtained from the double kissing strategy of the DK-crush technique.25–27 Figure 5 illustrates the principle of incorporating POT during two-stent bifurcation procedures. The first POT is performed after the first stent has been implanted, to appose the stent in the proximal main vessel and open the struts to facilitate optimal guidewire re-crossing. The second stent is implanted according to the preferred strategy, with further POT used as required to facilitate guidewire re-crossing. Final KBD is mandated, however, as demonstrated in Figures 5A and 6B, such KBD causes elliptical deformation of the stented proximal main vessel. This has the potential to impact negatively on the flow dynamics, but can be improved following a final POT which restores the circular morphology.28 The importance of POT to facilitate optimal guidewire re-crossing during two-stent bifurcation procedures is illustrated by a case report published by Wurtz and colleagues.2 They reported a patient who presented with stent thrombosis six years after undergoing Culotte bifurcation stenting. They showed, by OCT, that there had been inadvertent abluminal wiring during the original procedure. Instead of seeing a circular double layer of stent struts in the proximal main vessel, there was evidence that the side branch stent had been

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Coronary Figure 6: Improved strut apposition and restoration of circularity when POT was performed

this could have been avoidable if POT had been performed prior to re-wiring; however, this technique was not part of clinical practice at the time the original procedure was undertaken.

Bioresorbable scaffolds Bioresorbable scaffolds (BRS) have some expansion limitations beyond which there is a risk of strut fracture.29 Therefore, when selecting the most appropriate size, it is important to appreciate the dilation limitations. The expansion capacity of the Absorb scaffold (Abbott Vascular, Santa Clara, California) allows post-dilation up to 0.5 mm above the nominal diameter. An ‘aggressive’ POT should be avoided for BRS so it may be necessary to choose a diameter that is a little larger than the distal main vessel reference diameter and closer to the proximal main vessel reference diameter. The scaffold is deployed at nominal pressure, and then optimised using both an appropriately-sized balloon for the distal part of the stent as well as a larger balloon for the POT. If the SB appears compromised, the recommended technique is POT, followed by balloon inflation in the side branch, followed by re-POT.30 Bench studies suggest that for a 3.0 mm Absorb scaffold implanted in the main vessel, the side branch can be dilated with (up to) a 3.0 mm balloon inflated to a maximum of 10 atm.31 Importantly, because of the risk of scaffold fracture with overstretch, KBD with overlapping balloons is strongly discouraged.1

Conclusion Despite a good result on angiography (Ai), IVUS demonstrated that there was still significant mal-apposition at the proximal part of the LMS as well as elliptical deformation of the stented vessel (Aii). A final balloon inflation (POT) was performed with a 4.5 mm balloon (Bi). IVUS demonstrated good strut apposition as well as restoration of circularity (Bii).

completely crushed in the proximal main vessel. This was not evident on angiography at the time of the index procedure. Importantly,

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Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions). Circ Cardiovasc Interv 2017;10(2): pii. DOI: 10.1161/CIRCINTERVENTIONS.116.004497; PMID: 2812280527. 28. Rigatelli G, Dell’Avvocata F, Zuin M, et al. Complex coronary bifurcation revascularization by means of very minimal crushing and ultrathin biodegradable polymer DES: Feasibility and 1-year outcomes of the “Nano-crush” technique. Cardiovasc Revasc Med 2017;18:22–7. DOI: 10.1016/j. carrev.2016.07.003; PMID: 2756690428.

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29. O rmiston JA, Webber B, Ubod B, et al. An independent bench comparison of two bioresorbable drug-eluting coronary scaffolds (Absorb and DESolve) with a durable metallic drug-eluting stent (ML8/Xpedition). EuroIntervention 2015;11:60–7. DOI: 10.4244/EIJY15M02_03; PMID: 2568022529. 30. Derimay F, Souteyrand G, Motreff P, et al. Sequential Proximal Optimizing Technique in Provisional Bifurcation Stenting With Everolimus-Eluting Bioresorbable Vascular Scaffold:

Fractal Coronary Bifurcation Bench for Comparative Test Between Absorb and XIENCE Xpedition. JACC Cardiovasc Interv 2016;9:1397–406. DOI: 10.1016/j.jcin.2016.04.021; PMID: 2738883030. 31. Ormiston JA, Webber B, Ubod B, et al. Absorb everolimuseluting bioresorbable scaffolds in coronary bifurcations: a bench study of deployment, side branch dilatation and postdilatation strategies. EuroIntervention 2015;10:1169–77. DOI: 10.4244/EIJY14M05_08; PMID: 24835848

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Predilatation Prior to Transcatheter Aortic Valve Implantation: Is it Still a Prerequisite? Matteo Pagnesi, 1 Luca Baldetti, 1 Paolo Del Sole, 1 Antonio Mangieri, 1 Marco B. Ancona, 1 Damiano Regazzoli, 1 Nicola Buzzatti, 2 Francesco Giannini, 1 Antonio Colombo 1,3 and Azeem Latib 1 1. Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy; 2. Department of Cardiovascular and Thoracic Surgery, San Raffaele Scientific Institute, Milan, Italy; 3. Vita-Salute San Raffaele University, Milan, Italy

Abstract Predilatation has been historically considered a mandatory step before transcatheter aortic valve implantation (TAVI) since it facilitates valve crossing and prosthesis delivery, ensures optimal valve expansion and improves hemodynamic stability during valve deployment. However, as a result of procedural evolution over time, direct TAVI (without pre-implantation balloon aortic valvuloplasty) has emerged as an interesting option to simplify the procedure and to avoid potential valvuloplasty-related complications. Several real-world retrospective studies and one small randomised study have shown that direct TAVI (with both self-expanding and balloon-expandable prostheses) is feasible, safe and associated with outcomes similar to standard TAVI with pre-implantation balloon aortic valvuloplasty. In the absence of high-quality, robust evidence, the current review aims to discuss the advantages and disadvantages of omitting predilatation prior to TAVI.

Keywords Transcatheter aortic valve implantation, predilatation, direct transcatheter aortic valve implantation, balloon aortic valvuloplasty, aortic valve calcification, cerebral embolic risk, paravalvular leakage, postdilatation, permanent pacemaker. Disclosure: AL is on the advisory board of Medtronic (MN, USA). The other authors have no conflicts of interest to declare. Received: 18 June 2017 Accepted: 4 August 2017 Citation: Interventional Cardiology Review 2017;12(2):116–25. DOI: 10.15420/icr.2017:17:2 Correspondence: Azeem Latib, Interventional Cardiology Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. E: alatib@gmail.com

Transcatheter aortic valve implantation (TAVI) has become an established treatment option for patients with severe, symptomatic aortic stenosis at high or intermediate surgical risk.1–4 From the very beginning of TAVI technology, valve preparation by performing pre-implantation balloon aortic valvuloplasty (pre-BAV) has been considered a necessary step to facilitate device implantation and ensure optimal valve expansion.5 However, as a result of procedural evolution over time and increasing operator experience, direct TAVI (without predilatation) has recently emerged as a new option to simplify the procedure and to avoid potential BAV-related complications (cerebrovascular events, conduction disturbances, severe acute aortic regurgitation and even annular rupture).6–9 After the first pioneering experience of Grube et al.,10 several observational studies and one small randomised study have evaluated procedural and clinical outcomes of TAVI with and without predilatation (Table 1). Therefore, this review aims to discuss the advantages of both direct TAVI and standard TAVI with pre-BAV, in light of the current published evidence.

operators in exploring a direct TAVI approach; simultaneously, they raise an interesting question regarding the potential (or demonstrated) advantages of removing predilatation.

Procedural Time and Contrast Use As a logical result of removing one procedural step, this approach leads to shorter procedural time and lower total contrast volume use than TAVI with pre-BAV.12,13 This aspect may represent an interesting advantage for patients in whom a longer procedural time may be undesired, such as hemodynamically unstable patients, patients with severe left or right ventricular dysfunction or severe pulmonary hypertension (who, in addition, may not tolerate rapid pacing performed during balloon valvuloplasty). Furthermore, subjects at higher risk of contrast-induced nephropathy (e.g. those with pre-existing chronic kidney disease or diabetes mellitus) may benefit from lower contrast use during the procedure.14

Safety and Feasibility of Direct TAVI

Direct TAVI: Moving Toward a Simplified Approach In an effort to obtain a more simplified and straightforward procedure, direct TAVI has increasingly been studied and performed (Table 1). Recent analysis of the UK TAVI Registry has shown a decreasing trend in the proportion of TAVI patients undergoing predilatation between 2007 and 2014; moreover, among centres with high experience (>200 TAVI performed), the rate of direct TAVI was around 50 %, decreasing to 11 % among centres with low experience (1–50 TAVI performed).11 These findings confirm the interest of more experienced

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The omission of one procedural step may be justified only if the simplified approach is demonstrated to be feasible, safe and not associated with adverse outcomes. The largest study exploring postprocedural outcomes after direct TAVI is the abovementioned UK TAVI Registry, that included 5,887 patients undergoing TAVI with vs without pre-BAV. In that study, direct TAVI was not associated with a higher rate of adverse short-term outcomes, especially when using the balloon-expandable SAPIEN (Edwards Lifesciences Inc., Irvine, CA) valve. For the self-expanding CoreValve (Medtronic, Minneapolis, MN) prosthesis, the use of predilatation was associated with lower odds of

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Predilatation and TAVI Table 1: Studies Comparing the Outcomes of Patients Undergoing TAVI With and Without Predilatation

Longest Follow-up

Clinical Outcomes at

Follow-up

Procedural and 30-day

Access Route

Outcomes

THV Used

Similar rate of all-cause mortality, stroke, PVL and PPI in both groups.

STS Score (%)

Significantly lower number 30 days of rapid pacing in no pre-BAV group. Similar procedural time, fluoroscopy time, total contrast used, and 30-day outcomes (death, stroke, PVL, PPI) in both groups.

Similar rate of all-cause mortality in both groups.b

Age (years)

Ahn et al. Randomised; 60 30 30 83 (range 58–93) 7 (range 1–13) Sapien XT TF n = 50 201615 single-centre no pre-BAV; no pre-BAV; TA n = 10 81 (range 42–91) 6 (range 2–17) pre-BAV pre-BAV

Significantly lower rate of PPI 30 days (adjusted OR 1.30 [95 % CI 1.04–1.62])a in no pre-BAV group. Similar rate of moderate–severe PVL, stroke, MI, VARC-2 early safety, and 30-day death in both groups.b

Similar rate of all-cause mortality, CV mortality, CVE, MI, PPI, moderate– severe PVL and VARC-2 efficacy endpoint in both groups.b

Martin et al. Retrospective; 5,887 1,421 4,466 81.3 ± 7.5 4.9–5.0 ± 4.0–4.1 Sapien n = 3201 TF n = 4385 multicentre CoreValve n = 2467 TA n = 952 201711 Others n = 219 Others n = 545

Significantly lower rate of 30-day 1 year new-onset persistent LBBB in no pre-BAV group (29.7 % vs 40.7 %; p = 0.006). Similar rate of PD, moderate– severe PVL, device success and 30-day outcomes (all-cause death, CV death, CVE, MI, PPI, VARC-2 safety endpoint) in both groups.

Similar rate of all-cause mortality in both groups.b

BAV BAV

No pre- Pre-

Bernardi Retrospective; 761 389 372 81.8 ± 7.1 10.2 ± 7.9 CoreValve n = 577 TF n = 738 Sapien XT n = 184 Non-TF n = 23 et al. 201616 multicentre

Significantly lower fluoroscopy 14.8 ± 9.9 time (12.3 ± 5.1 vs 17.1 ± 8.4 min; months p < 0.001), contrast volume used (78.5 ± 37.1 vs 86.9 ± 41.1 mL; p = 0.048), and PVL rate (moderate– severe PVL 5.9 % vs. 0 %) in No preBAV group. Similar rate of PD, VARC-2 device success, and 30-day outcomes (death, CVE, MI, PPI) in both groups.

Similar rate of MACCE, all-cause mortality, MI and stroke in both groups.b

Study Design Study Population

82.5 ± 8.6 8.4 ± 5.2 Sapien n = 190 TF n = 423 Abramowitz Retrospective; 513 121 392c Sapien XT n = 323 TA n = 31 et al. 201618 single-centre Others n = 59

Significantly lower contrast 1 year volume used (134.1 ± 85.0 vs 155.0 ± 93.0 mL; p = 0.01) and higher rate of PD (35.6 % vs 21.5 %; p < 0.001), 30-day stroke (3.7 % vs 0.3 %; p < 0.01) and 30-day MACCE (7.3 % vs 3.4 %; p = 0.04) in no pre-BAV group. Similar rate of moderate–severe PVL, 30-day death, 30-day MI and 30-day PPI in both groups.

Pagnesi et al. Retrospective; 517 191 326 80.8 ± 7.5 no – CoreValve n = 216 TF single-centre pre-BAV; Evolut R n = 30 201617 79.9 ± 7.4 Sapien XT n = 210 pre-BAV Sapien 3 n = 61

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Age (years)

STS Score (%)

THV Used

Access Route

Procedural and 30-day

Follow-up

Clinical Outcomes at

Significantly lower procedural time Median: 21.4 months Similar rate of 1-year all(137.2 ± 66.9 vs 167.5 ± 83 min; (IQR 10.0–38.0) cause mortality in both p = 0.003) and contrast volume groups.b used (94.7 ± 35.9 vs 135.1 ± 51.1 mL; p < 0.001) in no pre-BAV group. Similar rate of PD, PVL, VARC-2 device success, PPI, stroke and 30-day death in both groups.b Significantly lower rate of moderate- 1 year severe PVL (7 % vs 33 %; p = 0.01) in no pre-BAV group. Similar rate of PD, VARC-2 device success, PPI and 30-day outcomes (all-cause and CV death, stroke, MI) in both groups. Similar rate of PD, moderate-severe 1 year PVL, VARC-2 device success and 30-day clinical outcomes (death, stroke, MI, PPI) in both groups. Significantly lower procedural time 30 days (56.7 ± 26.1 vs 85.6 ± 42.9 min; p < 0.001), fluoroscopy time (6.2 ± 3.9 vs 9.5 ± 5.7 min; p < 0.001), contrast volume used (85.4 ± 37.4 vs 131.9 ± 60.8 mL; p < 0.001), PD (16.5 % vs 25.1 %; p = 0.02), TAVI-in-TAVI (0 % vs 2.8 %; p = 0.005), 30-day all-cause death (2.9 % vs 6.8 %; p = 0.03), 30-day CV death (1.4 % vs 5.3 %; p = 0.01), 30-day VARC-2 safety endpoint (9 % vs 14.8 %; p = 0.04) in no pre-BAV group.

Ferrera Prospective; 204 102 102 83.1 ± 5.2 – CoreValve n = 64 TF n = 204 et al. 201657 single-centre Edwards BEV n = 140

Toutouzas Retrospective; 210 90 120 79 ± 17 no – CoreValve TF n = 194 et al. 201658 multicentre pre-BAV; Others n = 16 82 ± 6 pre-BAV

Kochman Retrospective; 24 8 16 78.1 ± 8.4 no – CoreValve TF n = 18 et al. 201459 single-centre pre-BAV; Others n = 6 83.3 ± 3.7 pre-BAV

Hamm et al. Retrospective; 678 278 400 81.4 ± 5.3 no – Sapien X n = 358 TF n = 373 201760 single-centre pre-BAV; Sapien 3 n = 320 TA n = 305 80.1 ± 5.6 pre-BAV

Lower rate of all-cause mortality, CV mortality and VARC-2 safety endpoint in no pre-BAV group. Similar rate of stroke and VARC-2 efficacy endpoint in both groups.

Similar rate of all-cause mortality in both groups.

Similar fluoroscopy time, total 1 year contrast used and rate of PD, moderate–severe PVL and 30-day outcomes (death, stroke, MI, PPI) in both groups.

Similar rate of 1-year allcause mortality in both groups.b

Longest Follow-up

Spaziano Retrospective; 281 223 58 82.7 ± 7.1 5.3 ± 3.5 Sapien 3 TF n = 232 et al. 201726 single-centre Others n = 49

Outcomes Significantly lower fluoroscopy 8.1 ± 4.4 months time (13.0 ± 5.5 vs 16.2 ± 6.6 min; p < 0.01) and total contrast used (71.3 ± 31.0 vs 81.0 ± 36.4 mL; p = 0.03) in no pre-BAV group. Similar rate of PD, PVL, VARC-2 device success and 30-day outcomes (death, CVE, MI, PPI) in both groups.

No pre- Pre-

BAV BAV Abramowitz Retrospective; 245 119 126c 82.0 ± 7.8 6.3 ± 3.0 Sapien 3 TF n = 237 et al. 201627 single-centre TA n = 3 Others n = 5

Study Design Study Population

Table 1: Cont.

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Similar rate of technical success, moderate–severe PVL, MI, PPI, VARC-2 device success, 30-day VARC-2 efficacy endpoint and 30-day stroke in both groups. Significantly lower procedural time 30 days (108.5 ± 35.6 vs 133.7 ± 46.9 min; p < 0.001) and 30-day death (2.5 % vs 11.8 %; p = 0.018) in no pre-BAV group. Similar total contrast used, PD, moderate-severe PVL, VARC-2 device success, stroke and PPI in both groups. Higher rate of technical success 30 days (96.7 % vs 81.7 %) and lower rate of 30-day outcomes (mortality [6.7 % vs 14.3 %], MI [0 % vs 5.6 %], CVE [5.0 % vs 11.9 %] and PPI [11.7 % vs 27.8 %]) in no pre-BAV group. No severe PVL in both groups. Significantly lower fluoroscopy 30 days time (13 vs 18.3 min; p = 0.01) and procedural time (104.9 vs 125.6 min; p < 0.001) in no pre- BAV group. Similar rate of PD, PVL, VARC-2 device success and 30-day outcomes (death, CVE, VARC-2 safety endpoint) in both groups. Significantly lower fluoroscopy 30 days time (306 [206–382] vs 341 [279–432] min; p = 0.04) in no pre-BAV group. Similar total contrast used, PD, moderate-severe PVL, CVE, PPI and 30-day death in both groups.b Similar rate of PD, PVL, VARC 30 days device success and 30-day outcomes (all-cause death, CV death, stroke, MI, PPI, VARC safety endpoint) in both groups. Significantly lower rate of moderate- 30 days severe PVL (9 % vs 33 %; p = 0.02) and higher VARC-2 success rate (85 % vs 64 %; p = 0.014) in no pre-BAV group. Similar rate of PD and 30-day

Islas et al. Consecutive 249 79 170 82 ± 5 – Sapien XT n = 166 TF patients; CoreValve n = 83 201523 single-centre

Grube et al. Retrospective; 186 60 126 80.1 ± 6.4 – CoreValve - multicentre no pre-BAV; 201110 81.9 ± 6.4 pre-BAV

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Aggarwal Retrospective; 154 78 76 80.6 no pre-BAV; – Sapien XT n = 111 TF 82.2 pre-BAV Sapien 3 n = 43 et al. 201661 single-centre

Kempfert Prospective; 128 88 40 80 no pre-BAV; 8.71 no pre-BAV; Sapien XT TA 80 pre-BAV 7.22 pre-BAV et al. 201562 single-centre

Wong et al. Retrospective; 121 50 71 84.3 ± 6.6 no 9.4 ± 5.3 no Sapien TF n = 71 single-centre pre-BAV; pre-BAV; TA n = 50 201563 84.4 ± 7.5 8.5 ± 4.6 pre-BAV pre-BAV

Fiorina et al. Retrospective; 110 55 45 83 ± 7 no pre-BAV; 10 ± 8 no pre-BAV; CoreValve TF n = 66 single-centre 83 ± 8 pre-BAV 7 ± 4 pre-BAV Others n = 34 201464

Similar rate of all-cause mortality, CV mortality, MI, disabling stroke, PPI and VARC-2 safety endpoint in both groups.

Similar rate of all-cause mortality, CV mortality, stroke, MI, PPI and VARC safety endpoint in both groups.

Similar rate of all-cause mortality in both groups.b

Similar of rate of allcause mortality, CVE and VARC-2 safety endpoint in both groups.

Lower rate of all-cause mortality, CVE, MI and PPI in no pre-BAV group.

Lower rate of all-cause mortality in no pre-BAV group.

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Age (years)

STS Score (%)

THV Used

Access Route

Procedural and 30-day

Follow-up

Significantly lower total lesion 30 days volume at post-procedural cerebral DW-MRI (89.5 ± 128.2 vs 235.4 ± 331.4 mm3; p = 0.01), procedural time (58.7 ± 31.6 vs 69.2 ± 41.7 min; p = 0.008), and contrast volume used (69.8 ± 22.5 vs 97.0 ± 50.8; p = 0.004) in no pre-BAV group. Similar rate of PVL and 30-day outcomes (death, MI, stroke) in both groups. Significantly lower fluoroscopy 30 days time (9.3 [95 % CI 8.1–10.5] vs 11.2 [95 % CI 9.8–13.8] min; p = 0.03), radiation dose (18.0 [95 % CI 15.5–20.9] vs 24.9 [95 % CI 20.8–28.4] Gy*cm2; p = 0.01) and contrast volume used (80 [95 % CI 80–100] vs 110 [95 % CI 100–120] mL; p = 0.001) in no pre-BAV group. Similar rate of PD, PVL, procedural success and 30-day outcomes (death, CVE, MI, PPI) in both groups. Significantly lower radiation dose 30 days (32 ± 22 vs 75 ± 50 Gy*cm2; p < 0.001), total contrast used (50 ± 24 vs 75 ± 50 mL; p < 0.001) and PPI (12 % vs 41 %; p = 0.029) in no pre-BAV group. Similar rate of PD, moderate–severe PVL, CVE and 30-day death in both groups. Significantly lower fluoroscopy 30 days time (13.3 ± 5.8 vs 17.8 ± 6.9 min; p = 0.01) and total contrast used (118.7 ± 47.9 vs 153.0 ± 53.2 mL; p = 0.02) in no pre-BAV group. Similar procedural time, PD, PVL,

Bijuklic et al. Consecutive 87 55 32 82.9 ± 6.8 no – Sapien XT n = 19 - patients; pre-BAV; Sapien 3 n = 68 201531 single-centre 83.8 ± 5.2 pre-BAV

Bandali et al. Retrospective; 81 35 46 84 (95 % CI 82–86) – Sapien XT TF single-centre 201665

Van Linden Retrospective; 66 49 17 83 ± 7 8 ± 5 Sapien 3 TA et al. 201566 single-centre

Conradi Retrospective; 52 26 26 81.3 ± 6.3 no 6 ± 3 no pre-BAV; Sapien XT n = 34 TF pre-BAV; 5 ± 2 pre-BAV Sapien 3 n = 18 et al. 201567 single-centre 81.7 ± 5.2 pre-BAV

Outcomes outcomes (all-cause death, CV death, MI, disabling stroke, PPI, VARC-2 safety endpoint) in both groups.

No pre- Pre-

BAV BAV

Study Design Study Population

Table 1: Cont. Clinical Outcomes at

Similar rate of all-cause mortality, CV mortality and VARC-2 early safety endpoint.

Similar rate of all-cause mortality in both groups.

Similar rate of all-cause mortality, MI, CVE and PPI in both groups.

Similar rate of all-cause mortality, MI and stroke in both groups.

Longest Follow-up

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Significantly lower procedural – time (34 [IQR 28.0–42.0] vs 50.5 [IQR 35.3–65.8] min) and fluoroscopy time (8.6 [IQR 6.6–12.9] vs 14.3 [IQR 10.8–16.9] min) in no pre-BAV group. Similar rate of PD and moderate– severe PVL in both groups. Significantly lower total contrast – used (138 ± 68 vs183 ± 78 mL; p < 0.01) in no pre-BAV group. Similar fluoroscopy time, procedural time, PD, moderate-severe PVL, VARC-2 device success, PPI, allcause death, CV death, MI, stroke in both groups and VARC-2 early safety endpoint. Significantly lower radiation dose – (42.0 [IQR 31.6–61.7] vs 56.6 [IQR 34.9–112.5] Gy*cm2; p = 0.03) and total contrast used (92.2 ± 20.5 vs 112 ± 31.0 mL; p = 0.006) in no pre-BAV group. Similar procedural time, fluoroscopy time, PD and moderate-severe PVL in both groups.

Kim et al. Retrospective; 163 154 9 81.9 (IQR 77.5–85.0) 4.3 (IQR 3.0–6.5) Sapien 3 TF multicentre 201724

Conradi Retrospective; 100 50 50 78 ± 8 no pre-BAV; 8 ± 7 no pre-BAV; Sapien XT TA 81 ± 7 pre-BAV 8 ± 5 pre-BAV et al. 201468 single-centre

Mollmann Retrospective; 56 26 30 81.9 ± 5.9 6.0 ± 2.9 Sapien XT TF et al. 201469 single-centre

–

This result was not confirmed after Bonferroni correction for multiple testing (adjusted OR 1.30 [95 % CI 0.91–1.86]). bResults derived from propensity score matched analysis. cModerate pre-BAV was performed in this group. BEV = balloon-expandable valve; CI = confidence interval; CV = cardiovascular; CVE = cerebrovascular event; IQR = interquartile range; LBBB = left bundle branch block; MACCE = major adverse cardiac and cerebrovascular event; MI = myocardial infarction; PD = postdilatation; PPI = permanent pacemaker implantation; pre-BAV = pre-implantation balloon aortic valvuloplasty; PVL = paravalvular leakage; STS = Society of Thoracic Surgeons; TA = transapical; TAVI = transcatheter aortic valve implantation; TF = transfemoral; THV = transcatheter heart valve; VARC-2 = Valve Academic Research Consortium-2.

Significantly lower rate of PPI (15.4 % vs 27 %; p = 0.042) in moderate pre-BAV group.

Lange et al. Retrospective; 237 123c 114 82 (range 53–99) 9.1 (range 2.1–23.7) CoreValve TF single-centre 201421

–

VARC-2 device success, disabling stroke, MI, PPI, VARC-2 early safety endpoint and 30-day death in both groups.

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Structural valve dysfunction before correction for multiple testing; however, this finding was not confirmed after multiplicity correction.11 These results are in line with a recent small prospective study that found similar early outcomes among 60 patients randomised to balloon-expandable TAVI (SAPIEN XT) with vs without predilatation.15 Moreover, recent large observational studies (including both balloon-expandable and selfexpanding valves) have confirmed that direct TAVI is associated with similar mid-term clinical outcomes compared to TAVI with pre-BAV.16–18 These real-world data, along with recent meta-analyses,12,13,19 suggest that simplified TAVI without predilatation is feasible, safe and achieves comparable clinical outcomes to standard TAVI with predilatation, justifying future research in this field.

Conduction Disturbances The omission of pre-BAV SAPIEN may theoretically reduce the iatrogenic damage to the conduction system, leading to a lower risk of conduction disturbances and, consequently, of new permanent pacemaker implantation (PPI) after TAVI. Indeed, new conduction disturbances may not only occur during valve implantation, but also during the predilatation step, especially in the case of high balloon/aortic annulus ratio.20 Lange et al. have shown that moderate predilatation performed with smaller valvuloplasty balloons is associated with a reduced rate of PPI after CoreValve implantation; therefore, the authors proposed a two-hit model, where the first hit to the conduction system is given by a large valvuloplasty balloon and is usually insufficient to determine an advanced conduction disturbance, whereas the second hit is given by valve deployment and may eventually lead to the final damage requiring PPI.21 In line with these considerations, a recent analysis of the Brazilian Transcatheter Aortic Valve Replacement registry has reported that avoiding pre-BAV reduces the rate of new-onset persistent left bundle branch block after TAVI, particularly when implanting a CoreValve prosthesis.16 Although that study failed to demonstrate an association between omission of pre-BAV and reduction of PPI, recent meta-analyses and the large UK TAVI registry suggest a signal towards lower PPI rate with direct TAVI.11–13 Nevertheless, as the decision to perform pre-BAV was left to the operator’s discretion in most published studies, a significant selection bias may have influenced these findings; only large randomised studies will clarify the impact of predilatation on conduction disturbances and PPI rate after TAVI.

Pre-procedural Imaging Planning In the absence of definitive conclusions on the usefulness of predilatation during TAVI, the optimal strategy is probably to tailor the procedure to the individual patient. In daily practice, the interventional cardiologist should take into account all potential advantages of omitting pre-BAV and, therefore, avoiding its related complications (conduction disturbances, the risk of mobilising aortic debris potentially embolising to the brain, severe acute aortic regurgitation leading to haemodynamic compromise, and even annular rupture);6–9,22 however, in some patients predilatation may still be useful to optimise valve implantation and should be considered when planning the procedure. In this context, pre-procedural imaging techniques may be pivotal in deciding whether to predilate or not before TAVI. A recent study evaluated the usefulness of transoesophageal echocardiography (TEE) to select ideal candidates for direct TAVI with both balloonexpandable (SAPIEN XT) and self-expanding (CoreValve) prostheses. Among patients fulfilling all the proposed TEE criteria (valve area >0.4 cm2; central orifice; absence of severe valve calcification; mobility of aortic cusps not severely restricted; no left ventricular outflow tract

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calcification; absence of calcium nodules in the landing zone; absence of severe aortic regurgitation), TAVI without pre-BAV was performed with a high rate of success and low rates of postdilatation, paravalvular aortic regurgitation and PPI implantation.23 Combining anatomical and functional information obtained with a multimodality approach (TEE and multidetector computed tomography [MDCT]) could represent the ideal strategy to identify the subset of patients who can safely undergo simplified TAVI without predilatation.

TAVI with Predilatation: Potential Advantages of ‘Preparing the Ground’ A main concern regarding the omission of predilatation is the risk of technical challenges during TAVI. Pre-BAV may facilitate valve crossing and delivery of the prosthesis across the stenotic valve (especially in patients with very small aortic valve area), ensure optimal valve expansion (by reducing radial counterforces) and improve haemodynamic stability during valve deployment. Interestingly, a range of technical difficulties has been reported when adopting a direct TAVI approach, including haemodynamic instability during device positioning in severely stenotic valves, severe underexpansion of the prosthesis in heavily calcified valves, inability to cross the valve, trapping of the prosthesis inside the left ventricle and coaxiality issues.16 Furthermore, as already mentioned, the UK TAVI registry showed a signal towards increased valve dysfunction among patients receiving a CoreValve prosthesis without pre-BAV (a finding that was, however, not confirmed after Bonferroni correction for multiple testing).11 Although bailout predilatation may represent an option to overcome pre-implantation technical issues,16,24,25 careful selection of patients needing pre-BAV before TAVI is advisable to avoid the risk of severe procedural complications. Pre-procedural planning by means of combined imaging techniques (TEE and MDCT) allows the identification of basic anatomical features in which a standard TAVI approach (with predilatation) should be considered, such as severe or asymmetric aortic valve calcification, small aortic valve area (<0.5 cm2), horizontal aorta (especially when implanting self-expanding prostheses) or bicuspid aortic valve anatomy.18,23,26–29 Pre-BAV may be very helpful also in situations where prosthesis sizing is not completely established or the potential risk of coronary obstruction requires further assessment (especially when coronary artery takeoffs are low).30 As MDCT has become the standard technique for valve sizing and coronary ostia evaluation before TAVI, these two indications are limited to a very low number of patients in the contemporary TAVI era; nonetheless, pre-BAV represents a rescue option for patients in whom MDCT cannot be performed or is not conclusive.

Cerebral Embolic Risk One of the proposed advantages of direct TAVI is to avoid the risk of debris embolisation during balloon valvuloplasty, potentially resulting in a lower rate of cerebrovascular events.10 However, a recent study evaluating cerebral ischemic lesions after TAVI has suggested the opposite idea. Bijuklic et al. have evaluated covert brain lesions detected by diffusion-weighted magnetic resonance imaging after TAVI in patients undergoing balloon-expandable valve (SAPIEN XT or SAPIEN 3) implantation with or without predilatation. The total lesion volume of cerebral ischemic lesions was significantly higher among patients undergoing direct TAVI; the incidence and number of cerebral lesions were only numerically (not significantly) higher in the direct TAVI group.31 These results seem in line with a recent study reporting

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Predilatation and TAVI Figure 1: Proposed Decision-making Algorithm for the Selection of Patients who can be Considered for Direct TAVI (Without Predilatation) TAVI planned

Inadequate assessment or uncertainty about: - Prosthesis sizing - Coronary ostia location

Multimodality imaging assessment

Clinical risk profile

High-risk clinical profile

Anatomic criteria

Functional criteria

Hemodynamic instability Severe CKD (eGFR <30 ml/min/1.73m2) Severe LV dysfunction (LVEF ≤25 %)* Severe COPD Severe pulmonary hypertension

Absence of severe/asymmetric valve calcification Absence of calcium nodules in the landing zone Absence of LVOT calcification Absence of horizontal aorta (AA ≥48˚)** Absence of bicuspid valve

AVA >0.5 cm2 Aortic mean gradient <50 mmHg Central valvular orifice Absence of severe AR

Favourable imaging criteria?

Shorter procedure adviseable?

YES

NO YES

Consider direct TAVI (without predilatation)

Consider TAVI with predilatation

The flowchart includes clinical and imaging factors that may help in deciding whether or not to perform predilatation prior to TAVI. *Especially if balloon-expandable valve implantation is planned; **especially if self-expanding valve implantation is planned. AA = aortic angulation; AR = aortic regurgitation; AVA = aortic valve area; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; GFR = glomerular filtration rate; LVOT = left ventricular outflow tract; PASP = pulmonary artery systolic pressure; TAVI = transcatheter aortic valve implantation.

a higher 30-day overt stroke rate in patients undergoing direct TAVI, especially when implanting self-expanding (CoreValve or Evolut R) prostheses; however, this finding was not confirmed after propensity score matching.17 The idea of a higher risk of cerebral damage when performing TAVI without predilatation seems counterintuitive as balloon dilatation of the aortic valve may per se be complicated by post-procedural stroke6,7,22,32 and one may suppose that pre-BAV before TAVI may confer an additive risk of neurological events. Conversely, it can be speculated that balloon inflation fragments calcific debris present on a heavily degenerated and diseased aortic valve, stabilises such debris through a homogeneous apposition onto aortic leaflets and the ascending aortic wall, and reduces the size of pieces that embolise during subsequent valve implantation. Studies evaluating transcranial Doppler-detected cerebral embolic load during TAVI have shown that only a limited number of high-intensity transient signals (a surrogate for microembolisation) occur during pre-BAV, while prosthesis positioning and deployment are the two phases associated with the highest embolic load,33–35 indirectly suggesting that the predilatation step does not significantly increase the cerebral embolic risk of the TAVI procedure. However, most published studies have shown a similar rate of clinical strokes in TAVI with and without pre-BAV11,12,15 and the reason for the higher risk of covert cerebral injury reported in the study of Bijuklic et al. remains completely speculative.31 Only future large, dedicated studies will definitively clarify the impact of predilatation on the risk of overt/covert cerebral injury

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after TAVI, especially if investigating the cerebral embolic load during all procedural steps.

Paravalvular Leakage An expected limitation of direct TAVI is the risk of suboptimal valve expansion, potentially resulting in higher incidence and severity of residual paravalvular leakage (PVL) after the procedure. The occurrence of PVL immediately after valve implantation may lead to an increased need for postdilatation, a step that may theoretically impair prosthesis durability and that has been specifically associated with a higher risk of cerebrovascular events.36–38 In line with these considerations, a recent study has reported a higher rate of postdilatation in patients undergoing direct transfemoral TAVI,17 a finding that was confirmed in a meta-analysis.12 Unfortunately, the largest available study did not evaluate the need for postdilatation,11 preventing us from drawing more robust conclusions on this procedural aspect. With respect to the impact of direct TAVI on significant PVL, most published studies have reported similar rates of residual moderate or severe PVL after TAVI with or without predilatation (Table 1), including the large UK TAVI registry.11 Interestingly, two meta-analyses have suggested a reduced risk of moderate or severe PVL with direct TAVI (a result that was, however, not confirmed in a subanalysis evaluating only transfemoral TAVI).12,13 Although this counterintuitive finding seems to suggest an improved valve positioning with direct TAVI, the retrospective nature of the studies included may have determined a relevant selection

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Structural bias. The choice of a predilatation strategy was left to the operators’ discretion, therefore it is likely that direct TAVI was performed more frequently in patients with favourable anatomical characteristics and the absence of severe or asymmetric aortic valve calcification. As the quantity and asymmetry of aortic valve calcification predict the severity of post-procedural PVL,39–44 this selection bias is of paramount importance. Moreover, other confounders such as device improvements and increasing the operator’s experience may have influenced these analyses. In the absence of high-quality, robust evidence on the incidence and severity of PVL after direct TAVI, definitive conclusions cannot be drawn; however, as PVL negatively affects clinical outcomes after TAVI,3,45–54 future large, randomised studies are needed to further address the risk of PVL when performing TAVI with or without predilatation.

‘Moderate’ Predilatation An interesting option that has been recently proposed is performing TAVI with a moderate predilatation, i.e. prior balloon valvuloplasty with a smaller balloon size. This approach could preserve the advantages of pre-BAV in ‘preparing the ground’ before valve implantation, avoiding the risks of predilatation with a standard or larger balloon. As already mentioned, Lange et al. have shown that moderate predilatation (use of valvuloplasty balloons with ≤23 mm diameter) reduces the rate of PPI in patients undergoing TAVI with the CoreValve prosthesis, without affecting procedural success.21 Although the use of smaller balloons may conceivably reduce the iatrogenic damage to the conduction system, a concern regarding moderate pre-BAV is impaired valve expansion, mainly when using self-expanding devices and in cases of severe valve calcification. Moreover, recent studies have reported similar procedural success and clinical outcomes after TAVI with moderate predilatation (average balloon diameter of 15–16 mm; mean balloon diameter/MDCT mean annulus diameter ratio of 0.62–0.65)

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 2. 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 3. 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 4. 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 5. Vahanian A, Himbert D. Transcatheter aortic valve implantation: could it be done without prior balloon valvuloplasty? JACC Cardiovasc Interv 2011;4:758–9. DOI: 10.1016/j.jcin.2011.05.006; PMID: 21777883 6. Ben-Dor I, Pichard AD, Satler LF, et al. Complications and outcome of balloon aortic valvuloplasty in high-risk or inoperable patients. JACC Cardiovasc Interv 2010;3:1150–6. DOI: 10.1016/j.jcin.2010.08.014; PMID: 21087751 7. Percutaneous balloon aortic valvuloplasty. Acute and 30-day follow-up results in 674 patients from the NHLBI Balloon Valvuloplasty Registry. Circulation 1991;84:2383–97. PMID: 1959194 8. Eltchaninoff H, Cribier A, Tron C, et al. Balloon aortic valvuloplasty in elderly patients at high risk for surgery, or inoperable. Immediate and mid-term results. Eur Heart J 1995;16:1079–84. PMID: 8665969 9. Saia F, Marrozzini C, Ciuca C, et al. Emerging indications, in-hospital and long-term outcome of balloon aortic valvuloplasty in the transcatheter aortic valve implantation era. EuroIntervention 2013;8:1388–97. DOI: 10.4244/ EIJV8I12A212; PMID: 23680956 10. Grube E, Naber C, Abizaid A, et al. Feasibility of transcatheter aortic valve implantation without balloon pre-dilation: a pilot study. JACC Cardiovasc Interv 2011;4:751–7. DOI: 10.1016/ j.jcin.2011.03.015; PMID: 21777882 11. Martin GP, Sperrin M, Bagur R, et al. Pre‐implantation balloon aortic valvuloplasty and clinical outcomes following transcatheter aortic valve implantation: a propensity score analysis of the UK registry. J Am Heart Assoc 2017;6:e004695.

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compared with direct TAVI with balloon-expandable valves.18,27 Of note, valve repositioning during implantation of newer self-expanding devices could arguably represent a form of mild predilatation; however, the relative role of this step with respect to pre-BAV is currently unknown. Future large, dedicated studies will better evaluate the potential advantages of moderate pre-BAV over standard or larger pre-BAV or direct TAVI in terms of procedural and clinical outcomes.

Conclusion A growing interest in direct TAVI (without predilatation) has emerged during the last few years in an effort to obtain a more simplified procedure and to avoid the potential complications associated with pre-BAV. Recent real-world observational experiences and a small randomised study suggest that direct TAVI is safe, feasible and associated with outcomes similar to standard TAVI with pre-BAV (Table 1). In the absence of strong available evidence, several clinical and anatomical characteristics may help the interventional cardiologist in deciding whether or not to predilate before TAVI (Figure 1). However, future studies are needed to deeply investigate the safety and outcomes of direct TAVI and to identify the right subset of patients who can safely undergo this simplified approach. The results of ongoing dedicated randomised trials (The preDIlatation in tRanscathEter aortiC Valve implanTation Trial [DIRECT], NCT02448927; Implantation of the Transcatheter Aortic Prosthesis SAPIEN 3 With or Without Prior Balloon Predilatation [DIRECTAVI], NCT02729519; Transcatheter Aortic Valve Implantation Without Predilation [SIMPLIFy TAVI], NCT01539746) and prospective multicentre registries (Transfemoral Transcatheter Aortic Valve Implantation With or Without Predilation of the Aortic Valve [EASE-IT TF],55 NCT02760771; Balloon Expandable Transcatheter Aortic Valve Implantation Without Predilation of the Aortic Valve [EASE-IT],56 NCT02127580) will provide additional evidence on these unresolved issues. n

DOI: 10.1161/JAHA.116.004695; PMID: 28214795 12. A uffret V, Regueiro A, Campelo-Parada F, et al. Feasibility, safety, and efficacy of transcatheter aortic valve replacement without balloon predilation: a systematic review and metaanalysis. Catheter Cardiovasc Interv 2017. DOI: 10.1002/ccd.27040; PMID: 28403562; epub ahead of press 13. Liao Y, Meng Y, Zhao Z, et al. Meta-analysis of the effectiveness and safety of transcatheter aortic valve implantation without balloon predilation. Am J Cardiol 2016;117:1629–35. DOI: 10.1016/j.amjcard.2016.02.036; PMID: 27026641 14. Giannini F, Latib A, Jabbour RJ, et al. The ratio of contrast volume to glomerular filtration rate predicts acute kidney injury and mortality after transcatheter aortic valve implantation. Cardiovasc Revascularization Med 2017. DOI: 10.1016/j.carrev.2017.02.011; PMID: 28342840; epub ahead of press 15. Ahn HC, Nielsen N-E, Baranowski J. Can predilatation in transcatheter aortic valve implantation be omitted? A prospective randomized study. J Cardiothorac Surg 2016;11:124. DOI: 10.1186/s13019-016-0516-x; PMID: 27491658 16. Bernardi FLM, Ribeiro HB, Carvalho LA, et al. Direct transcatheter heart valve implantation versus implantation with balloon predilatation: insights from the Brazilian transcatheter aortic valve replacement registry. Circ Cardiovasc Interv 2016 Aug;9(8). DOI: 10.1161/ CIRCINTERVENTIONS.116.003605; PMID: 27496637 17. Pagnesi M, Jabbour RJ, Latib A, et al. Usefulness of predilation before transcatheter aortic valve implantation. Am J Cardiol 2016;118:107–12. DOI: 10.1016/j.amjcard.2016.04.018; PMID: 27184169 18. Abramowitz Y, Jilaihawi H, Chakravarty T, et al. Feasibility and safety of balloon-expandable transcatheter aortic valve implantation with moderate or without predilatation. EuroIntervention 2016;11:1132–9. DOI: 10.4244/EIJV11I10A229; PMID: 26897291 19. Bagur R, Kwok CS, Nombela-Franco L, et al. Transcatheter aortic valve implantation with or without preimplantation balloon aortic valvuloplasty: a systematic review and meta-analysis. J Am Heart Assoc 2016; 5(6). DOI: 10.1161/ JAHA.115.003191; PMID: 27412897 20. Nuis RJ, Van Mieghem NM, Schultz CJ, et al. Timing and potential mechanisms of new conduction abnormalities during the implantation of the Medtronic CoreValve System

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Expert Opinion Will PARTNER 2 Change My Practice? Fadi J Sawaya and Lars Søndergaard The Heart Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

Abstract Transcatheter aortic valve implantation (TAVI) has become an established and increasingly-used technique to treat patients with severe aortic valve stenosis (AS) over the past decade. The clinical outcomes obtained with TAVI have been found to be equivalent to surgical aortic valve replacement (SAVR) in patients with a high-risk profile. Following the Placement of Aortic Transcatheter Valves (PARTNER) 1 trial, which demonstrated the utility of TAVI in inoperable and high-risk groups, the PARTNER 2 trial was implemented. PARTNER 2 reflects the current TAVI practice in Europe, confirms that transfemoral access is related to superior outcomes compared to SAVR in a selected population and demonstrates improved results with new-generation devices.

Keywords Aortic valve stenosis, surgical aortic valve replacement, transcatheter aortic valve implantation, transfemoral access, low risk, STS Disclosure: LS has received research grants from Medtronic, St Jude Medical, Boston Scientific, Symetis and Edwards Lifescience, and is a proctor for Medtronic, St Jude Medical, Boston Scientific and Symetis. FJS has no conflict of interest. Received: 15 December 2016 Accepted: 14 May 2017 Citation: Interventional Cardiology Review 2017;12(2):126–7. DOI: 10.15420/icr.2016:29:2 Correspondence: Lars Søndergaard, The Heart Center, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark. E: lars.soendergaard.01@regionh.dk

Over the past decade, transcatheter aortic valve implantation (TAVI) has become an established and increasingly-used technique to treat patients with severe aortic valve stenosis (AS). Studies have revealed that clinical outcomes obtained with TAVI are equivalent to surgical aortic valve replacement (SAVR) in patients with a high risk profile.1,2 The Placement of Aortic Transcatheter Valves (PARTNER) 1 trial demonstrated the utility of TAVI in inoperable and high-risk groups, and led to introduction of TAVI in the current American College of Cardiology/American Heart Association 2014 guidelines, which recommend TAVI in patients with severe AS who are deemed inoperable (class I, level B) or at high surgical risk (class IIa, level B).3 These excellent results were reproduced with the CoreValve extreme risk and high-risk pivotal trials.4,5 Given the excellent early results, increased operator experience and improved transcatheter device designs, a trial in intermediate-risk patients was imminent. PARTNER 2 cohort A is a randomised, controlled trial in 57 North American sites comparing TAVI and SAVR in 2,032 intermediaterisk patients with symptomatic severe aortic stenosis (aortic valve area: ≤0.8 cm2 or <0.5 cm2/m2 body surface area, with a mean aortic valve gradient >40 mmHg or peak jet velocity >4.0 m/s) using a second-generation valve (SAPIEN XT; Edwards Lifesciences).6 Participants were assessed by a multidisciplinary heart team and adjudicated by a case review committee. In this trial, the guideline was a risk score of at least 4 %; the upper limit applied by the case review committee was 8 %, but this value was not prespecified. Patients with a Society of Thoracic Surgery (STS) risk score of less than 4 % could also be enrolled if there were coexisting conditions that were not represented in the risk model.

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Patients were assessed for the eligibility of transfemoral (TF) access and randomised 1:1 to TF-TAVR versus SAVR. Patients who were not eligible for TF-TAVI were randomised 1:1 to transapical or transaortic TAVI versus SAVR. The primary endpoint was a composite of all-cause mortality or disabling stroke at 2 years. With an average STS score of 5.8 %, the primary endpoint of all-cause mortality or disabling stroke at 2 years was similar in the TAVI and SAVR study groups (19.3 % versus 21.1 %, p=0.25). The rate of major vascular complications was marginally higher after TAVI than SAVR at 30 days (7.9 % versus 5 %, p=0.008), which was offset by a higher incidence of life-threatening/disabling bleeding after SAVR (43.4 % versus 10.4 %, p<0.001). Moreover, acute kidney injury (1.3 % versus 3.1 %, p=0.006) and new-onset atrial fibrillation (9.1 % versus 26.4 %, p<0.001) were less frequent in the TAVI group, while rates of permanent pacemaker requirement were equivalent (8.5 % versus 6.9 %, p=not significant). At 2 years, echocardiographic parameters showed stable valve haemodynamics with good valve function. Paravalvular regurgitation (PVR) more than mild was found in only 3.7 % of patients, and was an improvement from the PARTNER 1 trial. It is also noteworthy that mild PVR (22.5 %) was not associated with increased mortality at 2 years. This pivotal trial adds more evidence to the efficacy and safety of TAVI. However, these results are relatively outdated, as newer valves, including the SAPIEN S3, designed with a lower profile and circumferential skirt, have showed a further decrease in major vascular complications and virtually-eliminated rates of PVL (1.7 %) in the parallel PARTNER S3i study.7 However, an increased rate of conduction abnormalities has

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Will PARTNER 2 Change My Practice? been reported for some of the newer transcatheter heart valves, which could potentially be a barrier towards their use, and remains one of the limitations of TAVI. More Importantly, a predefined subanalysis demonstrated a clear advantage of TF-TAVI over SAVR (primary endpoint 16.8 % versus 20.4 %, p=0.05). This finding was reproduced in a meta-analysis of the four current randomised trials,8 and demonstrated the superiority of the TF-TAVI group over SAVR (hazard ratio: 0.8, p=0.024). The Nordic Aortic Valve Intervention (NOTION) trial, which compared TAVI and SAVR in low-risk patients (81.8 % of participants’ STS score ≤4 %), demonstrated a trend towards reduced mortality in the TAVI cohort (96.5 % TF access).9 This has important implications for current practice, as more than 90 % of TAVI using the SAPIEN 3 valve are performed via the TF approach. It is important to note that the mean age of the enrolled patients was 82 years, with a mean STS score of 5.8 % in both arms, which was similar to the CoreValve High-Risk study (mean age: 83 years, mean STS score: 7.4 %). Therefore, although PARTNER 2 cohort A was portrayed as an intermediate-risk trial, it is largely reflective of current practice in most European institutions, where older patients with severe AS will be treated with TAVI, regardless of their risk score. There has been an increasing trend to implant surgical bioprosthesis in younger patients. In the Eastern Denmark registry, the average age of use of bioprosthesis decreased from 69 to 61 years from the period 2005–2006 (n=518) to 2013–2014 (n=735).10 Thus, it could be more interesting to pursue the role of TAVI in patients with AS, who are not only at low surgical risk, but also of a younger age, particularly due to a marked decrease in the age of patients receiving surgical bioprostheses. PARTNER 3 will randomise TF-TAVI with the SAPIEN 3 valve compared to SAVR with a bioprosthetic valve, with a primary composite endpoint at 1 year, including all-cause mortality, all strokes and rehospitalisation

odali SK, Williams MR, Smith CR, et al. Two-year outcomes K after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366(18):1686–95. DOI: 10.1056/NEJMoa1200384; PMID: 22443479. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aorticvalve replacement with a self-expanding prosthesis. N Engl J Med 2014;370(19):1790–8. DOI: 10.1056/NEJMoa1400590; PMID: 24678937. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63(22):2438–88. DOI: 10.1016/j.jacc.2014.02.537; PMID: 24603192. Adams DH, Popma JJ, Reardon MJ. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med

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in a low operative-risk population. The Evolut-R Low Risk Trial will randomise TAVI with the Evolut-R and CoreValve prostheses compared to SAVR with a bioprosthetic valve, with a primary composite endpoint at 2 years, including all-cause mortality or disabling stroke. The PARTNER 3 and CoreValve low-risk trials both have no upper age limit, and therefore, might not explore TAVI in younger patients with AS. This will be explored in the NOTION 2 trial, which will randomise patients (1:1) aged ≤75 years and with an STS score ≤4 % who have severe symptomatic aortic stenosis to TAVI versus SAVR using the TF approach. Bicuspid aortic valves and coronary artery disease are not an exclusion criteria, and any commercially-approved aortic bioprostheses can be used. The primary endpoint is the composite rate of all-cause mortality, stroke and MI at 1 year. We believe that the PARTNER 2 trial is reflective of the current TAVI practice in Europe, it confirms that TF access is related to superior outcomes compared to SAVR in a selected population and reflects the results of older-generation devices, with improved outcomes being demonstrated with new-generation devices. However, challenges with the PARTNER 2 trial still remain. First, it does not address the concern of valve durability, and issues associated with the TAVI procedure in younger/low-risk patients should be resolved before expanding indications. What is the best long-term antithrombotic therapy for younger (<75 years), low-risk AS patients after TAVI? Should they be screened (with CT, cardiovascular magnetic resonance imaging or trans-esophegeal echocardiography) for subclinical leaflet thrombosis, which has been recently demonstrated to occur after TAVI? How frequently should they be followed up after the TAVI procedure? Second, although the PARTNER 2 cohort A was presented as an intermediate-risk trial, it is largely reflective of current practice in Europe, and is concordant with pre-existing reports. Our approach to TAVI patients will continue, until results on trials with younger and low-risk patients are reported. n

2014;371(10):967–8. DOI: 10.1056/NEJMc1408396; PMID: 25184874. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol 2014;63(19):1972–81. DOI: 10.1016/ j.jacc.2014.02.556; PMID: 24657695. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374(17):1609–20. DOI: 10.1056/NEJMoa 1514616 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(10034):2218–25. DOI: 10.1016/S01406736(16)30073-3; PMID: 27053442.

iontis GCM, Praz F, Pilgrim T, et al. Transcatheter aortic S valve implantation vs. surgical aortic valve replacement for treatment of severe aortic stenosis: a meta-analysis of randomized trials. Eur Heart J 2016;37(47):3503–12. DOI: 10.1093/eurheartj/ehw225; PMID: 27389906. 9. Thyregod HG, Steinbruchel DA, Ihlemann N, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1-year results from the All-Comers NOTION Randomized Clinical Trial. J Am Coll Cardiol 2015;65(20):2184–94. DOI: 10.1016/j.jacc.2015.03.014; PMID: 25787196. 10. De Backer O, Luk NH, Olsen NT, et al. Choice of treatment for aortic valve stenosis in the era of transcatheter aortic valve replacement in Eastern Denmark (2005 to 2015). JACC Cardiovasc Interv 2016;9(11):1152–8. DOI: 10.1016/ j.jcin.2016.02.028; PMID: 27209252.

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Safety and Efficacy of Protected Cardiac Intervention: Clinical Evidence for Sentinel Cerebral Embolic Protection Ulrich Schäfer Department of General and Interventional Cardiology, University Hospital Eppendorf, Hamburg, Germany

Abstract Stroke is a well-documented potential risk of structural cardiac interventions. As a result of the far-reaching burden of stroke on patients, caregivers and the healthcare system, new medical interventions and therapies are being developed to help mitigate this risk. One such intervention is the recently FDA-cleared Sentinel™ Cerebral Protection System (Sentinel; Claret Medical, Santa Rosa, CA, USA) designed to capture and remove debris dislodged during transcatheter aortic valve replacement procedures. In the SENTINEL IDE Study, and in a more recent all-comers trial, Sentinel significantly reduced periprocedural strokes by 63 and 70 % respectively. In this paper, we review the growing body of evidence supporting the use of Sentinel in transcatheter aortic valve replacement and other endovascular procedures.

Keywords Embolic protection, ischemic stroke, transcatheter aortic valve replacement, Sentinel Disclosure: Ulrich Schäfer received travel support and speakers’ honoraria from Claret Medical. Received: 5 July 2017 Accepted: 12 August 2017 Citation: Interventional Cardiology Review 2017;12(2):128–32. DOI: 10.15420/icr.2017:19:2 Correspondence: Ulrich Schäfer, Department of General and Interventional Cardiology, University Heart Centre Hamburg, Martinistraße 52, 20251 Hamburg, Germany. E: u.schaefer@uke.de

As the field of interventional cardiology has grown, so too has interest in mitigating severe adverse outcomes such as stroke. Unfortunately, the risk of stroke is increased by many underlying disease conditions (atrial fibrillation, patent foramen ovale, carotid artery disease and other vascular disease affecting brain perfusion, etc.), making clear differentiation between cardiac intervention-related cerebral infarction and the effect of other coexisting factors very difficult. In this regard, the prevalence of atrial fibrillation in average transcatheter aortic valve replacement (TAVR) patient cohorts has been reported to be over 31 % (9 studies, 285/902 patients)1–9 and the prevalence of previous stroke has been reported as high as 10.8 % (14 studies, 111/1028 patients),6–14 confounding the attribution of stroke to TAVR procedures.

Covert Central Nervous System Infarction While clinically overt stroke is one of the most feared adverse events among patients undergoing invasive or interventional procedures, subclinical neurological events or covert central nervous system (CNS) infarctions are also a significant risk. In general, covert CNS infarctions are best detected by diffusion-weighted MRI in the absence of any clinically apparent symptoms. They are prevalent in approximately 20 % of the general population, but the risk and incidence rate increase drastically with age and in populations affected by certain medical conditions (see above), as well as following interventional and surgical procedures. The incidence of new lesions following TAVR, for instance, is estimated to be 68–91 %,15 with at least one study demonstrating evidence of new cerebral infarctions in 100 % of patients.16 As with clinically overt stroke, substantial evidence has shown that the presence of covert cerebral infarctions increases the risk of future stroke, cognitive decline, dementia and mortality. The same applies for surgical aortic valve interventions where even larger brain infarctions are seen.17–21

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Stroke Burden Stroke from any cause poses a tremendous strain on a patient, their family and the healthcare system. Hospitalisation due to stroke is costly, and continued expenditures including inpatient care, rehabilitation and long-term care exceed US $140,000 over a lifetime.22 Recent studies also conclude that these costs increase greatly with increased stroke severity and resulting disability.22,23

TAVR and Stroke In the last 15 years, TAVR has emerged as an important therapeutic option for patients with severe aortic stenosis, particularly those at increased risk of operative mortality or morbidity with traditional surgical aortic valve replacement (SAVR).24–28 Although TAVR has consistently demonstrated similar or better outcomes than SAVR,24–29 neurological complications remain a concern. Early in the TAVR experience, reports of clinical stroke rates up to 5 %,24,28 mainly occurring within 1 week of the procedure, garnered significant attention, and have been shown to be associated with lower 1-year survival rates.11 As TAVR populations, procedures and devices have matured, reported rates of overt clinical stroke within controlled clinical trials,29 and in real-world practice, remain a critical health issue. Newer, repositionable TAVR devices allow for more precise valve implantation, but this may be at the expense of higher embolic burdens, increasing the risk for stroke and death.21 In fact, the STS/ACC Transcatheter Valve Therapy Registry (TVT Registry), designed to benchmark safety and efficacy outcomes related to US commercial TVT procedures (>53,000 cases to date), showed no significant decline in 30-day site reported stroke rates from 2012 (2.6 %) to 2015 (2.2 %) despite new evolutions in TAVR devices.11 The TVT Registry also highlighted that stroke risk is independent of increased physician TAVR experience. This finding is corroborated by a multinational registry of over 1,900 subjects

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Sentinel Cerebral Embolic Protection Figure 1: An Example of the Sentinel Device

Source: Claret Medical, 2017.

in 80 international centres.30 It is important to emphasise that the TVT Registry collects information on site reported strokes, which does not require diagnosis of a stroke by a certified neurologist, thus likely underestimating the true stroke rate in the real-world setting. Further confounding the true stroke rate, the definition and classification of stroke has been controversial and has changed over the last decade.21

Figure 2: Example of the Sentinel Device in situ

As mentioned above, procedure-related stroke or new ischemic cerebral infarctions may result from a variety of patient- and disease-related causes such as severity of atherosclerosis, age, gender, hyperlipidaemia, history of atrial fibrillation and/or technical aspects of the procedure itself, including mechanical manipulation of instruments or interventional devices. A rapidly growing body of clinical evidence shows that embolic debris is generated in the vast majority of patients undergoing TAVR.12 Debris can be up to 1 cm in size, is from a variety of vascular and valvular tissue sources, and has been captured during the use of a variety of different transcatheter valves and interventional approaches.1

Sentinel Sentinel™ Cerebral Protection System (Claret Medical, Santa Rosa, CA, USA) is designed to protect the brain from the risk of stroke by filtering, capturing and removing debris dislodged during many interventional and surgical left heart, as well as endovascular, procedures. The device consists of two filters within a single 6 French delivery catheter percutaneously placed from the right radial (preferred) or brachial artery over a 0.014" guide wire. The filters are deployed in the brachiocephalic and the left common carotid arteries, the two main arteries supplying the brain, and are withdrawn into the catheter at the conclusion of the procedure (Figures 1 and 2). Since the initial proof of concept study in 2011, numerous manuscripts or presentations describing experience with Sentinel have been published. Sentinel has shown procedural success of greater than 90 % across multiple studies and therapies, which is paralleled by its strong safety profile (Table 1).1–3,12–15 Although MRI imaging evidence in terms of reduced lesion number and volume is variable across studies,2,3,13 detailed histopathological assessments have described near ubiquitous, and remarkably consistent, capture of a wide variety of debris types within the filters (Figure 2). Not surprisingly, due to the success experienced with Sentinel in TAVR procedures, other structural interventions known to be cardioembolic, including mitral valve interventions (MitraClip),31 left atrial appendage occlusion procedures

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Source: Claret Medical, 2017.

(LAAO)32 and thoracic endovascular aneurysm repair (TEVAR),33,34 have shown remarkably similar patterns of debris capture and procedural success with the use of cerebral embolic protection (CEP).

Patient Population The Sentinel device was originally conceived as an adjunctive therapy for TAVR; thus, the majority of published studies have been conducted in patients with severe, symptomatic aortic stenosis undergoing TAVR. To date, studies of Sentinel in conjunction with TAVR therapy have been conducted in similar patient populations, which makes comparisons and data pooling between studies possible. Indeed, although the current literature summary does not include any formal Sentinelspecific meta-analysis, a review and meta-analysis of cerebral embolic protection trials, including SENTINEL, has been published.35 Overall, patients included in studies of Sentinel with TAVR to date have been elderly and at increased risk of surgical mortality and morbidity (including perioperative stroke) based on traditional surgical risk scores such as the Society of Thoracic Surgeons and the Logistic EuroSCORE. Importantly, studies that have included baseline MRI imaging have found a wide range of pre-existing T2/FLAIR lesion volume, indicating

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Structural Table 1: Sentinel Studies with TAVR Safety and

MISTRAL-I,

Source: Van

MISTRAL-C, CLEAN-TAVI, SENTINEL-IDE, ALSTER

Procedural

Source: Van

Mieghem, et al.,

Source: Van

Success

Mieghem, et al.,

2015

2013

Study/Therapy TAVR-Histo

TAVR

Source: Haussig,

Mieghem, et al., et al., 2016c

Source: Schmidt, Study

et al., 2016

2016c TAVR

TAVR

CSI-Ulm-TAVR

Source: Kapadia,

TAVR

Source: Wohrle, 2017

TAVR-Histological TAVR

Study Type Prospective, Prospective, Randomised, Randomised, Randomised, Prospective, Prospective, single arm single arm clinical trial clinical trial clinical trial single arm consecutive all comers Patients (n)a

234

Death (n, %) 1 (2.5) 2 (3.0) 1 (3) 0 3 (1.3)

161

280

6 (3.7) [note: 2 (0.7) discharge, not 30-day

Stroke (n, %) Disabling Non-disabling

1 (2.5) 1 (2.5) 2 0 0 0

13 (5.6) 1 (0.62) 2 (0.9) 11 (4.8)

4 (1.4)

Acute Kidney Injury Stage 3 (n, %)

1 (2.5)

1 (0.4)

3 (1.1)b

Major Vascular Complication

4 (10)

5 (10)

21 (8.6)c

5 (1.8)

Patients with Debris (%)

100

86d

99 97

Procedural Successe (%)

100

99.6

Number of patients and clinical event rates apply specifically to the device-treated arm(s); bacute kidney injury stage 2 or 3; c1 (0.4 %) radial/brachial, thus device-related; dUnpublished data, Renu Virmani, MD, on file with CV Path Institute; esuccessful deployment and retrieval of both filters. TAVR = transcatheter aortic valve replacement.

that prior brain injury and gliosis, or white matter disease, are prevalent in this patient population. In addition to successful use of Sentinel with TAVR, a number of small feasibility studies have shown promise for the use of Sentinel with other endovascular therapies, including LAAO, TEVAR, MitraClip and valve-in-valve procedures.

Safety Outcomes Given the ease of use of the device and the high procedural success rates, it is not surprising that acute procedural events and 30-day safety events related to the use of Sentinel are rare. Published reports of Sentinel demonstrate consistently low rates of mortality and neurological events, and randomised trials have documented similar major adverse cardiac and cerebrovascular event rates in patients treated with Sentinel (Table 1). In the largest randomised study, SENTINEL, the Sentinel device was easily delivered and was compatible with standard TAVR workflow.13 Total procedure time was increased by approximately 13 min, and fluoroscopy time was increased by 3 min.13 The safety profile of Sentinel is underscored by a >92 % procedural success rate in more than 866 patients across 11 studies, and for multiple endovascular therapies.1,3,5,12,13

versus 8.2 % (p=0.05) for unprotected patients.37 When considering the more sensitive endpoint of any worsening of the National Institute of Health Stroke Scale, a study-level meta-analysis by Guistino et al. found a strong trend in favour of TAVR with cerebral embolic protection (M-H Risk Ratio 0.55 [0.27, 1.09], p=0.09) further supporting the results observed in both the CSI-Ulm and Sentinel trials. 38 These positive trends in stroke reduction are particularly important when considering the numerous studies that have confirmed the occurrence of stroke post-TAVR.

Mortality Seven studies have reported 30-day mortality after TAVR with Sentinel, with rates ranging from 0 to 3 %. Within the three randomised trials in which TAVR with Sentinel protection was compared to unprotected TAVR, no significant differences in 30-day mortality were observed between the device treatment and control groups, although deaths in the Sentinel groups were consistently numerically lower (Table 1). In addition to studies focused on the Sentinel device alone, a recent study-level meta-analysis of all randomised control trials for CEP to date found that, as a class, CEP devices showed a decreased risk of stroke and mortality over unprotected TAVR, which corresponded to an approximately 4.0 % reduction in absolute risk.35

Neurological Events The 30-day rates of overt neurological events, both stroke and transient ischemic attack, were low across all published studies of the Sentinel device. In the CSI-Ulm trial, the largest consecutively enrolled cohort of Sentinel in a commercial setting (n=802), the overall 7-day stroke rate when Sentinel CEP was used was 1.4 %, representing a statistically significant reduction when compared to a cohort of subjects who did not receive CEP at 4.2 % (p=0.03).36 A similar trend was observed in the randomised SENTINEL study (n=363), wherein the periprocedural (≤72 h) stroke rate for Sentinel-protected patients was reduced by 63 %; 3.0 % for patients protected with Sentinel,

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Other Clinical Events Because the deployment and retrieval of the Sentinel device slightly lengthens the TAVR procedure, there was some early concern about potential increases in acute kidney injury. The low rates of Stage 3 acute kidney injury reported in the early Netherlands experience (2.5 %)1 and SENTINEL Study (0.4 %)13 alleviate these concerns. Low rates of bleeding and vascular complications are similarly reassuring. In the SENTINEL Study, only 1 out of 231 patients (0.4 %) experienced a major vascular complication, a pseudoaneurysm, related to brachial access for the Sentinel device.

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Sentinel Cerebral Embolic Protection Histopathology and Morphometry

Figure 3: Example of Debris Captured by Sentinel

Seven of the published studies, as well as several conference proceedings, have reported histopathological analyses of debris captured by the Sentinel device. The methods for the histopathological analyses were similar across the studies and were performed by the same independent core laboratory. As described previously, regardless of the primary procedure (TAVR, Mitraclip, LAAO, TEVAR), all studies reported near ubiquitous capture of debris removed from the Sentinel device. Rates for debris capture per patient ranged from 75 to 100 % across studies. In order to better understand the prevalence and etiology of the debris captured by the filters, the Sentinel-H Study was conducted. Sentinel-H was a multicentre, all-comers study of 217 patients in Europe. In accordance with other Sentinel studies, debris was captured in 99 % of patients. As with other Sentinel studies, acute thrombus was found most commonly (85 %), and nearly always in conjunction with tissue-derived material, including arterial wall, valve tissue, calcification and myocardium. Organising/organised thrombus and foreign material were also common.39 In addition to the high rates of debris capture (Figures 3 and 4), the SENTINEL Study discovered that 1 in 4 patients had, on average, 25 particles in their filters that were greater than or equal to 0.5 mm in size.

Source: Claret Medical, 2017.37

Figure 4: Patients (%) with Debris Captured in the SENTINEL Study 99 %

98 %

94 %

50 %

Conclusion

35 %

Despite advances in TAVR therapies and techniques, stroke is and will continue to be the Achilles heel of structural heart and endovascular procedures. Indeed, the complexity of discriminating between clinical condition-related strokes and cardiac intervention-related strokes needs further refinement, but all would agree that reducing stroke, regardless of cause, should be a goal. Sentinel is a good step toward that goal. Across multiple studies, Sentinel has demonstrated a strong safety profile and a >92 % procedural success rate. The ease of use of the Sentinel device, combined with minimal disruption to the normal TAVR workflow, make it a viable adjunct therapy that could soon be considered a standard of care for TAVR, and possibly for other cardiac and vascular interventions. Studies to date using Sentinel have been performed in high-risk surgical patients who have an elevated ‘background noise’ of medical history. However, Sentinel has now been

an Mieghem NM, Schipper ME, Ladich E, V et al. Histopathology of embolic debris captured during transcatheter aortic valve replacement. Circulation 2013;127:2194–201. DOI: 10.1161/ CIRCULATIONAHA.112.001091; PMID: 23652860 Van Mieghem NM, van Gils L, Ahmad H, et al. Filter-based cerebral embolic protection with transcatheter aortic valve implantation: the randomised MISTRAL-C trial. EuroIntervention 2016;12:499–507. DOI: 10.4244/EIJV12I4A84; PMID: 27436602 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; PMID: 27532914 Naber CK, Ghanem A, Abizaid AA, et al. First-in-man use of a novel embolic protection device for patients undergoing transcatheter aortic valve implantation. EuroIntervention 2012;8:43–50. DOI: 10.4244/EIJV8I1A8; PMID: 22403768 Schmidt T, Akdag O, Wohlmuth P, et al. Histological findings and predictors of cerebral debris from transcatheter aortic valve replacement: the ALSTER experience. J Am Heart Assoc 2016;5:e004399. DOI: 10.1161/JAHA.116.004399; PMID: 27930358 Eggebrecht H, Schmermund A, Voigtländer T, et al. Risk of stroke after transcatheter aortic valve implantation (TAVI): a meta-analysis of 10,037 published patients. EuroIntervention 2012;8:129–38. DOI: 10.4244/EIJV8I1A20; PMID: 22391581 Nombela-Franco L, Webb JG, de Jaegere PP, et al. Timing, predictive factors, and prognostic value of cerebrovascular events in a large cohort of patients undergoing transcatheter aortic valve implantation. Circulation 2012;126:3041–53. DOI: 10.1161/CIRCULATIONAHA.112.110981; PMID: 23149669 Bosmans J, Bleiziffer S, Gerckens U, et al. The incidence and predictors of early- and mid-term clinically relevant

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10.

11.

12.

13.

14.

15.

15 % 7% ANY

Acute Thrombus & Tissue/ Foreign Material

Arterial Wall

Valve Tissue

Calcification

Foreign Material

Myo- Organising Acute cardium Thrombus Thrombus Alone

Tissue Type

Source: Claret Medical, 2017.37

cleared by the US FDA to be used in all TAVR patients regardless of surgical risk at the same time that TAVR expands to treat moderateand low-risk patients and potentially asymptomatic aortic stenosis patients. New repositionable TAVR devices facilitate more precise valve implantation but may cause higher embolic burden, which will further emphasise the role of cerebral embolic protection. n

neurological events after transcatheter aortic valve replacement in real-world patients. J Am Coll Cardiol 2015;66:209–17. DOI: 10.1016/j.jacc.2015.05.025; PMID: 26184612 Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686–95. DOI: 10.1056/NEJMoa1200384; PMID: 22443479 Kapadia S, Agarwal S, Miller DC, et al. Insights into timing, risk factors, and outcomes of stroke and transient ischemic attack after transcatheter aortic valve replacement in the PARTNER trial (placement of aortic transcatheter valves). Circ Cardiovasc Interv 2016;9:2 e002981. DOI: 10.1161/ CIRCINTERVENTIONS.115.002981; PMID: 27601428 Holmes DR, Jr, Nishimura RA, Grover FL, et al. Annual outcomes with transcatheter valve therapy: from the STS/ ACC TVT registry. J Am Coll Cardiol 2015;66:2813–23. DOI: 10.1016/j.jacc.2015.10.021; PMID: 26652232 Van Mieghem NM, El Faquir N, Rahhab Z, et al. Incidence and predictors of debris embolizing to the brain during transcatheter aortic valve implantation. JACC Cardiovasc Interv 2015;8:718–24. DOI: 10.1016/j.jcin.2015.01.020; PMID: 25946445 Kapadia SR, Kodali S, Makkar R, et al. Cerebral embolic protection during transcatheter aortic valve replacement. J Am Coll Cardiol 2016;69:367–77. DOI: 10.1016/j.jacc.2016. 10.023; PMID: 27815101 Schmidt T, Schluter M, Alessandrini H, et al. Histology of debris captured by a cerebral protection system during transcatheter valve-in-valve implantation. Heart 2016;102:1573–80. DOI: 10.1136/heartjnl-2016-309597; PMID: 27220695 Gress DR. The problem with asymptomatic cerebral embolic complications in vascular procedures: what if they are not asymptomatic? J Am Coll Cardiol 2012;60:1614–6. DOI: 10.1016/ j.jacc.2012.06.037; PMID: 22999732

16. P agnesi M, Martino EA, Chiarito M, et al. Silent cerebral injury after transcatheter aortic valve implantation and the preventive role of embolic protection devices: A systematic review and meta-analysis. Intl J Cardiology 2016;221:97–106. DOI: 10.1016/j.ijcard.2016.06.143; PMID: 27400304 17. Bernick C, Kuller L, Dulberg C, et al. Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. Neurology 2001;57:1222–9. PMID: 11591840 18. Gupta A, Giambrone AE, Gialdini G, et al. Silent brain infarction and risk of future stroke: a systematic review and meta-analysis. Stroke 2016;47:719–25. DOI: 10.1161/ STROKEAHA.115.011889; PMID: 26888534 19. Barber PA, Hach S, Tippett LJ, Ross L, Merry AF, Milsom P. Cerebral ischemic lesions on diffusion-weighted imaging are associated with neurocognitive decline after cardiac surgery. Stroke 2008;39:1427–33. DOI: 10.1161/STROKEAHA.107.502989; PMID: 18323490 20. Bokura H, Kobayashi S, Yamaguchi S, et al. Silent brain infarction and subcortical white matter lesions increase the risk of stroke and mortality: a prospective cohort study. J Stroke Cerebrovasc Dis 2006;15:57–63. DOI: 10.1016/ j.jstrokecerebrovasdis.2005.11.001; PMID: 17904049 21. Mokin M, Zivadinov R, Dwyer MG, Lazar RM, Hopkins LN, Siddiqui AH. Transcatheter aortic valve replacement: perioperative stroke and beyond. Expert Rev Neurother 2017;17:327–34. DOI: 10.1080/14737175.2017.1253475; PMID: 27786568 22. Ma VY, Chan L, Carruthers, KJ. The incidence, prevalence, costs and impact on disability of common conditions requiring rehabilitation in the US: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Arch Phys Med Rehabil 2014;95:986–95. DOI: 10.1016/j.apmr.2013.10.032; PMID: 24462839 23. Spieler JF, Lanoë JL, Amarenco P. Costs of stroke care according to handicap levels and stroke subtypes. Cerebrovasc

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Structural Dis 2004;17:134–42. DOI: 10.1159/000075782; PMID: 14707413 24. L eon 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 25. Leon MB. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. DOI: 10.1056/NEJMoa1514616v; PMID: 27040324 26. 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 27. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol 2014;63:1972–81. DOI: 10.1016/j. jacc.2014.02.556; PMID: 24657695 28. 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 29. 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

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2016;387:2218–25. DOI: 10.1016/S0140-6736(16)30073-3; PMID: 27053442 30. W endler O, Schymik G, Treede H, et al. SOURCE 3 registry: design and 30-day results of the European post approval registry of the latest generation of the Sapien 3TM transcatheter heart valve. Circulation 2017;116:025103. DOI: 10.1161/CIRCULATIONAHA.116.025103; PMID: 28104716 31. Frerker C, Schluter M, Sanchez OD, et al. Cerebral protection during MitraClip implantation: initial experience at 2 centers. JACC Cardiovasc Interv 2016;9:171–9. DOI: 10.1016/ j.jcin.2015.09.039; PMID: 26723763 32. Meincke F, Spangenberg T, Kreidel F, et al. Rationale of cerebral protection devices in left atrial appendage occlusion. Catheter Cardiovasc Interv 2017;89:154–8. DOI: 10.1002/ccd.26677; PMID: 27762092 33. Grover G, Rudarakanchana N, Perera A, et al. Cerebral embolic protection in thoracic aortic stent-grafting. ISET 2016. Available at: http://claretmedical.com/pdf/studies/ Grover%20ISET%202016%20TEVAR.pdf (accessed 22 August 2017) 34. Jánosi RA. Cerebral Protection against Embolization during Thoracic EndoVascular Aortic Repair. LINC 2016. Available at: http://claretmedical.com/pdf/studies/LINC_2016_Claret_ Janosi_TEVAR.pdf (accessed 22 August 2017)

35. G iustino G, Mehran R, Veltkamp R, Faggioni M, Baber U, Dangas GD. Cerebral embolic protection during TAVR: a clinical event meta-analysis. J Am Coll Cardiol 2017;4:463–70. DOI: 10.1016/j.jacc.2016.12.002; PMID: 28126163 36. Wohrle J. Coronary and Structural Interventions Ulm – Transcatheter Aortic Valve Replacement (CSI-Ulm-TAVR) University of Ulm. German Society for Cardiology (DGK) 2017 (in press). 37. Claret Medical. Sentinel System Instructions for Use. Santa Rosa, CA: Claret Medical, 2017. 38. Giustino G, Mehran R, Veltkamp R, Faggioni M, Baber U, Dangas GD. Neurological outcomes with embolic protection devices in patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis of randomized controlled trials. JACC Cardiovasc Interv 2016;9: 2124–33. DOI: 10.1016/j.jcin.2016.07.024; PMID: 27765306 39. Jensen CJ, Wolf A, Schmitz T, et al. Prevalence and etiopathology of thromboembolic debris during transcatheter interventional aortic valve replacement: results of the SENTINEL H-Study. EuroPCR 2016. Available at: www.pcronline. com/eurointervention/AbstractsEuroPCR2016_issue/ abstracts-europcr-2016/Euro16A-OP0439/prevalance-andetiopathology-of-thromboembolic-debris-during-transcatherinterventional-aortic-valve-replacement-preliminary-resultsof-the-sentinel-h-study.html (accessed 22 August 2017)

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Expert Opinion Guidelines for the Management of Patients with Aortic Stenosis Undergoing Non-cardiac Surgery: Out of Date and Overly Prescriptive Simon Kennon and Andrew Archbold Barts Heart Centre, St Bartholomew’s Hospital, London, UK

Abstract Patients with severe aortic stenosis who require non-cardiac surgery present a difficult clinical problem. The most recent clinical practice guidelines from the American College of Cardiology/American Heart Association and the European Society of Cardiology for the perioperative cardiovascular assessment and management of patients undergoing noncardiac surgery were both published in 2014. These guidelines are reviewed in the light of recently published randomised controlled trial data regarding the efficacy of transcatheter aortic valve implantation to treat aortic stenosis.

Keywords Aortic stenosis, non-cardiac surgery, ESC Guidelines, ACC/AHA Guidelines, PARTNER trial, surgical risk estimate Disclosure: SK has received consulting fees and research support from Edwards Lifesciences and hospitality from Edwards Lifesciences, Medtronic and Boston Scientific. Received: 3 July 2017 Accepted: 15 August 2017 Citation: Interventional Cardiology Review 2017;12(2):133–6. DOI: 10.15420/icr.2017:20:2 Correspondence: Simon Kennon, Barts Heart Centre, St Bartholomew’s Hospital, W Smithfield, London EC1A 7BE, UK. E: simon.kennon@bartshealth.nhs.uk

Patients with severe aortic stenosis who require non-cardiac surgery (NCS) present a difficult clinical problem. It is well established that their rate of postoperative cardiovascular complications is increased in comparison with patients without aortic stenosis,1–3 yet their optimal management remains uncertain. Reported prevalence rates for severe aortic stenosis range from 3.4 % in subjects more than 75 years of age to 18 % in those older than 90 years.4,5 The ageing population together with a greater willingness in recent years to undertake surgical interventions in the elderly means that such patients are faced with increasing frequency. These patients require careful preoperative assessment in order to determine the severity of aortic stenosis, the presence or absence of symptoms and the risks and benefits from NCS. The main challenge, however, is in deciding which patients should undergo aortic valve intervention prior to NCS. The most recent clinical practice guidelines from the American College of Cardiology/American Heart Association (ACC/AHA)6 and the European Society of Cardiology (ESC)7 for the perioperative cardiovascular assessment and management of patients undergoing NCS were both published in 2014. One of their key aims was to guide decision making regarding aortic valve intervention prior to NCS. This has proven challenging because no trials have investigated whether or not the cumulative risk of aortic valve intervention followed by NCS is lower than the risk of undertaking NCS alone without prior valve intervention. For this reason, both guidelines rely heavily on consensus of opinion (level C evidence), and cite their own society’s valve disease clinical practice guidelines in support of their recommendations. These recommendations deserve closer scrutiny in light of recently published randomised controlled trial data regarding the efficacy of transcatheter aortic valve implantation (TAVI) to treat aortic stenosis.

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Clinical Outcomes After NCS in Patients with Aortic Stenosis Historical series of patients with aortic stenosis who underwent NCS without prior aortic valve intervention reported high rates of postoperative cardiovascular complications. Adverse outcomes were more common with increasing severity of aortic stenosis, with symptomatic rather than asymptomatic aortic stenosis and with increasing complexity of NCS. Among 108 patients with aortic stenosis who underwent NCS at one centre between 1991–2000, for example,3 the rate of perioperative MI or death was 11 % in patients with moderate aortic stenosis (mean gradient 25–49 mmHg) and 31 % in patients with severe aortic stenosis (mean gradient ≥50 mmHg). Aortic stenosis conferred an adjusted OR for perioperative MI or death of 5.2 (95 % CI [1.6–17.0]) in comparison with 216 matched controls. In a more contemporary series of 634 patients who were matched to 2,536 controls,1 death or MI within 30 days after NCS was significantly more frequent in patients with moderate aortic stenosis (4.4 % versus 1.7 %; p=0.002) and severe aortic stenosis (5.7 % versus 2.7 %; p=0.02) compared to controls. Rates of death or MI in patients with symptomatic severe aortic stenosis, asymptomatic severe aortic stenosis and controls were 8.3 %, 4.7 % and 2.7 %, respectively. The difference between controls and study groups was significant in symptomatic patients (p=0.007) but not in asymptomatic patients (p=0.2).

Clinical Practice Guidelines for the Management of Patients Undergoing NCS Both the ACC/AHA and the ESC guidelines emphasise the importance of general measures in the management of patients with untreated valvular heart disease who are undergoing NCS. In particular, they

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Structural recommend careful selection of the mode of anaesthesia, use of invasive haemodynamic monitoring (arterial line, transoesophageal echocardiography, etc.), avoidance of rapid changes in volume status, aggressive treatment of arrhythmia and high-intensity postoperative ward care.

ESC Guidelines The European guidelines7 are prescriptive with their recommendations for preoperative aortic valve intervention. For patients with symptomatic severe aortic stenosis, aortic valve replacement (AVR) is recommended prior to elective NCS, provided valve surgery would not involve a high risk. In patients with symptomatic severe aortic stenosis for whom AVR would involve a high risk, balloon aortic valvuloplasty (BAV) or, preferably, TAVI “may be a reasonable therapeutic option”. It is recommended that the choice between TAVI and BAV take into account life expectancy and the urgency of NCS. For patients with severe aortic stenosis who are asymptomatic, the recommendations vary according to the NCS risk category (see Table 1). It is recommended AVR be undertaken prior to high-risk NCS, whereas no aortic valve intervention is recommended for patients undergoing low- or intermediate-risk surgery, in whom the risks of NCS are felt to be acceptable.8 If high-risk NCS is planned in patients with asymptomatic severe aortic stenosis who are at high risk for surgical AVR, it is recommended that elective surgery should be performed only if strictly necessary and using invasive haemodynamic monitoring.

ACC/AHA Guidelines These guidelines6 make the general recommendation that valvular intervention is effective in reducing perioperative risk in adults who meet standard indications for valvular intervention (replacement or repair) on the basis of symptoms and severity (Class I recommendation, level of evidence C). Specifically, they recommend that patients who have symptomatic severe aortic stenosis should undergo AVR before elective NCS. For patients with aortic stenosis who meet indications for AVR but are considered high risk or ineligible for AVR the guidelines note there are three options: undertaking NCS with untreated aortic stenosis, BAV and TAVI. The ACC/AHA guidelines state it is reasonable to perform elevated (moderate) risk elective NCS in patients with asymptomatic severe aortic stenosis with appropriate intraoperative and postoperative haemodynamic monitoring. Procedural mortality rates of 2–3 % and stroke rates of 1–2 % are reported in the literature relating to BAV,9,10 and small case series of patients with aortic stenosis who underwent NCS after BAV report low rates of postsurgical complications.11,12 The unpredictable effect of BAV on the severity of aortic stenosis and a restenosis rate of 50 % at 6 months, in combination with reducing vascular access sheath sizes for TAVI, however, make BAV an unattractive treatment option for most patients with aortic stenosis. Nonetheless, procedures are short, they require little technical expertise or expensive equipment, they rarely cause conduction disorders and they can be organised quickly. As a result, BAV remains a useful intervention prior to NCS in patients with severe aortic stenosis who require urgent surgery or who have an uncertain long-term prognosis. In discussing the potential use of TAVI, the ACC/AHA guidelines cite the 1-year mortality rates from the first Placement of Aortic Transcatheter Valves (PARTNER) trial: 24.2 % and 26.8 % for TAVI and AVR in cohort A, 30.7 % and 50.7 % for TAVI and medical treatment in cohort B.13,14 Perhaps more pertinent would have been the 30-day outcomes. In

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PARTNER A the 30-day mortality was 3.4 % following TAVI and 6.5 % following AVR (p=0.07). For the transfemoral cohort the “as treated” figures were 3.7 % and 8.2 % (p=0.046). Mean length of stay was 8 and 12 days (p<0.001) following TAVI and AVR, respectively. The guidelines go on to note there are no data that demonstrate the efficacy or safety of TAVI for patients with aortic stenosis who are undergoing NCS. Equally, however, there are no such data for surgical AVR.

Contemporary TAVI Data Three important randomised controlled trials and new observational data regarding the use of TAVI to treat severe aortic stenosis have been published since the clinical practice guidelines on preoperative management were developed. In a randomised controlled trial of 795 high-risk patients with an average Society of Thoracic Surgeons (STS) score of 7.4 %, TAVI using the Medtronic CoreValve® (Medtronic) self-expanding prosthesis achieved superior clinical outcomes to AVR.15,16 All-cause mortality rates for TAVI compared with AVR at 1- and 2-year follow up were 14.2 % versus 19.1 % (p=0.04) and 22.2 % versus 28.6 % (p<0.05), respectively, while 1-year stroke rates were 8.8 % in TAVI patients compared with 12.6 % in the surgical group (p=0.1). In the Nordic Aortic Valve Intervention (NOTION) trial, equivalent 1-year clinical outcomes following TAVI and AVR were demonstrated in 280 low-risk patients (mean STS score 3 %).17 Rates of all-cause mortality were 4.9 % and 7.5 % (p=0.38), while stroke rates were 2.9 % and 4.6 % (p=0.44) following TAVI and surgical AVR, respectively. The PARTNER 2a trial, which studied an intermediate-risk population for AVR (mean STS score 5.8 %), was published in April 2016.18 The combined incidence of death or stroke was 6.1 % versus 8.0 % (p=0.11) at 30 days and 14.5 % versus 16.4 % (p=0.24) 1 year after TAVI and AVR, respectively. Event rates were lowest in patients who were randomly allocated to undergo TAVI via the transfemoral route (12.3 % at 1 year) and were significantly lower in these patients than in patients who were allocated to undergo surgical AVR (15.9 %; p=0.05). The median length of postprocedure hospital stay was significantly shorter following TAVI than it was following AVR (6 days versus 9 days; p<0.001). Aortic regurgitation of moderate or greater severity was significantly (p<0.001) less common after AVR than after TAVI at all time points. The PARTNER 2a trial, however, was undertaken using the now semi-obsolete second-generation SAPIEN XT prosthesis (Edwards Lifesciences). Nonrandomised data have consistently demonstrated better results in cases utilising the third-generation SAPIEN 3 (Edwards Lifesciences) prosthesis, with 1-year rates of paravalvular leak (PVL) and mortality of 2.0 % and 6.5 %, respectively, in intermediate-risk patients.19 Finally, registry data relating to the Lotus valve (Boston Scientific) from a small cohort of 112 patients at high risk for AVR (average STS score 7.1 %) demonstrated moderate or more severe PVL in only 1 % of cases at 30 days with death or disabling stroke occurring in 5.9 %.20

Coronary Artery Disease and DAPT The clinical practice guidelines from the ACC/AHA21 and the ESC22 for the management of patients with valvular heart disease recommend that significant (>70 % reduction in luminal diameter) coronary artery disease be treated with coronary artery bypass grafting (CABG) undertaken at the time of AVR (level of evidence C). The guidelines for the management of patients undergoing NCS defer to the valvular

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Aortic Stenosis and Non-cardiac Surgery heart disease guidelines in respect to this issue. These guidelines make no recommendations for the management of coronary artery disease in patients undergoing TAVI, other than to state untreated coronary artery disease is a relative contraindication to TAVI, particularly in those with severe multivessel coronary artery disease. What is clear, however, is that dual antiplatelet therapy is required after percutaneous coronary artery intervention (PCI), but not necessarily required after combined CABG and AVR operations or after TAVI undertaken without prior coronary intervention. Dual antiplatelet therapy is commonly prescribed after TAVI,13,14,18 but there are no evidence-based guidelines to support their use and in general operators do not have the concerns about cessation of antiplatelet therapy after TAVI that they do after PCI. Thus, the presence of significant coronary artery disease is an important factor when deciding which form of aortic valve intervention should be undertaken prior to any NCS that cannot safely be performed in patients on antiplatelet therapy.

Table 1: Surgical Risk Estimate According to Type of Surgery or Intervention* Low Risk: <1 %

Intermediate Risk: 1–5 %

High Risk: >5 %

Breast

Endovascular aneurysm

Aortic

Dental

Head and neck

Major vascular

Endocrine (thyroid)

Renal transplant

Duodeno-pancreatic

Eye

Intrathoracic (non-major)

Liver resection

Carotid (asymptomatic)

Major orthopaedic

Oesophagectomy

Minor gynaecology Major neurology

Bowel perforation repair

Minor orthopaedic

Major gynaecological

Adrenal resection

Minor urology (TURP)

Major urology

Cystectomy

Reconstructive

Intraperitoneal (splenectomy, Lung or liver cholecystectomy) transplant

Superficial

Carotid (symptomatic)

Pneumonectomy

* 30-day risk of cardiovascular death or MI. TURP = transurethral resection of the prostate. Adapted from Glance et al., 201226 and Kristensen et al., 2014.7

Translating Evidence into Practice The main evidence for TAVI prior to the publication of the current clinical practice guidelines for the perioperative management of patients undergoing NCS came from the first PARTNER trial. This showed that TAVI is at least as effective as AVR in patients with severe aortic stenosis who are at high risk of complications from AVR. Since then, further data have been published that have consolidated the role of TAVI in high-risk patients and show that TAVI is also safe and effective in intermediate-risk patients. Current guidelines recommend that severe aortic stenosis is treated prior to all forms of NCS in symptomatic patients. European guidelines recommend that severe aortic stenosis is also treated in asymptomatic patients who are scheduled to undergo high-risk NCS. TAVI is recommended as an option prior to high-risk NCS only in symptomatic patients who are at high risk from AVR. TAVI is not mentioned as a treatment option for asymptomatic patients. In the context of patients who require treatment for aortic stenosis prior to NCS, however, TAVI has several advantages over AVR: the procedural mortality rate is lower in highand intermediate-risk patients, it is less invasive and the recovery time is quicker, which facilitates early NCS after the procedure. In addition, the latest iterations of TAVI prostheses require smaller sheath sizes promising further reductions in length of stay, with the potential for next-day discharge in some cases, and lower rates of PVL allay some of the concerns relating to long-term outcomes following TAVI.

garwal S, Rajamanickam A, Bajaj NS, et al. Impact of aortic A stenosis on postoperative outcomes after noncardiac surgeries. Circ Cardiovasc Qual Outcomes 2013;6(2):193–200. DOI: 10.1161/CIRCOUTCOMES.111.000091. PMID: 23481524. Goldman L, Caldera DL, Southwick FS, et al. Cardiac risk factors and complications in non-cardiac surgery. Medicine (Baltimore) 1978;57(4):357–70. PMID: 661558. Kertai MD, Bountioukos M, Boersma E, et al. Aortic stenosis: an underestimated risk factor for perioperative complications in patients undergoing noncardiac surgery. Am J Med 2004;116(1):8–13. PMID: 14706659. Osnabrugge RL, Mylotte D, Head SJ, et al. Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. J Am Coll Cardiol 2013; 62(11):1002–12. DOI: 10.1016/j.jacc.2013.05.015. PMID: 23727214. Rezzoug N, Vaes B, de Meester C, et al. The clinical impact of valvular heart disease in a population-based cohort of subjects aged 80 and older. BMC Cardiovasc Disord 2016;16:7. DOI: 10.1186/s12872-016-0184-8. PMID: 26754575. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/ AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 2014;64(22):e77–137. DOI: 10.1016/j.jacc.2014.07.944. PMID: 25091544. Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ ESA Guidelines on non-cardiac surgery: cardiovascular

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In recent years, the “Heart Team” has emerged as the key to clinical decision making for complex cardiac patients.23 Interventional cardiologists and cardiac surgeons who are directly acquainted with the relative merits of the different forms of intervention have become expert in assessing and managing patients with aortic stenosis.24,25 The ACC/ AHA guidelines for the management of valve disease21 give considerable focus to the Heart Valve Team for determining which patients with aortic stenosis should be treated by conventional AVR and which by TAVR. It is, therefore, curious that Heart Team-directed management is not recommended for the management of patients with aortic stenosis in the perioperative setting. Guidelines can provide useful recommendations for the management of single pathologies but evidence relating to the management of dual pathologies is necessarily sparse and it is in this context that the Heart Team is particularly valuable, more so in patients with a third pathology in the form of concomitant coronary artery disease.

Conclusion The next iterations of clinical practice guidelines for perioperative management of patients undergoing NCS should recognise the benefits of TAVI compared with conventional AVR in treating patients with severe aortic stenosis. When aortic valve intervention is indicated, the Heart Valve Team is best placed to decide which intervention is most appropriate. n

assessment and management: The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). Eur Heart J 2014;35(35):2383–431. DOI: 10.1093/eurheartj/ehu282. PMID: 25086026. 8. Calleja AM, Dommaraju S, Gaddam R, et al. Cardiac risk in patients aged >75 years with asymptomatic, severe aortic stenosis undergoing noncardiac surgery. Am J Cardiol 2010;105(8):1159–63. DOI: 10.1016/j.amjcard.2009.12.019. PMID: 20381670. 9. Khawaja MZ, Sohal M, Valli H, et al. Standalone balloon aortic valvuloplasty: indications and outcomes from the UK in the transcatheter valve era. Catheter Cardiovasc Interv 2013;81(2):366–73. DOI: 10.1002/ccd.24534. PMID: 22730270. 10. Ben-Dor I, Pichard AD, Satler LF, et al. Complications and outcome of balloon aortic valvuloplasty in high-risk or inoperable patients. JACC Cardiovasc Interv 2010;3(11): 1150–6. DOI: 10.1016/j.jcin.2010.08.014. PMID: 21087751. 11. Calicchio F, Guarracino F, Giannini C, et al. Balloon aortic valvuloplasty before noncardiac surgery in severe aortic stenosis: a single-center experience. J Cardiovasc Med (Hagerstown) 2017;18(2):109–113. DOI: 10.2459/ JCM.0000000000000331. PMID: 26885982. 12. Kogoj P, Devjak R, Bunc M. Balloon aortic valvuloplasty (BAV) as a bridge to aortic valve replacement in cancer patients who require urgent non-cardiac surgery. Radiol Oncol 2014;48(1): 62–6. DOI: 10.2478/raon-2013-0078. PMID: 24587781

13. S mith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364(23):2187–98. DOI: 10.1056/NEJMoa1103510. PMID: 21639811. 14. 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(17):1597–607. DOI: 10.1056/NEJMoa1008232. PMID: 20961243. 15. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aorticvalve replacement with a self-expanding prosthesis. N Engl J Med 2014;370(19):1790–8. DOI: 10.1056/NEJMoa1400590. PMID: 24678937. 16. Reardon MJ, Adams DH, Kleiman NS, et al. 2-year outcomes in patients undergoing surgical or self-expanding transcatheter aortic valve replacement. J Am Coll Cardiol 2015;66(2):113–21. DOI: 10.1016/j.jacc.2015.05.017. PMID: 26055947. 17. Thyregod HG, Steinbrüchel DA, Ihlemann N, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1-year results from the all-comers NOTION randomized clinical trial. J Am Coll Cardiol 2015;65(20):2184–94. DOI: 10.1016/j.jacc.2015.03.014. PMID: 25787196. 18. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374(17);1609–20. DOI: 10.1056/NEJMoa1514616. PMID: 27040324. 19. 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(10034);2218–25. DOI: 10.1016/S0140-

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Structural 6736(16)30073-3. PMID: 27053442. 20. M eredith Am IT, Walters DL, Dumonteil N, et al. Transcatheter aortic valve replacement for severe symptomatic aortic stenosis using a repositionable valve system: 30-day primary endpoint results from the REPRISE II study. J Am Coll Cardiol 2014;64(13):1339–48. DOI: 10.1016/j.jacc.2014.05.067. PMID: 25257635. 21. Nishimura RA, Otto CM, Bonow RO, et al. 2104 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 2014;63(22):e57–185. DOI: 10.1016/j.jacc.2014.02.536. PMID: 24603191.

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8 CORONARY CRT VALVE & STRUCTURAL HEART CRT ENDOVASCULAR TECHNOLOGY & INNOVATION ATHEROSCLEROSIS & RESEARCH CRT 2018 Keynote Address: President Barack Obama, March 5, 2018

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