ICR 10.2

Interventional Cardiology Review Volume 10 • Issue 2 • Summer 2015

Volume 10 • Issue 2 • Summer 2015

www.ICRjournal.com

Is Hyperaemia Essential for Accurate Functional Assessment of Coronary Stenosis Severity?

Barry Hennigan, Keith Robertson, Colin Berry and Keith Oldroyd

Integrating Physiology into the DNA of Coronary Revascularisation – A Historical Perspective, Contemporary Review and Blueprint for the Future of Coronary Physiology Sayan Sen and Justin Davies

Permanent Pacemaker Implantation after TAVR – Predictors and Impact on Outcomes

Marcel Weber, Jan-Malte Sinning, Christoph Hammerstingl, Nikos Werner, Eberhard Grube and Georg Nickenig

A Quick Guide to Paravalvular Leak Closure Sameer Gafoor, Jennifer Franke, Stefan Bertog, Simon Lam, Laura Vaskelyte, Ilona Hofmann, Horst Sievert and Predrag Matic

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Lifelong Learning for Cardiovascular Professionals

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Meeting the unment in Interventional Cardiology

Come and join our session at EuroPCR 2015

TNT Session

Visit our booth F27 ⁄ F28

Lesion and patient tailored DES choice: solution for CTO and diabetic patients Tuesday 19th May‚ 2015‚ from 17.00 to 19.00-Theatre Bleu Chairperson: R. Mehran Co-chairperson: M.C. Morice Panellists: O.Goktekin‚ R.Mohd Ali Speakers: A.Khashaba‚ G.Sardella Live Cases from ICPS - Massy, France

Case-in-point Session Absorbable polymer and polymer-free technologies: viable solutions for unmet needs in PCI Thursday 21st May, 2015, from 12:30 to 14:00 – Room 251 Chairperson: A. Colombo Co-chairperson: H. Moellmann Speakers: P. Stella, R. Romaguera, R. Garbo, K. Tigen

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Volume 10 • Issue 2 • Summer 2015

www.ICRjournal.com

Editor-in-Chief Simon Kennon Interventional Cardiologist and Head of the Transcatheter Aortic Valve Implantation Programme at the London Chest Hospital, Barts Health NHS Trust, London

Section Editor – Structural

Section Editor – Coronary Tim Kinnaird

Darren Mylotte

University Hospital of Wales, Cardiff

Galway University Hospitals, Galway

Fernando Alfonso

Eric Eeckhout

Marko Noc

Cardiac Department,Hospital Universitario de La Princesa, Madrid

Centre Hospitalier Universitaire Vaudois, Lausanne

Andrew Archbold

Juan Granada

Jeffrey Popma

London Chest Hospital, Barts Health NHS Trust, London

CRF Skirball Research Center, New York

Beth Israel Deaconess Medical Center, Boston

Olivier Bertrand

A Pieter Kappetein

London Chest Hospital, Barts Health NHS Trust, London

Quebec Heart-Lung Insitute, Laval University, Quebec

Thoraxcenter, Erasmus University Medical Center, Rotterdam

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Elliot Smith

Lars Søndergaard

Lutz Buellesfeld

Demosthenes Katritsis

University Hospital, Bern

Athens Euroclinic, Athens, Greece

Rigshospitalet - Copenhagen University Hospital, Copenhagen

Jonathan Byrne

Ajay Kirtane

Gregg Stone

King’s College Hospital, London

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

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

Antonio Colombo

Didier Locca

Nicolas Van Mieghem

San Raffaele Hospital, Milan

Lausanne University Hospital, Lausanne

Thoraxcenter, Erasmus University Medical Center, Rotterdam

Imperial College NHS Trust, London

Roxana Mehran

Renu Virmani

Mount Sinai Hospital, New York

CVPath Institute, Maryland

Carlo Di Mario

Jeffrey Moses

Mark Westwood

Royal Brompton & Harefield NHS Foundation Trust, London

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

London Chest Hospital, Barts Health NHS Trust, London

Justin Davies

Design & Production Tatiana Losinska • Publication Manager Michael Schmool Publishing Director Liam O’Neill • Managing Director David Ramsey Managing Editor editor@radcliffecardiogy.com •

Circulation Contact David Ramsey david.ramsey@radcliffecardiology.com Commercial Contact Michael Schmool michael.schmool@radcliffecardiology.com •

Cover image

Human heart for medical study © angelhell | istockphoto.com

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Published by Radcliffe Cardiology.

All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology.

Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice.

Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2015 All rights reserved

© RADCLIFFE CARDIOLOGY 2015

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Established: June 2006 Frequency: Tri-annual Current issue: Summer 2015

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 update on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format • Interventional Cardiology Review is a tri-annual journal comprising review articles, editorials, and case reports.

• 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 replicated in full online at www.ICRjournal.com

Editorial Expertise 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 from 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.

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion.

• The Managing Editor, following consultation with the Editor-in-Chief, Section Editors and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, 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 either 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.

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations.

Once approved, 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, formalise the working title and scope of the article.

• Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details.

• The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Managing Editor for further details: editor@radcliffecardiology.com. The ‘Instructions to Authors’ information is available for download at www.ICRjournal.com.

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

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

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in Interventional Cardiology Review unless otherwise stated.

Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor.

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

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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© RADCLIFFE CARDIOLOGY 2015

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Contents

Foreword 70

Simon Kennon, Editor-in-Chief, ICR

Coronary Physiology Assessment Debate

72

Is Hyperaemia Essential for Accurate Functional Assessment of Coronary Stenosis Severity?

Barry Hennigan, Keith Robertson, Colin Berry and Keith Oldroyd

79

Integrating Physiology into the DNA of Coronary Revascularisation – A Historical Perspective, Contemporary Review and Blueprint for the Future of Coronary Physiology

Sayan Sen and Justin Davies

Bifurcations 85

AXXESS™ Stent: Delivery Indications and Outcomes John Rawlins, Jehangir Din, Suneel Talwar and Peter O’Kane

Chronic Total Occlusion 90

Vascular Access and Chronic Total Occlusion Angioplasty David Smith, Ahmed Hailan and Alexander Chase

Structural Transcatheter Aortic Valve Implantation

94

Avoiding Coronary Occlusion and Root Rupture in TAVI – The Role of Pre-procedural Imaging and Prosthesis Selection

Marco Barbanti

98

Permanent Pacemaker Implantation after TAVR – Predictors and Impact on Outcomes

1 03

Balloon- or Self-Expandable TAVI: Clinical Equipoise?

Marcel Weber, Jan-Malte Sinning, Christoph Hammerstingl, Nikos Werner, Eberhard Grube and Georg Nickenig

John Jose, Gert Richardt and Mohamed Abdel-Wahab

Left Atrial Appendage 1 09

Real World Outcomes of Left Atrial Appendage Occlusion Apostolos Tzikas, Darren Mylotte and Martin Bergmann

Paravalvular Leak 1 12

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A Quick Guide to Paravalvular Leak Closure Sameer Gafoor, Jennifer Franke, Stefan Bertog, Simon Lam, Laura Vaskelyte, Ilona Hofmann, Horst Sievert and Predrag Matic

INTERVENTIONAL CARDIOLOGY REVIEW

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Foreword

Simon Kennon is an Interventional Cardiologist and Head of the Transcatheter Aortic Valve Implantation Programme at the London Chest Hospital, Barts Health NHS Trust, London. He trained at Manchester University, St Bartholomew’s Hospital, the London Chest Hospital and St Vincent’s Hospital, Melbourne. His research interests relate to aortic valve and coronary interventions.

T

his issue of Interventional Cardiology Review contains papers by leading proponents of both FFR and iFR. This is a complex field and I am delighted to have experts presenting their detailed but differing interpretations of the available data relating to

these important technologies.

Advances in both techniques and technology have transformed chronic total occlusion interventions over the last five years and David Smith discusses how vascular access techniques have contributed to improvements in procedural safety and procedural success.

In contrast, progress in treating coronary bifurcations has been more limited. Peter O’Kane discusses the Axxess stent, a new technology that offers access to both distal branches without limiting options for their treatment.

Marco Barbanti discusses how to avoid the two most feared complications of TAVI: root rupture and coronary occlusion. These complications form part of Mohamed Abdel-Wahab’s discussion of the differences between balloon and self-expandable TAVI prostheses. George Nickenig completes a trio of TAVI papers, discussing predictors of and outcomes following permanent pacemaker implantation after TAVI. It is clear that these issues are becoming increasingly important as we try to assess the role of TAVI in the treatment of intermediate risk patients.

The prevalence of atrial fibrillation will mean that Apostolos Tzikas paper summarising indications for and outcomes following left atrial occlusion will be useful to a wide range of different subspeciality cardiologists. Similarly, Sameer Gafoor’s discussion of percutaneous paravalvular leak closure procedures will be useful for both interventional and general cardiologists. n

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Coronary Physiology Assessment Debate

ON.

Is Hyperaemia Essential for Accurate Functional Assessment of Coronary Stenosis Severity?

Barry Hennigan, Keith Robertson, Colin Berry and Keith Oldroyd Golden Jubilee National Hospital, Clydebank, UK

Abstract Fractional flow reserve (FFR) requires the use of maximal hyperaemia as described in the original preclinical and clinical validation studies and subsequent practice changing randomized controlled trials. A perception that the need for hyperaemia (usually induced with adenosine) was one of the obstacles to more widespread adoption of FFR has led to interest in the use of resting non-hyperaemic indices to assess the functional significance of coronary stenoses. We examine the current evidence base and conclude that resting indices agree with FFR in only 80 % of lesions when a binary cut-off is employed but closer to 90 % when hybrid strategies utilising both resting indices and FFR are utilised. It seems counter intuitive to sacrifice diagnostic accuracy when in most patients and healthcare systems the induction of hyperaemia with adenosine is safe and emminently affordable.

Keywords instantaneous wave free ratio, iFR FFR, Pd/Pa, pressure wire, coronary physiology Disclosure: Dr Hennigan has previously received speaker fees from Volcano Corporation. Dr Robertson has no conflicts of interest to declare. Professor Berry has undertaken consultancy work and given lectures based on institutional contracts between his employer, the University of Glasgow and St Jude Medical. St Jude Medical has also provided support for research with pressure wires. Prof Oldroyd has received speaker fees and institutional grant support from St Jude Medical and speakers fees from Volcano.

Received: 5 December 2014 Accepted: 20 April 2015 Citation: Interventional Cardiology Review, 2015;10(2):72–8 Correspondence: Dr. Barry Hennigan, Cardiology Department, Golden Jubilee National Hospital, Agamemnon Street, Glasgow, G81 4DY. E: barryhennigan@nhs.net

The original studies of coronary balloon angioplasty performed by Andreas Gruentzig attempted to employ physiological guidance by measuring trans-stenotic gradients with over-the-wire angioplasty catheters.1 However, these catheters were of such large calibre that they contributed to the stenosis being assessed and in addition, measurements were made at rest as the importance of assessing functional stenosis severity during hyperaemia was not yet fully appreciated. The development of pressure and flow (Doppler) sensing coronary guide wires in the early 1990s led to a re-emergence of physiologically guided percutaneous coronary intervention (PCI). A series of studies using Doppler-derived measurements of coronary flow velocity to calculate coronary flow reserve (CFR) were conducted with variable results, partly related to the technical difficulty of recording stable flow velocity signals but mainly to the fact that CFR cannot separate out the contribution to inadequate myocardial blood flow of resistance in the stenotic large-calibre epicardial conduit vessels (the target for intervention) from that in the microcirculation. The concept of pressure-derived fractional flow reserve (FFR) was first described

by Pijls et al. in 19932 and following proof-of-concept studies, several clinical trials demonstrated that the use of FFR to guide PCI was not only associated with improved clinical outcomes but was also highly cost effective.3–6 Despite this, the worldwide use of FFR remains disappointingly low at around 5–10 % of all PCIs.7 This figure has been confirmed in a large recent survey by Toth et al.8 Various reasons have been proposed for the low utilisation of FFR, including the cost of the pressure wires as well as the cost, inconvenience

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and side effects associated with the induction of hyperaemia. In response to this, investigators have explored the ability of resting pressure-derived indices of stenosis severity to predict FFR and thereby to potentially remove the need for hyperaemia, at least in some patients. In this review we will discuss the role of one of these indices, the instantaneous wavefree ratio (iFR), and examine the strengths and weaknesses of iFR and FFR in detail with emphasis on the available evidence to date.

Physiology FFR is the ratio of mean distal coronary pressure and mean aortic pressure measured during maximal hyperaemia that is generally achieved through administration of a potent vasodilator such as adenosine, ATP or papaverine either by IV infusion or by intracoronary (IC) bolus injection. By rendering myocardial microvascular resistance constant and minimal, it is possible to separate out the impact of disease in the epicardial conduit artery on myocardial blood flow2. iFR was first described in 2011 following a proof-of-concept study in 157 coronary stenoses in which FFR was compared with resting (non-hyperaemic) trans-stenotic pressure gradients measured in a time period beginning 25 % into diastole and ending 5 ms before the onset of systole, the ‘wave-free’ period.9 It was proposed that coronary microcirculatory resistance was already constant in this window and as low as whole-cycle resistance during hyperaemia (Figure 1). In theory, this should allow accurate prediction of FFR, and in this initial study iFR was found to have a strong correlation with FFR with a receiver operating characteristic area under the curve (ROC AUC) of 93 % for

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Is Hyperaemia Essential for Accurate Functional Assessment of Coronary Stenosis Severity?

Figure 1: ADVISE Study 2012 Identification of Wave-Free Period in the Cardiac Cycle A

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Reproduced with Wave-intensity analysis (A) demonstrates the proximal and microcirculatory (distal) originating waves generated during the cardiac cycle. A wavefree period can be seen in diastole when no new waves are generated (shaded). This corresponds to a time period in which there is minimal microcirculatory (distal)–originating pressure (B), minimal and constant resistance (C), and a nearly constant rate of change in flow velocity (D). (Separated pressure above diastole is the residual pulsatile separated pressure component after subtraction of the diastolic pressure.)

iFR≤0.83 predicting FFR≤0.80. For decision making in the cath-lab, the investigators proposed that an iFR value of 0.83 could be equated to an FFR value of 0.80.

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Evidence to Support the Use of FFR The original validation of FFR demonstrated that below a cut-off value of 0.75 there was 93 % concordance between FFR and a triple gold standard of exercise stress ECG, single-photon emission computed tomography and dobutamine stress echo performed before and after PCI.3 The DEFER study clearly demonstrated that it was safe to postpone intervention on lesions with an FFR≥0.75.5 The FAME study demonstrated that in patients presenting with multivessel PCI, FFR guidance was associated with reduced rates of mortality or myocardial infarction (MI) at 2 years: 12.9 % in the angiography-guided group versus 8.4 % in the FFR-guided group (p=0.02).4 The FAME 2 study demonstrated a markedly reduced rate of death, MI, and urgent revascularisation in patients with stable angina with at least one lesion and an FFR≤0.80 when treated by PCI plus optimal medical therapy compared with optimal medical therapy alone: 4.3 % versus 12.7 % (HR 0.32; 95 % CI 0.19–0.53; p<0.001). In a subsequent landmark analysis of the clinical outcomes from day 7 to 2 years, essentially excluding periprocedural type 4 MI, the combined endpoint of death and non-fatal MI was significantly reduced by PCI (4.6 % versus 8.0 %; p=0.04) despite a 40 % crossover from medical therapy alone to PCI.5

FFR Beyond Physiological Assessment FFR assessment provides more than just physiological information.

The SYNTAX score is a widely used tool that can stratify patients into low, medium and high risk for PCI as opposed to surgical revascularisation.10 The functional SYNTAX score combines FFR data with

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Reproduced with permission.12 Figure (A) shows the normalised 1-year MACE rate from the study-level meta-regression. The optimal FFR threshold for a composite of death, MI, and revascularisation occurred at 0.75, rising to 0.90 after Poisson adjustment for variable length of follow-up suggesting a sensitivity to how events are temporally distributed after the procedure.

Figure (B) depicts the 1-year MACE rate on the basis of the unadjusted Cox regression from the patient-level meta-analysis. The optimal FFR threshold for a composite of death, MI and revascularisation occurred at 0.67, rising to 0.76 after adjustment for percent diameter stenosis, likely due to its significant correlation with FFR as detailed previously.

CABG = coronary artery bypass graft; FFR = fractional flow reserve; MACE = major adverse cardiac events; MI = myocardial infarction; PCI = percutaneous coronary intervention.

the angiographically derived SYNTAX score and potentially facilitates the selection of patients who will have equivalent outcomes with PCI or surgery.11 In terms of predicting an overall prognostic benefit from PCI, a recent meta-analysis with a combined endpoint of death, MI and revascularisation demonstrated that FFR<0.75–0.76 was associated with a clear beneficial effect of elective revascularisation (Figure 2).12

FFR at the Time of Diagnostic Angiography?

The data from the numerous trials mentioned above have firmly established the safety of FFR guidance in patients already referred for PCI. This has been supplemented by a large French registry in over 1,000 patients who had at least one intermediate lesion of 35 %–65 % diameter stenosis with overall treatment strategy recorded before and after FFR in addition to follow-up for 1-year endpoints.13 Final management changed in 43 % of cases including 33 % of patients initially assigned to receive no revascularisation, 56 % of patients assigned to PCI and in 51 % of patients assigned to coronary artery bypass graft surgery (Figure 3).

Major adverse cardiac event rates (death, MI or unplanned PCI) were similar at 1 year for patients whose treatment was reclassified and those

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Coronary Physiology Assessment Debate Figure 3: Details of the Final Revascularisation Strategy applied in Each Group of Revascularisation Strategy A Priori

Figure 5: Clinical Case: iFR versus FFR in Left Main Stem Disease

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Reproduced with CABG = coronary artery bypass graft surgery; PCI = percutaneous coronary intervention.

Moderate diffuse left main disease with an additional lesion in the mid left anterior descending artery. Pressure wire sensor in distal vessel with guide catheter disengaged during all measurements. Hyperaemia with intravenous adenosine. (a) Pd/Pa=0.92; (b) iFR 1=0.93; c) iFR 2=0.93; (d) FFR=0.71; (e) iFR with hyperaemia 1=0.62; (f) iFR with hyperaemia 2=0.59; (g) no significant drift on pullback to 0.98. Pd/Pa and iFR both non-ischaemic. FFR clearly ischaemic. Profound fall in iFR with hyperaemia refuting the concept that iFR is independent of adenosine. FFR = fractional flow reserve; iFR = instantaneous wave-free ratio.

Figure 4: iFR Diagnostic Performance in Stable Coronary Disease versus ACS ACS (n=78 lesions)

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Reproduced with permission.25 Left Panel. ROC curve showing diagnostic performance of iFR in the stable CAD group. Right Panel. ROC curve showing diagnostic performance of iFR in the ACS group. Comparison of the areas under the two independent ROC curves did not find any significant difference between the two groups. ACS = acute coronary syndrome; AUC = area under the curve; CABG = coronary artery bypass graft surgery; CAD = coronary artery disease; iFR = instantaneous wave-free ratio; PCI = percutaneous coronary intervention; ROC = receiver operating characteristic; SE = standard error.

who remained in their original treatment group following FFR (11.2 % versus 11.9 %; p=not significant).13 Similar findings were reported in the RIPCORD study from the UK.14

Problems with FFR Inducing Hyperaemia The debate regarding the clinical challenges with adenosine continues and is mainly focused on patient discomfort, cost and additional procedural time. The reality is that most patients, with the exception of those with severe asthma, tolerate adenosine15 and use of intracoronary adenosine in particular is associated with little additional procedural time or cost while preserving diagnostic accuracy. Other agents including regadenoson and nicorandil are also options for inducing hyperaemia and in some situations may be preferable to adenosine.16 There are theoretical concerns that some of the agents used to induce hyperaemia

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may introduce haemodynamic disturbances including hypotension and bradycardia, which may alter FFR and lesion classification. This was not borne out in a recent study which demonstrated no significant differences in FFR between a variety of hyperaemic agents and routes of administration.16 A strong correlation was found between IV adenosine/ ATP and IC nicorandil (r=0.962; p< 0.001 with a classification agreement of 91.2 %). Similarly, IV adenosine and IV regadenoson compared well (r=0.990; p<0.001 with a classification agreeement of 100 %).16

Cost The technology itself remains reasonably expensive; however, it is likely to become significantly cheaper with increased competition as new wires from alternative manufacturers come to the market. In addition, a pressure-sensing microcatheter is now commercially available. It is important to note that FFR guidance reduces inappropriate PCI and increases quality of life and is therefore cost effective in patients scheduled for multi-vessel PCI despite the associated expense of the pressure wire and hyperaemic agents.17

Grey-Zone FFR Values The original validation study as well as many subsequent reports confirmed a very high concordance for non-invasive evidence of ischaemia with FFR values ≤0.75.3,5 However, in order to improve sensitivity and minimise the risk of under-treatment an FFR cut-off value of ≤0.80 was adopted in the FAME and FAME 2 trials.3,4 This has resulted in the de facto creation of a so-called FFR grey-zone between 0.75 and 0.80 within which the need to perform revascularisation is unclear and there may in fact be over-treatment. Indeed, preliminary data from our group suggests that only one-third of patients with grey-zone FFRs have perfusion abnormalities in the corresponding artery when assessed using stress MRI.18 All 33 grey-zone stenoses in a recent study were found to be non-ischaemic using a combined reference standard of hyperaemic stenosis resistance index and myocardial perfusion scintigraphy.19 Another recent study assessed

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Is Hyperaemia Essential for Accurate Functional Assessment of Coronary Stenosis Severity?

3-year clinical outcomes in 150 patients with intermediate coronary lesions. Of these patients 56 had FFR 0.75–0.80 while the remaining 94 patients had FFR >0.80.20 Although target vessel revascularisation was higher in the patients with FFR 0.75–0.80 (14 % versus 3 %; p=0.020), there was no difference in rates if death or MI. This finding is consistent with the relationship between FFR and prognosis outlined above12 and emphasises that although there is a need for subsequent revascularisation in this group, they require careful consideration of the risk:benefit ratio of intervention.

Studies Comparing iFR with FFR The VERIFY study demonstrated that, in a consecutive cohort of 206 coronary stenoses of intermediate severity and compared with the FAME trial FFR cut-off value of ≤0.80, the diagnostic accuracy of iFR ≤0.80 was only 60 %.21 The ADVISE clinical registry reported that in 339 stenoses a different iFR cut-off of 0.89 provided a classification agreement between iFR and FFR of 80 % for the same FFR cut-off value of ≤0.80.22 The ADVISE 2 study compared iFR and FFR in 690 coronary stenoses.23 This dataset was used to derive a proposed hybrid strategy, which correctly classified 94 % of lesions by accepting an iFR>0.93 as being negative (non-ischaemic) and an iFR<0.86 as positive (ischaemic) and only requiring FFR to be measured in lesions with iFR values in between these limits. Compared with an FFR for all strategy, this avoided the use of adenosine in 70 % of stenoses (65 % of patients) at the expense of making a different treatment decision in 1 in 16 lesions.23 The RESOLVE study was an independent core laboratory re-analysis of coronary pressure recordings from 1768 patients drawn from several studies including both ADVISE and VERIFY.24 In the RESOLVE study, the diagnostic accuracy of iFR was 80.4 % at an optimal iFR binary cut-off value of ≤0.90. It was also demonstrated that to achieve ≥90 % diagnostic accuracy at each extreme, the adenosine-free iFR range had to be restricted to ≤0.88 and ≥0.93, which was only applicable to 65 % of the study lesions.24 (Figure 5) In a prospective study of 53 patients with an acute coronary syndrome (ACS) and 29 patients with stable angina, FFR and iFR in the non-culprit lesions of the ACS patients were calculated by two blinded operators.25 Using binary cut-off values, they demonstrated 81.3 % diagnostic concordance with FFR with positive and negative predictive values for iFR of 67 % and 89 %, respectively. Diagnostic accuracy was similar in both stable and unstable patient groups but was greatly improved by adoption of a hybrid approach with adenosine administration when iFR was 0.86–0.94, inclusive (Figure 4).25 It has previously been stated that the reason the VERIFY study reported an overall diagnostic accuracy for iFR versus FFR of only 60 % compared with 88 % in the ADVISE study is because in VERIFY, iFR was calculated using an in-house algorithm written in MatLab rather than the commercially available proprietary software.21 In fact, all raw data from VERIFY were provided to the independent core laboratory in the University of Columbia, New York for the RESOLVE study analysis. The correlation between iFR and FFR was stronger in the VERIFY study (r2=0.70 using the MatLab programme) than in the RESOLVE study (r2=0.66 using the proprietary software).24 Furthermore, the RESOLVE core lab analysis of the VERIFY dataset showed a mean difference in iFR values between the two different methodologies of -0.007, which is less than the mean difference between repeated measures of either parameter and therefore represents no difference at all.

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Table 1: Comparison of the Diagnostic Accuracy of Resting and Hyperemic Indices in Reference to Combined Reference Standard Comprising MPS and HSR Parameter

AUC

95 % Confidence Interval

p-value versus

versus

versus

FFR

BSR

iFR

versus iFRa

BSR

0.88

0.80–0.96

0.92

–

0.27

0.66

iFR

0.84

0.75–0.93

0.20

0.27

–

0.38

iFRa

0.86

0.78–0.95

0.49

0.66

0.38

–

Resting Pd/Pa 0.82

0.71–0.92

0.07

0.03

0.46

0.22

FFR

0.81–0.95

–

0.92

0.20

0.49

0.88

Reproduced with permission.20 iFR cohort: AUC for myocardial ischaemia using combined reference standard (n=85). AUC = area under the receiver operating characteristic curve; BSR = basal stenosis resistance index; FFR = fractional flow reserve; HSR = hyperaemic stenosis resistance index; iFR = instantaneous wave-free ratio; iFRa = instantaneous wavefree ratio during hyperaemia; MPS = myocardial perfusion scintigraphy; Pd/Pa = distal coronary pressure to aortic pressure ratio during resting conditions.

iFR versus Perfusion Scintigraphy and/ or Hyperaemic Stenosis Resistance as the Reference Standard A retrospective analysis of 85 stenoses with adequate resting measurements from which to derive iFR out of a dataset of 299 combined pressure and doppler flow coronary physiology studies was performed and compared with a combined reference standard comprising myocardial perfusion scintigraphy (MPS) and hyperaemic stenosis resistance index (HSR).19 Both of HSR and MPS needed to be positive for the lesion to be considered ischaemic. The optimal ischaemic cut-off values were 0.66 mmHg/cm/sec for basal stenosis resistance (BSR) (sensitivity 84.6 %, specificity 79.7 %), 0.82 for iFR (sensitivity 69.2 %, specificity 88.1%), and 0.75 for FFR (sensitivity 88.5 %, specificity 76.3 %). There was no significant difference in AUC for either resting parameter (BSR or iFR) and FFR with respect to the combined reference standard (Table 1).19 Although HSR has previously identified as being highly sensitive and specific for ischemia,26 this particular study has a number of significant limitations including a small sample size and the fact that the original validation of HSR was itself based on the MPS. This imaging modality has a high false-positive rate and importantly it was not repeated post revascularisation, which is possiby the most favourable means of assessing the diagnostic accuracy of any test for ischaemia. In addition, intracoronary adenosine was used to measure FFR in the low dose range of 20–40 μg. Previous studies have demonstrated that intracoronary doses of at least 100–200 μg are required to approximate the FFR achieved by IV adenosine infusion (Figure 6).27 This may lead to an underestimation of FFR, which in turn will erroneously increase the levels of agreement between the hyperaemic and non-hyperaemic indices. Sub-maximal hyperamiea would also be consistent with the absence of any difference between iFR and iFR during hyperaemia, a result entirely inconsistent with previously published data using IV adenosine. This study, however, showed no difference between Pd/Pa and iFR, consistent with the results of the RESOLVE meta-analysis.24 The CLARIFY registry reported data from 51 stenoses that had also been interrogated using combined pressure and flow velocity recordings.28 The authors defined HSR as the reference standard for ischaemia and determined that iFR at a cut-off value of <0.86 had an ROC AUC of 0.93 (95 % CI 0.85–1.00), while FFR<0.75 had an ROC AUC of 0.96 (95 % CI 0.89–1.00).29

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Coronary Physiology Assessment Debate Figure 6: Cumulative Percentage of Patients with FFR≤0.75 (n=46)

Cumulative FFR<0.75 (%)

60 50

51.2

Resting Pd/Pa

46.6

40 38 30

42

30

20 10 0

4 Baseline

60 μg

120 μg

180 μg

360 μg

720 μg

Bar graph shows the cumulative percentage of patients with FFR≤0.75 with increasing dose of intracoronary adenosine.28 FFR = fractional flow reserve.

Figure 7. Correlation of iFR versus Pd/Pa

1.0

0.8

n=1,000 patients

iFR

0.6

0.4

Pearson r=0.97 Linear slope=1.39 Intercept=-0.39 95 % limits=±0.06

0.2

0.0

0.0

0.2

0.4

0.6

0.8

1.0

Reproduced with permission.34 Data from the 1,000 patients relate iFR to the mean relative pressure at rest (average distal coronary pressure divided by aortic pressure, or ‘rest Pd/Pa’).

Best fit (black solid line) and 95 % CI (dashed line) demonstrate a highly linear relationship, with r=0.97 (p<0.001). iFR = instantaneous wave-free ratio; Pd/Pa = distal coronary pressure to aortic pressure ratio during resting conditions.

iFR Versus Coronary Flow Velocity Reserve as the Reference Standard In the JUSTIFY study, a retrospective dataset compared iFR with FFR in terms of their ability to predict coronary flow velocity reserve (CFVR).30 While CFVR is a useful parameter, it has generally been superseded

by FFR due to marked dependence on systemic haemodynamics (heart rate, blood pressure, contractility) and difficulties in obtaining reproducible flow measurements. It is known that at least 30 % of lesions have discordant CFVR and FFR results and therefore it was unsurprising that FFR ROC AUC was 0.72 (CI 0.65–0.79). In this population iFR appeared to have a stronger correlation with CFVR with an ROC AUC of 0.82 (CI 0.76–0.88; p<0.001).30 The scenario of a lesion with a conventionally ischaemic FFR value but ‘preserved’ CFVR will be discussed later in this review.

Innovations with iFR A particularly challenging group to assess physiologically are patients with tandem lesions or diffuse disease. In a proof-of-concept study coronary arteries were assessed using a motorised pullback system with calculation of iFR values per millimeter length of vessel.31 The investigators suggested that iFR may have the potential to be used in PCI planning for the determination of physiological lesion length as

Oldroyd_FINAL2.indd 76

The relationship between resting gradient (Pd/Pa) and FFR was described in advance of the development of iFR in a retrospective analysis of 528 pressure-wire studies in 483 patients demonstrating a strong correlation between resting Pd/Pa and FFR (Spearman’s rank correlation coefficient 0.74).32 In fact, it was shown that a resting Pd/ Pa of ≤0.87 had a positive predictive value (PPV) of 100 %, while a resting Pd/Pa of ≥0.96 had a negative predictive value (NPV) of 93.9 % in reference to FFR≤0.80. Similarly, when FFR ≤0.75 was used to define an ischaemic stenosis, Pd/Pa≤0.85 had a PPV of 95 %, while a resting Pd/Pa of ≥0.93 had an NPV of 95.7 %. The authors calculated that using these cut-off values, adenosine interrogation would have been avoided in 53 % of the FAME study population (FFR≤0.80) and 34 % of the DEFER study population (FFR<0.75), effectively coining the hybrid method for pressure wire assessment.32 Another, more recent, study retrospectively analysed 570 lesions in 527 patients applying a Pd/ Pa adenosine zone range of 0.87–0.99 to achieve 100 % diagnostic accuracy with reference to FFR≤0.80, which would have avoided the use of adenosine in only 14.6 % of lesions.33 The authors reported that with a Pd/Pa adenosine zone of 0.88–0.96, 46.8 % of lesions would have been assessed without adenosine while maintaining 96 % agreement with an FFR for all strategy.

Resting Pd/Pa Versus iFR

Relative resting pressure (rest Pd/Pa)

76

well as predicting the physiological response to PCI of single lesions when a number of tandem lesions are assessed.31 Given that iFR can be performed rapidly in multiple vessels, there are also potential practical and theoretical advantages in bifurcation disease.

In the large RESOLVE meta-analysis, which used an independent corelab, no significant difference was found between iFR and Pd/Pa in reference to FFR≤0.80 with an overall diagnostic accuracy of 80 % for both indices (using the optimal ROC determined cut-off points of 0.90 for iFR and 0.92 for Pd/Pa.24 The relationship between iFR and Pd/Pa was explored again in a separate study of 1,000 patients with no observable diagnostic advantage of using iFR over Pd/Pa (Figure 7).34 These are important observations for operators who elect to trade off concordance with FFR against the need for hyperaemia, as although iFR analysis is currently only possible using proprietary software, all pressure wire systems are capable of providing resting Pd/Pa.

Problems with iFR iFR is not Independent of Hyperaemia iFR assumes that microvascular resistance is already constant and minimal in the wave-free period. Both the VERIFY study and the analysis from Johnson et al. clearly demonstrate that this is not the case.22,34 In the VERIFY study, average iFR values fell significantly following the induction of hyperemia from 0.82 ± 0.16 versus 0.64 ± 0.18 with hyperaemia (95 % CI 0.17–0.20; p=0.0001). At an individual level, iFR decreased with hyperaemia in 97 % of the lesions studied (Figure 8). In the study by Johnson et al, myocardial resistance during the diastolic wave-free period, calculated from simultaneous pressure and flow data, was 250 % higher at rest than during hyperaemia.34 The authors recommend that if clinicians have access to iFR in their cath-labs they should measure at rest and again during hyperaemia; this will make it abundantly clear that it is not, as advertised, an ‘adenosine-independent index of stenosis severity’.

Loss of Diagnostic Accuracy When binary cut-off values are used for decision making, as in the ongoing randomised trials of iFR guidance versus FFR guidance,

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Is Hyperaemia Essential for Accurate Functional Assessment of Coronary Stenosis Severity?

DEFINE FLAIR (NCT02053038) and iFR Swedeheart (NCT02166736), the currently available data clearly confirm that avoiding the use of adenosine altogether translates into a different treatment decision in 20 % of lesions compared with an FFR for all strategy. Given wide enough non-inferiority margins and the knowledge that 80 % of the population recruited will have convergent iFR and FFR results, it is likely that these studies will show non-inferiority. However, such a result would conceal a mix of both inappropriate PCI and incomplete revascularisation in the iFR-guided group compared with an FFR-guided strategy.

Figure 8: iFR Readings Before (REST) and After Induction of Hyperemia (HYP) in the VERIFY Study 1.0

0.8

0.82 ± 0.16

0.64 ± 0.18

To the authors’ knowledge, there are no randomised controlled trials comparing the hybrid iFR/FFR decision tree with an FFR for all strategy.

SYNTAX II (NCT02015832) does employ this option but is an observational study. The currently available data are less comprehensive than for binary cut-off decision-making but avoiding the use of adenosine in between 50–60% of patients may translate into a different treatment decision in around 10 % of patients. Again, this will conceal a mixture of inappropriate PCI and incomplete revascularisation.

Beyond these concerns, if iFR was employed at the time of initial diagnostic angiography, as in the RIPCORD study, then patients will likely have divergent management decisions compared with an FFR for all strategy.14 This will translate not just into different patterns of

iFR [ - ]

0.6

0.4

0.2

0.0

REST

HYP

Reproduced with permission.21 iFR = instantaneous wave-free ratio.

stent implantation but different overall management in terms of which patients undergo revascularisation and by which technique.

a given coronary vessel and myocardial territory at high myocardial oxygen demand.

Whether employed in patients already scheduled for PCI or within a binary cut-off or hybrid strategy there is another major concern about using iFR or indeed any resting index of stenosis severity to determine the need for revascularisation. The flow increase associated with hyperaemia when interrogating a large-calibre vessel with a proximal stenosis is much greater than that of a small diameter vessel supplying a small myocardial territory.35 This means that some prognostically important lesions may exhibit small resting pressure gradients and therefore non-ischaemic iFR results which become manifestly ischaemic FFR results during hyperaemia. On the basis that some of these lesions have ‘non-ischaemic’ CFR values >2.0, it has been argued that the FFR result is false and the iFR result is correct. Thus, in the study by van de Hoef et al, half of the patients with discordant iFR and FFR values were ‘ischaemic’ according to the combined reference standard of MPS/HSR, and the other half were ‘non-ischaemic’.20 Notwithstanding the limitations of this study as described above, this indicates that approximately 50 % of treatment decisions will likely be incorrect. Furthermore, a CFR >2.0 does not in any way exclude myocardial ischaemia and may still be too low for

Recommendations

1.

2.

3.

4.

5.

Gruntzig A. Transluminal dilatation of coronary-artery stenosis. Lancet 1978;1 (8058):263.

Pijls NH, van Son JA, Kirkeeide RL, et al. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty. Circulation 1993;87 (4):1354–67.

Pijls NHJ, Fearon WF, Tonino PAL, 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.

De Bruyne B, Pijls NH, Kalesan B, et al; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367 (11):991–1001.

De Bruyne B, Fearon WF, Pijls NH, et al; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI or stable

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6.

7.

8.

9.

iFR was originally described as an adenosine-independent index of stenosis severity, but it has since been unequivocally demonstrated otherwise. The use of iFR is promoted by some groups on the grounds that the loss of diagnostic accuracy is an acceptable price to pay in return for reducing (hybrid iFR/FFR) or avoiding altogether (binary iFR) the need to use adenosine. Given the large evidence base for FFR that establishes clinical efficacy, cost-effectiveness and prognostic benefit, we do not consider this to be an acceptable trade-off. Beyond this, there are currently no clinical outcome studies with iFR. As such, it is counterintuitive and contrary to current clinical guidelines to recommend iFR over FFR. IV adenosine is the gold standard technique for inducing steady state maximal hyperaemia, but if operators do not wish to use it due to concerns over cost, time or side-effects, we suggest a policy of high-dose IC adenosine, which should minimise procedural delays as well as costs while providing high-quality data with minimal adverse effects. Healthcare providers need to examine their reimbursement policies to enable cardiologists to utilise this proven adjunct to PCI to the benefit of patients without financially stressing their institutions. n

coronary artery disease. N Engl J Med 2014;371 (13):1208–17.

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.

Dattilo PB, Prasad A, Honeycutt E, et al. Contemporary patterns of fractional flow reserve and intravascular ultrasound use among patients undergoing percutaneous coronary intervention in the United States: insights from the National Cardiovascular Data Registry. J Am Coll Cardiol 2012;60 (22):2337–9.

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.

Sen S, Escaned J, Malik IS, et al. Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study. J Am Coll Cardiol 2012;59 (15):1392–402.

10. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381 (9867):629–38.

11. Nam CW, Mangiacapra F, Entjes R, et al; FAME Study Investigators. Functional SYNTAX score for risk assessment in multivessel coronary artery disease. J Am Coll Cardiol 2011;58 (12):1211–8.

12. 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.

13. Van Belle E, Rioufol G, Pouillot C, et al; Investigators of the Registre Français de la FFR–R3F. 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.

14. Curzen N, Rana O, Nicholas Z, et al. Does routine pressure wire assessment influence management strategy at coronary

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Coronary Physiology Assessment Debate angiography for diagnosis of chest pain?: the RIPCORD study.

Circ Cardiovasc Interv 2014;7(2):248–55.

15. Layland J, Carrick D, Lee M, et al. Adenosine: physiology, pharmacology, and clinical applications. JACC Cardiovasc Interv 2014;7 (6):581–91.

16. Lim WH, Koo BK, Nam CW, et al. Variability of fractional flow reserve according to the methods of hyperemia induction.

Catheter Cardiovasc Interv . 2015;85(6):970–6.

17. Siebert U, Arvandi M, Gothe RM, et al. Improving the quality of percutaneous revascularisation in patients with multivessel disease in Australia: cost-effectiveness, public health implications, and budget impact of FFR-guided PCI. Heart Lung Circ 2014;23 (6):527–33.

18. Watkins S. Validation of First Pass Magnetic Resonance Myocardial Perfusion Imaging using Fractional Flow Reserve.

MD thesis. University of Glasgow, Glasgow, 2009.

19. van de Hoef TP, Meuwissen M, Escaned J, et al. Headto-head comparison of basal stenosis resistance index, instantaneous wave-free ratio, and fractional flow reserve: diagnostic accuracy for stenosis-specific myocardial ischaemia. EuroIntervention 2014 [Epub ahead of print].

20. Shiono Y, Kubo T, Tanaka A, et al. Long-Term Outcome After Deferral of Revascularization in Patients With Intermediate Coronary Stenosis and Gray-Zone Fractional Flow Reserve.

Circ J 2015;79(1):91–5.

21. Berry C, van ‘t Veer M, Witt N, et al. VERIFY (VERification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in EverydaY Practice): a multicenter study in consecutive patients. J Am Coll Cardiol 2013;61 (13):1421–7.

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22. Petraco R, Escaned J, Sen S, et al. Classification performance of instantaneous wave-free ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: results of the ADVISE registry. EuroIntervention 2013 May 20;9 (1):91-101.

23. Escaned J. Oral Presentation of ADVISE 2 Results. Presented at: TCT Conference, San Francisco, CA; 30 October 2013.

24. Jeremias A, Maehara A, Généreux P, et al. Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa with fractional flow reserve: the RESOLVE study. J Am Coll Cardiol 2014;63(13):1253–61.

25. Indolfi C, Mongiardo A, Spaccarotella C, et al. The instantaneous wave-free ratio (iFR) for evaluation of nonculprit lesions in patients with acute coronary syndrome and multivessel disease. Int J Cardiol 2014;178C :46–54.

26. Meuwissen M, Siebes M, Chamuleau SA, et al. Hyperemic stenosis resistance index for evaluation of functional coronary lesion severity. Circulation 2002;106 (4):441–6.

27. Leone AM, Porto I, De Caterina AR, et al. Maximal hyperemia in the assessment of fractional flow reserve: intracoronary adenosine versus intracoronary sodium nitroprusside versus intravenous adenosine: the NASCI (Nitroprussiato versus Adenosina nelle Stenosi Coronariche Intermedie) study. JACC Cardiovasc Interv 2012;5 (4):402–8.

28. De Luca G, Venegoni L, Iorio S, et al. Effects of increasing doses of intracoronary adenosine on the assessment of fractional flow reserve. JACC Cardiovasc Interv 2011;4 (10):1079–84.

29. Sen S, Asrress KN, Nijjer S, et al. Diagnostic classification of the instantaneous wave-free ratio is equivalent to

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fractional flow reserve and is not improved with adenosine administration. Results of CLARIFY (Classification Accuracy of Pressure-Only Ratios Against Indices Using Flow Study).

J Am Coll Cardiol 2013;61 (13):1409–20.

Petraco R, van de Hoef TP, Nijjer S, et al. Baseline Instantaneous Wave-Free Ratio as a Pressure-Only Estimation of Underlying Coronary Flow Reserve: Results of the JUSTIFYCFR Study (Joined Coronary Pressure and Flow Analysis to Determine Diagnostic Characteristics of Basal and Hyperemic Indices of Functional Lesion Severity-Coronary Flow Reserve).

Circ Cardiovasc Interv 2014;7(4):492–502 Nijjer SS, Sen S, Petraco R, et al. Pre-angioplasty instantaneous wave-free ratio pullback provides virtual intervention and predicts hemodynamic outcome for serial lesions and diffuse coronary artery disease. JACC Cardiovasc Interv 2014;7 (12):1386–96.

Mamas MA, Horner S, Welch E, et al. Resting Pd/Pa measured with intracoronary pressure wire strongly predicts fractional flow reserve. J Invasive Cardiol 2010;22 (6):260–5.

Kwon TG, Matsuzawa Y, Li J, et al. Clinical usefulness of nonhyperemic baseline Pd/Pa as a hybrid baseline Pd/Pa-fractional flow reserve strategy. Coron Artery Dis 2015;26 (1):49–55.

Johnson NP, Kirkeeide RL, Asrress KN, et al. Does the instantaneous wave-free ratio approximate the fractional flow reserve? J Am Coll Cardiol 2013;61 (13):1428–35.

De Bruyne B, Pijls NH, Bartunek J, et al. Fractional flow reserve in patients with prior myocardial infarction.

Circulation 2001;104 (2):157–62.

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Coronary Physiology Assessment Debate

Integrating Physiology into the DNA of Coronary Revascularisation – A Historical Perspective, Contemporary Review and Blueprint for the Future of Coronary Physiology Sayan Sen and Justin Davies International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College, London, UK

Abstract The clinical and economic benefits of physiologically guided revascularisation have been demonstrated, yet its clinical adoption remains unacceptably low. Recently, new indices of stenosis severity have been introduced that aim to improve adoption by circumventing the limitations of existing indices. The most validated of these new indices is the instantaneous wave-free ratio (iFR). This review will describe the physiological basis of this index, how it avoids the problems of existing indices such as fractional flow reserve (FFR) and the clinical validation studies of iFR to date. We will then describe a novel use of iFR, which has the potential to transform the use of physiology in the catheter lab and finally integrate physiology into the DNA of coronary revascularisation.

Keywords iFR, FFR, hyperaemia, tandem lesions, virtual PCI Disclosure: Justin Davies is a Consultant to Volcano Corporation and Medtronic. Justin Davies and Imperial College own intellectual property regarding instantaneous wave-free ratio (iFR), which is licensed by the Imperial College to Volcano Corporation. Imperial College London is coordinating the Functional Lesion Assessment of Intermediate Stenoses to guide Revascularisation (FLAIR) study, which is supported by an unrestricted grant from Volcano Corporation. All the authors have had travel expenses to conferences supported by industry, including Volcano Corporation, St Jude Medical, Medtronic, Pfizer and AstraZeneca.

Received: 29 March 2015 Accepted: 29 April 2015 Citation: Interventional Cardiology Review, 2015;10(2):79–84 Correspondence: Sayan Sen, International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, 59–61 North Wharf Road, London W2 1LA UK. E: sayan.sen@imperial.ac.uk

The use of physiology to guide revascularisation in patients with coronary disease has been demonstrated to improve clinical outcomes and reduce costs.1,2 Despite this, its adoption into clinical practice is very low,3 moreover, when it is employed it is used simplistically – only to determine if the vessel is ischaemic or not.

Recently, several new indices of stenosis severity have been introduced that aim to improve adoption by addressing some of the major limitations of the existing clinical standard – fractional flow reserve (FFR).4,5 The most validated of these indices is the instantaneous wavefree ratio (iFR).4 This review will highlight the clinical problem in terms of hyperaemia-based indices, the physiological background of iFR, overview its validation studies and discuss the potential of ongoing clinical outcome studies.

presumption has led some to believe that the haemodynamic significance of a stenosis can only be assessed during maximal hyperaemia.8–10 This has significant clinical and physiological implications that have directly impacted the adoption of FFR and simultaneously hindered the development of novel indices.7 Clinically, hyperaemic agents such as adenosine cannot be administered to all patients, almost always cause patient discomfort and their administration adds significant time to the procedure. Even in the most practiced hands, in institutions that routinely perform physiological measurements, an FFR assessment has been shown to add at least 10 minutes to the diagnostic procedure.11

The Clinical Problem

Scientifically, the overly simplistic assumption that a single dose of adenosine can achieve maximal hyperaemia in every single patient regardless of myocardial territory and co-morbidity is now coming under increasing scientific scrutiny. A plethora of factors can influence the degree of hyperaemia achievable, including the dose of hyperaemic agent, its route of administration, left ventricular end diastolic pressure, right atrial pressure, age, gender, concomitant medication, diet and even the sleep pattern of the patient.12–20

The main physiological foundation of FFR is that it can only make inferences about the haemodynamic significance of a stenosis under conditions of maximal hyperaemia.6,7 Superficial interpretation of this

Physiologically, it is increasingly evident that maximal hyperaemia is impossible to achieve in the catheter lab and given the sheer number

Finally, the unique potential of hyperaemia-free indices will be discussed; to determine if they can fundamentally transform the use of physiology from a tool that can only ascertain if revascularisation is required into a tool that can also guide how the revascularisation procedure should be performed.

© RADCLIFFE CARDIOLOGY 2015

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Pressure (mm Hg)

Figure 1: The iFR is Identified in Real-time Permitting Beat-bybeat Calculation of iFR Wave-free period

120 100 80 60 40

0

Time (ms) Pd wave-free period Pa wave-free period

400

= iFR

This uncertainty has led clinicians to administer ever-increasing doses of adenosine and even adding other drugs to try and reassure themselves that ‘maximal hyperaemia’ is achieved. However, this only serves to create confusion because the FFR treatment threshold of 0.8 had not been validated against ischaemia at higher doses of adenosine making interpretation of the FFR value challenging and importantly not supported by outcome data. All these factors contribute to the poor ‘usability’ of FFR in the clinical domain – reflected in single figure adoption rates for FFR across most of the world despite a wealth of evidence being established for over 20 years.3

Can the Lessons of the Past Help us Find a Solution?

The wave-free period is automatically identified and marked with a green line. Instantaneous wave-free ratio (iFR) is the pressure ratio calculated during this phase of the cardiac cycle.

Figure 2: Studies Comparing iFR to FFR using Imperial-derived Algorithm (Green) or Investigator-derived Algorithms (Blue) ADVISE ADVISE registry

In recognition of the above limitations of FFR, hyperaemia-free indices have been introduced.4,5 These indices aim to circumvent the myriad limitations created by the need for administrating a hyperaemic agent in the hope of facilitated adoption by making procedures quicker, cheaper, safer and independent of the variability of attaining maximal hyperaemia. The most validated hyperaemia free index is iFR.4 iFR is not dependent on maximal hyperaemia and therefore shifts the paradigm away from maximal hyperaemia for the assessment of stenosis severity. This is based on a wealth of physiological data over the last 30 years that has clearly demonstrated that maximal hyperaemia is not required if stenosis assessment is made during a specific phase of the cardiac cycle.24–26 In a seminal experiment by Gould in 1978 it was demonstrated that the haemodynamic significance of stenoses could in fact be determined under basal conditions.24 Using combined pressure and flow velocity analysis he identified a phase in the cardiac cycle during which stenoses could reliably be differentiated into mild, moderate and severe. Using meticulous manual post hoc analysis of pressure and flow data he clearly demonstrated that the optimal period of the cardiac cycle to assess a stenosis was when intra-coronary haemodynamics are free of the confounding effects of the contracting and relaxing myocardium. This period within diastole has been studied in detail in several studies over the last 30 years and all indices derived over this period have been demonstrated to be at least as accurate as FFR and most importantly not reliant on maximal hyperaemia.26,27 Despite the clear physiological advantages of these indices over FFR, their clinical use was hindered by the need for simultaneous flow velocity measurements (which are challenging and time consuming to perform) and post hoc manual analysis of the pressure and flow traces; preventing real-time stenosis assessment.

South Korean registry

AMC

FORECAST RESOLVE

ADVISE II

ADVISE in practice 75

80

85

90

iFR – FFR categorisation match (%) ACS = acute coronary syndromes; ADVISE = Adenosine Vasodilator Independent Stenosis Evaluation; AMC = Academic Medical Center (Amsterdam) FORECAST = TCT-230 Instantaneous Wave-Free Ratio and Gradient: New Promising Adenosine-Independent Alternative To Fractional Flow Reserve; RESOLVE = Multicenter Core Laboratory Comparison of the Instantaneous Wave-Free Ratio and Resting P d /P a With Fractional Flow Reserve. It can be seen that there is a consistent agreement of instantaneous wave-free ratio (iFR) to fractional flow reserve (FFR) of approximately 80 %.

of variables affecting hyperaemia isolating the patients in which hyperaemia has been insufficient is equally impossible.21–23 This is particularly true of pressure-derived hyperaemic indices, such as FFR, which by definition do not measure flow and are therefore most vulnerable to this limitation.

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Recently, using combined pressure and flow assessment in humans wave intensity analysis identified a period within diastole when intra-coronary haemodynamics are also free of all wave activity, which is caused by relaxation and contraction of the myocardium.4 More importantly, using sophisticated computational algorithms this period can now be isolated in real-time on a beat-to-beat basis using the pressure waveform alone; making clinical use of this period feasible in daily clinical practice. It is during this period that iFR is calculated4 (see Figure 1).

Given the well-documented physiology of this period of the cardiac cycle and its unique suitability for stenosis assessment it is not surprising that iFR has been found to be able to determine the haemodynamic significance of stenoses. Furthermore because iFR can be measured within seconds, does not require hyperaemic agents and uses existing pressure wire technology its potential to improve adoption of physiology

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Figure 3: Comparison of iFR and FFR to an Independent Measure of Stenosis Severity in Five Studies Including Over 500 Lesions

Myocardical perfusion

De Ward et al.

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Hyperaemic <0.01 stenosis resistance Coronary <0.01 flow reserve Positron emisson ns tomography

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Figure 5: How Resting Flow and Hyperaemic Flow Vary with Stenosis Severity and the Impact on Tandem Lesion Assessment

5 0 5 10 Difference in accuracy (%)

CLARIFY = CLassification Accuracy of Pressure-Only Ratios Against Indices Using Flow Study.

Adenosine-free instantaneous wave-free ratio (iFR) has equivalent diagnostic accuracy to adenosine-mediated fractional flow reserve (FFR). The administration of adenosine, therefore, does not improve diagnostic accuracy. In fact, in two studies, there is a signal suggesting that the resting index of iFR appears to be a more representative measure of the severity of the stenosis.

Figure 4: DEFINE-FLAIR Study Design DEFINE-FLAIR

FFR>0.8 defer PCI

FFR≤0.8 perform PCI

iFR guided PCI

iFR≥0.9 defer PCI

iFR<0.9 perform PCI

30 day, 1,2 and 5 year follow-up Functional Lesion Assessment of Intermediate Stenoses to guide Revascularisation (DEFINEFLAIR) will be the largest prospective, randomised trial in physiology ever performed. It will compare instantaneous wave-free ratio (iFR)-guided revascularisation with fractional flow reserve (FFR)-guided revascularisation. Importantly it will be the first assessment of each of the indices in clinically relevant populations.

to realise the clinical and economic benefits of physiologically guided revascularisation is clear.28

iFR Validation Studies to Date The classification match of iFR to FFR has been studied in over 3,500 vessels, this series of studies has definitively identified a treatment threshold of <0.9 for iFR.4,29–36 The agreement of iFR to FFR in the above studies has consistently been found to be approximately 80 % depending on the distribution of stenoses in the study population (see Figure 2). Interpretation of this statistic should take account of the fact that the classification match of two FFR measurements across the same lesion is not 100 % but 85 %.37,38 A finding suggested by the DEFER study39,40 but recently confirmed using modern pressure wire technology.41 Such classification agreement between two FFR measurements across the same lesion is not surprising given the biological variability of any physiological measurement especially if that measurement

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Increase in hyperaemic flow

FFR guided PCI

Minimal change in rest flow

N=2,500, 1:1 randomisation

Rest and Hyperemic flow pre-PCI of distal lesion

Immediate lesion requiring physiological assessment In ACS: intermediate non-culprit lesion

Rest and Hyperemic flow post-PCI of distal lesion

Function lesion assessment of intermediate stenosis to guide revascularisation

It can be seen that resting flow is maintained constant until the vessel is almost sub totally occluded. By contrast, hyperaemic flow declines as stenosis severity increases. Flow measured just distal to the first stenosis at rest (Panel A) is the same as that in exactly the same position when when the distal lesion has been treated (Panel B). However, flow measured just distal to the first stenosis during hyperaemia (Panel A) is not the same as that in exactly the same position when the distal lesion has been treated (Panel B). This means that the resting index of instantaneous wave-free ratio (iFR) is able to isolate the significance of the proximal lesion but the hyperaemic index of fractional flow reserve (FFR) is unable to as treatment of the distal lesion leads to a significant increase in hyperaemic flow and therefore change in FFR.

is reliant on the heterogeneous and unpredictable effects of a hyperaemic agent.42 While FFR is viewed as a clinical standard for ischaemia it is widely accepted that there is no true gold standard test for ischaemia.43 Therefore, when two indices such as iFR and FFR agree so closely how do we interpret the significance of stenoses when iFR and FFR disagree? Several studies have attempted to look at this (see Figure 3).23,36,42–45 Each has taken iFR and FFR and compared with another index of stenosis severity. The salient findings of this body of research in over 500 stenoses are clear: 1. When iFR and FFR disagree – FFR is not necessarily correct.

2. Hyperaemia does not improve diagnostic accuracy.

The Joined Coronary Pressure and Flow Analysis to Determine Diagnostic Characteristics of Basal and Hyperemic Indices of Functional Lesion Severity-Coronary Flow Reserve (JUSTIFY-CFR) was the largest of these studies to systematically assess how iFR and FFR agree with underlying flow. It demonstrated that when iFR and FFR disagree that iFR was

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Coronary Physiology Assessment Debate Figure 6: iFR-pullback Provides an Adenosine-free Measure of Serial Stenosis Severity

differences between iFR and FFR that may make iFR more clinically useful than FFR. Indeed the ability of iFR to be independent from the response of the microcirculation to a hyperaemic agent suggests that, it may also have a role in conditions that have traditionally been considered unsuitable for FFR assessment. The assessment of disease in the acute coronary syndrome population, vessels with tandem lesions, patients with renal failure, diabetes and hypertension are all vulnerable to a variable response of the microcirculation to hyperaemic stimuli â&#x20AC;&#x201C; a limitation circumvented with resting indices. The role of iFR and FFR in these populations will be further elucidated in the Functional Lesion Assessment of Intermediate Stenoses to guide Revascularisation (DEFINE-FLAIR) and iFR SWEDEHEART studies.

Randomised Clinical Outcome Studies Designed to Address the Clinically Important Questions Using instantaneous wave-free ratio (iFR)-pullback it is possible to differentiate between diffuse and focal disease. These measurements are made in real-time, without the need for adenosine or similar hyperaemic agent. Using iFR-pullback it is possible to identify which stenosis is responsible for the largest pressure loss, and direct therapy towards treatment of that stenosis, potentially minimising stent length and simultaneously reducing the time and cost of the procedure.

Figure 7: Co-registration of Physiology and Anatomy

Using instantaneous wave-free ratio (iFR)-pullback it is possible to differentiate between diffuse and focal disease. These measurements are made in real-time, without the need for adenosine or similar hyperaemic agent. Using iFR-pullback it is possible to identify which stenosis is responsible for the largest pressure loss, and direct therapy towards treatment of that stenosis, potentially minimising stent length and simultaneously reducing the time and cost of the procedure.

more indicative of the underlying flow characteristics of the vessel.44 Furthermore in the clinically relevant 0.6â&#x20AC;&#x201C;0.9 FFR range, in which most of our patients fall, iFR was significantly more accurate than FFR. Some have highlighted concerns with regards to the doses of hyperaemic agent, choice of reference test and therefore the validity of these studies.

The meticulous validation of FFR during its development serves as template for the validation of new indices. It should be noted that FFR was validated against the same reference tests during its development, using doses of adenosine and routes of administration identical to the studies now comparing iFR with FFR. Should we discount these pivotal FFR studies too? If so, what should be done with the guidelines and scientific recommendations supporting FFR that were based upon these?

The above studies clearly challenge the dogma that hyperaemia is necessary for stenosis assessment but also point to major potential

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In reality the adoption of any new index will be based on large randomised clinical trials with hard outcome end-points. But for clinicians to be able to translate the results of these studies to the patients they treat the trials must include patients in which physiological assessment is routinely made in clinical practice.

Prior to the Adenosine Vasodilator Independent Stenosis Evaluation (ADVISE) registry FFR had never been systematically studied in clinically relevant patient populations.44 The mean FFR values in the Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention (FAME) and FAME II studies were 0.71 and 0.64, respectively; significantly lower than mean FFR values in contemporary studies that have included intermediate lesions.24,44 This suggests that the FAME populations are significantly different from the patients we assess in clinical practice today.

To address this, iFR clinical outcome studies have been designed to centre on clinically relevant patient populations. Their inclusion and exclusion criteria are aimed at truly capturing the patients in whom physiology is performed in clinical practice. As a result, regardless of iFR, DEFINE-FLAIR (NCT02053038, see Figure 4) and iFR SWEDEHEART (NCT02166736) will provide the first and largest prospective real-world randomised controlled trial database for FFR in clinically relevant patient populations.

In addition there are several other unique aspects of these studies that will have direct clinical impact: 1. They will provide the largest prospective evaluation of physiology to guide revascularisation in non-culprit vessels in acute coronary syndrome patients.

2. They will provide the largest prospective evaluation of postpercutaneous coronary intervention (PCI) physiology assessment to predict clinical outcomes.

3. They will provide the largest prospective evaluation of physiology to guide multi-vessel revascularisation. Combined, these studies will include at least three times the number of patients in FAME I and FAME II combined.

4. FLAIR includes over 40 centres in over 18 countries and will therefore provide the first and largest prospective comparison of physiology outcomes between different global geographical regions.

5. These studies will also provide a contemporary insight into the outcomes of the major clinical patient subsets of diabetes, renal failure and hypertension.

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DEFINE-FLAIR and iFR SWEDEHEART will therefore provide a definitive prospective assessment of the role of both iFR and FFR in clinical practice and address some of the major uncertainties hitherto unaddressed in this field.

Regardless of the current debate upon the physiology of basal versus hyperaemia indices the data from these studies will definitively answer if hyperaemia is still required to safely assess stenosis severity and guide revascularisation. Given the simplicity and reduced uncertainty of iFR assessment they therefore have the potential to dramatically increase the adoption of physiology, finally permitting realisation of the clear health and cost benefits of such an approach.

Integrating Physiology into the DNA of Revascularisation – A Blueprint for the Future To date, FFR has generally been used in a binary fashion to inform the clinician if the vessel should be treated or not. The physiology of resting haemodynamics means that it is possible for indices such as iFR to provide a further dimension to the role of physiology in the catheter lab by not only guiding when to treat but also where to treat. This is particularly useful in the increasingly prevalent subset of patients with diffuse coronary disease and tandem stenosis. In these patients iFR has the potential to reduce the prevalence of abnormal physiology post-PCI by ensuring that the correct lesion is targeted.

The reliance of FFR on maximal hyperaemia has prevented it from being used to isolate individual stenosis severity in vessels with tandem lesions.45,46 This is because when trying to assess the significance of a proximal stenosis the distal stenosis will blunt hyperaemic flow across the proximal lesion, therefore placement of the pressure sensor in between the two stenoses will under-estimate the severity of the proximal lesion. When the distal lesion is treated, hyperaemic flow is much higher and the FFR of the proximal vessel significantly different (see Figure 5).

1.

T onino PAL, De Bruyne B, Pijls NHJ, et al., Fractional flow reserve versus angiography for guiding percutaneous coronary intervention, N Engl J Med , 2009;360:213–24.

2. De Bruyne B, Fearon WF, Pijls NHJ, et al. Fractional flow reserve-guided PCI for stable coronary artery disease, N Engl J Med , 2014;371:1208–17.

3. Kleiman NS, Bringing it all together: integration of physiology with anatomy during cardiac catheterization, J Am Coll Cardiol , 2011;58:1219–21.

4. Sen S, Escaned J, Malik IS, et al., Development and validation of a new adenosine-independent index of stenosis severity from coronary wave–intensity analysis, J Am Coll Cardiol , 2012;59:1392–402.

5. Van de Hoef TP, Petraco R, van Lavieren MA, et al., Diagnostic accuracy of basal stenosis resistance index (BSR) is higher than that of instantaneous wave-free ratio (iFR): validation of basal stenosis resistance index in an independent cohort of simultaneous pressure and flow measurements, J Am Coll Cardiol , 2013;62:B193.

6. Pijls NH, van Son JA, Kirkeeide RL, et al., Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty, Circulation, 1993;87:1354–67.

7. Pijls NHJ, Tonino PAL, The crux of maximum hyperemia: the last remaining barrier for routine use of fractional flow reserve, JACC Cardiovasc Interv , 2011;4:1093–5.

8. Pijls NHJ, Van’t Veer M, Oldroyd KG, et al., Instantaneous wave-free ratio or fractional flow reserve without HyperemiaNovelty or nonsense?, J Am Coll Cardiol , 2012;59:1916–7.

9. Rudzinski W, Waller AH, Kaluski E, Instantaneous wave-free ratio and fractional flow reserve: close, but not close enough!, J Am Coll Cardiol, 2012;59:1915–6; author reply 1917–8.

10. Finet G, Rioufol G, A new adenosine-independent index of stenosis severity: why would one assess a coronary stenosis differently?, J Am Coll Cardiol , 2012;59:1915; author reply 1917–8.

11. Ntalianis A, Trana C, Muller O, et al., Effective radiation dose, time, and contrast medium to measure fractional flow reserve, JACC Cardiovasc Interv , 2010;3:821–7.

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Baseline indices, by contrast, are uniquely suited to the isolation of a specific stenosis in the context of tandem lesions. This is due to the fact that baseline flow is maintained constant until stenosis grades of greater than 85 %.47 As a result, iFR is able to isolate specific stenosis severity within a vessel with multiple lesions (see Figure 6). When the distal lesion is treated, in contrast to hyperaemic flow, baseline flow does not significantly change and therefore the pressure drop across the proximal stenosis and iFR remains similar48 (see Figure 5).

This ability to predict post-PCI iFR provides the potential to extend the role of physiology in interventional cardiology. Rather than simply informing us that a vessel is ischaemic, real-time hyperaemia-free point-to-point calculation of iFR along the entire vessel combined with co-registration with imaging will permit the possibility of virtual PCI. The clinician will therefore be able to determine (i) if a stent is required (ii) where the stent should be placed and (iii) the length of the stent to get the best haemodynamic result within a matter of seconds and remove the need for multiple hyperaemic pullback runs (see Figure 7).

Such an approach can be expected to significantly reduce stent length, procedural time and costs while simultaneously improving adoption in a patient population that is currently poorly served by FFR.

Conclusion The routine use of physiology to guide revascularisation is unacceptably low. To improve adoption iFR has been introduced. This index is based on established physiology, can be measured within seconds, does not require hyperaemic agents and uses existing pressure wire technology.

Importantly, it has the potential to extend the role of physiology by permitting accurate assessment of vessels with diffuse disease or tandem lesions. The unique characteristics of iFR physiology combined with modern imaging opens the potential of virtual PCI: for the first time allowing physiology to tell us not only if we need a stent but where and therefore how to stent to get the best outcomes for our patients. n

12. Sun LJ, Wang GS, Cui M, et al., Factors influencing the functional significance in intermediate coronary stenosis, J Geriatr Cardiol , 2015;12:107-12.

13. Matsumoto H, Nakatsuma K, Shimada T, et al., Effect of caffeine on intravenous adenosine-induced hyperemia in fractional flow reserve measurement, J Invasive Cardiol , 2014;26:580–5.

14. Echavarría-Pinto M, Gonzalo N, Ibañez B, et al., Low coronary microcirculatory resistance associated with profound hypotension during intravenous adenosine infusion: implications for the functional assessment of coronary stenoses, Circ Cardiovasc Interv, 2014;7:35–42.

15. 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;84:416–25.

16. Tarkin JM, Nijjer S, Sen S, et al., Hemodynamic response to intravenous adenosine and its effect on fractional flow reserve assessment: results of the Adenosine for the Functional Evaluation of Coronary Stenosis Severity (AFFECTS) study, Circ Cardiovasc Interv, 2013;6:654–61.

17. Leonardi RA, Townsend JC, Patel CA,et al., Left ventricular end-diastolic pressure affects measurement of fractional flow reserve, Cardiovasc Revasc Me d, 2013;14:218–22.

18. Butt M, Khair OA, Dwivedi G, et al., Myocardial perfusion by myocardial contrast echocardiography and endothelial dysfunction in obstructive sleep apnea, Hypertension, 2011;58:417–24.

19. Olsen RH, Pedersen LR, Jürs A, et al., A randomised trial comparing the effect of exercise training and weight loss on microvascular function in coronary artery disease, Int J Cardiol , 2015;185:229–35.

20. Layland J, Wilson AM, Whitbourn RJ, et al., Impact of right atrial pressure on decision-making using fractional flow reserve (FFR) in elective percutaneous intervention, Int J Cardiol, 2013;167:951–3.

21. Barbato E, Sarno G, Berza CT, et al., Impact of alpha- and beta-adrenergic receptor blockers on fractional flow reserve and index of microvascular resistance, J Cardiovasc Transl Res , 2014;7:803–9.

22. De Luca G, Venegoni L, Iorio S, et al., Effects of increasing

doses of intracoronary adenosine on the assessment of fractional flow reserve, JACC Cardiovasc Interv, 2011;4:1079–84.

23. S en S, Asrress KN, Nijjer S, et al., Diagnostic classification of the instantaneous wave-free ratio is equivalent to fractional flow reserve and is not improved with adenosine administration: Results of CLARIFY (Classification Accuracy of Pressure-Only Ratios Against Indices Using Flow Study), J Am Coll Cardiol , 2013;61:1409–20.

24. Gould KL, Pressure-flow characteristics of coronary stenoses in unsedated dogs at rest and during coronary vasodilation, Circ Res , 1978;43:242–53.

25. Marques KMJ, Spruijt HJ, Boer C, et al., The diastolic flowpressure gradient relation in coronary stenoses in humans, J Am Coll Cardiol , 2002;39:1630–6.

26. Marques KMJ, van Eenige MJ, Spruijt HJ, et al., The diastolic flow velocity-pressure gradient relation and dpv50 to assess the hemodynamic significance of coronary stenoses, Am J Physiol Heart Circ Physiol , 2006;291:H2630–5 27. Kern MJ, An adenosine-independent index of stenosis severity from coronary wave-intensity analysis: a new paradigm in coronary physiology for the cath lab?, J Am Coll Cardiol , 2012;59:1403–5.

28. Petraco R, Escaned J, Sen S, et al. Classification performance of instantaneous wave-free ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: results of the ADVISE registry, EuroIntervention , 2013;9:91–101.

29. Park JJ, Petraco R, Nam CW, et al., Clinical validation of the resting pressure parameters in the assessment of functionally significant coronary stenosis; results of an independent, blinded comparison with fractional flow reserve, Int J Cardiol, 2013;168:4070–5.

30. Escaned J, ADVISE II: Late breaking clinical trial, TCT Oral Present , 2013.

31. Indolfi C, Mongiardo A, Spaccarotella C, et al., The instantaneous wave-free ratio (iFR) for evaluation of nonculprit lesions in patients with acute coronary syndrome and multivessel disease, Int J Cardiol , 2015;178:46–54.

32. Petraco R, Al-Lamee R, Gotberg M, et al. Real-time use of instantaneous wave-free ratio: Results of the ADVISE in-practice: An international, multicenter evaluation of

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Coronary Physiology Assessment Debate instantaneous wave-free ratio in clinical practice, Am Heart J , 2014;168:739–48.

33. J eremias A, Maehara A, Genereux P, et al., Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa With fractional flow reserve: The RESOLVE Study, J Am Coll Cardiol , 2014;63:1253–61.

34. Van de Hoef TP, Meuwissen M, Escaned J, et al., Headto-head comparison of basal stenosis resistance index, instantaneous wave-free ratio, and fractional flow reserve: diagnostic accuracy for stenosis-specific myocardial ischaemia, EuroIntervention , 2014 [Epub ahead of print].

35. Johnson NP, Kirkeeide RL, Asrress KN, et al., Does the instantaneous wave-free ratio approximate the fractional flow reserve?, J Am Coll Cardiol , 2013;61:1428–35.

36. Petraco R, Escaned J, Sen S, et al., How high can “accuracy” be for iFR (or IVUS, or SPECT, or OCT...) if using fractional flow reserve as the gold standard?, EuroIntervention , 2013;9:770–2 37. Petraco R, Sen S, Nijjer S, et al., Fractional flow reserveguided revascularization: practical implications of a diagnostic gray zone and measurement variability on clinical decisions, JACC Cardiovasc Interv , 2013;6:222–5 38. Bech GJW, Bruyne BD, Pijls NHJ, et al., Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis a randomized trial, Circulation ,

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2001;103:2928–34.

39. K ern MJ, Lerman A, Bech JW, et al., Physiological assessment of coronary artery disease in the cardiac catheterization laboratory a scientific statement from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology, Circulation , 2006;114:1321–41.

40. 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;8:307–14.

41. 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;84:416–25.

42. Pijls NH, De Bruyne B, Peels K, et al., Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses, N Engl J Med , 1996;334:1703–8.

43. De Waard G, Danad I, da Cunha RP, et al., Hyperemic FFR and baseline iFR have an equivalent diagnostic accuracy when compared to myocardial blood flow quantified by H215O PET perfusion imaging, J Am Coll Cardiol , 2014;63:A1692.

44. Petraco R, van de Hoef TP, Nijjer S, et al., Baseline instantaneous wave-free ratio as a pressure-only estimation of underlying coronary flow reserve: results of the JUSTIFY-

45.

46.

47.

48.

49.

CFR Study (Joined Coronary Pressure and Flow Analysis to Determine Diagnostic Characteristics of Basal and Hyperemic Indices of Functional Lesion Severity-Coronary Flow Reserve), Circ Cardiovasc Interv , 2014;7:492–502.

Sen S, Nijjer S, Petraco R, Malik IS, Francis DP, Davies J, Instantaneous wave-free ratio: numerically different, but diagnostically superior to FFR? Is lower always better?, J Am Coll Cardiol , 2013;62:566.

Bruyne BD, Pijls NHJ, Heyndrickx GR, et al., Pressurederived fractional flow reserve to assess serial epicardial stenoses theoretical basis and animal validation, Circulation , 2000;101:1840–7.

Kim H-L, Koo BK, Nam CW, et al., Clinical and physiological outcomes of fractional flow reserve-guided percutaneous coronary intervention in patients with serial stenoses within one coronary artery, JACC Cardiovasc Interv , 2012;5:1013–8.

Gould KL, Lipscomb K, Calvert C, Compensatory changes of the distal coronary vascular bed during progressive coronary constriction, Circulation , 1975;51:1085–94.

Nijjer SS, Sen S, Petraco R, et al., Pre-angioplasty instantaneous wave-free ratio (iFR) pullback provides virtual intervention and predicts hemodynamic outcome for serial lesions and diffuse coronary artery disease, JACC Cardiovasc Interv , 2014 [Epub before print].

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Bifurcations

AXXESS™ Stent: Delivery Indications and Outcomes John Rawlins, Jehangir Din, Suneel Talwar and Peter O’Kane Dorset Heart Centre, Royal Bournemouth Hospital, Castle Lane East, Bournemouth, UK

Abstract The successful treatment of coronary bifurcation lesions remains one of the challenges of interventional cardiology. The current consensus of the European Bifurcation Club based on published data advocates a provisional strategy, treating the main vessel (MV) with a single stent covering the side branch (SB), with bailout SB stenting as required. The success of this approach may be limited by failure to attain SB access after MV stenting but is preferred in most situations over routine SB plus MV stent techniques, which are associated with a significant increase in the rate of major adverse cardiac events. The AXXESS self-expanding biolimus-eluting stent has been developed as a solution to these challenges within the coronary circulation and maintains provisional MV stent approach but with added assurance of maintained SB access. It has a unique conical structure that is positioned spanning the carina, with scaffold extending into the carina of both the MV and SB. The purpose of this article is to describe the indication, implantation technique and outcome data supporting the use of the AXXESS stent in the treatment of coronary bifurcation lesions.

Keywords AXXESS stent, bifurcation, self-expanding, biolimus, provisional Disclosure: Dr Rawlins, Dr Din, Dr Talwar have no conflicts of interests to disclose. Dr O’Kane is as a proctor for Biosensors for the implantation of AXXESS. Received: 18th March 2015 Accepted: 22nd April 2015 Citation: Interventional Cardiology Review, 2015;10(2):85–9 Correspondence: Dr Peter O’Kane, Dorset Heart Centre, Royal Bournemouth Hospital, Castle Lane East, Bournemouth, BH7 7DW, UK. E: peter.o’kane@rbch.nhs.uk

A bifurcation lesion within the coronary arterial circulation is defined as a stenosis occurring at, or adjacent to, a significant division of a major epicardial coronary artery.1 Bifurcation lesions account for 1–20 % of all percutaneous coronary interventions (PCIs), and treatment remain technically challenging despite advances in PCI techniques and thirdgeneration drug-eluting stent (DES) technology. In general, outcomes are less favourable, with an increase in the rates of major adverse cardiac events (MACE), target lesion revascularisation (TLR) and target vessel revascularisation.2,3 Recommendations from the European Bifurcation Club (EBC)1 derived from a systematic evaluation of over 10 years of data comparing a provisional single stent (main vessel [MV] only) with a planned two stent (MV plus side branch [SB]) conclude that a provisional singlestent approach should be the technique of choice for the treatment of the majority of bifurcation lesions. If SB coverage is then required, either a T or T and protrude (TAP) technique can be adopted to secure Thrombolysis in Myocardial Infarction flow.1 Favourable results with this technique, however, is dependent on successful SB rewiring, which may be technically challenging, particularly when SB vessels contain significant ostial disease. Difficulties may also be encountered when treating disease in the distal MV once the SB has been treated with TAP configuration and especially with a long neocarina protruding into the MV. Despite their overall recommendations, the EBC concede that there will always remain a role for an upfront two-stent strategy covering both MV and SB.1 There are a number of two-stent strategies available, as outlined in the comprehensive review by Louvard et al.4 None of these have demonstrated any benefit over provisional MV stenting

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in the randomised trials, with the exception of the double kiss (DK) crush technique.5 Despite this, MV and SB two-stent techniques continue to be performed by PCI operators largely because the SB disease is considered to be causative of ischaemia or the SB would be significantly compromised by an MV-only stent strategy and needs to be protected first with a stent.

To be certain of ostial coverage, all two-stent bifurcation techniques (crush/TAP/culotte etc) result in neocarina formation, with multiple metallic stent layers overlapping. Compounding this is the inherent geometric disparity between the Y-shape of the bifurcation and the cylindrical tube of an expanded stent.6 This can delay healing, with reduced intima formation over these sites, which may explain the higher incidence of procedural myocardial infarction (MI), stent thrombosis and restenosis that has been observed with such techniques.7 The carina itself is subject to high shear stress and flow, and hence often free from significant atheroma. Systematic histopathological analysis has confirmed this, questioning the benefit of covering this area with metal (Figure 1).8 An interventional technique that avoids creation of a neocarina, leaving it ‘metal free’ and facilitating SB access may, therefore, offer advantages in the treatment of complex bifurcation lesions.

One solution to these issues is the dedicated AXXESS™ bifurcation stent system (Biosensors Interventional Technologies, Singapore). This follows a provisional strategy while offering predictable access to the SB and MV in the long term, with the absence of metallic layers at the carina. The aim of this article is to describe the AXXESS system and the techniques employed at implantation, and to summarise the growing evidence base to support its use in the treatment of complex coronary bifurcation lesions.

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Bifurcations Figure 1: Histopathological Distribution of Atheroma at the Carina B

Main vessel proximal

20 mm

A

A

C

B

D

G

G E

F

Main vessel distal

Side branch

High shear C

(mm) 1.6

Low shear

Plaque thickness

1.4 1.2

†

1

*†

0.8

*†‡

0.6

*†‡

0.4

*†‡

0.2 0 (mm)

A

B

C

D

E

F

G

Necrotic core thickness

0.6

0.3 †

0.2

*†‡

0.1

Indications for Implantation Any Medina classification of bifurcation can be treated using the AXXESS system. However, the angle between the MV and SB should not be greater than 70o and, ideally, the SB should be a minimum of 2.5 mm in diameter and have minimal calcification. In order to clearly define the bifurcation angle, two orthogonal radiographic projections are often required. As it elutes Biolimus A9, the standard contraindications for drug-eluting devices apply. There are no restrictions in location, with devices being used successfully throughout the coronary circulation, including the left main bifurcation;10,11 however, it cannot be overexpanded and careful vessel sizing (often requiring intravascular imaging) should be performed.

It can be implanted for the full range of coronary interventional indications, including acute coronary syndromes and stable angina.12 AXXESS is particularly useful in the treatment of Medina class 1,0,0 lesions, as it is often the only device required in these cases. When treating all other Medina classes, additional distal overlapping DES in either MV or SB may be required.

0.5

0.3

The AXXESS system is conventionally 7 French (7 Fr) compatible, although can be delivered through a specific 6 Fr guide catheter with an internal lumen diameter of 0.072” (e.g the Adroit guide, Cordis Miami, Florida, USA; but only with a single guide wire). It is delivered through a hydrophilic-coated rapid-exchange system comprising a delivery catheter, mounted stent and cover sheath (Figure 2). The stent is delivered following gradual withdrawal of this sheath, with the technique for implantation being described in detail below. One radiopaque gold marker exists at the proximal edge, with three at the distal edge arranged at equal intervals on the circumference to visually guide optimal placement (Figure 2). It is positioned spanning the carina into the ostium of both the MV and the SB.

*†‡

Technique of Implanting an AXXESS™ Stent *†‡

The Biosensors AXXESS Biolimus A9™ eluting coronary bifurcation stent system is a conically shaped self-expanding DES, constructed from a nickel-titanium alloy (nitinol). The stent is designed to dynamically adapt to the Y shape of the carina up to an angle of 70o, maintaining native geometry without metallic struts, and facilitating long-term SB access (Figure 2).

Although the AXXESS device can be delivered through any 7 Fr-guiding system, when considering guide shape, support should be maximised to facilitate device delivery. Two separate guide wires (any moderate support 0.014” wire) should be advanced distally into the MV and SB. The use of dedicated stents, particularly self-expanding devices, require thorough lesion preparation, particularly in more complex calcified lesions (e.g. Medina 1,1,1). Consequently, noncompliant balloons, cutting balloons and adjunctive devices such as rotational atherectomy should be considered early to optimise final position, minimal luminal area and stent expansion. Passage of a ‘winged’ cutting balloon distal to the target lesion is an indicator that the AXXESS device can be delivered into the appropriate position.

Predilatation is therefore strongly recommended before delivering the AXXESS stent, with vessel preparation of both MV and, in the majority of cases, into the ostium of the SB if disease is present.

The stent has an abluminal polymer coating composed of polylactic acid, that is biodegradable into carbon dioxide and water within 6–9 months of deployment, and the semi-synthetic sirolimus analogue Biolimus A9™, which has antiproliferative effects and has been proven superior over first-generation sirolimus-eluting DES.9 The AXXESS™ stent is CE marked and has UK approval. It is currently available in 3.0 mm (expandable to 3.75 mm) and 3.5 mm (expandable to 4.25 mm) diameters, and in two lengths (11 and 14 mm). A 4.0 x 9 mm device has been developed and used in a limited number of cases in the UK, mainly in the left main stem (LMS), where a bifurcation angle of 120o can be spanned. However, this iteration of the device it is not currently available.

The AXXESS™ stent is advanced onto the wire of the distal vessel with the sharpest bend to the proximal MV. This can be either branch, but in a series of over 100 implanted devices evaluated by our group it was positioned on the MV wire in 92 % of cases.10 The distal markers of the AXXESS stent are advanced beyond the carina in the distal vessel. The whole device is then gently retracted, alongside simultaneous gradual pullback of the actuator, slowly retracting the sheath. This allows progressive flaring of the three distal markers across the carina. Angiographically, this is visualised when one marker appears to be in either MV or SB, with the other two markers positioned in the other vessel, spanning the carina. While the cover

0

A

B

C

D

E

F

G

p<0.05 vs A(*), vs B (†), vs C & D (‡) Panel A shows a histopathological section of a large calibre coronary bifurcation, illustrating the lack of atheroma at the carina - indicated by area G. Histograms in panel C describe plaque thickness and necrotic core thickness throughout the bifurcation, with the histogram bars referring to the area of the bifurcation illustrated in Panel B (A,B,C etc). This systematic evaluation describes the atheroma distribution across this area. Reporduced from Nakazawa et al8 with permission from the American College of Cardiology.

The AXXESS Stent

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Figure 2: Biosensors AXXESS™ Biolimus A9™ Eluting System

Figure 3: AXXESS Deployment Sequence

Di

Dii

A

1. Position

4. Deploy

2. Deploy partly at carina

5. Retract sheath

3. Advance

6. Final result

A B

E

Deployment marker Distal stent marker

SB

C

MV

Proximal stent marker

Cover sheath marker

F

Panel A illustrates an AXXESS stent, with Panel B demonstrating its deployed position within a bench bifurcation model. Note, the SB wire has been removed for illustration purposes. The key features are annotated in Panel C, with the proximal and distal radio-opaque gold markers indicated by the circles. Distally, two markers are positioned within the MV, and one in the SB when deployed. Panel D illustrates the actuator handle. In panel Di, the safety catch is in place, and should remain so until the device has been advanced across the lesion and moves freely within the vessel. Once removed (panel Dii) AXXESS deployment can occur with retraction of the actutator. Panels E and F illustrate the AXXESS system within the hydrophilic cover sheath, as seen radiographically (Panel F) and on a bench (Panel E). The arrows demonstrate the proximal stent marker (green), the mid shaft stent deployment marker (yellow) and the distal stent marker (red). MV = main vessel; SB = side branch.

Note that the side branch wire has been removed for illustration purposes. The distal device marker is positioned within the main vessel (Panel 1). The hydrophilic sheath is the gradually retracted and the device partly deployed at the carina (Panel 2). Sheath retraction is halted with once the sheath marker has reached the mid-stent marker (Panel 3 – indicated by the yellow lines), and the AXXESS system is then advanced gently onto the carina. The sheath can then be fully retracted (Panel 4 – mid-stent marker again illustrated with yellow lines) and the device deployed (Panels 5 and 6).

SB were stented distal to the AXXESS stent, then standard final kissing balloon dilatation (FKBD) should be performed in the majority of cases.

Tips and Tricks sheath contains more than half the stent length (identified by the deployment marker on the delivery catheter), further adjustment of the stent position is possible. It is often helpful to confirm adequate carina spanning by gently advancing the device forward while the cover sheath remains in this position, as adjustments can still be made at this point. This should be visualised in two orthogonal radiographic projections to ensure separation of the three markers into the MV and SB. It should be stressed, however, that the device cannot be recaptured and the cover sheath cannot be re-advanced over the expanded stent.

The final positioning manoeuvre occurs with gentle forward pressure applied with the device spanning the carina, and full retraction of the covered sheath using the actuator. Ideally, the device should be placed 2–3 mm distal to the carina to maximise distal vessel stent coverage (Figure 3).

Following deployment of the AXXESS stent, the jailed wire can then be withdrawn and reintroduced if needed, with easy access maintained into the other branch. Further stents can then be advanced if required and deployed in the distal MV or SB. If a distal stent is required, then the operator should aim for a minimal overlap of 1–2 mm between the AXXESS and any further stents. Similarly, significant proximal disease to the edge of the AXXESS stent in the MV can be treated with overlapping DES as appropriate. In the authors’ experience, Biomatrix devices have been used, conventionally, as they carry the same polymer and drug, although any DES could be used. As the AXXESS stent is self-expanding, post-dilatation is often not required.

If no stent is placed in the SB distal to the AXXESS stent, often a final hugging balloon dilatation with the SB is performed. An appropriate non compliant (NC) balloon is placed within the distal marker of the AXXESS stent in the SB against an NC balloon in the MV. If both MV and

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The successful deployment of an AXXESS device is achievable by the majority of PCI operators; however, the simple steps outlined above should be followed to minimise this risk of complications. It is advisable to undergo a short period of proctoring before attempting implantation solo as the delivery of the device differs from a conventional balloon expandable stent, as is detailed above. Adjunctive use of intracoronary imaging permits clear definition of the bifurcation anatomy and suitability for a dedicated device, and also facilitates appropriate lesion preparation that permits optimisation of the final stent result. It is recommended in the early learning curve of a new operator that such imaging is performed. While AXXESS can be used safely in the left main stem, it is not advisable for AXXESS implantation to be attempted in this circumstance until a number of successful AXXESS deployments have been undertaken in non-left main bifurcation lesions.

There are a small number of potential problems that maybe encountered during implant that can be mitigated by careful technique. These are outlined below, along with simple solutions that are effective in the majority of cases.

Problem 1: Failed to deliver AXXESS Delivery device failure should be considered a possibility when planning the case. However, with a careful strategy and appropriate equipment this risk is minimised. As detailed above, it is important to select a supportive guiding catheter along with good distal supportive guide-wires at the outset. Lesion preparation is crucial, with ideally 1:1 balloon sizing and predilation with NC, with or without cutting balloons as appropriate. Failure to prepare the vessel adequately is the most common reason for device delivery failure and can easily be overcome with more debulking. It is safe to remove the device if the cover sheath remains fully closed but caution should be taken once the distal stent is exposed. If this circumstance is encountered, it is

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Bifurcations Figure 4: Tips and Tricks for Successful AXXESS Delivery Problem 4:

Problem 1: 7 Fr supportive guiding catheter

Gradual positioning & expansion

Problem 3:

Two supportive guide wires

Problem 2:

Tips for AXXESS success

Leave safety catch in place until in vivo

Flush 2 ml saline with mandrill in

Adequate proximal landing zone

Optimal angiographic projections

Adequate lesion preparation

Figure 5: Optical Frequency Domain Imaging of Axxess at Implant and 6 Months Follow Up C

B

Ai

OFDI at implant

Covered with thin layered neointima Side branch ostium LAD Proximal LAD Distal OFDI at 6 months:

AXXESS stent D

Serial OFDI images of a successfully deployed AXXESS stent at implant (Panels A, B, and C) and at 6 months (Panel D). The carina is undiseased and free from metal, as indicated by the * in Panels A and B, with the side branch lumen well maintained. Panel C demonstrates the different call structure of the AXXESS system (yellow circle) versus a biomatrix stent in the distal main vessel (green circle). Panel D demonstrates the neo-intimalisation at 6 months in a second case, with good strut coverage and clear maintenance of side branch patency. OFDI = Optical Frequency Domain Imaging.

safer to deploy in the main vessel rather than trying to remove the device once cover sheath retraction has commenced.

Problem 2: AXXESS Delivered too Proximally Device being delivered too proximally can be a consequence of problem 1 or hasty device deployment. If this has occurred, with the struts clearly proximal to the carina and not spanning the ostium of either branch, then (after appropriate post dilatation as required) a second AXXESS device may be delivered through the first and placed in a more appropriate position distally. Care should be taken to remove the SB wire prior to AXXESS deployment to avoid wire trapping.

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If the device is delivered too distally, it will be unable to expand fully and span across the carina. This may be corrected if the device is only just distal of the carina with a kissing balloon inflation that may flare the struts across the carina. If this is ineffective, or the device is positioned in such a way that this is clearly not possible, then it can be used safely and effectively as a provisional MV stent. The SB may be accessed through the device and the procedure completed using a culotte technique with FKBD if SB stenting is required or a provisional approach can be adopted.

Problem 4: Distal Stent Overlap

The central flow chart describes the factors that should be considered during stent implantation, along with the problems that may be encountered. Problem 1 – unable to pass AXXESS stent; solution – further lesion preparation. Problem 2 – AXXESS deployed too proximally; solution – post dilatation and introduction of second AXXESS device deployed distal to first. Problem 3 – AXXESS deployed too distally; solution – treat AXXESS as provisional main vessel stent with kissing balloon inflation/completion of culotte as appropriate. Problem 4 – distal stent deployed in too distal position, missing overlap; solution – deploy further stent across gap to ensure ostial lesion coverage.

A

Problem 3: AXXESS Delivered too Distally

If a stent is required distally to the AXXESS device, then care should be taken with the positioning of the proximal stent edge to ensure overlap. If there is a suspicion that a gap remains between the two devices, then this should be confirmed using intracoronary imaging (intravascular ultrasound [IVUS] or optical coherence tomography [OCT]) and a further short stent used to cover as appropriate.

The majority of problems with the delivery and positioning of AXXESS can be predicted. By simply considering the factors detailed in Figure 4 when planning the procedure, the risk of a serious complication can be minimised.

Outcomes There is a growing body of literature that supports the use of the AXXESS system in the treatment of coronary bifurcation lesions.

The first-in-man AXXESS PLUS trial reported results at 6 months in 139 patients who underwent implantation across 13 centres, with low rates of TLR (7.5 %) and late-lumen loss (0.09 mm).13 There was a low rate of periprocedural complications (MACE rate 5% (n=7), non-Qwave MI 4.3% (n=6)), with a late-stent thrombosis rate of 2.1 % (three patients, two of who associated with premature cessation of antiplatelet therapy).

This trial has been followed with the prospective DIVERGE study, that assessed 302 patients across 14 centres in Europe, Australia and New Zealand.14 The cumulative MACE rate at 9 months was 7.7 % (0.7 % death, 3.3 % non Q-wave MI, 1.0 % Q-wave MI and 4.3 % TLR). This is comparable to the equivalent MV stent (Biomatrix) with the 9-month MACE rate in the Biolimus arm of the LEADERS trial being reported as 9.2 %.15 Importantly, 64 % of patients treated with AXXESS had additional DES (in both MV or SB) and all DES used were first-generation sirolimus-eluting devices. Stent thrombosis was observed in 1.0 % of patients (0.7 % subacute and 0.3 % late), the overwhelming majority of which occurred within the additional DES rather than the AXXESS device. The overall restenosis rate was 6.4 %. Both the AXXESS PLUS and the DIVERGE study have now reported 5 years results – pooled data represent a patient population of 432 patients. The overall MACE rate was reported at 21.3 % (6.5 % death, 8.6 % MI and 12.4 % ischaemia-driven TLR).16 This is comparable to the MACE rate of 22.8 % observed in the Biolimus arm of the LEADERS study at 5 years,9 and to the 5-year MACE rate of at 18.3 % in the MV-only arm in the NORDIC bifurcation trial.3 Importantly, among the DIVERGE cohort, 36 % of patients with true bifurcation lesions were treated using a single device only, or with a single additional stent in either MV or SB.17 This is an equivalent approach to a provisional technique, but maintaining SB access, and leaving the carina free from metallic scaffold. Indeed, the

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AXXESS™ Stent: Delivery Indications and Outcomes

MACE rate in this sub-group was 18 %, again comparable to the provisional MV-only arm of the NORDIC trial.3 Importantly, this was not significantly different to the MV-plus-SB group using AXXESS (MACE rate of 23.3 %). Whereas, when a two-stent technique was employed within the NORDIC trial the overall MACE rate was 28.2 %, which was significantly different to the MV-only stent arm. The overall MACE rate for the MV arm of nordic bifurcation at 5 years was 18.3 %.

The DIVERGE14 and AXXESS PLUS trial13,15 both had stringent inclusion criteria, with the treated lesion dimensions restricted to just 10 mm extension into the MV proximal to the bifurcation, and 15 mm into either branch (MV and SB). They excluded lesions with angiographically apparent heavy calcification. It may be considered that this does not reflect ‘real-world’ practice, but observational data are available to support the use of AXXESS in more complex lesion subsets. In our data series from over 100 implants across four UK centres, the device has been successfully deployed in a variety of situations, including heavily calcified vessels that require rotablation, chronic total occlusions and in vessels that contain multiple bifurcations and where angles exceed 70o. The overall complication rate was low, with a single access site-related retroperitoneal bleed, and a single coronary perforation following post dilatation of the MV AXXESS stent, representing a 2 % complication rate,12 similar to that in other published series.16 The single randomised trial in the literature, the COBRA study,18 compares the use of the AXXESS system alongside Biomatrix stents with a two-stent culotte strategy using Xience Pro stents (Abbott Vascular, Illinois, USA) in a cohort of 40 patients with true bifurcation lesions. The trial was conducted at two European centres, with FKB inflations being performed in all cases. All patients were restudied at 9 months with quantitative coronary angiography (QCA) and OCT. There were no significant differences observed in the OCT primary

1.

2.

3.

4.

5.

6.

7.

Lassen JF, Holm NR, Stankovic G, et al. Percutaneous coronary intervention for coronary bi-furcation disease: consensus from the first 10 years of the European Bifurcation Club meet-ings. EuroIntervention 2014;10 :545–60.

Hildick-Smith D, de Belder AJ, Cooter N, et al. Randomized trial of simple versus complex drug-eluting stenting for bifurcation lesions: the British Bifurcation Coronary Study: old, new, and evolving strategies. Circulation 2010;121 :1235–43.

Maeng M, Holm NR, Erglis A, et al. Long-term results after simple versus complex stenting of coronary artery bifurcation lesions: Nordic Bifurcation Study 5-year follow-up results.

J Am Coll Cardiol 2013;62 :30–4.

Louvard Y, Thomas M, Dzavik V, et al. Classification of coronary artery bifurcation lesions and treatments: Time for a consensus! Catheter Cardiovasc Interv 2008;71 :175–83.

Chen S-L, Santoso T, Zhang J-J Ye F, et al. A randomized clinical study comparing double kissing crush with provisional stenting for treatment of coronary bifurcation lesions.

Results from the DKCRUSH-II (Double Kissing Crush versus Provisional Stenting Technique for treatment of coronary bifurcation lesions) trial. J Am Coll Cardiol 2011;57 :914–20.

Morlacchi S, Chiastra C, Cutrì E, et al. Stent deformation, physical stress, and drug elution obtained with provisional stenting, conventional culotte and Tryton-based culotte to treat bifurcations: a virtual simulation study. EuroIntervention 2014;9 :1441–53.

Behan MW, Holm NR, Curzen NP, et al. Simple or complex stenting for bifurcation coronary lesions: a patient-level pooled-analysis of the Nordic Bifurcation Study and the

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8.

9.

10.

11.

12.

13.

endpoint – the proportion of uncovered struts per bifurcation segment – with a trend towards a higher proportion of uncovered struts in the AXXESS group. However, both the mean stent area and mean lumen area in the proximal MV were significantly greater when the AXXESS system had been used. This was consistent with the QCA findings, with in-stent late-lumen loss significantly lower within the AXXESS arm at both the bifurcation core and within the segment of disease covered with the AXXESS stent (0.04 mm versus 0.39 mm; p=0.002) There was no significant differences in clinical outcomes reported at 1 year, as could be expected from this small cohort.

This finding is consistent with the results of the IVUS subgroup of the DIVERGE study that demonstrated a 26 % increase in luminal volume at 6 months.19 This is likely to be a consequence of the self-expanding nature of the AXXESS device, maximising luminal gain from a PCI bifurcation procedure. The OCT findings at 6 months are illustrated in Figure 5.

There remains a lack of large-scale prospective randomised data evaluating the use of the AXXESS system. Despite this, cohort reports and the prospective data presented above have indicated that the system is safe, effective and with rates of adverse outcomes that are comparable to to that observed in large-scale randomised biolimuseluting stent trials.

Conclusion The AXXESS system presents a novel solution for the treatment of de novo coronary bifurcation lesions. It has been proven to be associated with low rates of MACE and stent thrombosis, and has a number of theoretical benefits over conventional two-stent strategies. Prospective data support its use in complex coronary bifurcations, however, its use has yet to be studied in a large-scale randomised controlled trial. n

British Bifurcation Coronary Study. Circ Cardiovasc Interv 2011;4 :57–64.

Nakazawa G, Yazdani SK, Finn AV, et al. Pathological findings at bifurcation lesions: the impact of flow distribution on atherosclerosis and arterial healing after stent implantation.

J Am Coll Cardiol 2010;55 :1679–87.

Serruys PW, Farooq V, Kalesan B, et al. Improved safety and reduction in stent thrombosis associated with biodegradable polymer-based biolimus-eluting stents versus durable polymer-based sirolimus-eluting stents in patients with coronary artery disease: final 5-year report of the LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) randomized, noninferiority trial. JACC Cardiovasc Interv 2013;6 :777–89.

García E, Unzué Vallejo L, Rodríguez-Rodrigo FJ. Placement of a single Axxess stent as new treatment strategy for Medina 1,0,0 left main stem bifurcation lesion. J Invasive Cardiol .

2014;26 :E45–47.

Rana O, Sastry S, Fath-Ordoubin O, et al. Worlds first Series of Left main bifurcation treated with AXXESS 4.0x9mm dedicated bifurcation Stent. J Am Coll Cardiol 2014;64 (11_S):. doi:10.1016/j.jacc.2014.07.273 Shah N, Rana O, Fath-Ordoubadi F, et al. Early UK experience of the AXXESS dedicated bifurcation stent. J Am Coll Cardiol 2013;62 (18_s1):B121–B121.

Grube E, Buellesfeld L, Neumann FJ, et al. Six-month clinical and angiographic results of a dedicated drug-eluting stent for the treatment of coronary bifurcation narrowings. Am J Cardiol 2007;99 :1691–7.

14. Verheye S, Agostoni P, Dubois CL, et al. 9-month clinical, angiographic, and intravascular ultrasound results of a prospective evaluation of the Axxess self-expanding biolimus A9-eluting stent in coronary bifurcation lesions: the DIVERGE (Drug-Eluting Stent Intervention for Treating Side Branches Effectively) study. J Am Coll Cardiol 2009;53 :1031–9.

15. Windecker S, Serruys PW, Wandel S, et al. Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial. Lancet 2008;372 :1163–73.

16. Verheye S, Copt S, Grube E. Very long-term effect of bifurcation treatment with biolimus A9-eluting dedicated stent based on the pooling of the five year results from two prospective, multi centre trials (DIVERGE and AXXESS PLUS).

EuroIntervention EuroPCR supplement 2014. Euro14A-OP165.

17. Buysschaert I, Dubois CL, Dens J, et al. Three-year clinical results of the Axxess Biolimus A9 eluting bifurcation stent system: the DIVERGE study. EuroIntervention 2013;9 :573–81.

18. Dubois C. Complex Coronary Bifurcation lesions: Randomised Comparison of a strategy using dedicated self-expanding Biolimus A9-eluting stent vs. a culotte strategy using Everolimus eluting stents: Primary results from the multi centre COBRA trial. Oral presentation. Presented at EuroPCR 2014, Paris, France, May 2014.

19. Buysschaert I, Sanidas E, Hasegawa T, et al. Baseline and 9 months IVUS analysis of the bi-furcation-dedicated biolimus A9-eluting Axxess stent system: the DIVERGE IVUS substudy.

Catheter Cardiovasc Interv 2014;84 :1062–70.

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Chronic Total Occlusion

ON.

Vascular Access and Chronic Total Occlusion Angioplasty Da v id Smit h , A h m e d H a i l a n a n d A l e x a n d e r Ch a s e Regional Cardiac Centre, Morriston Hospital, Swansea, UK

Abstract The hybrid algorithim approach, together with innovative new technologies, has lead to increased interest in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) and increasing procedural success rates. Unlike non-CTO PCI, there is an increased rate of femoral access. When considering arterial access in CTO PCI, a balance is needed between anticipated procedural difficulty, planned CTO strategy and the desire to minimise the risk of vascular access-related complications. We review the evidence for best practice with respect to femoral puncture technique and also assess the technologies and techniques available to place larger inner diameter catheters into the radial artery.

Keywords Chronic total occlusion, percutaneous coronary intervention, vascular access, angioplasty Disclosure: The authors have no conflicts of interest to declare.

Received: 26 March 2015 Accepted: 30 April 2015 Citation: Interventional Cardiology Review, 2015;10(2):90–3 Correspondence: Dr D Smith, Consultant Cardiologist, Regional Cardiac Centre, Morriston Hospital, Swansea, SA6 6NL, UK E: dave.smith@wales.nhs.uk

Radial vs Femoral Access In recent years several large registries and randomised controlled trials have demonstrated a mortality benefit for trans-radial over transfemoral percutaneous coronary intervention (PCI), likely mediated by reduced bleeding complications.1–4 Building on the pioneering Japanese experience, the advent of the hybrid algorithim approach, coupled with innovative new technologies has lead to a global renewed focus and enthusiasm for chronic total occlusion (CTO) PCI with marked increase in procedural success rates.5 This approach combines the skill sets of antegrade wire escalation (AWE), antegrade dissection re-entry (ADR), retrograde wire escalation and retrograde dissection re-entry (RDR) with keen attention to minimising procedure time, contrast volume and radiation exposure (see Figure 1).

an essential step and when unsuccessful, a frequent mode of failure.

The radial and ulnar arteries infrequently have an inner luminal diameter larger than 2.5 mm in men at the wrist making insertion of a 7F sheath (outer diameter 3.06 mm) a usual maximum in men and 6F sheath (outer diameter 2.67 mm) in women.7,8 The requirement for an 8F system has resulted in CTO PCI bucking the trend towards transradial PCI with high use of trans-femoral access. This has implications for training of medical and nursing staff (operative and after care) in increasingly radial dominant centres. Below we discuss the evidence for best practice with respect to femoral puncture technique and also assess the technologies and techniques available to place larger inner diameter catheters into the radial artery.

Femoral Artery Puncture Techniques Arterial Access in CTO PCI One challenge, however, in CTO PCI remains the risks of multiple and larger vascular access. Whilst for conventional PCI the direction of travel is towards miniaturisation with smaller French sizes and sheathless approaches,6 in CTO PCI, larger French systems are required to offer capability across the full spectrum of techniques (see Table 1).

In addition, CTO procedures are often dependent on visualisation of the occluded vessel by contra-lateral collaterals requiring dual access sites and contra-lateral coronary injection hence immediate potential to double the risks of access complication. Furthermore the thrombotic risk of equipment in both coronary circulations requires meticulous anticoagulation management with a target activated clotting time (ACT) greater than 300s measured systematically every 20–30 minutes. This contrasts with a target of 250s for conventional single access site nonCTO PCI and might exacerbate any access related bleed.

Table 1 describes the procedural techniques as accommodated by different guide catheter sizes. 8F is required to accommodate two over-the-wire (OTW) technologies and also offers greater passive guide catheter back-up to facilitate penetration of the CTO proximal cap,

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Optimal location of the anatomical puncture site is the most crucial factor in minimising arterial complication rates. Arteriotomy positions below the common femoral artery (CFA) bifurcation or above the origin of the inferior epigastric artery (IEA) are associated with significant vascular complications.9 There is marked variability in inter-individual anatomy and surface landmarks may not reflect optimal puncture position.

Traditionally, the inguinal ligament was used as a suitable landmark because it acts as a surrogate marker for the IEA and retroperitoneum.10 The ‘ideal’ anatomical puncture site is over the mid-portion femoral head, above the CFA bifurcation and below the inguinal ligament.11 Pitta et al. cited vascular complication rates of 18 % when punctures were performed outside of these anatomical landmarks.9 In particular, arterial cannulation above the inguinal ligament (and above the inferior epigastric artery) increases the risk of retroperitoneal haemorrhage due to a lack of ability to compress the femoral artery using the femoral head.12 There are three commonly used techniques to gain femoral arterial access: anatomical landmarks, fluoroscopy guided and ultrasound guided punctures. Anatomical landmarks including skin crease location, maximal palpated pulse intensity and bony landmarks are not reliable methods.10

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Table 1: Potential Required Equipment in CTO PCI and Vascular Access Guide and Access 6 Fr

Devices All balloon sizes

Techniques Anchor balloon

Limitations Limited balloon trapping option. Possible with FineCross

(internal diameter 1.80 mm)

All stent sizes

Over the wire balloon

and 2.1F Tornus. An OTW system will require wire

Any arterial access

Tryton bifurcation stent

Two monorail catheters

docking to exchange

IVUS

Two micro-catheters

No simultaneous OTW option .e.g STRAW*

OCT

Rotablator 1.25–1.5 mm burr

0.9 mm Laser atherectomy catheter

Guide catheter extension

Micro-catheter

Corsair

Tornus

FineCross

Valet

Venture

Twinpass

Stingray catheter

7 Fr

Above plus

Balloon trapping for

(internal diameter 2.06 mm)

Laser 1.4–1.7 mm

equipment exchange

Radial (7.5 Sheathless)

Rotablator 1.75 mm burr

Femoral

Axxess bifurcation stent

8 Fr

Above plus

Two over the wire systems

(internal diameter 2.29 mm)

Laser 2.0 mm

IVUS guided CTO PCI

Radial (8.5 Sheathless)

Rotablator 2 mm burr

No simultaneous OTW option .e.g STRAW

Unable to deliver 2.5 mm burr

Femoral CTO: chronic total occlusion; PCI: percutaneous coronary intervention; STRAW: Subintimal transcatheter withdrawal of haematomas.

Fluoroscopy-guided Femoral Punctures Fluoroscopic landmarks have been widely used in every day interventional practice and are described in Figure 2. The clinical benefits of this modality have not been reported in randomised trials.

However, use of fluoroscopic-guided femoral arterial access has been demonstrated to reduce bleeding-related complications in female patients.13 In addition, prospective registry data have demonstrated fluoroscopy use prior to arterial puncture was associated with a lower incidence of pseudoaneuryms (0.3 % vs. 1.15 %, p=0.017), any arterial injury (0.7 % vs. 1.9 %, p<0.01), and hospitalisation (2.1 days vs. 2.4 days, p<0.01).14 Recent multicentre observational data has also demonstrated an extremely low incidence of vascular-access complications (0.89 %) in CTO PCI cases performed by femoral arterial access (81 % 8F sheaths) using routine fluoroscopic guidance.15

Ultrasound (US) Guided Femoral Arterial Access The important role of US guided venous cannulation is unquestionable.

US guided arterial puncture in interventional cardiology is increasingly being adopted as the method of choice, especially in more complex cases such as CTO PCI. Utilisation of ultrasound-guided femoral access can enable direct visualisation of the CFA bifurcation and identify anterior puncture of the needle through the CFA.11 The success of ultrasoundguided femoral arterial puncture was demonstrated in the Femoral Arterial Access With Ultrasound (FAUST) trial, with a reduced number of puncture attempts, improved first pass success rates, reduced time to successful access and reduced vascular complications.16

Micropuncture Technique Arterial puncture with a small 21-gauge micropuncture needle with a 0.018-inch guide wire (Cook Medical, Bloomington, USA) theoretically increases the chances of obtaining haemostasis with manual compression if the puncture is in a vein. A single-centre, retrospective

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study that compared a 21-gauge needle vs. an 18-gauge needle has shown no significant difference in access site complications.

Randomised data is therefore needed to determine whether the micropuncture technique can reduce vascular complications.11

Access Site Management Uncontrolled hypertension has been identified as a risk factor for femoral access complication and optimal blood pressure control should be achieved prior to sheath removal.11 Data on vascular closure devices (VCD) are controversial and have provided mixed results, with early studies reporting increased rates of vascular complications while more contemporary registries have reported less bleeding complications compared to manual haemostasis.11 An appropriately powered randomised trial comparing newer generation VCD (after an appropriate learning curve) and manual haemostasis is needed to determine the preferred strategy for obtaining haemostasis. Minimising sheath dwell time may also improve outcomes. Early arterial sheath removal after PCI has been associated with reduced bleeding complications.17

Tips and Techniques To Use Larger Guides Trans-Radially Passage of larger guiding catheters up the radial artery is limited by absolute vessel size and arterial spasm. In a recent multicentre registry containing over 1900 transradial procedures the incidence of radial spasm was 2.7 %, with multiple puncture attempts and use of larger introducer sheaths (7F) being independent predictors of radial spasm.18 Intra-arterial vasodilators reduce the incidence of radial spasm although the optimal “spasmolytic” cocktail remains to be identified and their use in some patients may result in hypotension and bradycardia. The use of hydrophilic sheaths and catheters can also further reduce spasm.19

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Chronic Total Occlusion Figure 1: The North American Total Occlusion Algorithim 1. Dual injection 2. 1. Ambiguous proxial cap 2. Poor distal target 3. Appropriate “interventional” collaterals No Antegrade Yes 4. Antegrade wiring

Yes 3. Lesion length <20 mm

6. Retrograde

No 5. Antegrade dissection and reentry Controlled (Stingray)

Retrograde true lumen puncture

Retrograde dissection and reentry

Wire based (LaST)

7. Switch strategy Reproduced with permission of Prof C Thompson.

Figure 2: Technique to Optimise Femoral Arterial Access A

B

C

D

into the aortic root ((alongside the 0.035” wire) and a 2.0 mm monorail balloon inflated two-thirds in and one third exiting the guide to provide a soft rounded shoulder tip.20 In a male patient with a 7F sheath experiencing resistance to 7F guide passage the same technique using a 2.5 mm balloon is often successful. Another technique to provide a more tapered tip to facilitate guide passage is a mother-in-child configuration, so the guide is lead by a smaller diameter section, e.g. use of a 4F Judkins Right 4 (JR4) or multipurpose (MPA) inside a 6F guide (requires either a longer 4F diagnostic >110 cm or shorter 90 cm guide), or similarly a 5F JR4 or MPA inside a 7F guide.

An elegant innovative solution is the use of sheathless guiding catheters. These are commercially available (Asahi Intecc Co Ltd, Aichi) in 6.5F, 7.5F and 8.5F sizes with inner diameters (I.D.) identical to 6F, 7F and 8F guides respectively. The outer diameters (O.D.), however, are less than a standard 5F sheath for 6.5F sheathless, <6F sheath for 7.5F sheathless and <7F sheath for the 8.5F sheathless and can hence be anatomically accommodated in the majority of radial arteries. The same principle is employed by “home-made” sheathless guides using commercially available tapered introducers with standard guide catheters. This has the advantage of free choice of shape and manufacturer of guide. Introducers include the Shuttle (Cook Medical, Bloomington, USA), a carotid device: 5F Shuttle introducer in 7F guide; 6F Shuttle introducer in 8F guide. The use of sheathless guides requires specific expertise as the highly hydrophilic coating may increase catheter instability. An additional drawback is that use of 150 cm devices, such as microcatheters in retrograde cases, may require guide catheters less than 100 cm, especially in taller patients.

Sheathless guides are not available in shorter lengths. However, to overcome this, the tapered introducers from the Asahi commercial sheathless guides can be used inside conventional 90 cm guides for the same purpose and when guide exchange is required.

The Second Access Site

(A) The blue line defines the level of the inguinal ligament as determined by traditional landmarks (line drawn between the anterior superior iliac crest and the symphysis pubis).

The dashed black lines divide the femoral head into upper, mid and lower thirds with the ideal puncture site located in the mid third. The location of the inguinal skin crease (arrows) relative to the femoral head is variable making it an unreliable marker compared with the bony landmarks described above. (B) Femoral angiogram demonstrating puncture of the common femoral artery at the level of mid-femoral head. The upper arrow shows the inferior epigastric artery and the lower arrow the level of common femoral artery bifurcation. (C) Screening over the femoral head with the arterial puncture needle in place aids identification of an appropriate puncture site. (D) Following sheath insertion a check angiogram is performed to confirm the location of the puncture site relative to the femoral head.

Produced with permission of Dr S Walsh.

Spasm can also be minimised by gradual graded gentle dilatation by tapered introducers. If resistance is encountered when upsizing from a 5F catheter to a 6F guide and forearm angiography has excluded an anatomical variation such as a radial loop or accessory artery, often balloon assisted tracking is sufficient to allow the new catheter to pass.

In this technique a coronary guidewire is passed into the guide and

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Within the hybrid algorhythm the second access site allows contralateral coronary injections for visualisation of the target for AWE and ADR techniques and a 6F system will suffice. However adopting a retrograde approach either as a primary strategy or bail-out for failed antegrade approach requires a capability for passage of guidewires, microcatheters and balloons into the donor vessel (giving rise to septal or epicardial collaterals). 6F is a minimum but 7F has advantages of better contrast delivery, better passive support and importantly the ability to use a wider range of equipment and techniques. (see Table 1) It is therefore evident that the selection of 6F guide catheters may profoundly limit some of the potential CTO techniques such that larger diameter guides are needed when more complex techniques are planned or anticipated. Recommendation of radial vs. femoral access for the second arterial site is also difficult due to the fact that no randomised data exists on transradial access in CTO PCI and all of the registry data is single centre or single operator derived and conducted by operators with specific experience in transradial PCI.21 Radial access therefore constitutes a valuable alternative to femoral access in CTO PCI in high volume radial centres, with anticipated equipment and techniques taken into consideration.

Radial vs Femoral Dominance Promotion of a high volume of radial access may interfere with the equally important goal of maintaining proficiency in the femoral approach, which is indispensable in a variety of procedures. As with the radial approach, outcomes depend on the experience of operators and

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Vascular Access and Chronic Total Occlusion Angioplasty

centres. Rafie et al. reported higher vascular access complication rates (12.5 %) when default radial operators in a single centre undertook PCI cases via the femoral approach.22 As expected, use of femoral access was associated with increased case complexity and larger arterial sheaths and femoral access was performed without fluoroscopic screening. In contrast, a recent multicentre study has demonstrated an extremely low incidence of vascular-access complications (0.89 %) in CTO PCI cases performed by default radial operators when femoral arterial access is performed using routine fluoroscopic guidance.15

Conclusion When considering arterial access in CTO PCI, a balance is needed between anticipated procedural difficulty, planned CTO strategy and the

1.

1.

2.

3.

4.

5.

Chase AJ, Fretz EB, Warburton WP, et al. Association of the arterial access site at angioplasty with transfusion and mortality: the M.O.R.T.A.L study (Mortality benefit Of Reduced Transfusion after percutaneous coronary intervention via the Arm or Leg). Heart 2008;94 :1019–25.

Mamas MA, Anderson SG, Carr M, et al. British Cardiovascular Intervention Society; National Institute for Cardiovascular Outcomes Research.Baseline bleeding risk and arterial access site practice in relation to procedural outcomes after percutaneous coronary intervention. J Am Coll Cardiol 2014;64 :1554–64.

Jolly SS, Yusuf S, Cairns J, et al.; RIVAL trial group. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet 2011;377 :1409–20.

Valgimigli M, Gagnor A, Calabr P, et al; MATRIX Investigators.

Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial. Lancet 2015. pii: S0140–6736(15)60292–6 [ePub head of print].

Christopoulos G, Menon RV, Karmpaliotis D, et al. The efficacy and safety of the “hybrid” approach to coronary chronic total occlusions: insights from a contemporary multicenter US registry and comparison with prior studies. J Invasive Cardiol 2014;26 :427–32.

Kiemeneij F, Yoshimachi F, Matsukage T, et al. Focus on maximal miniaturisation of transradial coronary access materials and techniques by the Slender Club Japan and Europe: an overview and classification. EuroIntervention

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6.

7.

8.

9.

10.

11.

12.

13.

14.

desire to minimise the risk of vascular access-related complications.

The requirement for larger French systems, particularly in more complex cases has resulted in high use of trans-femoral access in CTO PCI. This has implications for training of medical and nursing staff both in terms of both peri-procedural and post-procedural care in increasingly radial access dominant centres. The miniaturisation of angioplasty equipment continues and is expected to increase the feasibility of transradial CTO interventions.

To reduce the risk of femoral access site complications, femoral access should be achieved with fluoroscopic guidance which is readily available in every catheter lab. A strategy of US guided puncture may become more commonplace in the future. n

2015;10 :1178–86.

Saito S, Ikei H, Hosokawa G, Tanaka S. Influence of the ratio between radial artery inner diameter and sheath outer diameter on radial artery flow after transradial coronary intervention. Catheter Cardiovasc Interv 1999;46 :173–8.

Ashraf T, Panhwar Z, Habib S, et al, Size of radial and ulnar artery in local population. JPMA 2010;60 :817.

Pitta SR, Prasad A, Kumar G, et al. Holmes DR, Location of Femoral Artery Access and Correlation with Vascular Complications. Catheter Cardiovasc Interv 2011;78 :294–99.

Schnyder G, Sawhney N, Whisenant B, et al. Common femoral artery anatomy is influenced by demographics and comorbidities: implications for cardiac and peripheral invasive studies. Catheter Cardiovasc Interv 2001;53 :289–95.

Turi ZG, Fluoroscopy guided vascular access: asking the right question, but getting the wrong answer? Catheter Cardiovasc Interv 2009;74 :540–2.

Lee MS, Applegate B, Rao SV, et al. Minimizing femoral artery access complications during percutaneous coronary interventions: A comprehensive review. Catheter Cardiovasc Interv 2014;84 :62–9.

Ahmed B, Piper WD, Malenka D, et al. Significantly improved vascular complications among women undergoing percutaneous coronary intervention: a report from the Northern New England Percutaneous Coronary Intervention Registry. Circ Cardiovasc Interv 2009:2 :423–9.

Fitts J, Ver LP, Hofmaster P, Malenka D. Fluoroscopy-guided femoral artery puncture reduces the risk of PCI-related vascular complications. J Interv Cardiol 2008;21 :273–8.

Fairley SL, Lucking AJ, McEntegart M, et al. Routine Use of

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16.

17.

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19.

20.

21.

Fluoroscopic-Guided Femoral Arterial Puncture to Minimise Vascular Complication Rates in Coronary CTO Intervention: Multi-Centre Experience in the UK. Submitted to Circulation Intervention Feb 2015.

Seto AH, Abu-Fadel MS, Sparling JM, et al. Real-time ultrasound guidance facilitates femoral arterial access and reduces vascular complications: FAUST (Femoral Arterial Access With Ultrasound Trial), JACC Cardiovasc Interv , 2010;3 :751–8.

Sherev DA, Shwa RE, Brent BN. Angiographic predictors of femoral access site complications: implication for planned percutaneous coronary intervention, Catheter Cardiovasc Interv 2005;65 :196–202.

Goldsmit A, Kiemeneij F, Gilchrist IC, et al. Radial artery spasm associated with transradial cardiovascular procedures: results from the RAS registry. Catheter Cardiovasc Interv 2014;83 :32–6.

Kristic I, Lukenda J. Radial artery spasm during transradial coronary procedures. J Invasive Cardiol 2011;23 :527–31.

Patel T, Shah S, Pancholy S, et al. Balloon-assisted tracking: a must-know technique to overcome difficult anatomy during transradial approach. Catheter Cardiovasc Interv 2014;83 :211–20.

Burzotta F, De Vita M, Lefevre T, et al. Radial approach for percutaneous coronary interventions on chronic total occlusions: technical issues and data review. Catheter Cardiovasc Interv 2014;83 :47–57.

Rafie IM, Uddin MM, Ossei-Geming N, et al. Patients undergoing PCI from the femoral route by default radial operators are at high risk of vascular access-site complications. EuroIntervention 2014;9 :1189–94.

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Structural Transcatheter Aortic Valve Implantation

Avoiding Coronary Occlusion and Root Rupture in TAVI – The Role of Pre-procedural Imaging and Prosthesis Selection Marco Barbanti Ferrarotto Hospital, University of Catania, Catania, Italy

Abstract Coronary occlusion and rupture of the aortic root or annulus remain two major concerns of transcatheter aortic valve implantation technique. Despite their relatively low frequency they raised the interest of the scientific community as they carry an extremely poor prognosis. Prosthesis type and size selection is part of the patient selection process that allows the operator to prevent these complications. In this article, the techniques used either during pre-TAVI screening or during the procedure itself to avoid coronary occlusion and aortic rupture will be discussed.

Keywords TAVI, complications, coronary occlusion, bailout PCI, aortic rupture Disclosure: The author has no conflicts of interest to declare.

Received: 25 March 2015 Accepted: 22 April 2015 Citation: Interventional Cardiology Review, 2015;10(2):94–7 Correspondence: Marco Barbanti, Division of Cardiology–Ferrarotto Hospital, University of Catania, Italy. E: mbarbanti83@gmail.com

Transcatheter aortic valve implantation (TAVI) is an effective treatment for patients with severe aortic valve stenosis and high operative risk.1 Despite its widespread adoption across the world, this procedure is still associated with several complications.2 Many of these, because their relatively high frequency (conduction disturbances, vascular complications, cerebrovascular events, paravalvular regurgitation, etc.), have been a field of deeper research aimed at defining potential predictive factors, clinical sequelae and procedural management.3–5 Nonetheless, TAVI has also been associated with very rare but life-threatening complications, such as coronary ostia obstruction and aortic rupture.6,7 Because of their extremely poor prognosis, prevention of these complications is of particular interest.

In this scenario, prosthesis type and size selection is part of the patient selection process that allows the operator to prevent these complications and finally determine procedural outcome.7,8 In this review, the techniques used either during pre-TAVI screening or during the procedure itself to avoid coronary occlusion and aortic rupture will be discussed

Coronary Occlusion The occurrence of coronary occlusion after TAVI was first described in 2006.9 In contemporary series its incidence has usually been less than 1 %, ranging from 0 % to 4.1 %.2 A recent systematic review showed that reported cases of coronary obstruction following TAVI occurred more frequently in women and patients receiving a balloon-expandable transcatheter heart valve (THV) (SAPIEN, Edwards Lifesciences, Irvine, CA, US), and the left coronary artery was the most commonly involved.6 In native aortic valves, coronary ostia obstruction is related to two main procedural factors: 1) In the vast majority of cases it occurs due

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to the displacement of a bulky calcified native valve over a coronary ostium; 2) the second option is more hypothetical: it occurs following an obstruction by a portion of the THV frame or the sealing cuff placed directly over a coronary ostium; however, no cases of coronary obstruction related to the struts of the THV frame or to the cuff/ leaflets of the transcatheter valve itself have been reported to date.

In both cases there are some anatomic features (narrow sinus of Valsalva, bulky leaflet calcifications, low-lying coronary ostia) that have been involved in its pathogenesis (see Figure 1). In a multicentre study enrolling 44 patients who suffered symptomatic coronary occlusion among a large series of 6,688 TAVIs, Ribeiro and colleagues demonstrated that lower-lying coronary ostium (<12 mm) and shallow sinuses of Valsalva (<30 mm) were the strongest anatomic factors associated with coronary obstruction. 8 Nevertheless, the risk of coronary occlusion remains difficult to assess, and no definite criteria exist to exclude patients deemed at high risk. However, this study suggests that greater caution should be applied when we are dealing with patients candidate to TAVI having such anatomical features.

A careful evaluation by means of multimodality imaging can help to highline the bulkiness of the native cusps, the height of the coronary ostia and the dimensions of the sinus of Valsalva.

In daily clinical practice, these evaluations can be made by using multidetector computed tomography (MDCT), which allows for a granular 3D reconstruction of the aortic root, providing extremely reliable assessment of dimensions and calcium distribution (see Figure 2).10,11 3D echocardiogram is also an important tool for aortic root measurements and for pre-procedural assessment of the coronary ostia, but it is limited by its inability of characterise aortic root calcifications.12

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Avoiding Coronary Occlusion and Root Rupture in TAVI

Figure 1: Schematic Representation of Four Aortic Root Scenarios

Figure 2: Multidetector Computed Tomography Reconstruction of the Aortic Root in One Patient Undergoing Evaluation Pre-transcatheter aortic valve implantation (TAVI)

A

B

LMCA

High coronary ostium height

RCA > 12 mm

Wide sinuses of Valsalva 17 mm

Sov > 30 mm LM > 12 mm

A

SoV 32 mm

B 33 mm

High coronary ostium height

RCA > 12 mm

Shallow sinuses of Valsalva

32.5 mm

C

RCA

Sov < 30 mm

22 mm LM > 12 mm

C

Low coronary ostium height

RCA > 12 mm

Wide sinuses of Valsalva (A) Double-oblique transverse at the level of the sinuses of Valsalva; (B) measurement of (B) left main coronary artery (LMCA); (C) right coronary artery (RCA).

Sov > 30 mm

LM < 12 mm

Figure 3: Simultaneous Aortography and Balloon Aortic Valvuloplasty Showing the Patency of Both Left Coronary Artery (LCA) and Right Coronary Artery (RCA) while the Balloon is Fully Inflated

D

Low coronary ostium height

RCA > 12 mm

Shallow sinuses of Valsalva Sov < 30 mm LM < 12 mm

LCA

(A) Wide sinuses of Valsalva (SoV) and high coronary ostia take off, and (B) shallow SoV and and high coronary ostia take off: in these two cases the risk of coronary occlusion is quite remote. (C) Wide SoV and low coronary ostia take off: a careful individual assessment should be made, also considering the calcium burden at the level of the cusps. Such cases can be performed with success, but more caution should be applied (a protection wire down to the left anterior descending may be considered), (D) shallow SoV and low coronary ostia take off: these cases are at high risk of coronary occlusion and they may represent a contraindication to transcatheter aortic valve implantation (TAVI).

When coronary obstruction does occur, clinical presentation is generally characterise by severe hypotension, ST-segment changes and procedural ventricular arrhythmias.6,8 Successful management may require temporary cardiopulmonary support and revascularisation.

When the MDCT assessment shows that a certain aortic root anatomy may be prone to develop coronary impairment after valve deployment, a pre-implant balloon valvuloplasty with simultaneous associated aortography may be useful to ensure the patency of the coronary ostia during balloon inflation; according to this technique, when the balloon is fully inflated, the coronary ostium could be occluded by the calcified cusps crushed against the wall of the sinuses of Valsalva (see Figure 3). In that case, the operator could consider terminating the procedure and considering other options.13 Alternatively, few strategies could be adopted: 1) implanting the prosthesis slightly lower into the left ventricle outflow tract (LVOT), in order to reduce the movement of the cusps toward the coronary ostia and the sinus walls (when the CoreValve prosthesis [Medtronic Inc., Minneapolis, MN, US] is implanted); 2) placing a coronary wire in the periphery of the left anterior descending in order to be ready to restore the patency of the coronary ostia by ballooning and/or stenting the left main, if it should be needed.6 If the patency of the coronary cannot be restored and the haemodynamic is poor, the valve should immediately be snared (CoreValve), or removed from its anatomical position by using an oversized balloon (i.e. SAPIEN prosthesis) and pulled up out into the ascending aorta to allow coronary perfusion to be re-established.14 Recently, Ribeiro and co-workers showed that PCI was the preferred strategy for the treatment of coronary obstruction following TAVI.8

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RCA

(A) Double-oblique transverse at the level of the sinuses of Valsalva; (B) measurement of (B) left main coronary artery (LMCA); (C) right coronary artery (RCA).

Importantly, PCI was feasible (attempted in 75 % of the patients) and had a success rate of 81.8 % (see Figure 4). Still, urgent coronary artery bypass graft (CABG) or mechanical haemodynamic support were needed in 14 % and 36 % of the patients, respectively.8

Valve-in-Valve Coronary obstruction is three- to fourfold more common after TAVI in degenerated surgical bioprostheses compared with native valve TAVI.15 Recently, Dvir and colleagues reported a coronary obstruction incidence of 3.5 % of patients.15 The main predisposing factor in the setting of aortic valve-in-valve procedures is the proximity of the coronary ostia to the anticipated final position of the displaced bioprosthetic leaflets after THV implantation. Therefore, predisposing factors for coronary obstruction may include a supraannular bioprosthetic valve, a narrow and low-lying sinotubular junction, bulky bioprosthetic leaflets, low-lying coronaries in narrow

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Structural Transcatheter Aortic Valve Implantation Figure 4: Case Example of Left Main Occlusion After CoreValve Implantation A

B

Figure 5: Implantation of a 26-mm CoreValve Prosthesis into a Degenerated 24 mm Toronto SPV Root (St Jude) A

B

C

CoreValve 26 mm

D

C

D

LMCA LMCA

E

F

LMCA RCA

During (B) and after valve deployment good coronary flow in both left main coronary artery (LMCA) and right coronary artery (RCA) was documented (C, D and E). However, after 3 minutes, patient developed severe hypotension and cardiogenic shock. The aortography showed the complete occlusion of both coronaries caused by the displacement of bioprosthetic leaflets after CoreValve expansion (F).

(A) Aortography after complete prosthesis deployment implant showing subtotal occlusion of left main trunk resulting from a bulky calcified leaflet displaced over the ostium (red arrow) after a 26 mm CoreValve implantation; (B)Drug-eluting stent placed inside the left main before deployment; (C) Drug-eluting stent during deployment inside the left main; (D) Angiography after stent implantation shows a patent coronary artery without any stenosis.

Figure 6: Case Example of Severe LVOT Calcification on MDCT

Multidetector Computed Tomography Reconstruction of the LVOT in One Patient Undergoing Evaluation pre-TAVI in double-oblique transverse (left panel) and coronal (right panel) projections displaying severe LVOT calcification.

aortic root and reimplanted coronaries.15 Bearing these concepts in mind, it appears logical that stentless bioprosthetic valves or those that are internally stented (eg, Mitroflow, Sorin; Trifecta, St Jude Medical) may be at a higher risk because the leaflets of these bioprostheses may extend outward in a tubular fashion after valve implantation beyond the surgical device frame (see Figure 5).15,16 In this setting, meticulous fluoroscopic and cardiac MDCT assessment may identify most cases at risk.16

Aortic Root Rupture Aortic root rupture after TAVI shares several aspects with coronary occlusion: 1) the frequency: a recent meta-analysis and a multicentre study reported a cumulative LVOT and annulus rupture rates of 1.1 % and 0.9 %, respectively;2,7 2) this complication is a particular concern with balloon-expandable prostheses because of the significant force applied during balloon deployment;7,17 3) clinical presentation, which can be dramatic: patients experiencing aortic root rupture (particularly

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those with uncontained rupture) develop sudden haemodynamic compromise and cardiogenic shock often unresponsive to inotropes.7 In such cases, median sternotomy and conversion into conventional aortic valve replacement usually represents the sole resort.

Nevertheless, uncontained aortic root rupture is burdened by a very high mortality rate (75 % in our previous series). Differently, periaortic haematoma (also named ‘contained aortic root rupture’) carries a better prognosis, even though it belongs to the spectrum of the same pathology.7,17 Indeed, among 11 cases of periaortic haematoma reported in the same study, all patients were alive at 30 days.7 The question is: is it possible to predict aortic rupture and to apply any strategy to prevent it? In this context, 3D MDCT has been shown to provide a deeper understanding of aortic annular geometry and allow for prediction of aortic rupture.10 Recently, we showed that there are at least two important features associated with annular rupture/periaortic haematoma: 1) moderate or severe LVOT/ subannular calcification (see Figure 6), and 2) significantly oversized prostheses (≥20 % area oversizing).7 Calcification in the LVOT is a particular concern in the context of TAVI, because this is a rigid, thinwalled structure. Therefore, detailed assessment of the distribution of calcium within the aortic root and LVOT may provide important additional information regarding the risk of aortic root injury. A recent observation suggests high LVOT/subannular region it is calcium located below the non-coronary cusp that is most predictive of aortic root injury.18 The reason for this finding is not entirely clear. Previous observations have suggested that the left aortic sinus may be the most vulnerable area with regard to aortic root injury possibly due to lack of supporting cardiac structures in this area.17,19 However, it may be speculated whether the culprit site is located at the site of calcification or at the aortic wall opposite to the calcification due to THV migration away from hard calcified areas during balloon expansion.

Historically, it has been shown that a certain degree of annular oversizing (5–1 5 % by area) is essential to mitigate the risk of significant paravalvular regurgitation with balloon-expandable valves.20 However, greater oversizing (>20 % by area) is indicated in borderline

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or transitional annulus, considering that available balloon-expandable valves have been available in 3 mm diameter increments, with nominal expanded diameters of 20, 23, 26 and 29 mm.21 In such situations (particularly when significant LVOT calcification, shallow sinuses of Valsalva or highly calcified aortic cusps are present), it may be safer to proceed with self-expanding (CoreValve, etc.) or inflatable (Direct Flow) TAVI platforms, which are rarely associated with annular rupture, when post-dilation is not performed. Alternatively, a recent approach of intentionally underexpanding balloon-expandable THVs by underfilling the deployment balloon has been proposed;21 this technique produced predictable reduction of THV expansion without adversely affecting procedural or short-term clinical or echocardiographic outcomes.21 Finally, in those cases of incomplete THV expansion causing residual paravalvular regurgitation, greater caution should be taken when

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Nishimura RA, Otto CM, Bonow RO, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines, 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 :2438–88 Généreux P, Head SJ, Van Mieghem NM, et al., Clinical outcomes after transcatheter aortic valve replacement using valve academic research consortium definitions: a weighted meta-analysis of 3,519 patients from 16 studies, J Am Coll Cardiol , 2012;59 :2317–26.

Athappan G, Gajulapalli RD, Sengodan P, et al., Influence of transcatheter aortic valve replacement strategy and valve design on stroke after transcatheter aortic valve replacement: a meta-analysis and systematic review of literature, J Am Coll Cardiol , 2014;63 ():2101–10.

Toggweiler S, Leipsic J, Binder RK, et al., Management of vascular access in transcatheter aortic valve replacement: part 2: Vascular complications, JACC Cardiovasc Interv , 2013;6 :767–76 Siontis GC, Jüni P, Pilgrim T, et al., Predictors of permanent pacemaker implantation in patients with severe aortic stenosis undergoing TAVR: a meta-analysis, J Am Coll Cardiol , 2014;64 :129–40.

Ribeiro HB, Nombela-Franco L, Urena M, et al., Coronary obstruction following transcatheter aortic valve implantation: a systematic review, JACC Cardiovasc Interv , 2013;6 :452–61.

Barbanti M, Yang TH, Rodes Cabau J, et al., Anatomical and procedural features associated with aortic root rupture during balloon-expandable transcatheter aortic valve replacement, Circulation , 2013;128 :244–53.

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8.

9.

10.

11.

12.

13.

14.

15.

performing balloon postdilatation in patients with significant LVOT calcification or shallow sinuses of Valsalva. This important factor will be likely addressed with the introduction of the new generation of balloon-expandable THV (SAPIEN 3, Edwards Lifesciences, Irvine, CA). In fact, it was recently demonstrated that a lesser degree of MDCT area oversizing might be employed for this new balloonexpandable THV.22

Conclusions Coronary occlusion and rupture of the aortic root or annulus remain two major concerns of transcatheter aortic valve implantation technique.

Despite their relatively low frequency they raised the interest of the scientific community as they carry an extremely poor prognosis.

Prosthesis type and size selection is part of the patient selection process that allows the operator to prevent these complications. n

Ribeiro HB, Webb JG, Makkar RR, et al., Predictive factors, management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: insights from a large multicenter registry, J Am Coll Cardiol , 2013;62 :1552–62.

Webb JG, Chandavimol M, Thompson CR, et al., Percutaneous aortic valve implantation retrograde from the femoral artery, Circulation , 2006;113 :842–50.

Willson AB, Webb JG, Freeman M, et al., Computed tomography-based sizing recommendations for transcatheter aortic valve replacement with balloon-expandable valves: comparison with transesophageal echocardiography and rationale for implementation in a prospective trial, J Cardiovasc Comput Tomogr , 2012;6 :406–14.

Achenbach S, Delgado V, Hausleiter J, et al., SCCT expert consensus document on computed tomography imaging before transcatheter aortic valve implantation (TAVI)/ transcatheter aortic valve replacement (TAVR), J Cardiovasc Comput Tomogr , 2012;6 :366–80.

Khalique OK, Kodali SK, Paradis JM, et al., Aortic annular sizing using a novel 3-dimensional echocardiographic method: use and comparison with cardiac computed tomography, Circ Cardiovasc Imaging , 2014;7 :155–63.

Barbanti M, Sgroi C, Immè S, et al., Usefulness of contrast injection during balloon aortic valvuloplasty before transcatheter aortic valve replacement: a pilot study, EuroIntervention , 2014;10 :241–7.

Ussia GP, Barbanti M, Sarkar K, et al., Transcatheter aortic bioprosthesis dislocation: technical aspects and midterm follow-up, EuroIntervention , 2012;7 :1285–92.

Dvir D, Webb JG, Bleiziffer S, et al., Valve-in-Valve International Data Registry Investigators. Transcatheter aortic

valve implantation in failed bioprosthetic surgical valves, JAMA , 2014;312 :162–70.

16. Dvir D, Leipsic J, Blanke P, et al., Coronary obstruction in transcatheter aortic valve-in-valve implantation: preprocedural evaluation, device selection, protection, and treatment, Circ Cardiovasc Interv , 2015;8 ():pii: e002079.

17. Blanke P, Reinohl J, Schlensak C, et al., Prosthesis oversizing in balloon expandable transcatheter aortic valve implantation is associated with contained rupture of the aortic root, Circ Cardiovasc Interv , 2012;5 :540–8.

18. Hansson NC, Nørgaard BL, Barbanti M, et al., The impact of calcium volume and distribution in aortic root injury related to balloon-expandable transcatheter aortic valve replacement, J Cardiovasc Comput Tomogr , 2015; in press.

19. Hayashida K, Bouvier E, Lefèvre T et al., Potential mechanism of annulus rupture during transcatheter aortic valve implantation, Circ Cardiovasc Interv , 2013;82 :E742–E746.

20. Dvir D, Webb JG, Piazza N, et al., Multicenter evaluation of transcatheter aortic valve replacement using either SAPIEN XT or CoreValve: Degree of device oversizing by computedtomography and clinical outcomes, Catheter Cardiovasc Interv , 2015 [Epub ahead of print].

21. Barbanti M, Leipsic J, Binder R, et al., Underexpansion and ad hoc post-dilation in selected patients undergoing balloonexpandable transcatheter aortic valve replacement, J Am Coll Cardiol , 2014;63 :976–81.

22. Yang TH, Webb JG, Blanke P, et al., Incidence and Severity of Paravalvular Aortic Regurgitation With Multidetector Computed Tomography Nominal Area Oversizing or Undersizing After Transcatheter Heart Valve Replacement With the Sapien 3: A Comparison With the Sapien XT, JACC Cardiovasc Interv , 2015;8 :462–71.

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ION.

Permanent Pacemaker Implantation after TAVR – Predictors and Impact on Outcomes Marcel Weber, Jan-Malte Sinning, Christoph Hammerstingl, Nikos Werner, Eberhard Grube and Georg Nickenig University of Bonn, Department of Internal Medicine II, Cardiology, Pulmonology and Angiology, Germany

Abstract The number of patients undergoing transcatheter aortic valve replacement (TAVR) worldwide is increasing steadily. Atrioventricular conduction disturbances, with or without the need for permanent pacemaker (PPM) implantation, are one of the most common adverse events after TAVR. Among transcatheter heart valves (THV), rates of conduction abnormalities vary from less than 10 % to more than 50 %. Depending on the reported data referred to, historical data showed that up to one-third of the patients required implantation of a PPM following TAVR. Although generally considered as a minor complication, PPM may have a profound impact on prognosis and quality of life after TAVR. Current data support the hypothesis that conduction abnormalities leading to pacemaker dependency result from mechanical compression of the conduction system by the prosthesis stent frame and individual predisposing conduction defects such as right bundle-branch block (RBBB). With several large randomised trials and registry studies having been published recently and second generation THV having been introduced, the debate about predictors for pacemaker implantation and their impact on outcome after TAVR is still ongoing.

Keywords Transcatheter aortic valve replacement (TAVR), Pacemaker, Aortic stenosis, conduction abnormalities, left bundle branch block, atrioventricular block Disclosure: Dr Sinning, Prof Werner, Prof Grube and Prof Nickenig receive research grants and speaker honoraria from Medtronic and Edwards Lifesciences.

Dr Grube works as proctor for Medtronic. The other authors have no conflicts of interest to declare.

Received: 17th March 2015 Accepted: 27th April 2015 Citation: Interventional Cardiology Review, 2015;10(2):98–102 Correspondence: Marcel Weber, Department of Internal Medicine II, Cardiology, Pulmonology and Angiology, University Hospital Bonn, Sigmund-Freud-Str.25, 53105 Bonn, Germany; E: marcel.weber@ukb.uni-bonn.de

Transcatheter aortic valve replacement (TAVR) has emerged as the treatment of choice among inoperable patients with symptomatic severe aortic stenosis and as a treatment alternative to surgical aortic valve replacement (SAVR) for high-risk surgical patients1–3.

Subsequently, the number of patients undergoing TAVR worldwide is steadily increasing and the complications related to valve implantation have been well-recognised.

Conduction disturbances after SAVR have been extensively documented and are in part predicted by pre-existing conduction abnormalities4. According to recent data, PPM implantation is necessary in approximately five per cent of patients undergoing SAVR. Among transcatheter heart valves (THV), rates of conduction abnormalities vary from less than 10 % to more than 50 %. Depending on the reported data referred to, historical data showed that up to one-third of patients required implantation of a PPM following TAVR5. Since the debate about predictors for pacemaker implantation and their impact on outcome after TAVR is still ongoing, this review will assess the current status quo.

Predictors of PPM Implantation Pre-existing Conduction Abnormalities and Anatomical Conditions Patients undergoing TAVR have similar rates of pre-existing conduction disease as SAVR patients, which are described at 40–50 % in both

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surgical and transcatheter populations4,6. In an early study with the self-expanding Medtronic CoreValve Prosthesis (MCP, Medtronic, Minneapolis, Minnesota), left bundle-branch block (LBBB) at baseline, increased interventricular septal diameter (>17 mm) and increased noncoronary aortic cusp thickness (>8 mm) were highly predictive for PPM (receiver operating characteristic area 0.93±0.055, P< 0.001)7. In this analysis, non-coronary aortic cusp thickness was the strongest predictor (P=0.002, correlation coefficient =0.655). A similar study by Baan et al.8 found in 34 MCP patients that small left-ventricular outflow tract diameter, left axis deviation, significant mitral annular calcification and lower post-implant valve area are predicting post-TAVR PPM. Several studies showed that right bundle-branch block (RBBB) at baseline is one of the most significant predictors of PPM after TAVR9–14. Additionally, baseline first-degree atrioventricular (AV) block10, left anterior hemiblock12 and intraprocedural AV block15 are important predictors for PPM dependence.

Most of the previously mentioned studies looked at a low number of cases. In contrast to the recent meta-analysis of Siontis et al., RBBB (n=2158; risk ratio (RR): 2.89 (CI: 2.36–2.54), p<0.01), baseline AV block (n=1381; RR: 1.52 (CI: 1.15–2.01), p<0.01), and left anterior hemiblock (n=1065; RR: 1.62 (CI: 1.17–2.25), p<0.01) were the strongest predisposing conduction disturbances for PPM16. Figure 1 emphasises the close anatomical relationship of the cardiac conduction system referring to the aortic valve and highlights the importance of pre-existing conduction abnormalities as a predictor for PPM after TAVR.

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Prosthesis Type and Time of PPM Prosthesis Type

Figure 1: Short Axis View Reconstruction of Aortic Valve by Computer Tomography

The incidence of AV conduction disturbances as a result of TAVR and the subsequent requirement for permanent pacing differs between the two most widely used bioprostheses, the balloon-expandable Edwards SAPIEN valve (ESV) (Edwards Lifesciences, Irvine, California) and the self-expanding MCP. PPM implantation has been reported with a rate between 5–14.2 % [2,13,17–19] for the former Edwards valves (Edwards SAPIEN and Edwards SAPIEN XT) and 13.3 % for the new Edwards SAPIEN 3 THV20, whereas the need for PPM has been higher with use of the MCP (up to 24 % in the FRANCE-2 [French Aortic National CoreValve and Edwards] registry and 33 % in the UK CoreValve registry)21,15.

Early data showed a more liberal pacemaker implantation strategy after MCP TAVR and resulted in higher PPM rates, whereas newer data of the Advance II trial, which were presented at EuroPCR 2014 (ADVANCE II: Low incidence of permanent pacemaker for self -expandable valve by Petronio A. S. et al. at Euro PCR 2014, May 22, Paris, France) show that PPM rate was reduced to 13.3 % at 30 days’ follow up when MCP was deployed according to best recommendation practice (implantation depths <6 mm). Recent data of the CoreValve Extreme Risk pivotal trial revealed a PPM implantation rate of 21.6 % at 30 days22.

RVOT: right ventricular outflow tract, RCA: right coronary artery, LCA: left coronary artery, RCC: right coronary cusp, NCC: non-coronary cusp, LCC: left coronary cusp, LBB: left bundlebranch, HIS: HIS-bundle, LA: left atrium.

In addition to the above-mentioned THVs, four so-called next-generation devices have been evaluated in recent trials. The multicentre nonrandomised DISCOVER trial (100 patients) recently assessed the outcomes of the non-metallic direct-flow medical THV in surgical high-risk patients. The device is fully repositionable and retrievable until polymer exchange. In DISCOVER, the overall PPM rate at 30 days was 17 %23.

2.5 times more often after MCP than after ESV implantation and is also associated with reduced recovery28. In another MCP analysis, a proportion of AV conduction disturbances after the intervention has been shown to recover over time at three months of follow-up, and only 40 % of the PPM patients for high-degree AVB still had an AVB underlying their paced rhythm29. Due to the relatively low sample size of these studies, this issue needs further investigation.

The REPRISE studies assessed the outcomes with the new mechanically expanding LOTUS valve, which can be fully retrieved, redeployed or repositioned. The 30-day results of the REPRISE II trial (120 patients), which was a prospective, single-arm, multicentre study showed a PPM rate of 28.6 % at 30 days24, which might be explained by the fact that all patients with borderline aortic annulus had to undergo TAVR with the larger 27 mm prosthesis, since the 25 mm prosthesis was not available at that time.

Data in relation to the appropriate time point of pacemaker implantation are rare. Simms et al. published a cohort of 100 TAVR patients who received the MCP. Average time to pacemaker implantation was four-and-a-half days (confidence interval: 2.8–6.2)30. In another cohort with the MCP prosthesis (n=270), median time to implantation of a pacemaker was four days (interquartile range [IQR], 2.0 to 7.75 days)15.

Bagur et al (n=411) reported that PPM was performed at a median of two days (IQR: 0–4 days) after TAVR with ESV10.

Thirty-day outcomes from the multicentre European pivotal trial for transapical transcatheter aortic valve implantation with the selfexpanding Medtronic engager valve prosthesis (Medtronic, Inc., Minneapolis, MN, USA), which consists of a self-expanding nitinol frame and a bovine pericardial tissue valve, revealed a 30-day PPM rate of 26 %25.

The exact time point for PPM implantation is still an ongoing debate.

Another aspect, which has to be kept in mind, is the fact that selfexpanding prostheses may lead to delayed injuries of the conduction system. So far, there is no explicit data for the best time point for PPM implantation in patients after Boston Lotus, Medtronic engager or Jena valve implantation.

The transapical JenaValve™ THV system showed a 30-day pacemaker implantation rate of 9.1 %26. Other new transcatheter valves are currently under development, and will be evaluated in the near future.

Pre- and Post-dilatation and Prosthesis Sizing

Persistence of Conduction Abnormalities and time to Pacemaker Implantation: Persistence of conduction disturbances and high-degree AV block over time is not yet clear, and seems to differ between MCP and ESV. Houthuizen reports approximately 40 % of patients developed a new LBBB after TAVI; most of these persisted at follow-up, but MCP had a twofold lower tendency to resolve27. A new LBBB occurs

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The close relationship of the conduction system to the aortic annulus may lead to a mechanical interaction between the prosthesis stent frame of the transcatheter valve prosthesis and the left bundlebranch, which in turn may translate into the occurrence of an LBBB and eventually into a higher grade or complete atrio-ventricular block.

A study by Lange et al.31 analysed the impact of valvuloplasty balloon catheter size on the need for PPM in a larger cohort of 237 patients without prior pacemaker, who underwent TAVR with the MCP. In this analysis, the overall incidence of PPM was 21.1 %, but was significantly higher when a 25 mm balloon was used (27.1 %) than when a 23 mm

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Structural Transcatheter Aortic Valve Implantation Table 1: Predictors of Permanent Pacemaker Implantation Following Transcatheter Aortic Valve Implantation

rate. A recent analysis showed a low post-dilatation rate of 4 % after Edwards SAPIEN 3 TAVR33.

Author, no.

The degree of prosthesis oversizing may lead to a higher incidence of PPM. Schroeter et al. found larger or significantly oversized prostheses to be an independent risk factor for PPM implantation following TAVR with the MCP35. In contrast, a study of Binder et al. with 89 patients receiving a SAPIEN XT THV showed that annular area oversizing was not associated with new conduction disturbances and permanent pacemaker implantation36. If this difference can be explained by the fact that the ESV prosthesis is oversized to a lesser degree to prevent annulus rupture remains unclear and needs further investigation.

Valve Type

patients

In-hospital /

Multivariate

30-day

predictors

incidence n (%) D’Ancona

Edwards SAPIEN

20 (6.2)

Age

Edwards SAPIEN

30 (7.3)

Pre-existing RBBB

Bleiziffer

Edwards SAPIEN

Edwards SAPIEN Peri-procedural

et al.42, n=159

(n=35)

6 (17) CoreValve complete AVB

et al.41, n=322 Bagur et al.10, n=411

CoreValve (n=124) 33 (27) Ledwoch

Edwards SAPIEN

et al.[13], n=1147 (n=232)

Edwards

CoreValve (n=912) CoreValve 352 Khawaja

CoreValve

Absence of prior

SAPIEN 33 (14.2) valve surgery Porcelain aorta

(38.6)

CoreValve

82 (33.3)

Peri-procedural

et al.15 n=243

complete AVB Balloon pre-dilatation Prolonged baseline QRS duration 29 mm prosthesis

De Carlo

CoreValve

66 (24.0)

et al.12, n=275

Depth of implantation Pre-existing RBBB Pre-existing LAHB Longer PR at baseline

Chorianopoulos CoreValve

46 (35.4)

Pre-existing RBBB

48 (27.6)

Depth of implantation

et al.11, N=130 Munoz-Garcia

CoreValve

et al.14, n=174

Pre-existing RBBB Use of the traditional system

Calvi

CoreValve

52 (32.1)

Pre-existing RBBB

Siontis et al.16,

CoreValve and

Median 28 %

Male gender

n=11 210

Edwards SAPIEN

(CoreValve)

Pre-existing first-

Median 6 %

degree AV-block

(Edwards

Pre-existing left

SAPIEN)

anterior hemiblock

et al.9, n=162

Implantation Depths and Approach Many studies have shown that the CoreValve prosthesis implantation depth is a predictor for PPM. The deeper the CoreValve frame protrudes into the left ventricular outflow tract, the more likely the patient is to develop an LBBB. In an early study by Piazza et al.37, the mean implantation depth was 10.3 mm in those patients with new LBBB versus 5.5 mm in those without LBBB. Another study proposed a cutoff of 6.0 mm as an independent predictor of the development of a high-degree AV block and the requirement for permanent pacing29.

This finding was confirmed for the MCP prosthesis by several other recently published studies8,38,39,12. Additionally, implantation of balloonexpandable transfemoral THVs with increased implantation depth is associated with clinically significant new conduction disturbances and permanent pacemaker implantation36. These effects also apply to ESV implantation via a transapical approach40.

The PPM incidence regarding TAVR approach is difficult to assess because patient population and risk profile are often different. A recent meta-analysis of Siontis et al.16 suggested a trend towards lower risk of PPM after MCP TAVR with the transfemoral approach compared with the transsubclavian approach (p=0.07). The same meta-analysis found no difference in PPM risk after ESV TAVR depending on the approach (transapical versus transfemoral; n=2136; risk ratio: 0.89, 95 % CI: 0.64-1.25; p=0.89).

Pre-existing right bundle-branch block

Cost and Outcome of PPM Implantation

Intraprocedural

Cost

AV-block CAD, coronary artery disease; LAHB, left anterior hemiblock; LVOT, left ventricular outflow tract; RBBB, right bundle-branch.

or smaller balloon was used (15.4 %) for the balloon valvuloplasty (BAV). When stratified by THV size (26 or 29 mm), there was still a stepwise increase in PPM rate with each increase in balloon size. This association of balloon size with need for a PPM remained significant after multivariable adjustment for baseline patient characteristics.

These results suggest that pacemaker rates after TAVR may be reduced by using undersized BAV balloons or even avoidance of predilation. Two randomised studies are currently ongoing to investigate direct TAVR without pre-dilatation with the MCP (SIMPLIFY TAVI Trial; NCT01539746) and the ESV (EASE-IT Trial; NCT02127580). Interestingly, in another study post-dilation after MCP, implantation had no effect on the requirement for PPM. The reason for this observation might be the relatively short time period when the aortic annulus is exposed to high pressure from repeated valvuloplasty31. Post-dilatation after ESV TAVR ranges between 20–41 %32–34 and shows no impact on PPM

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Patients with AV conduction disturbances after TAVR are disposed to prolonged hospitalisation and use of in-hospital continuous telemetry43, both of which result in a considerable increase of overall cost of the TAVR procedure. Data from the FRANCE registry found that receiving a pacemaker was associated with a 36 % increase in cost44. Gutmann et al. assessed elevated procedural costs of €1,946 in case of PPM implantation in a German healthcare analysis45. Compared with surgical aortic valve replacement (SAVR), in-hospital costs were higher in TAVR patients than in SAVR patients (€40,802 versus €33,354, respectively; p=0.010)46). Reducing PPM rate would have an impact on the cost-effectiveness of TAVR relative to that of SAVR.

Outcome The impact of new-onset LBBB, with or without need for PPM implantation, on patient outcome after TAVR is still under debate.

Houthuizen et al. found negative effects of a procedure-related LBBB on survival in a group of 679 patients after TAVR. They described an all-cause mortality of 37.8 % (n=88) in 233 patients with new-onset

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LBBB and 24.0 % (n=107) in patients without LBBB (p=0.002) after a median follow-up of 450 days. Consecutively, a procedure-related LBBB was an independent predictor for all-cause mortality (hazard ratio: 1.54; confidence interval (CI): 1.12–2.10) in this cohort47.

Schymik et al. confirmed that a persistent new-onset LBBB was associated with increased mortality in a cohort of 634 patients who were treated by either an MCP or ESV prosthesis. The one-year all-cause mortality rate was also higher in patients with persistent new-onset LBBB (20.8 %, n=41) than in patients without LBBB (13.0 %, n=57; p=0.010). Multivariate regression analysis revealed again that persistent new-onset LBBB was an independent predictor of all-cause mortality at one year (HR 1.84, 95 % CI 1.35–2.02).

Clinical Implication Temporarily inserted pacing leads are mandatory for rapid pacing during the procedure as well for at least 24 hours after TAVR for therapy of delayed bradycardia. Patients with self-expanding valves like the MCP should be monitored for at least 48 hours after TAVR54. In case of new-onset LBBB or AV block, ECG monitoring should be continued for five days. In particular, those patients with pre-existing conduction disturbances such as RBBB or first-degree AV block should be carefully monitored with daily ECG. Pacemaker rates after TAVR may be safely decreased by avoiding pre-dilatation or use of undersized balloons31, as well as correct positioning of the prosthesis37.

Future Considerations However, Buellesfeld et al. recently published data on 353 patients undergoing TAVR with the CoreValve prosthesis and found that PPM implantation had no impact on major adverse cardiac and cerebrovascular events or mortality outcome one year after TAVR48.

Other study groups found no difference in mortality regarding LBBB or PPM49–51. Hoffmann et al. found a significantly higher left ventricular ejection fraction in patients after TAVR without LBBB (59±10 %) as compared with those with LBBB during 12 months of follow-up (51±12 %; p=0.052), but found no difference in clinical outcome52.

These findings were confirmed by Nazif et al. who presented the

Increasing data from observational studies involving new valve technologies, such as the Direct Flow Medical (Santa Rosa, CA, USA), the Lotus Aortic Valve prosthesis (Boston Scientific Corporation, Marlborough, Massachusetts), the JenaValve™ system (JenaValve Technology GmbH, Munich, Germany), the transfemoral Medtronic Evolut R, and the transapical Medtronic Engager (Medtronic, Minneapolis, Minnesota) show promising results and improve outcomes by minimising procedure-related complications. Future studies might give new answers on predictors and outcome after TAVR regarding PPM.

one-year results of the PARTNER trial and focused on new-onset LBBB which was not associated with significant differences in one-year mortality, cardiovascular mortality or repeat hospitalisation.

However, it was associated with increased PPM implantation during hospitalisation (8.3 % versus 2.8 %, p=0.005) and the ejection fraction failed to improve after TAVR in patients with new LBBB and remained lower at six months to one year (52.8 % versus 58.1 %, p=0.001)53. The independent predictors of the outcome in patients with new-onset LBBB (including the protective or detrimental effect of pacemaker implantation after TAVR) are currently unclear and still need further investigation.

Conclusion

1.

Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med , 2012;366 (18):1696–1704.

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 (17):1597–1607.

3. Smith 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.

4. Bagur R, Manazzoni JM, Dumont E, et al.(2011) Permanent pacemaker implantation following isolated aortic valve replacement in a large cohort of elderly patients with severe aortic stenosis. Heart 2011;97 (20):1687-94.

5. Erkapic D, De Rosa S, Kelava A, et al. Risk for permanent pacemaker after transcatheter aortic valve implantation: a comprehensive analysis of the literature. J Cardiovasc Electrophysiol 2012;23 (4):391–7.

6. Fraccaro C, Buja G, Tarantini G, et al. Incidence, predictors, and outcome of conduction disorders after transcatheter self-expandable aortic valve implantation. Am J Cardiol 2011;107 (5):747–754.

7. Jilaihawi H, Chin D, Vasa-Nicotera M, et al. Predictors for permanent pacemaker requirement after transcatheter aortic valve implantation with the CoreValve bioprosthesis. Am Heart J 2009;157 (5):860–6.

8. Baan J, Jr., Yong ZY, Koch KT, et al. Factors associated with cardiac conduction disorders and permanent pacemaker implantation after percutaneous aortic valve implantation with the CoreValve prosthesis. Am Heart J 2010;159(3):497–503.

9. Calvi V, Conti S, Pruiti GP, et al. Incidence rate and predictors of permanent pacemaker implantation after transcatheter aortic valve implantation with self-expanding CoreValve prosthesis. Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing 2012;34 (2):189–195.

10. Bagur R, Rodes-Cabau J, Gurvitch R, et al. Need for permanent pacemaker as a complication of transcatheter aortic valve implantation and surgical aortic valve replacement in elderly patients with severe aortic stenosis

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Despite being less invasive than open SAVR, TAVR remains associated with potential procedure-related complications. New LBBB and the need for PPM implantation are the most frequent adverse events after TAVR. The incidence of significant conduction disturbances is dependent on the TAVR prosthesis used and has decreased as a result of improved implantation techniques. In addition, nextgeneration devices with reduced interaction with the LVOT might further decrease conduction disturbances after TAVR. Minimising PPM rate is important, especially as TAVR technology could be increasingly applied to younger and healthier patients. n

and similar baseline electrocardiographic findings. JACC Cardiovasc Interv 2012;5 (5):540–51.

11. Chorianopoulos E, Krumsdorf U, Pleger ST,et al. Incidence of late occurring bradyarrhythmias after TAVI with the selfexpanding CoreValve((R)) aortic bioprosthesis. Clin Res Cardiol 2012;101 (5):349–355.

12. De Carlo M, Giannini C, Bedogni F, et al. Safety of a conservative strategy of permanent pacemaker implantation after transcatheter aortic CoreValve implantation. Am Heart J 2012;163 (3):492–499.

13. Ledwoch J, Franke J, Gerckens U, et al. Incidence and predictors of permanent pacemaker implantation following transcatheter aortic valve implantation: Analysis from the German transcatheter aortic valve interventions registry.

Catheter Cardiovasc Interv 2013.

14. Munoz-Garcia AJ, Hernandez-Garcia JM, Jimenez-Navarro MF, et al. Factors predicting and having an impact on the need for a permanent pacemaker after CoreValve prosthesis implantation using the new Accutrak delivery catheter system. JACC Cardiovasc Interv 2012;5 (5):533–9.

15. Khawaja MZ, Rajani R, Cook A, et al. (2011) Permanent pacemaker insertion after CoreValve transcatheter aortic valve implantation: incidence and contributing factors (the UK CoreValve Collaborative). Circulation 2011;123 (9):951–60.

16. Siontis GC, Juni P, Pilgrim T, et al. Predictors of permanent pacemaker implantation in patients with severe aortic stenosis undergoing TAVR: a meta-analysis. J Am Coll Cardiol 2014;64 (2):129–140.

17. 1Webb JG, Altwegg L, Boone RH, et al. Transcatheter aortic valve implantation; impact on clinical and valve-related outcomes. Circulation 2009.

18. Laynez A, Ben-Dor I, Barbash IM, et al.(2012) Frequency of conduction disturbances after Edwards SAPIEN percutaneous valve implantation. Am J Cardiol 2012;110 (8):1164–8.

19. Eltchaninoff H, Prat A, Gilard M, et al. Transcatheter aortic valve implantation: early results of the FRANCE (French Aortic National CoreValve and Edwards) registry. Eur Heart J 2011;32 (2):191–7.

20. Webb J, Gerosa G, Lefèvre T, et al. Multicenter evaluation of a next-generation balloon-expandable transcatheter aortic valve. Journal of the American College of Cardiology 2014;64 (21):2235–43.

21. Hayashida K, Morice MC, Chevalier B, et al. Sex-related differences in clinical presentation and outcome of transcatheter aortic valve implantation for severe aortic stenosis. J Am Coll Cardiol 2012;59 (6):566–71.

22. 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.

23. Schofer J, Colombo A, Klugmann S, et al. Prospective multicenter evaluation of the direct flow medical transcatheter aortic valve. J Am Coll Cardiol 2014;63 (8):763–8.

24. Meredith 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.

25. Sündermann SH, Holzhey D, Bleiziffer S, Treede H, Falk V Medtronic Engager™ bioprosthesis for transapical transcatheter aortic valve implantation. EuroIntervention 2013;9 (S):S97–S100.

26. Treede H, Mohr FW, Baldus S, et al.(2012) Transapical transcatheter aortic valve implantation using the JenaValve system: acute and 30-day results of the multicentre CE-mark study. Eur J Cardiothorac Surg 2012;41 (6):e131–8.

27. Houthuizen P, van der Boon RM, Urena M, et al. Occurrence, fate and consequences of ventricular conduction abnormalities after transcatheter aortic valve implantation.

EuroIntervention 2014;9 (10):1142–50.

28. Franzoni I, Latib A, Maisano F, et al. Comparison of incidence and predictors of left bundle branch block after transcatheter aortic valve implantation using the CoreValve versus the Edwards valve. Am J Cardiol 2013;112 (4):554–9.

29. Guetta V, Goldenberg G, Segev A, et al. Predictors and course of high-degree atrioventricular block after

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31.

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33.

34.

35.

36.

37.

38.

transcatheter aortic valve implantation using the CoreValve Revalving System. Am J Cardiol 2011;108 (11):1600–5.

Simms AD, Hogarth AJ, Hudson EA, et al. Ongoing requirement for pacing post-transcatheter aortic valve implantation and surgical aortic valve replacement.

Interactive Cardiovascular and Thoracic Surgery 2013;17 (2):328–33.

Lange P, Greif M, Vogel A, et al. vReduction of pacemaker implantation rates after CoreValve(R) implantation by moderate predilatation. EuroIntervention 2014;9 (10):1151–57.

Nombela-Franco L, Rodes-Cabau J, et al. Predictive factors, efficacy, and safety of balloon post-dilation after transcatheter aortic valve implantation with a balloonexpandable valve. JACC Cardiovasc Interv 2012;5 (5):499–512.

Amat-Santos IJ, Dahou A, Webb J, et al. Comparison of hemodynamic performance of the balloon-expandable SAPIEN 3 versus SAPIEN XT transcatheter valve. Am J Cardiol 2014;114 (7):1075–82.

Daneault B, Koss E, Hahn RT, et al. Efficacy and safety of postdilatation to reduce paravalvular regurgitation during balloon-expandable transcatheter aortic valve replacement.

Circ Cardiovasc Interv 2013;6 (1):85–91.

Schroeter T, Linke A, Haensig M, et al.Predictors of permanent pacemaker implantation after Medtronic CoreValve bioprosthesis implantation. Europace 2012;14 (12):1759–63.

Binder RK, Webb JG, Toggweiler S, et al. Impact of postimplant SAPIEN XT geometry and position on conduction disturbances, hemodynamic performance, and paravalvular regurgitation. JACC Cardiovasc Interv 2013;6 (5):462–68.

Piazza N, Onuma Y, Jesserun E, et al. Early and persistent intraventricular conduction abnormalities and requirements for pacemaking after percutaneous replacement of the aortic valve. J Am Coll Cardiol Intv 2008;1 (3):310–16.

Ferreira ND, Caeiro D, Adao L, et al. (2010) Incidence and

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predictors of permanent pacemaker requirement after transcatheter aortic valve implantation with a self-expanding bioprosthesis. Pacing and clinical electrophysiology : PACE 2010;33 (11):1364–72.

Munoz-Garcia AJ, Hernandez-Garcia JM, Jimenez-Navarro MF, et al. Changes in atrioventricular conduction and predictors of pacemaker need after percutaneous implantation of the CoreValve(R). Aortic valve prosthesis.

Revista española de cardiologia 2010;63 (12):1444–51 Gutierrez M, Rodes-Cabau J, Bagur R, et al.

Electrocardiographic changes and clinical outcomes after transapical aortic valve implantation. Am Heart J 2009;158 (2):302-8.

D’Ancona G, Pasic M, Unbehaun A, Hetzer R Permanent pacemaker implantation after transapical transcatheter aortic valve implantation. Interactive Cardiovascular and Thoracic Surgery 2011;13 (4):373–6.

Bleiziffer S, Ruge H, Horer J, et al. Predictors for new-onset complete heart block after transcatheter aortic valve implantation. JACC Cardiovasc Interv 2010;3 (5):524–30.

Nazif TM, Dizon JM, Hahn RT, et al. Predictors and clinical outcomes of permanent pacemaker implantation after transcatheter aortic valve replacement: the PARTNER (Placement of AoRtic TraNscathetER Valves) trial and registry. JACC Cardiovasc Interv 2015;8 (1 Pt A):60–69.

Chevreul K, Brunn M, Cadier B, et al. Cost of transcatheter aortic valve implantation and factors associated with higher hospital stay cost in patients of the FRANCE (FRench Aortic National CoreValve and Edwards) registry. Archives of Cardiovascular Diseases 2013;106 (4):209–219.

Gutmann A, Kaier K, Sorg S, et al. Analysis of the additional costs of clinical complications in patients undergoing transcatheter aortic valve replacement in the German health care system. International Journal of Cardiology 2015;179 :231–7.

46. Osnabrugge RL, Head SJ, Genders TS, et al. Costs of transcatheter versus surgical aortic valve replacement in intermediate-risk patients. Ann Thorac Surg 2012;94(6):1954–60.

47. Houthuizen P, Van Garsse LA, Poels TT, et al. Left bundle-branch block induced by transcatheter aortic valve implantation increases risk of death. Circulation 2012;126 (6):720–8.

48. Buellesfeld L, Stortecky S, Heg D, et al. Impact of permanent pacemaker implantation on clinical outcome among patients undergoing transcatheter aortic valve implantation. J Am Coll Cardiol 2012;60 (6):493–501.

49. Linke A, Wenaweser P, Gerckens U, et al. Treatment of aortic stenosis with a self-expanding transcatheter valve: the international multi-centre ADVANCE study. Eur Heart J 2014;35 (38):2672–84.

50. Testa L, Latib A, De Marco F, et al. Clinical impact of persistent left bundle-branch block after transcatheter aortic valve implantation with corevalve revalving system.

Circulation 2013;127 (12):1300–7.

51. Urena M, Webb JG, Tamburino C, et al. Permanent pacemaker implantation after transcatheter aortic valve implantation: impact on late clinical outcomes and left ventricular function. Circulation 2014;129 (11):1233–43.

52. Hoffmann R, Herpertz R, Lotfipour S, et al. Impact of a new conduction defect after transcatheter aortic valve implantation on left ventricular function. JACC Cardiovasc Interv 2012;5 (12):1257–63.

53. Nazif TM, Williams MR, Hahn RT, et al. Clinical implications of new-onset left bundle-branch block after transcatheter aortic valve replacement: analysis of the PARTNER experience. Eur Heart J 2014;35 (24):1599–1607.

54. Holmes DR, Jr., Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/ STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol 2012;59 (13):1200–1254.

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ION.

Balloon- or Self-Expandable TAVI: Clinical Equipoise?

J ohn Jose, G e r t Ri c h a r d t a n d M o h a m e d A b d e l - Wa h a b Heart Center, Segeberger Kliniken GmbH (Academic Teaching Hospital of the Universities of Kiel, Lübeck and Hamburg), Bad Segeberg, Germany

Abstract Transcatheter aortic valve implantation (TAVI) has become an effective treatment option for patients with severe aortic stenosis and high surgical risk or contraindications for surgical aortic valve replacement. Most of the currently available prostheses employ either balloon-expandable or self-expandable designs. Presently, there is a paucity of data directly comparing these two widely used prosthesis types. Forthcoming trials will reveal whether newer designs of both technologies translate into fewer complications and better outcomes, with expansion of TAVI indications. This manuscript reviews features and clinical outcomes of balloon- and self-expanding prostheses, summarising current data from registries and trials.

Keywords TAVI, balloon-expandable, self-expandable, aortic stenosis, device success.

Disclosure: Dr Jose is currently supported by an EAPCI grant in Interventional Cardiology which is partially sponsored by Medtronic. Prof Richardt reports receiving lecture fees from Edwards Lifesciences and Boston Scientific. Prof Abdel-Wahab is a proctor for Boston Scientific.

Received: 14 February 2015 Accepted: 29 April 2015 Citation: Interventional Cardiology Review, 2015;10(2):103–8 Correspondence: Dr. Mohamed Abdel-Wahab, MD, FESC, Heart Center, Segeberger Kliniken GmbH, Am Kurpark 1, 23795 Bad Segeberg, Germany E: mohamed.abdel-wahab@segebergerkliniken.de

Transcatheter aortic valve implantation (TAVI) has undergone tremendous technological advancements since the first successful implantation in 2002 for symptomatic severe aortic valve stenosis (AS).1 It is currently considered as the standard of care for severe AS patients who have high surgical risk or may be deemed unsuitable for surgery.2 Broadly, there are two main categories of transcatheter aortic valve prostheses: balloon-expandable (BE) and self-expandable (SE).

Limited data exists as to whether there are significant differences in clinical outcomes with these two different prosthesis types. As newer prosthesis generations become available and the indications for TAVI expand to include additional patients and indications, such as those with intermediate surgical risk,3 valve-in-valve procedures4 and bicuspid AS,5 it has become relevant to have comparative efficacy and safety data of contemporary BE and SE prostheses. This evidence-based focused review aims to provide an overview of the valve characteristics and the factors influencing prosthesis selection, imbibing data from the literature on the clinical outcomes of BE and SE TAVI prostheses.

Transcatheter Prosthetic Valve Designs, Implantation Techniques and Access Routes As mentioned earlier, most of the currently available prostheses employ either BE or SE technologies. Although these technologies are considered broadly comparable, differences exist and device characteristics play a role in prosthesis selection. A balloon-expandable aortic stent valve, consisting of a trileaflet bovine pericardial valve tissue mounted in a stainless steel frame, was the first BE valve prototype implanted in humans.1 Subsequent improvements of the valve and the delivery systems resulted in newer generations of BE prosthesis: Edwards SAPIEN, SAPIEN XT and SAPIEN 3 valves (Edwards Lifesciences, Irvine, CA) (see Table 1, Figure 1).6 The Edwards SAPIEN valve, which was available in 23/26 mm sizes requiring 22/24 Fr

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delivery catheters respectively, consisted of a tubular slotted stainless steel stent frame with unidirectional trileaflet bovine pericardial tissue and a fabric skirt made of polyethylene terephthalate that improved sealing. The SAPIEN XT valve consists of a trileaflet pericardial bovine valve mounted in a cobalt chromium stent frame having fewer rows, columns and vertical struts between commissures to reduce the valve profile. This valve is available in 20/23/26/29 mm sizes, and is implanted through 16 Fr (20/23 mm valves), 18 Fr (26 mm valve) or 20 Fr (29 mm valve) expandable sheaths. The SAPIEN 3 is the latest generation of the BE valves also having a trileaflet pericardial bovine valve mounted in a cobalt chromium stent, but incorporating an additional outer fabric skirt to further reduce paravalvular leak.

The CoreValve (Medtronic Inc; Minneapolis, MN), prototype of SE valves, is comprised of trileaflet porcine pericardial tissue sutured into a wire frame of nitinol, a nickel-titanium alloy that has temperatureassociated shape memory features.7 The valve has three components: a high radial strength inflow segment that extends 4-6 mm below the annulus, a supra-annular segment containing the leaflet, and an outflow segment that aligns the stent with the aortic root.7 The first generation SE CoreValve was available in 26/29 mm inflow diameter sizes with an 18 Fr diameter delivery system. Current generation of CoreValve is available in 23/26/29/31 mm sizes and 18 Fr delivery systems (see Table 2, Figure 2).

A balloon aortic valvuloplasty is usually performed prior to both SE and BE valve implantation, though this step is commonly omitted in current clinical practice. The BE valve is implanted by positioning the valve under fluoroscopy, angiography ± transoesophageal echocardiography guidance with balloon inflation for valve expansion under rapid pacing, which minimises cardiac output in order to avoid

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Structural Transcatheter Aortic Valve Implantation Figure 1: Characteristics of the balloon-expandable Edwards SAPIEN, SAPIEN XT and SAIEN 3 valves.

Delivery system

Valve sizes, mm

Indicated vessel size, mm

Sheath size, Fr

Sheath model

Expanded length, mm

Retroflex 3

23/26

≥7mm

22/24

Retroflex

16.1

Novaflex

20/23/26/29

6/6/6.5/7

16/16/18/20

eSheath

17.2

Commander

23/26/29

5.5/5.5/6

14/14/16

eSheath

20

Edwards Sapien Valve

Sapien XT Valve

Sapien 3 Valve

Pictures provided by Edwards Lifesciences

Table 1: Characteristics of Balloon-expandable SAPIEN XT and SAPIEN 3 Valves SAPIEN XT

SAPIEN 3

Valve sizes, mm

20/23/26/29

23/26/29

Aortic annulus dimension,

16–19 (20)

18–22 (23)

mm by TEE

18–21 (23)

21–25 (26)

22–25 (26)

24–28 (29)

25–27 (29) Sheath size, Fr

16,18,20

14,16

Leaflet tissue

Bovine

Bovine

Table 2: Characteristics of self-expanding CoreValve CoreValve

Evolut R

Valve sizes, mm

26/29/31

23/26/29/32?

Aortic annulus

20–23 (26)

18–20 (23)

dimension, mm

23–27 (29)

20–23 (26)

26–29 (31)

23–26 (29) 26–29? (32)

Sheath size, Fr

18

14Fr-Equivalent System with InLineTM Sheath

Leaflet tissue

Porcine

Porcine

Repositionable

Limited

Yes (partial)

embolisation during deployment. The SE CoreValve is implanted by slow release of the valve at a marker band depth of 1-1.5 mm to obtain a final valve implantation depth of ~4 mm.7 The SE design allows partial repositionability with the newer generation devices (such as CoreValve Evolut R, Medtronic, Minneapolis, MN, Table 1) prior to final release, as opposed to BE technology where no repositioning is possible. The newer generation SE Lotus valve allows full repositionability prior to final implantation.

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In the majority of patients, the retrograde transfemoral route is the preferred choice for implantation of both BE and SE prostheses.8 BE prostheses have also been delivered transapically, as well as through direct aortic access via minithoracotomy.9 The latter approaches are especially suitable in patients with severe peripheral artery disease and heavily calcified ascending aorta who are at risk of embolic complications. The SE CoreValve has also been delivered from the direct aortic in addition to the subclavian/axillary artery routes as an alternative in patients in whom the transfemoral route is contraindicated.10 The subclavian/transaxillary approach experience for BE valves is limited to a few cases.11,12

Clinical Outcomes Data directly comparing SE and BE valves are limited and most of the data on clinical outcomes have been generated from registries and non-comparative randomised trials (see Table 3).13–18 Furthermore, there are no long-term comparative outcome studies. To date, the multicentre Comparison of Transcatheter Heart Valves in High Risk Patients with Severe AOrtIc Stenosis: Medtronic CoreValve versus Edwards SAPIEN XT (CHOICE) trial is the only randomised clinical trial directly comparing SE and BE valves (see Table 3).20

Mortality and Stroke Rate Data from large multicentre registries and non-comparative randomised trials showed no difference in mortality between the 2Transcatheter Valves (PARTNER; cohort B) multicentre trial, which compared BE Edwards SAPIEN valve implantation with standard therapy including balloon aortic valvuloplasty, showed lesser mortality rate (43.4 % versus 68 %) and better functional class in the TAVI group at two years of follow-up.18,21–23 This trial was followed by the prospective single arm CoreValve Extreme Risk US Pivotal Trial study of SE CoreValve implantation, which reported a one-year allcause mortality or major stroke rate of 26 %.19 Further data from randomised controlled trials of BE (PARTNER Cohort A trial) and SE

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(The CoreValve High Risk US Pivotal Trial) TAVI showed comparable and reduced mortality rates respectively as compared with surgical aortic valve replacement.18,22,24 Recent studies have shown decreased mortality rates with newer devices. In the SAPIEN 3 prospective study, transfemoral implantation of newer generation BE SAPIEN 3 valve resulted in a very low 30-day mortality of 2.1 % with no disabling strokes.25 Non-transfemoral access was associated with higher rates of mortality as well as stroke rates in this study. Finally, in the direct comparative CHOICE trial there was no significant difference in the 30-day mortality rates between the BE and SE groups (4.1 % for BE SAPIEN XT versus 5.1 % for SE CoreValve group).20 Similarly, comparative rates of embolic events were reported for SE and BE valves in several studies.27 In a large meta-analysis of neurological events after TAVI, 30-day event rates for CoreValve or SAPIEN prostheses were 3.1 % and 4.2 % respectively, the difference being non-significant.26 A statistically non-significant higher incidence of minor strokes was noted in the BE group in the CHOICE trial.20 The higher profile first generation BE SAPIEN prosthesis is likely to cause embolic events during stent positioning, whereas the lower profiled SE CoreValve may cause events mainly during stent deployment, due to shaving of calcific material from the native valve surface.28 Significantly more embolic events were observed during post-dilatation and repositioning with CoreValve as compared with BE valves.28 The unique advantage of resheathability and repositionability of modern SE valves may also translate into a higher liability to embolic events, though this remains hypothetical.

Profiles of both these devices have been improved to reduce stroke risk in newer generations, with the SE CoreValve Evolut R having incorporated an integrated sheathed delivery system and the BE SAPIEN 3 system with an atraumatic and smooth catheter profile with enhanced steerability.

Vascular Complications The use of larger 22/24 F sheaths with the first generation BE SAPIEN valve was associated with a high rate of vascular complications as opposed to the smaller profile SE CoreValve.29 Recently, lower-profile BE valve systems such as the SAPIEN XT and SAPIEN 3 have become available with significant reduction in vascular complications. No significant difference between SE and BE groups with regard to vascular complications or bleeding was noted in the CHOICE trial (any vascular complication in 14 % for BE SAPIEN XT versus 12.8 % for SE CoreValve; p=0.78).20

Device Success The composite endpoint of device success defined by the Valve Academic Research Consortium (VARC) evaluates acute device and procedural characteristics, and requires absence of prosthesis stenosis/regurgitation and correct implantation of only one valve for a successful procedure. In the CHOICE trial, the primary endpoint of device success was seen in 95.9 % of 121 patients treated with the BE device as compared with 77.5 % of 120 patients treated with the SE device (relative risk 1.24, 95 % CI 1.12–1.37).20 This difference in device success rates was largely driven by rates of more than mild valvular regurgitation, seen in 18.3 % of SE CoreValve patients versus 4.1 % of BE SAPIEN XT patients (p<0.001), and the more frequent need for implantation of a second valve in the SE CoreValve group, at 5.8 % versus 0.8 % (p=0.03).

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Figure 2: The CoreValve and Evolut R valves.

CoreValve

Evolut R

Pictures provided by Medtronic

Table 3: Clinical Outcomes

Trials

30-day

30-day

Post-procedural

mortality

stroke

more than mild aortic regurgitation

SE

BE

SE

BE

SE

CHOICE20

BE

5.1 %

4.1 %

2.6 %

5.8 %

18.3 %

4.1 %

PARTNER I B21

-

5%

-

6.7 %

-

15%

CoreValve US

8.4%

-

4.0 %

-

15.3 %

-

extreme risk13 UK Registry13

5.8 %

8.5 %

4.0 %

4.2 %

17.3 %

9.6 %

France 2

9.4 %

9.6 %

4.3 %

3.8 %

21.5 %

13 %

Registry14 SE = self-expandable, BE = balloon-expandable; SE being CoreValve and BE, SAPIEN and SAPIEN XT valves

Post-TAVI Aortic Regurgitation Procedure-related incidence of aortic regurgitation, which includes transvalvular and paravalvular forms, is associated with increased short- and long-term mortality after TAVI and is a major limiting factor to its expanded use. 18,19 Paravalvular aortic regurgitation results from poor annulus-prosthesis apposition and several factors, such as heavily calcified cusps, annulus-prosthesis mismatch and suboptimal prosthesis positioning, are thought to be responsible in both the SE and BE valve implantations. Transvalvular or central aortic regurgitation can be the result of leaflet restriction or damage during crimping or implantation as well as overdilatation of the valve.30 Some degree of aortic regurgitation, mostly mild, is observed in the majority of TAVI patients up to one-year follow-up. The incidence of more than mild aortic regurgitation after TAVI was found to be 7.4 % in a meta-analysis of post-TAVI outcomes.31 In another recent meta-analysis, the pooled estimate of more than mild post-TAVI aortic regurgitation was 11.7 % with a 95 % confidence interval of 9.6–14.1.32 In the UK TAVI registry, paravalvular regurgitation occurred more commonly in the SE CoreValve implants as compared with the BE SAPIEN implants (17.3 % versus 9.6 %).13 A similar finding was observed in the meta-analysis by Athappan et al.32 who reported more than mild aortic regurgitation to be more common with use of

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Structural Transcatheter Aortic Valve Implantation Table 4: Comparison of selected newer generation BE valves

Valve sizes, mm

Colibri

Innovare

24

20/22/24/26

(21,27 in development) Sheath/introducer size, Fr

14

24

Leaflet tissue

Porcine

Bovine

Route of implantation

Transfemoral

Transapical

the SE CoreValve as compared with the BE valves (16.0 % vs. 9.1 %, p = 0.005). In the landmark CHOICE trial, the incidence of more than mild aortic regurgitation by angiography was 4.1 % in the BE group as compared with 18.3 % in the SE group (p<0.001).20 In fact, the primary endpoint in this trial was mainly driven by a significantly lower frequency of more than mild aortic regurgitation as well as a lower need for an additional device in the BE group. Implantation of the BE SAPIEN 3 valve resulted in no severe aortic regurgitation at 30 days of follow-up in a recently published trial, and the rate of more than mild aortic regurgitation was as low as 3.5 %.25 Sherif et al. 33 investigated anatomic predictors of paravalvular regurgitation after SE CoreValve implantation and found the angle of the left ventricular outflow tract (LVOT) to the ascending aorta (AA) as well as the device depth in relation to the noncoronary cusp to be independent predictors. Paravalvular regurgitation was more likely in patients with greater LVOT-AA angle as a result of the incomplete sealing of the paravalvular space. Too low as well as too high implantations also facilitated regurgitation via the uncovered struts and the space between prosthesis and annulus respectively. Despite high implantation and adequate sizing employed in the CHOICE trial, higher rate of regurgitation was observed in the CoreValve group, raising concerns regarding inadequate radial strength of SE devices, which can be a contributing factor for regurgitation. Longterm studies are necessary to chart the progression of paravalvular regurgitation with time, since geometric remodelling of the annulus with a reduction in the degree of regurgitation may occur over time.

Such reductions in severity of regurgitation may be of relevance for SE prostheses.

Need for New Pacemaker The risk factors for development of high-grade heart block requiring permanent pacemaker in observational studies include use of SE valve and pre-existing right bundle branch block.34 In patients receiving the SE valve, the risk of requiring a permanent pacemaker can be as high as 42.5 % whereas the risk of this complication for BE valve is similar to that observed after balloon valvuloplasty or surgical valve replacement in clinical trials.35 Similar results were reproduced in the CHOICE trial, where 37.6 % of SE patients required a new pacemaker as compared to 17.3 % in the BE group.20 Higher incidence of significant heart block in SE valve patients could be explained by the interaction of its nitinol frame with the interventricular septum. Radial forces of the CoreValve stent are greater on the LVOT, especially if the LVOT diameter is small or tissue stiffness is high. Excessive radial force, especially in low implants, may contribute to heart block.36 Furthermore, SE CoreValve implantation is associated with a higher incidence of new left bundle branch block when compared to BE valve implantation and surgical valve replacement.37 Newer generation repositionable SE devices may help in reducing the pacemaker rate with a more targeted implantation.

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Rare Complications Occlusion of coronary artery ostia is a rare but life-threatening cause of ischaemia and hypotension following TAVI, with the majority of such complications reported after BE valve implantation. A recent large series reported an incidence of 0.81 % for BE versus 0.34 % for SE valves (p=0.02).38 Factors predisposing to coronary artery occlusion include small aortic sinuses, aortic annulus to coronary ostium distance less than 1 cm and significant asymmetric valve calcification. This complication was also reported to be more frequent in women and in patients with prior surgical bioprosthesis.

In the randomised CHOICE trial, two patients belonging to the BE group had coronary obstruction as opposed to none in the SE group.20 Annulus rupture is another rare life-threatening complication and risk factors include BE valve implantation, small annular size, bulky calcification and aggressive predilatation.39,40 The reported incidences of valve embolism, valve malpositioning and need for more than one valve implantation are higher with SE valves.41 Implantation of ≥ 2 valves was higher in the SE group in the CHOICE trial (5.8 % for SE versus 0.8 % for BE).20 However, nearly half of BE valve embolisations occur towards the left ventricle as opposed to SE valves, which usually require surgery and are associated with a high mortality rate.4 BE valve embolisations are generally caused by anatomic and technical factors, which may be avoided with procedural planning. In recent years, a few cases of valve thrombosis with both BE and SE valves have been reported.

Valve Durability Valve durability is important for the expansion of TAVI to younger patients, and both prosthesis types have been found to be durable in short- and intermediate-term studies. Toggweiler et al.42 evaluated the long-term haemodynamic changes of BE valves at five years’ followup and observed a decrease in mean aortic valve area of 0.06 cm 2/ year and an increase in mean transvalvular gradient of 0.27 mmHg/ year with no cases of structural valve failure. Similarly, the CoreValve CE Pivotal Study demonstrated excellent durability at four years in patients who were treated with the SE CoreValve System.7

Differential Indications for TAVI In the early days of TAVI, prosthesis selection was largely determined by the size of the aortic annulus and that of the iliofemoral arteries, with the SE CoreValve being favoured in patients with larger aortic annulus and smaller iliofemoral arteries. In recent times, annulus morphology has influenced valve selection and SE CoreValve, thought to have the ability to adapt to various annular and root anatomies, is preferred by some operators for patients with an asymmetric aortic annulus on multislice computed tomography. Operator experience with regard to volume of cases being performed and familiarity with the device is likely to play a significant role in prosthesis selection, with low-volume centres more likely to use only one device type for all patients. Nevertheless, availability of a wide size array of newer generation BE and SE prostheses have made TAVI feasible for a wide range of patients with complex anatomies.

Traditionally, bicuspid AS is considered as a contraindication for TAVI because of the increased risk of associated adverse aortic events such as progressive aortic dilatation with device migration, aortic dissections, and significant paravalvular regurgitation owing to more frequent elliptical shape and asymmetric annulus. As a consequence of technological improvements and experience, TAVI has been increasingly performed with reasonable success in selected

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Table 5: Comparison of selected newer generation SE valves Portico

Lotus

Acurate

Engager

Centera

Jena

Valve sizes, mm

23/25

23/25/27

23/25/27

23/26

23/26/29

23/25/27

Aortic annulus dimension, mm

19–21 (23)

20–23 (23)

20–23 (23)

21–27

18–21 (23)

21–22.9 (23)

21–23 (25)

23–25 (25)

23–25 (25)

21–24 (26)

23–24.9 (25)

25–27 (27)

25–27 (27)

24–27 (29)

25–27 (27)

Sheath size, Fr

18

18/20

18

30

14

32

Leaflet tissue

Bovine

Bovine

Porcine

Bovine

Bovine

Porcine

Repositionable

Partial

Complete

Partial

Partial

Partial

Partial

patients with bicuspid aortic valve stenosis. Because of the potential complications mentioned above, these patients may be favoured to receive a repositionable SE valve prosthesis. Patients with minimal aortic valve calcification and predominant regurgitation are also likely to benefit from SE valve prostheses.

Finally, SE valves may have a beneficial role in patients undergoing valve-in-valve TAVI for small degenerated aortic bioprosthetic valves, where fewer gradients are achieved due to supra-annular valve function. On the other hand, BE valves could be used for valve-invalve implantations for all four valve positions, namely tricuspid, pulmonary, mitral and aortic, whereas the SE CoreValve could only be used in the aortic position.

Newer Generation Devices Since the first TAVI in 2002, a reasonable number of randomised trials and registries exist that provide valuable insights as to what is an optimal SE or BE prosthesis. An ideal BE prosthesis is one that has a low profile and allows optimal and accurate positioning within the native aortic valve and annulus with minimal risk of complications.

An ideal SE valve is one that should be completely retrievable to allow precise device positioning, has a design that permits coronary artery access as well as optimal radial strength and ability to adapt to various annulus and root anatomies to provide adequate seal.

New generations of SE and BE devices address many of the major deficiencies of the first generation valves in terms of accuracy of positioning, repositionability, ease of use and enhanced features to minimise paravalvular leakage. Newer BE prostheses such as SAPIEN 3 and Colibri (Colibri Heart Valve, Broomfield, USA) and newer SE valves such as Evolute R and Lotus hold some promise in this regard.6 The Colibri valve is a low-profile (14-Fr) pre-crimped, and prepackaged ready-for-use BE valve made of three independent pieces of porcine pericardium, which are created using a unique folding method and sewn into a stainless steel laser-cut frame. Another newer BE valve is the Innovare valve (Braile Biomedical, Brazil), which consists of a trileaflet bovine pericardial valve mounted in a cobaltchromium alloy, available in sizes of 20/22/24/26 mm (see Table 4).43

1.

2.

3.

Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description.

Circulation 2002;106 :3006–8.

Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)].

Eur J Cardiothorac Surg 2012;42 :S1–44.

Piazza N, Kalesan B, van Mieghem N, et al. A 3-center comparison of 1-year mortality outcomes between

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4.

5.

Newer SE and mechanical valves such as Lotus (Boston Scientific, Natick, MA), Acurate (Symetis SA, Ecublens, Switzerland), Portico (St. Jude Medical, St Paul, MN), Centera (Edwards Lifesciences, Irvine, CA), Engager (Medtronic Minneapolis,MN) and JenaValve (JenaValve Technology GmbH, Munich, Germany) aim to address potential limitations of earlier SE devices, such as lack of repositionability and ease of use, and offer important advantages (see Table 5).44–48 For instance, the non-flared inflow end of the Portico valve permits higher implantation depth with minimal left ventricular outflow tract protrusion, thereby reducing the risk of heart block.45 Because the valve leaflets are fully functional in the partially deployed state, extent of paravalvular regurgitation can be assessed prior to full release. The next generation Lotus valve provides a high radial strength and is also capable of being completely retrieved if necessary.44 It has an adaptive seal at the inflow portion that serves to improve apposition to the native annulus and reduce paravalvular regurgitation.

Finally, the Direct Flow (Direct Flow Medical, Santa Rosa, CA) is a new distinctive prosthesis having a non-metallic valve frame and a flexible low-profile delivery system that allows repositionability and repeated assessment of full haemodynamic performance before final implantation. It consists of a bovine pericardial tissue valve that is mounted between two inflatable polyester rings and has the ability to adapt to the native aortic annulus and the left-ventricular outflow tract.49

Conclusion In conclusion, a wide array of devices is currently available falling into the broad category of SE or BE valves, with a shift of the factors that dictate prosthesis selection – sheath and device dimensions in the early days to factors such as frame design, radial force and the anatomical characteristics of the annulus and root in the present era. Results from the CHOICE trial have provided some insights into short-term outcomes after SE and BE valve implantations; but as newer devices become available and indications for TAVI expand, long-term outcome comparative trials are needed to conclusively dictate device selection.

Recently-launched technologies and devices are in their initial phases, and as more scientific data focusing on individual patient characteristics become available, indications for TAVI may expand to intermediate-risk and other population subsets of aortic valve disease. n

transcatheter aortic valve implantation and surgical aortic valve replacement on the basis of propensity score matching among intermediate-risk surgical patients. JACC Cardiovasc Interv 2013;6 :443.

Makkar RR, Jilaihawi H, Chakravarty T, et al. Determinants and outcomes of acute transcatheter valve-in-valve therapy or embolization: a study of multiple valve implants in the U.S. PARTNER trial (Placement of AoRTic TraNscathetER Valve Trial Edwards SAPIEN Transcatheter Heart Valve). J Am Coll Cardiol 2013;62 :418.

Mylotte D, Lefevre T, Søndergaard L, et al. Transcatheter aortic valve replacement in bicuspid aortic valve disease.

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Kumar R, Latib A, Colombo A, et al. Self-expanding prostheses for transcatheter aortic valve replacement. Prog Cardiovasc Dis 2014;56 :596–609.

Zajarias A, Cribier AG. Outcomes and safety of percutaneous aortic valve replacement. J Am Coll Cardiol 2009;53:1829.

Lardizabal JA, O’Neill BP, Desai HV, et al. The transaortic approach for transcatheter aortic valve replacement: initial clinical experience in the United States. J Am Coll Cardiol

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10. Petronio AS, De Carlo M, Bedogni F, et al. Safety and efficacy of the subclavian approach for transcatheter aortic valve implantation with the CoreValve revalving system. Circ Cardiovasc Interv 2010;3 :359.

11. Sharp AS; Michev I, Colombo A. First trans-axillary implantation of Edwards SAPIEN valve to treat an incompetent aortic bioprosthesis. Catheter Cardiovasc Interv 2010;75 :507–10.

12. Ruggieri VG, Bedossa M, Verhoye JP. Urgent trans-axillary valve-in-valve procedure using the Edwards 16-F expandable introducer. Catheter Cardiovasc Interv 2014;83 :E178–82.

13. Moat NE, Ludman P, de Belder MA, et al. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry. J Am Coll Cardiol 2011;58 :2130–8.

14. Gilard M, Eltchaninoff H, Iung B, et al. FRANCE 2 Investigators.

Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med 2012;366:1705–15.

15. Abdel-Wahab M, Comberg T, Büttner HJ, et al. Aortic regurgitation after transcatheter aortic valve implantation with balloon- and self-expandable prostheses: a pooled analysis from a 2-center experience. JACC Cardiovasc Interv 2014;7 :284–92.

16. Chieffo A, Buchanan GL, Van Mieghem NM, et al.

Transcatheter aortic valve implantation with the Edwards SAPIEN versus the Medtronic CoreValve Revalving system devices: a multicenter collaborative study: the PRAGMATIC Plus Initiative (Pooled-RotterdAm-Milano-Toulouse In Collaboration). J Am Coll Cardiol 2013;61 :830–6.

17. Nombela-Franco L, Ruel M, Radhakrishnan S, et al.

Comparison of hemodynamic performance of selfexpandable CoreValve versus balloon-expandable Edwards SAPIEN aortic valves inserted by catheter for aortic stenosis.

Am J Cardiol 2013;111 :1026–33.

18. Kodali SK, Williams MR, Smith CR, et al. PARTNER Trial Investigators. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366 :1686–95.

19. 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.

20. Abdel-Wahab M, Mehilli J, Frerker C, et al. Comparison of balloon-expandable versus self-expandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial. JAMA 2014;311 :1503.

21. Leon MB, Smith CR, Mack M, et al. PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.

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22. Smith CR, Leon MB, Mack MJ, et al. PARTNER Trial Investigators. Transcatheter versus surgical aorticvalve replacement in high-risk patients. N Engl J Med 2011;364 :2187–98 23. Makkar RR, Fontana GP, Jilaihawi H, et al; PARTNER Trial Investigators. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 2012;366 :1696–704.

24. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis.

N Engl J Med 2014;370 :1790.

25. Webb J, Gerosa G, Lefèvre T, et al. Multicenter evaluation of a next-generation balloon-expandable transcatheter aortic valve. J Am Coll Cardiol 2014;64 :2235–43.

26. Eggebrecht H, Schmermund A, Voigtlander A, et al. Risk of stroke after transcatheter aortic valve implantation (TAVI): a meta-analysis of 10 037 published patients. EuroIntervention 2012;8 :129–38.

27. Kahlert P, Al-Rashid F, Doettger P, et al. Cerebral embolization during transcatheter aortic valve implantation: a transcranial Doppler study. Circulation 2012;126 :1245–55.

28. Erdoes G, Bascani R, Huber C, et al. Transcranial Doppler-detected cerebral embolic load during transcatheter aortic valve implantation. Eur J Cardiothorac Surg 2012;41 :778–83 29. Leon MB, Gada H, Fontana GP. Challenges and future opportunities for transcatheter aortic valve therapy.

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30. Holmes DR Jr, Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/ STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol 2012;59 :1200.

31. Généreux P, Head SJ, Van Mieghem NM, et al. Clinical outcomes after transcatheter aortic valve replacement using valve academic research consortium definitions: a weighted meta-analysis of 3,519 patients from 16 studies.

J Am Coll Cardiol 2012;59 :2317–26.

32. Athappan G, Patvardhan E, Tuzcu EM, et al. Incidence, predictors, and outcomes of aortic regurgitation after transcatheter aortic valve replacement: meta-analysis and systematic review of literature. J Am Coll Cardiol 2013;61 :1585–95 33. Sherif MA, Abdel-Wahab M, Stöcker B, et al. Anatomic and procedural predictors of paravalvular aortic regurgitation after implantation of the Medtronic CoreValve bioprosthesis.

J Am Coll Cardiol 2010;56 :1623–9.

34. Koos R, Mahnken AH, Aktug O, et al. Electrocardiographic and imaging predictors for permanent pacemaker requirement after transcatheter aortic valve implantation.

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35. Zahn R, Gerckens U, Grube E, et al. German Transcatheter Aortic Valve Interventions-Registry Investigators:Transcatheter aortic valve implantation:first

results from a multicentre real-world registry. Eur Heart J 2011;32 :198–204.

36. Testa L, Latib A, De Marco F, et al. Clinical impact of persistent left bundle branch block after transcatheter aortic valve implantation with CoreValve Revalving System.

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37. Poels TT, Houthuizen P, Van Garsse LA. Frequency and prognosis of new bundle branch block induced by surgical aortic valve replacement. Eur J Cardiothorac Surg 2015;47:e47–53.

38. Ribeiro HB, Webb JG, Makkar RR, et al. Predictive factors, management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: insights from a large multicenter registry. J Am Coll Cardiol 2013;62 :1552–62.

39. Eker A, Sozzi FB, Civaia F, et al. Aortic annulus rupture during transcatheter aortic valve implantation: safe aortic root replacement. Eur J Cardiothorac Surg 2012;41 :1205.

40. Aminian A, Lalmand J, Dolatabadi D. Late contained aortic root rupture and ventricular septal defect after transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2013;81 :e72.

41. Khatri PJ, Webb JG, Rodes-Cabau J, et al. Adverse effects associated with transcatheter aortic valve implantation: A Meta-analysis of Contemporary Studies. Ann Intern Med 2013;158 :35–46.

42. Toggweiler S, Humphries KH, Lee M, et al. Five-year outcome after transcatheter aortic valve implantation. J Am Coll Cardiol 2013;61 :413–19.

43. Gaia DF, Palma JH, Ferreira CB, et al. Transcatheter aortic valve implantation: results of the current development and implantation of a new Brazilian prosthesis. Rev Bras Cir Cardiovasc 2011;26 :338–47.

44. Meredith IT, Hood KL, Haratani N, et al. Boston Scientific Lotus valve. EuroIntervention 2012;8 (Suppl Q):Q70–4.

45. Spence MS, Lyons K, McVerry F, et al. New St. Jude Medical Portico transcatheter aortic valve: features and early results.

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48. Kempfert J, Rastan AJ, Mohr FW, et al. A new self-expanding transcatheter aortic valve for transapical implantation – firstin-man implantation of the JenaValve™. Eur J Cardiothorac Surg 2011;40 :761–3.

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Left Atrial Appendage

Real World Outcomes of Left Atrial Appendage Occlusion Apostolos Tzikas, 1 Darren Mylotte 2 and Martin Bergmann 3 1. AHEPA University Hospital, Thessaloniki, Greece; 2. Galway University Hospital, Galway, Ireland; 3. Cardiologicum Hamburg, Hamburg, Germany

Abstract Percutaneous left atrial appendage occlusion (LAAO) is a device-based therapy for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF). Recently, the Watchman device (Boston Scientific, St Paul, MN, US) was approved in the US by the Food and Drug Administration (FDA) based on the results of two randomised clinical trials that evaluated LAAO in patients eligible for oral anticoagulation (OAC) therapy. However, in real-word clinical practice LAAO is typically offered to patients ineligible for OAC therapy, as they appear to have limited treatment options and consequently worse prognosis. Although LAAO has shown favourable clinical outcomes in OAC-ineligible patients in single or multicentre observational studies, these results need to be confirmed in randomised clinical trials.

Keywords Atrial fibrillation, stroke, prevention, device, closure Disclosure: Dr Tzikas is a proctor for St Jude Medical; Dr. Mylotte has no conflicts of interest to declare; Dr Bergmann is a proctor for Boston Scientific and Coherex Inc. Received: 8 April 2015 Accepted: 20 April 2015 Citation: Interventional Cardiology Review, 2015;10(2):109–11 Correspondence: Apostolos Tzikas, Asklipiou 10, 57001, Thessaloniki, Greece. E: aptzikas@yahoo.com

Atrial fibrillation (AF), the most common arrhythmia, is associated with a significantly increased risk of morbidity and mortality due to a fivefold increase in the frequency of thromboembolic stroke.1 The gold standard treatment for the prevention of AF-related thromboembolism is oral anticoagulation (OAC), based on an individualised patient risk assessment with either the CHADS2 or the CHA2DS2-VASc score.2 However, up to 20 % of patients with AF cannot take OAC therapy,3 and there exists a considerable bleeding risk among those that can tolerate OAC: intracranial bleeding occurs in 1 % of patients taking warfarin per annum, whereas survivors of a haemorrhagic stroke are generally considered inappropriate for anticoagulation for life.4,5 In addition, OAC is associated with significant morbidity and its associated cost implications: for example, OAC-related gastrointestinal (GI) bleeding causes repeated hospitalisations and blood transfusions, and carries a mortality rate of up to 10 %.6 The HASBLED score is the most widely used tool to estimate the risk of major bleeding for patients on OAC therapy.7 Novel OACs have been shown to be either non-inferior or superior to warfarin therapy with equivalent or decreased bleeding events. Nevertheless, there remains an annual 2–3 % incidence of major bleeding.8 The left atrial appendage (LAA) is a well-documented source of cardiac emboli in patients with non-valvular AF.9 Percutaneous LAA occlusion (LAAO) is a device-based therapy that has emerged as an alternative to OAC in patients with non-valvular AF.10–15 Evidence confirming the efficacy of LAAO is largely derived from the PROTECT AF randomised clinical trial, in which the Watchman device (Boston Scientific, Marlborough, MA, US) was found to be non-inferior to warfarin for the primary efficacy endpoint of stroke, cardiovascular death and systemic embolism.10 Importantly, four-year follow-up data from the PROTECT AF trial demonstrated significantly reduced all-

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cause mortality with the Watchman device compared with warfarin therapy.11 Conversely, the PREVAIL study, a similar randomised trial that was performed to evaluate the high incidence of safety concerns in the PROTECT AF trial, failed to confirm non-inferiority of the Watchman device compared with warfarin due to an unexpectedly low number of events in the control group.12 Nevertheless, the study proved safety of the implantation process even in new centres. In Europe, the Watchman device acquired Conformité Européenne (CE) approval in 2005. The relatively small number of patients in randomised trials, however, has hindered the approval of the device in the US by the Food and Drug Administration (FDA) for several years. After three consecutive expert panels, the FDA eventually approved the Watchman device on 13 March 2015, based on all available data including new, unpublished data from the PREVAIL trial.16 The FDA stated that the device is indicated to reduce the risk of thromboembolism from the LAA in patients with non-valvular AF who: 1. Are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores and are recommended for anticoagulation therapy; 2. Are deemed by their physicians to be suitable for warfarin; and 3. Have an appropriate rationale to seek a non-pharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared with warfarin.

Another device widely used for LAAO is the Amplatzer Cardiac Plug (ACP, St Jude Medical, Plymouth, MN, US). This device was also commercially available in Europe in 2008 following CE mark approval. The ACP has not been evaluated in a randomised setting; however, a large multicentre clinical study and several single-centre reports showed favourable results in terms of safety and efficacy.14

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Left Atrial Appendage In December 2013, a second-generation Amplatzer device, the Amplatzer Amulet (St Jude Medical, Plymouth, MN, US), also received CE mark approval and initial small series have suggested promising clinical results.15 Additional devices that have acquired CE mark approval include the Lariat (SentreHEART, Inc., Redwood City, CA, US), which is FDA-approved for unspecific ‘soft tissue occlusion’, and the Wave Crest device (Coherex Medical, Salt Lake City, UT, US).17,18 Several other novel devices continue development in clinical or preclinical studies.

Today, the main controversy about LAAO relates to the absence of randomised clinical trial evidence evaluating its safety and efficacy in patients with contraindications to OAC therapy: the Watchman device was assessed in warfarin-eligible patients. In OACcontraindicated patients, there remain however limited or no options that provide adequate stroke prevention. These patients present significant healthcare and social problems, especially the more elderly cohorts that suffer cardioembolic stroke.19 The most recent European Society of Cardiology (ESC) Guidelines on the management of AF suggest that “Interventional, percutaneous LAA closure may be considered in patients with a high stroke risk and contraindications for long-term oral anticoagulation” (IIb indication, Level of evidence B).20 Furthermore, the 2014 ESC/European Association of CardioThoracic Surgeons Guidelines on myocardial revascularisation state that “Percutaneous LAA closure and antiplatelet therapy may be considered in patients with atrial fibrillation undergoing PCI if a high stroke risk and contraindication for long-term combined antiplatelet + oral anticoagulation therapy is present” (IIb indication, Level of evidence B).21 In fact, these guidelines reflect the use of LAAO in the real world. In a 22-centre, non-randomised study that included 1,047 patients who underwent LAAO with the ACP device, the most common indication for LAAO were (1) previous major bleeding (4 7%), followed by (2) high risk for bleeding (35 %), and (3) avoidance of triple (dual antiplatelet + OAC) therapy for coronary artery disease and coronary stenting (22 %).14 In the ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology (ASAP) study, a non-randomised evaluation of the Watchman device in patients with a contraindication to OAC therapy, a history of haemorrhagic/ bleeding tendencies was the most common reason for warfarin ineligibility (93 %).13 Nevertheless, it should be noted that currently there is no universally accepted definition of contraindication to OAC therapy, so in the real world the criteria for offering LAAO vary significantly between centres.

Although contraindication to OAC is the most common indication for LAAO there is no standardised strategy for antithrombotic medication post-LAAO. For example, LAAO with Watchman should be followed by 45 days of warfarin plus aspirin therapy, and then aspirin monotherapy for life. This strategy arises from PROTECT AF trial protocol and does not take into consideration patients with contraindications to OACs.10 In the ASAP study protocol warfarin was replaced by clopidogrel or ticlopidine.13 Dual anti-platelet therapy for a period of 1 to 3 months and aspirin for up to 6 months is recommended after LAAO with an Amplatzer device (either ACP or Amulet), however, this strategy is empirical and comes from experience with other Amplatzer closure devices; yet there are no data to support it.14,15 Therefore, in real world clinical practice,

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antithrombotic therapy after LAAO is individualised based on anecdote rather than clinic trial evidence. Physicians should take into account the patient’s history of bleeding, comorbid medical conditions, the completeness of LAAO, and potential for device thrombosis, etc.

Incomplete LAAO is defined as the presence of a leak on color flow Doppler on transesophageal echocardiography (TEE).22,23 A small leak (1–5 mm colour flow jet) is not infrequent after LAAO with the Watchman or the ACP device, but it was not reported to be associated with adverse clinical outcome.14,22,23 Post LAAO device thrombosis on follow-up TEE occurs in approximately 4 % of patients and is usually successfully treated with a brief period (e.g. 4 weeks) of OAC or low molecular weight heparin. Similar to incomplete LAAO, device thrombosis has not been associated with increased adverse event rates.10,14 Management of device thrombosis, however, can be a challenge especially for patients with a very high risk of bleeding, and there remain few available data to guide treatment and follow-up strategies.

The LAA has a relatively fragile, thin-walled structure and considerable variability exists among patients. Moreover, a transseptal approach is almost always needed for endocardial LAAO, whereas a dry pericardial puncture is used for epicardial LAAO. Therefore, it is clear that the procedure requires special operator skills and has a significant learning curve. The most common safety event after LAAO is serious pericardial effusion.11,14 Periprocedural stroke, device embolisation and accessrelated major bleeding have also been reported. Nevertheless, procedural safety is anticipated to improve as operators increasingly perform LAAO and several other structural heart disease interventions and newer devices with improved design features become readily available.24 Another significant challenge for LAAO therapy will be to prove its non-inferiority (or superiority) to the novel OAC drugs. Currently, there have been no randomised comparisons between these therapies.

One argument against the widespread adoption of LAAO therapy is that the use of aspirin post-LAAO carries a bleeding risk equivalent to apixaban. However, the study on apixaban showing such low bleeding events excluded all patients with prior bleeding and recruited in general a low-risk population (average CHADs 2.1).25 Indeed, there exist a considerable number of patients who are contraindicated to all antithrombotic drugs, and in these patients the safety and efficacy of LAAO without any post-procedure antithrombotic medication should be tested. Several special patient populations could potentially benefit from LAAO: patients with severe renal impairment who are extremely difficult to manage with warfarin and cannot take the novel OACs, patients on dialysis or patients who suffer a ‘stroke on OAC’, one of the few occasions when OAC is not stopped after the procedure. Finally, the severity of stroke in the presence of a LAAO device needs to be assessed.

In conclusion, the management of patients with non-valvular AF is a major health problem. Warfarin or the novel OAC drugs are considered a first-line therapy for AF-related stroke prevention but many patients cannot take it due to a prohibiting high risk of bleeding.

For those patients LAAO is a reasonable, device-based preventive therapy. Favourable clinical outcomes in observational studies need to be confirmed in randomised clinical trials. n

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Viles-Gonzalez JF, Kar S, Douglas P, et al. The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial fibrillation: a PROTECT AF substudy. J Am Coll Cardiol . 2012;59 :923–9.

Freixa X, Tzikas A, Sobrino A, et al. Left atrial appendage closure with the Amplatzer™ Cardiac Plug: Impact of shape and device sizing on follow-up leaks. Int J Cardiol .

2013;168 :1023–7.

Tzikas A, Freixa X, Ibrahim R. Left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation: ready for the prime time? Expert Rev Cardiovasc Ther . 2013;11 :1587–9.

Connolly SJ, Eikelboom J, Joyner C, et al.; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med . 2011;364 :806–17.

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Paravalvular Leak

ON.

are. eclare.

A Quick Guide to Paravalvular Leak Closure Sameer Gafoor, Jennifer Franke, Stefan Bertog, Simon Lam, Laura Vaskelyte, Ilona Hofmann, Horst Sievert and Predrag Matic CardioVascular Center, Frankfurt, Germany

Abstract Paravalvular leak (PVL) is a seldomly covered aspect of structural heart disease. However, this is a condition that frequently presents after valvular replacement. This article will cover the diagnosising and treating PVL (i.e. imaging, access, and device selection). In addition, specific aspects of aortic and mitral PVL closure will be covered in this review.

Keywords aortic, mitral, valve, leak, paravalvular, paravalvar, closure, plug, regurgitation, severe, paravalvar leak closure, paravalvular leak closure Disclosure: The authors’ institution has ownership interest in or has received consulting fees, travel expenses or study honoraries from the following companies: Abbott, Access Closure, AGA, Angiomed, Arstasis, Atritech, Atrium, Avinger, Bard, Boston Scientific, Bridgepoint, Cardiac Dimensions, CardioKinetix, CardioMEMS, Coherex, Contego, CSI, EndoCross, EndoTex, Epitek, Evalve, ev3, FlowCardia, Gore, Guidant, Guided Delivery Systems, Inc., InSeal Medical, Lumen Biomedical, HLT, Kensey Nash, Kyoto Medical, Lifetech, Lutonix, Medinol, Medtronic, NDC, NMT, OAS, Occlutech, Osprey, Ovalis, Pathway, PendraCare, Percardia, pfm Medical, Rox Medical, Sadra, SJM, Sorin, Spectranetics, SquareOne, Trireme, Trivascular, Velocimed, Veryan.

Acknowledgement(s): Figures reprinted from Eurointervention March 20 2014, Volume 9 Issue 11, Pages 1359–63 by Gafoor et al.12 with permission from Europa Digital and Publishing obtained March 30, 2015.

Received: 30th March 2015 Accepted: 24 April 2015 Citation: Interventional Cardiology Review, 2015;10(2):112–7 Correspondence: Prof Horst Sievert, CardioVascular Center Frankfurt Seckbacher Landstrasse 65 60389 Frankfurt, Germany; E: info@cvcfrankfurt.de

Paravalvular leak (PVL) occurs when there is backflow around a prosthetic valve. This can occur through a variety of causes.

Paravalvular Leak is accompanied by regurgitation and is often a significant problem for patients with bioprosthetic or mechanical heart valves.1 Often manifesting as heart failure (85 % of all presenting symptoms) and hemolysis (13–47 % of all presenting symptoms and signs),2,3 PVL has a prevalence rate as high as 5–17 % of all mechanical valves.4–6 The mechanism of leaks is not well understood. The alignment between sewing ring and annulus may be incomplete because of significant annular calcification. The tissue around valves can weaken as a result of chronic infection. Even the sutures themselves may not allow significant apposition of the valve with the annulus. All of these factors can lead to significant PVL. How can PVL be treated? Unfortunately, repeat surgery portends a worse prognosis, with mortality rates for the first redo, second redo or third redo surgery of 13 %, 15 %, and 35 %, respectively2. Each repeat operation is less likely to be successful. Therefore there is ample room for percutaneous approaches.

It is important to select the right patients for PVL closure. Prior to beginning a case, it is important to exclude active infection, valve instability, and/or cardiac thrombus.5 Indications for PVL closure include patients with significant regurgitation accompanied by symptoms of congestive heart failure and/or hemolysis. Important contraindications to PVL closure may include presence of active local or systemic infection, active ischemia, mechanical instability

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of the prosthetic valve, intracardiac thrombus, and patients with a life expectancy due to comorbidities that is less than 6 months.

Paravalvular Leak: Imaging Successful PVL closure begins with efficient imaging. There are a variety of methods available to diagnose PVL, including transthoracic echocardiography (TTE), transoesophageal echocardiography (TEE), computerised tomography (CT) and magnetic resonance imaging (MRI). Among these, there is no one optimal diagnostic method; each has significant advantages and disadvantages. The important pieces of information to ascertain during imaging are location, size, shape, severity and the number of leaks.

It is important to know the valve type prior to any imaging (often available from the surgical report), and it can also be helpful to know its orientation and the suturing technique that was used. Orientation of the valve varies, but often the preferred mitral orientation for tiltingdisc valves is with the major orifice toward the left ventricular free wall as opposed to the septum. For the aortic position, the preferred orientation is with the major orifice to the right posterior aortic wall.

Suturing techniques may also vary, ranging from non-everting mattress (with or without sub-annular pledgets), everting mattress (with or without supra-annular pledgets), simple interrupted, figure-of-eight, and continuous/running sutures. The choice of suture technique depends on valve type and surgeon preference.

Echocardiography allows for direct comparison of pre- and intra-procedural results. However, echocardiography is prone to artifact from prosthetic shadowing.7 Aortic PVL can be diagnosed

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and evaluated often by TTE, whereas mitral PVL often requires TEE (although TTE may be useful for original diagnosis). 3D echocardiography adds the ability to determine the path of a leak, which can often take a serpentine course. The authors perform all PVL interventions with TEE guidance (often with 3D characterisation of leak size and course).

CT and MRI add further information. Retrospective ECG-gated reconstruction allows diastolic and systolic characterisation. CT can also provide the accurate imaging angle for intervention and closure.

Unfortunately, artifacts secondary to calcification or the valve can blur the leak itself, making it difficult to visualise. CT, in comparison to MRI, has better spatial resolution, however requires contrast dye and involves exposures to more radiation.8

Location A clock face is often used to describe both aortic and mitral PVLs (Figure 1, Figure 2). The three commissures are assigned an hour on the clock face: between left and right coronary sinus is 5 o’clock, between right and non-coronary sinus is 8 o’clock, non-coronary and left coronary sinus is 11 o’clock. This lexicon helps in communication between imager and operator and also helps to monitor leaks preand post-closure. Statistically, aortic leaks are most often between 7 and 11 o’clock (46 %) and also between 11 and 3 o’clock (36 %) 9 Both clock face and anatomical criteria can be used to describe mitral PVL location. Location is based on the mitral valve annulus and is described as medial, lateral, anterior or posterior. The clock face for the mitral valve starts at the 12 o’clock position between the aortic valve and mitral valve A2, then the 3 o’clock position is the posteromedial commissure and interatrial septum and the 6 o’clock position is the posterior annulus midpoint. According to this system, mitral PVL is found often between 10 and 2 o’clock (45 %) and between 6 and 7 o’clock (37 %).9

Figure 1: Location and Sizing of Aortic Paravalvular Leaks A

B

Posterior

C

D

12

Device 2

IAS Medial

9

AV

6 Anterior

RAO

3

Lateral

LAO Device 1

Image Intensifier

Aortic paravalvular leak in patient after CoreValve transcatheter aortic valve implantation. Here we see one aortic valve in 120 degree view (A) that on biplane view (B) has at least two areas of major leak (blue arrows). A schematic of part B is shown in C, where the leaks are shown in relation to the IAS and the AV. One leak, which is green, is located near the IAS at the 10-11 o’clock position on the clock face, which is also posterior and medial. This would be in the region of the noncoronary cusp of the original AV. The other leak (in orange) is located near 4 o’clock on the clock face, and is mostly lateral and located in the region of the original right coronary cusp. The bottom of panel C shows how the image intensifier would visualise the lesion. An extreme left anterior oblique (LAO) angulation would overlap the orange and green paravalvular leak above each other. However an right anterior oblique (RAO) angulation would allow both to be seen adjacent to the valve. In D, we see a post-procedure RAO angulation on fluoroscopy, with two devices in each of the major paravalvular leaks on each side of the CoreValve. AV = aortic valve; IAS = interatrial septum.

Figure 2: Location and Sizing of Mitral Paravalvular Leaks A

Anterior

B

A0

12

Sizing Although the course of the leak may be serpentine, with an orifice that is crescentic or oval in shape, some assumptions can be made about size of the PVL. Echocardiography of the vena contracta of the leak can be used to estimate the size, although this method is not perfect. With the advent of 3D imaging, the leak can be measured in multiple directions. CT and MRI may provide more information if an echocardiogram is unclear. The authors do not recommend balloon sizing as it is associated with a risk of balloon rupture as a consequence of sharp edges due to annular calcium. Measurement of the leak will dictate the choice of device for PVL access, and in turn the delivery system guide or sheath size.

3

Ao +

LAA

Lateral

LAA

9

++

Medial MV

IAS

6 Posterior

C

D

Paravalvular Leak: Access Aortic or medial mitral PVLs can be approached by transfemoral access. The authors’ preference is to use a 0.035” wire, often a hydrophilic one (e.g. Terumo Glidewire, Terumo Medical Corporation, Somerset, NJ, USA) inside a 5 Fr diagnostic catheter (JR4 or MP). The wire crosses the leak and the catheter follows the wire. This wire is substituted for a stiff 0.035” wire (e.g. Amplatzer Extra Stiff Wire, St. Jude Corporation, Minneapolis MN, USA). The delivery system guide or sheath is then advanced over the stiff wire, which is then removed, and the device is placed in correct position. If more support is needed for the catheter or delivery system to cross the leak, a rail can be made (either by transseptal access and snare or by externalising the wire through transapical access). If the aortomitral curtain is crossed, it is

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Images for patient with two mitral paravalvular leaks (asterisk) at various locations in relation to the Ao, LAA and IAS (A). In the schematic shown in B, one can see that the anatomy is distorted, with the MV being more medial compared with normal anatomy. The two leaks are seen as well. On the clock face (orange disc) with the aortic valve as the 12 o’clock position, one leak is at the 2 o’clock position (one asterisk) and another leak is at the 9 o’clock position (two asterisks). In relation to spatial position, one leak is anterior and medial (one asterisk) and the other leak is lateral (two asterisks). This illustrates the difficulty of using one naming system, especially in distorted valve anatomy after replacement. The lateral leak is shown in C as a large crescentic leak, with measurements of 16 x 6 mm. The anteromedial leak is shown in D, with a measurement of 9 x 3 mm. Ao = aorta; IAS = interatrial septum; LAA = left atrial appendage; MV = mitral valve.

often necessary to protect this from significant stress by covering a bare wire with a catheter at all times. For a medial mitral leak, a JR4 or IM catheter can be helpful.

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Paravalvular Leak Figure 3: Aortic Paravalvular Leak, Single Device A

B

C

D

E

F

74-year-old male patient with paravalvular leak in relation to mechanical aortic valve. The leak is an eccentric leak in the region of the non-coronary cusp and measured 10 x 3 mm on echocardiogram. Right femoral arterial access was obtained and a 5 Fr sheath was placed.

A 5 Fr AL1 guide catheter and Terumo hydrophilic 0.035” wire were used to cross the leak in a retrograde fashion (A). This catheter was exchanged over an Amplatz Extra Stiff Wire for a 7 Fr Cook Shuttle Sheath, which was placed in the left ventricle (B). A 0.014” Ironman Wire was placed as access protection through the paravalvular leak into the left ventricle. A 10 mm PDA occluder device was attempted but was unsuccessful in closing the defect (C) and was removed. The 0.014” wire stayed in place (D). A 4 Fr 125 cm JR4 catheter was placed coaxial inside the shuttle sheath to traverse the paravalvular leak over the 0.014” wire and to reestablish the shuttle sheath across the leak (not pictured). Then a 12/3 mm AVP III device was placed across the leak (E). After fluoroscopic and echocardiographic confirmation of minimal leak and good valve function, the device was released (F).

Figure 4: Aortic Paravalvular Leak, Multiple Leaks A

C

F

I

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Paravalvular Leaks: Device Selection

E

G

H

J

After having a mechanical aortic valve in 2008, this patient presented 4 years later with symptoms of heart failure and severe regurgitation. A 5 x 11 mm paravalvular leak was noted near the left coronary cusp and 5 x 8 mm paravalvular leak in the area of the non-coronary cusp (A and B). A 5 Fr MP catheter and 0.035” hydrophilic wire was used to cross the leak near the non-coronary cusp. This was then exchanged over an Amplatz ES 0.035” wire (C) for a 10 Fr Cook shuttle sheath. This was then used to advance an AVP III size 5 x 14 mm device (D), which was then deployed (E). Similar access was obtained through the other femoral artery and a similar technique was used to cross the leak near the left coronary cusp. An AVP III 5 x 14 mm device was also implanted (F, G, H). Follow-up echocardiographic views at 42 and 117 degrees show the position of the non-coronary cusp (blue arrow) and left coronary cusp (red arrow) devices (I, J).

Both aortic and mitral valve leaflets moved well on transoesophageal echocardiography.

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When a mitral PVL cannot be crossed through other methods or if there are mechanical heart valves in both aortic and mitral positions, transapical access can be considered. In addition to echocardiographic/fluoroscopic visualisation to determine the position of the ventricular apex, it is also important to perform concomitant coronary angiography to avoid the coronary arteries. A sheath (often 4 Fr) is delivered and heparin is given. A device is often used to close the entry site (e.g. Amplatzer PDA Occluder, St. Jude Corporation).

The authhors recommend this as a third and last option, as there is an increased risk of complications from tamponade, hemothorax or puncture of a coronary artery. Follow-up TTE and chest X-ray are highly recommended at 24 hours after procedure/discharge.

There are only a few devices designed specifically for PVLs, thus other devices have often been used. The ideal device has the appropriate size and shape for the leak and does not interfere with the valve leaflets. Furthermore, it does not interfere with other vital structures, such as the coronary ostia in the case of aortic valves or left ventricular outflow tract in the case of mitral valves. Optimally, only one device is needed.

B

D

Sometimes transseptal access is needed, either for mitral PVLs or difficult aortic PVLs. Any transseptal system should be used, and this should be performed under transoesophageal guidance.

The authors recommend an inferior and midway between superior and posterior position for puncture for most leaks, although it is just as important to make sure the transseptal puncture is performed safely as it is to find a specific spot to cross the septum that will allow crossing of the leak. For difficult aortic PVLs, the leak is crossed during retrograde femoral approach and a rail is formed by snaring the wire in the left atrium. For transseptal access, heparin 10,000 units should be administered.

The device size is dependent on measurements from echocardiogram (TEE and 3D whenever possible). Angiography helps in the case of aortic PVL when this can be seen next to the valve. Some may use external catheter size to approximate leak size, but this is also dependent on calcification and tortuosity, which can cause difficulty in a catheter’s ability to cross the leak. The authors follow this general algorithm: for a small cylindrical leak, an Amplatzer Vascular Plug (AVP) II or PDA Occluder may be best; for an oval or crescentic leak, the AVP III is more ideal; if the leak is small or has significant angulation, an AVP IV is better as it is more flexible.

Recently, the Occlutech PLD (Helsingborg, Sweden) device has obtained CE mark approval. There are two devices, one square and one rectangular, both made of nitinol braided mesh. Waist size is chosen similar to the defect size, and this ranges from 3 to 7 mm with circular waist for the square device (requiring 5–7 Fr sheath) and from 4 x 2 to 12 x 5 mm for the rectangular device (requiring 5–8 Fr sheath).10

Putting it all together: Aortic Paravalvular Leak Retrograde transfemoral approach is the optimal strategy for aortic PVL. TEE is used for imaging, with description of the leak on the clock face as described above. Once the leak is crossed with a hydrophilic wire, it is crossed again with a 5 Fr diagnostic catheter (often JR4, MP or Amplatz-1). Defect size determines device size, which dictates size of the guide catheter or long sheath to deliver the device. This is exchanged

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over a stiff wire (often Amplatz Extra Stiff) for a delivery system guide catheter or sheath (e.g. Cook Shuttle Sheath, Cook Corporation, Bloomington, IN, USA). The device is then delivered through this delivery system. TEE then assesses changes with the regurgitant jet. Prior to release, it is important to check for absence of coronary ostia coverage and free movement of the valve leaflets.

If there is significant tortuosity or difficulty crossing the leak, more support can be obtained by building a rail. A transseptal rail involves transseptal access with subsequent snaring of the original wire within the left atrium. An apical ventricular rail involves left ventricular puncture and having the wire through the apex. Figures 3 and 4 demonstrate aortic PVL closure.

Subsequent aortic angiography is often necessary to rule out coronary compression and evaluate the valve for regurgitation. The valve should not have an increased gradient and should have free-moving leaflets. If the device was implanted in the area of the non-coronary cusp, special attention should be given to the anterior mitral valve leaflet.

Figure 5: Mitral paravalvular leak, one device A

B

C

D

E

F

G

H

I

Putting it all together: Mitral Paravalvular Leak After evaluating the leak with TEE, the first approach is to try the simplest approach: retrograde transfemoral approach with a 5 Fr IM or JR4 catheter and a hydrophilic 0.035” guidewire. Once this is across the leak, the wire can be exchanged for a stiff wire and then the delivery system (guide catheter or long sheath). The wire is removed, the device is advanced, and then the device is deployed. By deploying the first disc within the left atrium, it is simpler to visualise on TEE. If there is an issue with support, transseptal access with snare can be used to make a rail. As mentioned above, it is important to protect the aortomitral continuity with a catheter whenever possible.

When the retrograde transfemoral approach is not successful, an antegrade transseptal approach can have some benefits. It is important to cross posteriorly to avoid the aorta and superiorly to have enough catheter room to reach both medial and lateral leaks. A similar approach with a 0.035” hydrophilic wire, 5Fr JR4 or MP catheter, stiff wire exchange, and then exchange for delivery system (guide catheter or long sheath) is used. If support is still an issue, a transarterial rail is recommended. Another option is to advance the transseptal sheath through the defect. Some centers have used an Agilis system (St. Jude Corporation) if the catheter is unable to reach the defect or if the puncture site was suboptimal. The advantage that this offers is increased steerability; the disadvantage is a larger transseptal puncture and increased cost of the procedure. Figures 5, 6 and 7 show examples of mitral PVLs. After the device is placed, TEE should show mobile mitral leaflets, open pulmonary veins, and if the leak was anterior, an unobstructed mitral valve. Angiography is insufficient to make this determination. The authors do no recommend release of a device until these requirements are satisfied.

Several years after placement of a mechanical mitral valve prosthesis and tricuspid ring, the patient developed severe mitral regurgitation with reversal of flow in pulmonary veins. This was due to two paravalvular mitral leaks, one anterolateral (orifice 6 x 15 mm) and one posterior (orifice 10 x 8 mm). The anterolateral leak was close to a section of tissue that interfered with leaflet motion; therefore decision was made to only pursue the posterior leak. Rather than approach the leak retrograde, the decision was made to approach the leak antegrade due to presumed easier access to the posterior leak. After placement of a 5Fr sheath in the right femoral artery and a 9 Fr sheath in the right femoral vein, transseptal puncture was performed.

Antegrade crossing was obtained (wire and diagnostic catheter) but the sheath did not cross (B). Therefore a 5Fr JR4 catheter and 0.035” Terumo wire were introduced through the aorta and the leak was crossed retrograde; the Terumo wire was advanced and snared through a transvenous/transseptal sling in the left atrium and externalized (C, D). This allowed the transseptal 9Fr sheath to be advanced through the leak. A 10 mm Amplatzer muscular VSD occluder was brought through the leak but caused mitral valve impingement (E). Therefore, this was removed and retrograde access from the aorta and sling in the left atrium was again obtained (F). Next an Amplatzer 10 mm PDA occluder was placed across the defect (G, H), which did not interfere with mitral leaflet movement. Echocardiography showing final device position is seen (I).

Special situations Multiple leaks In cases of multiple leaks, the authors recommend closing the major leak only at first, as if there is significant infection/hemolysis, the offending device can be identified. If multiple devices are placed, perhaps one is not the infectious source and therefore should not be removed. The authors place multiple devices or close multiple leaks if there is uncertain follow-up or with two equally sized large leaks.

One approach for multiple device placement is the same-sheath approach: both devices go through the same sheath one after the other. Device one crosses the leak and is deployed. Next, the wire and delivery catheter are used to cross the leak again, and the second device is advanced and deployed. With this method, only one access is needed. However, the first device needs to be fully released before the second device can be advanced.

There are many ways to characterise device success, but the device should treat the problem it is there to solve – there should be a

Another method is with new access. Contralateral femoral access and device advancement may be sufficient for aortic PVL (Figure 2). In the case of mitral PVL, this requires a transseptal approach and dilating the septal access point to accommodate a larger sheath. The larger

sizeable decrease in regurgitation and improvement in symptoms. The patient should have a TTE for aortic leak and TEE for mitral leak at 6 months (or earlier if symptoms are present). If there is hemolysis, the hemoglobin/hematocrit should also be monitored.

sheath should be a sum of the sheaths required for the individual devices (if the two devices need two 6 Fr sheaths, the septum should be crossed with a 12 Fr sheath). Then two (or three wires for three devices) are used to cross the sheath, these wires are exchanged

Device success

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Paravalvular Leak Figure 6: Mitral Paravalvular Leak, Multiple Leaks A

B

C

D

E

F

G

H

I

J After patient had placement of a bioprosthetic mitral valve replacement (MVR). in 2004, he developed one long paravalvular leak that extended over 1/4 of the bioprosthetic valve. A 5 Fr sheath was placed in the right femoral artery. A 5 Fr JR4 catheter and 0.035” Terumo hydrophilic wire were used to cross the leak (A). After femoral venous access with a 6 Fr sheath, transseptal access was obtained. A snare was used to externalise the Terumo wire from the left atrium through the right femoral vein. An Amplatz Extra Stiff Wire was used to exchange the transseptal sheath for an 18 Fr sheath. Through this three Amplatz ES wires were used to exchange this for three 6 Fr Cook shuttle sheaths (B,C). Through these three sheaths, two 12 mm AVP 2 devices and one 10 mm AVP 2 were advanced into the leak (D, E) and deployed (F, G). The position of the devices is also visible on echocardiogram (H). When deploying mitral PVL devices antegrade, it is important to make sure the mitral valve leaflets are not affected by the ventricular side of the device (I) – this requires readjustment and redeployment so the leaflets are not affected (J).

for stiff wires, and the prior large sheath is switched to the multiple delivery systems. The independent devices are then delivered (see Figures 4 and 5).

Preserving PVL access with device placement When the wire crosses the leak only with great difficulty (e.g. tortuous anatomy and/or suboptimal transseptal catheter position), it is also possible to preserve PVL access during device placement with an 0.014” coronary wire (Figure 1). This allows the ability to preserve access – which is crucial if the device must be removed because it is not the correct size or causes leaflet compromise. However, this carries with it the risk that the wire will not be retrievable after the device is released.

Complications Complications will occur but must be avoided when possible.

These include valve interference (3.5–5.0 %), stroke, endocarditis, post-procedural hemolysis, device erosion, emergent cardiac surgery (0.7–2.0 %) and death (1.4–2.0 %). One study showed major adverse events at 30 days (death, myocardial infarction, stroke, major bleeding and emergency surgery) at a rate of 8.7 %. Embolised devices from the aortic position are often large and go to the iliac bifurcation and can be removed percutaneously; those from the mitral position may be caught at the left ventricular outflow tract and may require surgery.

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Figure 7: Mitral Paravalvular Leak, Multiple Leaks A

B

C

D

E

F

G

H

I

J

K

L

The patient presented with severe mitral paravalvular leak. He presented with an anteromedial leak from 1–4 o’clock (orifice 4 x 19 mm), and by 5 o’clock a second leak (orifice 4 x 3 mm).

The large orifice is seen on echocardiography (A). A 5 Fr sheath was placed in the right femoral artery. A 5 Fr JR4 catheter and 0.035” hydrophilic wire was advanced across the anteromedial leak. A 6 Fr sheath was placed in the right femoral vein. Transseptal access was obtained and a snare was used to grab and externalise the wire (B, C). An Amplatz ES wire was then used to exchange this transseptal sheath for a 10 Fr sheath. Through this 10 Fr sheath, two Amplatz ES wires were used to exchange for two 6 Fr Cook shuttle sheaths (D). Two AVP II size 10 mm were advanced and deployed (E, F). The leak at 5 o’clock was approached retrograde. The 5 Fr sheath in the right femoral artery was upsized to a 6 Fr sheath. A 5 Fr JR4 catheter and Terumo wire was used to cross the leak (F). A snare was advanced transseptally into the left atrium, used to capture the wire (G), and then externalised. An 8 mm AVP II was advanced (H) and deployed (I, J). The mitral valve leaflets moved normally. The devices are visible on transoesophageal echocardiography from atrial (K) and ventricular aspect (L). Figures published with permission (12).

Devices that embolise from the aortic position may travel anywhere.

Larger devices are less likely to locate cranially and are often found at the iliac bifurcation. The same holds true for devices that embolise from the mitral position, as most are small enough to pass through the left ventricular outflow tract and the aortic valve.

Post-procedural hemolysis is often due to shearing as blood flows through the now smaller orifice at a higher velocity. While this may worsen the clinical condition, this may also be well tolerated and resolves spontaneously after complete endothelialisation. This may take months.

Long-term survival Technical success rate has reported as 77–86 %, and there has been 67–77 % clinical improvement. A study by Ruiz et al. reported long-term survival at 6, 12 and 18 months as 91.9, 89.2 and 86.5 %, respectively.8 Sorajja et al. found 1–2 year survival after PVL closure of 70–75 % with an estimated 3-year survival rate of 64.5 %.11 n

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Genoni M, Franzen D, Vogt P, et al. Paravalvular leakage after mitral valve replacement: improved long-term survival with aggressive surgery? Eur J Cardiothorac Surg 2000;17 :14–9.

De Cicco G, Russo C, Moreo A, et al. Mitral valve periprosthetic leakage: Anatomical observations in 135 patients from a multicentre study. Eur J Cardiothorac Surg 2006;30 :887–91.

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Prevalence and severity of paravalvular regurgitation in the Artificial Valve Endocarditis Reduction Trial (AVERT) echocardiography study. J Am Coll Cardiol 2004;44 :1467–72.

Zoghbi WA. New recommendations for evaluation of prosthetic valves with echocardiography and doppler ultrasound. Methodist Debakey Cardiovasc J 2010;6 :20–6.

Ruiz CE, Jelnin V, Kronzon I, et al. Clinical outcomes in patients undergoing percutaneous closure of periprosthetic paravalvular leaks. J Am Coll Cardiol 2011;58 :2210–7.

Krishnaswamy A, Kapadia SR, Tuzcu EM. Percutaneous

paravalvular leak closure- imaging, techniques and outcomes.

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10. Goktekin O, Vatankulu MA, Tasal A, et al. Transcatheter transapical closure of paravalvular mitral and aortic leaks using a new device: first in man experience. Catheter Cardiovasc Interv 2014;83 :308–14.

11. Sorajja P, Cabalka AK, Hagler DJ, Rihal CS. Long-term follow-up of percutaneous repair of paravalvular prosthetic regurgitation. J Am Coll Cardiol 2011;58 :2218–24.

12. Gafoor S, Steinberg DH, Franke J, et al. Tools and techniques--clinical: paravalvular leak closure. EuroIntervention 2014;9 :1359–63.

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Lifelong Learning for Cardiovascular Professionals

Supporting lifelong learning for cardiovascular professionals

www.radcliffecardiology.com Register for free access to: • L eading review journals Arrhythmia & Electrophysiology Review, Cardiac Failure Review, European Cardiology Review and Interventional Cardiology Review; • W ebinars – Clinics and case reviews from respected opinion leaders; • Round Table Events – Discussions and opinions of assembled peer groups comprising of cardiovascular authorities; • A database of over two thousand reviews, case repor ts and editorials.

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logists, io rd ca al n o ti en rv te in r fo e The new PCR programm al artery disease er h ip er p h it w ts n ie at p g n worldwide, treati

E H T E V A S DATES! Mission In light of so many patients with untreated peripheral disease, the PCR Istanbul Peripheral Course is aimed to increase the proficiency of teams, across the world, to solve the clinical problems of this specific population. Crafted by and for interventional cardiologists, the Course’s intent is to facilitate capacity building, responding to demand for education from an international audience.

Target audience PCR Istanbul Peripheral is an international peripheral Course for interventional cardiologists, who are already doing peripheral procedures or interested in starting peripheral activities in their cathlabs. Moreover, it is open to the whole endovascular community as well as nurses and technicians.

th 28th November 6 2 -

2015 Istanbul, Turkey

Course objectives g Review patient selection and indications for peripheral procedures g Highlight technical differences and similarities between coronary, structural heart and peripheral procedures g Convey the importance of familiarisation with new tools and devices g Facilitate adaptation of interventional cardiology skills to peripheral environment g Discuss complication management and prevention Founding Course Directors Alberto Cremonesi, Ömer Göktekin Course Co-Director Thomas Zeller

www.pcristanbulperipheral.com

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LEADERSHIP IN LIVE CASE DEMONSTRATION

F E B R U A R Y 11-13, 2016

JOINT INTERVENTIONAL MEETING IN PARTNERSHIP WITH

, Italy

w w w . j i m - v a s c u l a r . c o m ORGANIZING SECRETARIAT Victory Project Congressi • Via C. Poma, 2 - 20129 Milan - Italy Phone +39 02 89 05 35 24 • Fax +39 02 20 13 95 • E-mail info@victoryproject.it Ad216x303JIM.indd 121

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Inte r d i s c ip lin ar y Endovascular Aortic Symposium

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September 27-29 Lisbon/Por tugal Endovascular techniques continue to be essential to modern aortic therapy, and so Europe’s largest IR meeting, CIRSE 2015, will be hosting a parallel, multidisciplinary symposium dedicated to this topic: IDEAS 2015.

Join Barry Katzen, Frank Veith, Mike Dake, Juan Parodi, Goetz Richter and many more of the field’s foremost experts as they discuss a range of key topics in EVAR and TEVAR.

HIGHLIGHTS INCLUDE: • • • • • •

Current and potential future optimal imaging strategies for surveillance after EVAR What does the evidence tell us about the management of aortic dissection?

Strategies for aortic arch and thoracoabdominal aneurysms Hybrid techniques Prevention and management of endoleaks and complications Ruptured abdominal aortic aneurysms: do the trials provide more questions than answers?

and much more...

www.aorticideas.org I N N O V AT I O N | E D U C AT I O N | I N T E R V E N T I O N

Cardiovascular and Inter ventional Radiolo gical So ciet y of Europ e

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LIVE CASES LIVE L IC VA E SES CASES

CSI 2014 – CONGENITAL, STRUC TURAL AND VALVULAR HEART INTERVENTIONS JUNE 24 – 27, 2015 | FRANKFURT, GERMANY CSI will give you a comprehensive overview of major topics in catheter therapy of congenital, structural and valvular heart disease and is designed for adult and pediatric interventional cardiologists, cardiothoracic surgeons, anesthesiologists, imaging specialists, nurses, technicians and any other medical specialty involved in these procedures. Engineers, device design specialists, and inventors have also discovered CSI as a stimulating environment with unparalleled opportunities to learn from and network with physicians.

Our program includes lectures from leading experts in the field, live case demonstrations, hands-on simulation training, master class sessions and an industry exhibition. The high number of live cases and the close interaction between the audience, panel and operators makes CSI unique.

TH E CS I 2015 PR O GR AM W IL L IN CLUD E: P IN NO VATIO N (I2 ) – CS I FO CU S W OR KS HO P IM AG IN G – CS I FO CU S W OR KS HO AT IO NS – LIV E CA SE DE MO NS TR IN G EX PE RT S – LE CT UR ES FR OM LE AD Y EV ER Y DAY – TR AI NI NG HU B – AL L DA ST ER CL AS S SE SS IO NS – ST EP -BY- ST EP AN D MA SE SS IO NS – LU NC H AN D EV EN IN G – IN DU ST RY EX HI BI TIO N – CS I SO CI AL EV EN T

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On the first day of the conference there will be two simultaneous programs dedicated to specific topics within the field: 1) CSI Focus Workshop Imaging – this covers all aspects of echo, CT, MRI, and other most advanced imaging techniques needed before, during, and after structural, valvular, and congenital heart interventions. The workshop is designed to provide physicians with the necessary imaging tools for safe and effective procedural performance and to familiarize attendees with techniques that are on the horizon.

2) CSI Focus Workshop Innovation (i²) – this one-of-a-kind conference will bring together clinicians, device developers, engineers, company leaders, and regulatory advisors to discuss the process of device design and development from bench to bedside.

Learn what it takes to turn an initial idea into an approved product.

If you have an idea for a device, make sure to attend this program!

We hope that CSI 2015 will provide you with an exciting learning and networking experience and allow you to become familiar with the newest techniques, technology and concepts.

Come and join us in Frankfurt to learn, discuss and share!

JUNE 24 – 27, 2015 FOR MORE INFORMATION OR TO REGISTER PLEASE VISIT OUR WEBSITE:

www.csi-congress.org

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Program and registration online www.toptencardiology.com

Department of Cardiology An International 1-day Cardiology Meeting

Top Ten in Cardiology 3rd Edition - October 2nd 2015 Lausanne, Switzerland Program Directors : Martin Fromer MD, Pierre Vogt MD

With the contributions of : Thomas Arentz MD, Bad Krozingen University, Germany

Sanjay Sharma MD, St George University of London, United Kingdom

Salim Yusuf, MD McMaster University, Canada

Didier de Cannière MD, UniversitÊ Libre de Bruxelles, Belgium

Scott D. Solomon MD, Harvard Medical School, USA

Mooly Auerbach MD, Biosense Webster, Israel

John Chapman MD, University Pierre and Marie Curie, France

Hugo Vanermen MD, University of Leuven, Belgium

Alphons Vincent MSc, Medtronic, Switzerland

Yoram Rudy MD, Washington University in St Louis, USA

Michael A Weber MD, Downstate College of Medicine, USA

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