AER 4.2 by Radcliffe Cardiology

Arrhythmia & Electrophysiology Review Volume 4 • Issue 2 • Autumn 2015

www.AERjournal.com

Volume 4 • Issue 2 • Autumn 2015

Mechanisms of Heart Block After Transcatheter Aortic Valve Replacement – A Review of Cardiac Anatomy, Clinical Predictors and Mechanical Factors that Contribute to Permanent Pacemaker Insertion Mark Y Lee, Srinath C Yeshwant, Sreedivya Chava and Daniel L Lustgarten

Arrhythmogenic Right Ventricular Cardiomyopathy – Antiarrhythmic Therapy Simon Ermakov and Melvin Scheinman

Is Mapping of Complex Fractionated Electrograms Obsolete? Manav Sohal, Rajin Choudhury, Philippe Taghji, Ruan Louw, Michael Wolf, Joel Fedida, Yves Vandekerckhove, Rene Tavernier, Mattias Duytschaever and Sébastien Knecht

Developments in Cardiac Resynchronisation Therapy Geoffrey F Lewis and Michael R Gold

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Subcutaneous Implantable 3-lead ECG Simultaneous Cardioverter Defibrillator RA LEAD I

ISSN - 2050-3369

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A new Mapping Experience CONFIDENSE™ Mapping Module offers CARTO® 3 System users a complete and streamlined high-density mapping solution.

KEY BENEFITS Continuous Mapping: Automated data acquisition (when physician set-criteria are met) Tissue Proximity Indication: Proximity-based filtering of points acquired with MEM catheters Wavefront Annotation: An automated annotation algorithm that incorporates both unipolar and bipolar signals Map Consistency: System identifies outlying points when certain criteria are met

A successful ablation requires a Smart Touch.† SMART-AF TRIAL: ATRIAL ARRHYTHMIA-FREE

Force

(12 MONTHS POSTPROCEDURE)1 SUCCESS RATE (%)*

81% 88

stability

100% 80% 60% 40% 20%

Time

0% Overall success in primary effectiveness IN SELECTED TARGET RANGE cohort

≥ 80% ≥ 85%

1. Natale A, Reddy V, Monir G, et al. Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the prospective, multicenter SMART-AF Trial. J Am Coll Cardiol. 2014;64(7):647-656 *Success defined as freedom from any symptomatic atrial arrhythmia (atrial fibrillation, atrial flutter, atrial tachycardia). Further sub-analysis showed that a success rate of 88% when the investigator stayed within their preselected CF range ≥85% of the (≥85%: n=32; <85%: n=73).

† A constant challenge in catheter ablation is optimising electrode -issue contact. With excellent contact, energy coupling to tissue is optimised and less energy is dissipated into the circulating blood pool. Thus, more predictable and reliable lesions can be created with excellent catheter contact to the endocardium (ESC guidelines.)

Biosense Webster A Division of Johnson & Johnson Medical NV/SA Leonardo Da Vincilaan 15 - 1831 Diegem, Belgium - Tel: +32-2-7463-401 - Fax: +32-2-7463-403 Please refer to the instructions for use accompanying each device before use. For healthcare professionals only. © Johnson & Johnson NV/SA 2015. All rights reserved. 021790-140923-022402-141002

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Volume 4 • Issue 2 • Autumn 2015

Editor-in-Chief Demosthenes Katritsis Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Implantable Devices

Andrew Grace

Karl-Heinz Kuck

Angelo Auricchio

University of Cambridge, UK

Asklepios Klinik St Georg, Hamburg, Germany

Fondazione Cardiocentro Ticino, Lugano, Switzerland

Etienne Aliot

Warren Jackman

Christopher Piorkowski

University Hospital of Nancy, France

University of Oklahoma Health Sciences Center, Oklahoma City, US

University of Dresden, Germany

University Hospital Uppsal, Sweden

Mark Josephson

Johannes Brachmann

Beth Israel Deaconess Medical Center, Boston, US

ALFA – Alliance to Fight Atrial Fibrillation, Venice-Mestre, Italy

Klinikum Coburg, II Med Klinik, Germany

Josef Kautzner

Frédéric Sacher

Pedro Brugada

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Bordeaux University Hospital, LIRYC Institute, France

Samuel Lévy

Richard Schilling

Carina Blomström-Lundqvist

University of Brussels, UZ-Brussel-VUB, Belgium

Hugh Calkins Johns Hopkins Medical Institutions, Baltimore, US

A John Camm St George’s University of London, UK

Riccardo Cappato IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

Ken Ellenbogen Virginia Commonwealth University School of Medicine, US

Sabine Ernst Royal Brompton and Harefield NHS Foundation Trust, UK

Andreas Götte

Aix-Marseille Université, France

Antonio Raviele

Cecilia Linde

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

Karolinska University, Stockholm, Sweden

William Stevenson

Gregory YH Lip University of Birmingham Centre for Cardiovascular Sciences, UK

Francis Marchlinski University of Pennsylvania Health System, Philadelphia, US

Jose Merino Hospital Universitario La Paz, Spain

Fred Morady Cardiovascular Center, University of Michigan, US

Brigham and Women’s Hospital, Harvard Medical School, US

Richard Sutton National Heart and Lung Institute, Imperial College, London, UK

Juan Luis Tamargo University Complutense, Madrid, Spain

Sotirios Tsimikas University of California San Diego, US

Panos Vardas

St Vincenz-Hospital Paderborn and University Hospital Magdeburg, Germany

Sanjiv M Narayan Stanford University Medical Center, US

Hein Heidbuchel

Marc A Vos

Mark O’Neill

Hasselt University and Heart Center, Jessa Hospital, Hasselt, Belgium

King’s College, London, UK

University Medical Center Utrecht, The Netherlands

Gerhard Hindricks

Carlo Pappone

Katja Zeppenfeld

Maria Cecilia Hospital, Italy

Leiden University Medical Center, The Netherlands

University of Leipzig, Germany

Carsten W Israel JW Goethe University, Germany

Sunny Po Heart Rhythm Institute, University of Oklahoma Health Sciences Center, US

Heraklion University Hospital, Greece

Douglas P Zipes Krannert Institute of Cardiology, Indianapolis, US

Managing Editor Becki Davies • Design Manager Tatiana Losinska Managing Director David Ramsey • Publishing Director Liam O’Neill Digital Commercial Manager Ben Sullivan • Account Executive Ryan Challis •

•

In partnership with

•

Editorial Contact Becki Davies | managingeditor@radcliffecardiology.com Circulation & Commercial Contact | David Ramsey david.ramsey@radcliffecardiology.com Cover image | shutterstock.com • Cover design Tatiana Losinska

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2015 All rights reserved © RADCLIFFE CARDIOLOGY 2015

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Established: October 2012

Aims and Scope • Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in the arrhythmia and electrophysiology sphere. • Arrhythmia & Electrophysiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Arrhythmia & Electrophysiology Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-today clinical practice. • The journal endeavours, through its timely teaching reviews, to support the continuous medical education of both specialist and general cardiologists, and disseminate knowledge of the field to the wider cardiovascular community.

Structure and Format

Frequency: Tri-annual

Current Issue: Autumn 2015

• 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: managingeditor@radcliffecardiology.com. The ‘Instructions to Authors’ information is available for download at www.AERjournal.com

• Arrhythmia & Electrophysiology Review is a tri-annual journal comprising review articles and editorials. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Arrhythmia & Electrophysiology Review is replicated in full online at www.AERjournal.com

All articles included in Arrhythmia & Electrophysiology Review are available as reprints (minimum order 1,000). Please contact Liam O’Neill at liam.oneill@radcliffecardiology.com

Editorial Expertise

Distribution and Readership

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

Arrhythmia & Electrophysiology Review is distributed tri-annually through controlled circulation to general and specialist senior cardiovascular professionals in Europe. All manuscripts published in the journal are free-to-access online at www.AERjournal.com and www.radcliffecardiology.com

Reprints

Abstracting and Indexing Arrhythmia & Electrophysiology Review is abstracted, indexed and listed in Embase, Scopus, Google Scholar and Summon by Serial Solutions.

Copyright and Permission Peer Review • On submission, all articles are assessed by the Editor-in-Chief or Managing Editor 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.

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

Online All manuscripts published in Arrhythmia & Electrophysiology Review are available free-to-view at www.AERjournal.com and www.radcliffecardiology.com. Also available at www.radcliffecardiology.com are other journals within Radcliffe Cardiology’s portfolio: Interventional Cardiology Review, Cardiac Faiilure Review and European Cardiology Review. n

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Browse through 19 000 presentations & 150 topics

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Contents

Foreword

What is Established and What is New in Ablation of Persistent Atrial Fibrillation? Karl-Heinz Kuck (Section Editor – Clinical Electrophysiology and Ablation) and Andreas Metzner

Asklepios Klinik St Georg, Hamburg, Germany

Arrhythmia Mechanisms echanisms of Heart Block after Transcatheter Aortic Valve Replacement M – A Review of Cardiac Anatomy, Clinical Predictors and Mechanical Factors that Contribute to Permanent Pacemaker Insertion

Mark Y Lee, Srinath C Yeshwant, Sreedivya Chava and Daniel L Lustgarten

University of Vermont, Vermont, US

Clinical Arrhythmias Arrhythmogenic Right Ventricular Cardiomyopathy – Antiarrhythmic Therapy

Simon Ermakov 1 and Melvin Scheinman 2

1. Stanford University Hospital and Clinics, California, US; 2. University of California‚ San Francisco, US

Monitoring the Effects and Antidotes of the Non-vitamin K Oral Anticoagulants

Nur A Rahmat 1 and Gregory YH Lip 1,2

1. University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK; 2. Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

Early Repolarisation – What Should the Clinician Do?

Manoj N Obeyesekere 1 and Andrew D Krahn 2

1. Cabrini and Epworth Healthcare Groups, Victoria, Australia; 2. The Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada

100

Anticoaguation in Atrial Fibrillation – Current Concepts

Demosthenes G Katritsis, 1 Bernard J Gersh 2 and A John Camm 3

1. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, US; 2. Mayo Medical School, Rochester, Minnesota, US; 3. St George’s University of London, UK

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Contents

Diagnostic Electrophysiology & Ablation

A Decade of CFAE Mapping – Still Seeking More Specific Tools to 108 Identify Sources and Substrate of Persistent Atrial Fibrillation Amir Jadidi and Thomas Arentz

Arrhythmia Division, Department of Cardiology, University Heart Centre Freiburg - Bad Krozingen, Germany

109

Is Mapping of Complex Fractionated Electrograms Obsolete?

Manav Sohal, Rajin Choudhury, Philippe Taghji, Ruan Louw, Michael Wolf, Joel Fedida, Yves Vandekerckhove, Rene Tavernier, Mattias Duytschaever and Sébastien Knecht

Department of Cardiology, AZ Sint-Jan, Bruges, Belgium

Device Therapy 116 The Entirely Subcutaneous Defibrillator – A New Generation and

Future Expectations

Hussam Ali, Pierpaolo Lupo and Riccardo Cappato

Arrhythmia & Electrophysiology Research Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy; Arrhythmia & Electrophysiology Unit II, Humanitas Gavazzeni Clinics, Bergamo, Italy

122

Developments in Cardiac Resynchronisation Therapy

Geoffrey F Lewis and Michael R Gold

Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, US

129 Sex Differences in Utilisation and Response to Implantable Device Therapy Deepika Narasimha and Anne B Curtis

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Department of Medicine, University at Buffalo, Buffalo, New York, US

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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 CanniĂ¨re MD, UniversitĂŠ 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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Foreword

What is Established and What is New in Ablation of Persistent Atrial Fibrillation?

atheter-based ablation of atrial fibrillation (AF) is an established treatment option for symptomatic patients who are refractory to drug-based treatment, as implemented in the latest guidelines for the

management of AF.1 The accepted and recommended cornerstone of all ablation strategies for AF is electrical isolation of the pulmonary veins (PV).2 However, in addition to PV isolation (PVI), ablation strategies for persistent or even long-standing persistent AF are heterogeneous. They may be characterised by PVI as the sole ablation target but can be extended to ablation of complex fractionated atrial electrograms (CFAE) and/or linear lesions.3–6 The recently published prospective, randomised, multicentre Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR-AF II) study demonstrated that pure PVI in patients with persistent AF is not less effective than more extensive ablation strategies such as ablation by way of linear lesions (mitral isthmus line and roof line) or ablation of CFAE.7 In this regard the second-generation cryoballoon has proven its potential for safe, effective and time-efficient PVI. One-year clinical outcome success after cryoballoon-based PVI in patients with paroxysmal AF (PAF) ranges between 80 % and 90 %.8–10 Cryoballoon-based PVI is also starting to demonstrate encouraging results in persistent AF; however these findings need further evaluation.11,12 In addition, novel invasive and

non-invasive mapping systems allowing for focal impulse and rotor mapping (FIRM) are under investigation; they will broaden our comprehension of the underlying pathophysiology of AF and might potentially extend or change our ablation options and strategies in PAF as well as in persistent AF.13–16 Karl-Heinz Kuck (Section Editor – Clinical Electrophysiology and Ablation) and Andreas Metzner Asklepios Klinik St Georg, Hamburg, Germany

2. 3.

Camm AJ, Lip GY, De Caterina R, et al; ESC Committee for Practice Guidelines. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–47. Kirchhof P, Auricchio A, Bax J, et al. Outcome parameters for trials in atrial fibrillation: executive summary. Eur Heart J 2007;28:2803–17. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044–53. Cappato R, Calkins H, Chen SA, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:32-8. Tilz RR, Rillig A, Thum AM, et al. Catheter ablation of longstanding persistent atrial fibrillation: 5-year outcomes of the Hamburg Sequential Ablation Strategy. J Am Coll Cardiol 2012;60:1921–9. Scherr D, Khairy P, Miyazaki S, et al. Five-year outcome of catheter ablation of persistent atrial fibrillation using

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termination of atrial fibrillation as a procedural endpoint. Circ Arrhythm Electrophysiol 2015;8:18–24. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812–22. 8. Metzner A, Reissmann B, Rausch P, et al. One-year clinical outcome after pulmonary vein isolation using the secondgeneration 28-mm cryoballoon. Circ Arrhythm Electrophysiol 2014;7:288–92. 9. Wissner E, Heeger CH, Grahn H, et al. One-year clinical success of a 'no-bonus' freeze protocol using the secondgeneration 28 mm cryoballoon for pulmonary vein isolation. Europace 2015;17:1236–40. 10. Ciconte G, Ottaviano L, de Asmundis C, et al. Pulmonary vein isolation as index procedure for persistent atrial fibrillation: One-year clinical outcome after ablation using the second-generation cryoballoon. Heart Rhythm 2015;12:60–6. 11. Lemes C, Wissner E, Lin T, et al. One-year clinical outcome after pulmonary vein isolation in persistent atrial fibrillation using the second-generation 28 mm cryoballoon: a retrospective analysis. Europace 2015; pii: euv092. Epub ahead of print. 7.

12. Ciconte G, Baltogiannis G, de Asmundis C, et al. Circumferential pulmonary vein isolation as index procedure for persistent atrial fibrillation: a comparison between radiofrequency catheter ablation and second-generation cryoballoon ablation. Europace 2015;17:559–65. 13. Narayan SM, Krummen DE, Shivkumar K, et al.Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012;60:628–36. 14. Narayan SM, Krummen DE, Clopton P, et al. Direct or coincidental elimination of stable rotors or focal sources may explain successful atrial fibrillation ablation: on-treatment analysis of the CONFIRM trial (Conventional ablation for AF with or without focal impulse and rotor modulation). J Am Coll Cardiol 2013;62:138–47. 15. Revishvili AS, Wissner E, Lebedev DS, et al. Validation of the mapping accuracy of a novel non-invasive epicardial and endocardial electrophysiology system. Europace 2015;17:1282–8. 16. Haissaguerre M, Hocini M, Shah AJ, et al. Noninvasive panoramic mapping of human atrial fibrillation mechanisms: a feasibility report. J Cardiovasc Electrophysiol 2013;24:711–7.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

23/08/2015 11:40

Arrhythmia Mechanisms

Mechanisms of Heart Block after Transcatheter Aortic Valve Replacement – Cardiac Anatomy, Clinical Predictors and Mechanical Factors that Contribute to Permanent Pacemaker Implantation Mark Young Lee, Srinath Chilakamarri Yeshwant, Sreedivya Chava and Daniel Lawrence Lustgarten University of Vermont, Vermont, US

Abstract Transcatheter aortic valve replacement (TAVR) has emerged as a valuable, minimally invasive treatment option in patients with symptomatic severe aortic stenosis at prohibitive or increased risk for conventional surgical replacement. Consequently, patients undergoing TAVR are prone to peri-procedural complications including cardiac conduction disturbances, which is the focus of this review. Atrioventricular conduction disturbances and arrhythmias before, during or after TAVR remain a matter of concern for this high-risk group of patients, as they have important consequences on hospital duration, short- and long-term medical management and finally on decisions of device-based treatment strategies (pacemaker or defibrillator implantation). We discuss the mechanisms of atrioventricular disturbances and characterise predisposing factors. Using validated clinical predictors, we discuss strategies to minimise the likelihood of creating permanent high-grade heart block, and identify factors to expedite the decision to implant a permanent pacemaker when the latter is unavoidable. We also discuss optimal pacing strategies to mitigate the possibility of pacing-induced cardiomyopathy.

Keywords TAVR, aortic stenosis, permanent pacemaker, atrioventricular block Disclosure: Dr Lustgarten has served as a consultant and received research support/honoraria from Boston Scientific and Medtronic, Mark Young Lee, Srinath Chilakamarri Yeshwant and Sreedivya Chava have no conflicts of interest to declare. Received: 16 June 2015 Accepted: 09 August 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(2):81–5 Access at: www.AERjournal.com Correspondence: Mark Young Lee, University of Vermont, 111 Colchester Ave, McClure Campus MCHV 1, Burlington, VT 05401, US. E: Mark.Lee@uvmhealth.org

Aortic stenosis (AS) is the most common valvular heart disease in industrialised countries with a prevalence of about 5 % in the general population aged greater than 75 years. During the past decade, transcatheter aortic valve replacement (TAVR) has emerged as a valuable, minimally invasive treatment option for patients presenting with symptomatic severe AS, who due to their advanced age and relevant comorbidities are at prohibitive risk for conventional surgery,1 whereas surgical aortic valve replacement (SAVR) remains the gold standard for the treatment of symptomatic AS in patients with low to moderate surgical risk.2 However, many patients begin to experience AS-related symptoms late in their lives when multiple comorbidities preclude surgery as an option. As a result, before the advent of TAVR, patients considered high- or extreme-risk surgical candidates were once limited to conventional medical therapy. Ever since the first device was deployed in 2002, TAVR has enabled inoperable patients the opportunity to experience survival rates equivalent to their surgical counterparts with considerably less procedural risk.1 Therefore, the number of patients undergoing TAVR has increased steadily, and the complications related to valve implantation have been well defined. The development of atrioventricular (AV) conduction disturbances is one of the most commonly encountered complications associated with TAVR. Between 3 and 6 % of patients undergoing surgical replacement of their aortic valve will develop complete heart block (CHB),3 while considerably higher rates have been reported in the setting of TAVR in individual studies.4 In this review, we aim to explore the significance

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of conduction disturbances preceding and resulting from TAVR. We have focused on data that raise concerns around creating chronic left ventricular (LV) dyssynchrony in this patient population, either as a consequence of creating left bundle branch block (LBBB), or from chronic right ventricular (RV) pacing. Additionally, we reviewed a number of factors that predispose TAVR patients to develop conduction disturbances, and clinical factors that can be used to identify those patients likely to require permanent pacing and alternatively those in whom it may be worth waiting longer prior to committing to permanent pacemaker (PPM) implantation. Shy of unique valve designs, it has become clear there are only modest improvements an operator can make to avoid the complication of heart block and this complication is simply part of the procedure. It is critical to anticipate it and think prospectively about the ideal pacing mode for the individual patient to prevent chronic LV dyssynchrony in those patients at highest risk.

Mechanisms of Heart Block Anatomical Relationship of the Cardiac Conduction System and the Aortic Root Since the 16th century when Leonardo da Vinci conducted the first known cadaveric studies of the heart, the aortic root complex has been studied extensively. With the advent of percutaneous valves, there has been renewed interest in understanding the anatomy of the aortic valve, particularly with respect to the conduction system since the proximity of the latter to the aortic root can result in its disruption during valve deployment.

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Arrhythmia Mechanisms Figure 1: Positional Variation of the Atrioventricular Conduction Axis A

Compact AVN

MS RBB

AVB

AVB RV

F RA

Compact MS AVN

RC RBB

RA RV

LV AVB

AVB

AVB RV

LV VS

A: Typical positions of the compact atrioventricular node in the triangle of Koch, which is defined by the tendon of Todaro (purple dots), the tricuspid valve (blue dots) and the ostium of the coronary sinus, and the atrioventricular bundle in the infra-anterior border of the membranous septum. Right chamber view in the corrected anatomical position. B–C: Positional variation of the atrioventricular bundle within the ventricular septum just below the membranous septum. The atrioventricular bundle positioned in the right and left halves of the ventricular septum, respectively. Sections through the centre of the membranous septum. D–F: The exposed atrioventricular bundle before (D) and after (E) dissection, and histological findings (F), respectively. AVB = atrioventricular bundle; AVN = atrioventricular node; CS = coronary sinus; LV = left ventricle; MS = membranous septum; RA = right atrium; RBB = right bundle branch; RC = right coronary cusp; RV = right ventricle; TT = tendon of Todaro; TV = tricuspid valve; VS = ventricular septum. Modification after Kawashima T, Sasaki H. Gross anatomy of the human cardiac conduction system with comparative morphological and developmental implications for human application. Ann Anat 2011;193:1–12. Reprinted from Kawashima T, et al.5 © 2014, with permission from Elsevier.

Within the right atrium, the AV node is positioned at the base of the atrial septum and is located using landmarks that form the triangle of Koch – the tendon of Todaro, the orifice of the coronary sinus and the insertion point of the tricuspid valve septal leaflet. The anteroposterior relationship of the AV node with respect to the apex of the triangle of Koch varies between individuals as does the length of the non-penetrating (or most proximal) portion of the His bundle. The non-penetrating portion of the His bundle traverses the membranous septum to become the penetrating His bundle, which then physically divides into the respective bundle branches. Inter-individual variation in the penetrating bundle length and depth of septal penetration and variation in the location of the proximal portion of left bundle determine how susceptible these structures are to injury during TAVR. These anatomical variations have been elegantly characterised by Kawashima and Sato.5 Specifically, they describe three major variants in these anatomical relationships that, depending on which is present, determine the susceptibility of a patient to developing complete or LBBB. In an autopsy series of 115 elderly patients, 50 % were found to have a relatively right-sided AV bundle, 30 % a left-sided AV bundle, and in around 20 % the bundle coursed under the membranous septum just below the endocardium. In the latter two variants, the AV bundle is particularly exposed and susceptible to injury. LBBB susceptibility is determined by how soon the left bundle appears on the left side of the septum, and injury to both is further affected by the relative positioning of the membranous septum with respect to the aortic cusps, see Figure 1.

SAVR showed similar survival rates at a median of 8 months, but revealed higher rates of PPM implantation using the transcatheter approach compared with surgical AVR.6 Conduction abnormalities from SAVR are attributed to the surgical method – suturing along the sewing ring near the membranous septum, removal of the native aortic valve and the resultant oedema. TAVR obviates some of these concerns, but raises with it a slew of device-specific issues including differences in size and shape, deployment method and vascular access site. The susceptibility to AV block in the TAVR setting is device specific, as has been well-described in meta-analyses, with incidence ranging between 24.5 % and 25.8 % in the CoreValve device compared with 5.9 % to 6.5 % in the SAPIEN valve.7 The increased risk of AV block with the CoreValve has been attributed partly to the valve design (self-expanding versus balloon-expandable) and the potential for a deeper valve implantation into the left ventricular outflow tract (LVOT). The aforementioned mechanism may result in more injury to the AV node and left bundle branches, which may be delayed because of the self-expanding nature of the prosthesis and tissue oedema.3,8,9 A Spanish study (n=65; CoreValve only) reported a frame depth in the LVOT of 11.1 mm as an independent predictor of PPM insertion with 81 % sensitivity and 84.6 % specificity.10 Furthermore, the self-expanding property of the CoreValve stent is thought to impart a significant degree of persistent radial force to the aortic annulus, particularly at the level of the frame skirt, which is adjacent to the LVOT and may contribute to a higher incidence of post-implant heart block.11 In contrast, the balloon-expandable bovine SAPIEN valve has a smaller profile (14–19 mm in length) and is composed of either stainless steel or cobalt-chromium. SAPIEN valve has a cylindrical shape and is associated with much lower need for permanent pacing. Finally, the prosthesis:LVOT diameter ratio was recently identified as a novel predictor for permanent pacemaker implantation even among patients undergoing TAVR with SAPIEN valve (for each 0.1 increment, OR 1.29; 95 % CI [1.10–1.51]; p=0.002).7 Hence pre-operative evaluation is probably relevant in mitigating the probability of provoking heart block in terms of both device selection and sizing.

Transfemoral Versus Apical Access Whether or not TAVR is performed via the transfemoral (TF) or transapical (TA) approach does not seem to significantly impact pacemaker implant incidence. A recent single-centre retrospective study from the US comparing TF versus TA access (n=123 high-risk AS patients) found no significant differences with respect to 30-day mortality, MI or stroke; the same was true for the secondary endpoint of pacemaker insertion (TF 9.1 % vs TA 12.3 %; p=0.574).12

Clinical Predictors of AV Block It is easy to generalise conduction abnormalities to mechanical factors alone, but the involved patient population has multiple comorbidities that are probably relevant to this issue. As with any operation, procedural complications increase with a patient’s age and comorbidities. In severe aortic stenosis, common cardiac risk factors including diabetes mellitus, hypertension and congestive heart failure have been associated with the development of LBBB and bradyarrhythmias, irrespective of whether or not these patients underwent surgical or transcatheter AVR.13

Mechanical Effects of Bioprosthetic Valves on the Conduction System

Indications for Permanent Pacemakers

Currently, two TAVR devices are in clinical use – the self-expanding CoreValve (Medtronic) and the balloon-expandable SAPIEN valve (Edwards). A network meta-analysis of randomised trials (n=1,805 patients) comparing TAVR (using CoreValve or SAPIEN valve) versus

Pacemaker indications following TAVR encompass a gamut of disease states including sinus node dysfunction, atrial fibrillation with slow ventricular response and symptomatic bradycardia.14 The PARTNER registry showed, however, that 80 % of single- or dual-chambered

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pacemakers were implanted for high-degree or CHB.4 Physiologically, this can be explained, as new-onset LBBB is the most common conduction disturbance after TAVR. In patients with pre-existing right bundle branch block (RBBB), CHB will inevitably occur, and expert consensus recommends placing a temporary transvenous pacemaker not only for patients with complete AV dissociation, but for those at risk for heart block. The question then becomes quite challenging, as physicians have to decide, first, which patients with AV block are candidates for permanent pacing; and, second, just when a pacemaker should be implanted. To answer these questions, case series involving CoreValve were performed and revealed a surfeit of factors predictive of PPMs following TAVR, including left axis deviation, mitral annular calcification and narrow LVOT diameter, to name just a few.3,15 Admittedly, these case series sampled a small number of patients and were mainly hypothesis generating until larger registries could be examined.

Device-specific (CoreValve versus SAPIEN valve) Clinical Predictors In 2014, a meta-analysis across 41 studies (n=11,210 TAVR patients) revealed a 17 % incidence of PPMs. The aim of this study was to identify clinical determinants predictive of PPM implantation. Both CoreValve and SAPIEN valve were included in the study. Crude relative risks of 14 eligible variables were examined and the following were identified as predictors of PPM implantation following TAVR: male gender (RR 1.23; p< 0.01), first-degree AV delay (RR 1.52; p<0.01), left anterior hemi-block (RR 1.62; p< 0.01), RBBB (RR 2.89; p<0.01) and intraprocedural AV block (RR 3.49; p< 0.01). As stated, data on the SAPIEN valve were limited and these clinical variables were applied mainly to patients that received the CoreValve bioprosthesis.4 The PARTNER registry houses the largest database of SAPIEN valve patients and a recent subset analysis outlined predictors of permanent pacemakers specifically for the SAPIEN device. Of 1,973 SAPIEN valve cases, PPM was required in 8.8 % of patients. Multivariable analysis revealed baseline RBBB (OR 7.03; 95 % CI [4.92–10.06]; p=0.002), LVED diameter (for each 1 cm, OR 0.68; 95 % CI [0.53–0.87]; p=0.003) and prosthesis to LVOT diameter (mentioned earlier) as significant predictors. Furthermore, patients who received PPMs had higher rates of mortality and repeat hospitalisation at one year (42 % vs 32.6 %; p=0.007).7 Extrapolating the results across multiple studies, baseline RBBB is a consistent predictor of PPM insertion irrespective of the device used (CoreValve versus SAPIEN valve). As previously discussed, new LBBB manifests frequently after TAVR, reported to appear in up to 65 % of patients, and when compounded with RBBB it will lead to CHB. Other determinants of PPM implant, such as prosthesis to LVOT diameter, point toward the mechanical effects of conduction abnormalities, highlighting the close proximity of the aortic annulus to the AV bundle and its branches, Table 1.

Table 1. Predictors of Permanent Pacemaker Implantation Following TAVR Based on Literature Review Author

Predictors of PPM

Valve

insertion *

type

Number of patients (% of new PPMs)

Nazif

• RBBB (OR 7.03)

SAPIEN

n=1,973 (8.8 %)

et al7

• LVED diameter per 1 cm

valve

increment (OR 0.68) • Prosthesis to LVOT diameter per 0.1 increment (OR 1.29) Siontis

• Male gender (RR 1.23)

et al14

• 1st degree AV delay (RR 1.52) SAPIEN valve • Left anterior hemi-block

CoreValve

n=11,210 (SAPIEN valve 6 %, CoreValve 28 %)

(RR 1.62) • Intraprocedural AV block (RR 3.49) • RBBB (RR 2.89) • CoreValve valve (RR 2.54) PPM – permanent pacemaker; RBBB – right bundle branch block. * P<0.01

conduction among patients with PPMs through interrogation of their devices at 1 to 40 months’ follow-up. Of the 167 patients with PPMs after TAVR, only 44 % were pacemaker dependent, defined by the persistence of high-degree AVB or absence of ventricular escape at VVI 30 bpm.17 These findings propose an important paradigm shift focusing less on who will develop, but rather who will remain in heart block. Recently, a new wrinkle has been added to the discussion of periprocedural heart block. Urena and colleagues performed a prospective study of 435 patients and identified new arrhythmias in 16.1 % of patients during the 1 day preceding TAVR. The arrhythmias discovered by 24-hour continuous monitoring included paroxysmal atrial fibrillation, advanced AV block, severe bradycardia and nonsustained ventricular tachycardia, accounting for one-third of post-procedural conduction abnormalities. Since there was no control group in this study, it is unclear if the arrhythmias found on continuous monitoring were attributable to severe aortic stenosis. Nevertheless, these findings pose the possibility that what we deem as novel arrhythmias following TAVR may not be new. More importantly, if these findings by Urena are validated in future studies, management of TAVR patients would change, as pre-procedural arrhythmias were associated with higher cerebrovascular events.18 As of this writing, most patients will receive a PPM within 1 week of TAVR for high-degree or CHB.19 However, careful review of PPM indications from procedure reports from the PARTNER registry revealed a diagnosis of sick-sinus syndrome in 17 % of patients, higher than found in previously published reports. Additionally, there was a noticeable difference in PPM rates between the continued access registry and randomised trial (9.6 % versus 5.6 %), indicating that PPM insertion is partly driven by variable physician threshold.7

Timing of PPM Implant The challenge with peri-procedural heart block is determining when to implant a PPM. Guidelines related to timing do not exist and for obvious reasons AV block after TAVR exhibits dynamic properties. Nazif and colleagues reported resolution of LBBB in approximately 40 % of SAPIEN valve patients just one month following TAVR, consistent with previous studies that demonstrated ranges between 30–50 %7,16. Furthermore, a single-centre prospective study demonstrated recovery of native

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Sequelae of PPM Significance of LBBB We touched upon the mechanism and rates of new LBBB in previous sections and now shift our focus to its prognostic significance. Overall, mortality data in patients who develop new LBBB after TAVR are conflicted. The largest study published to date (n=1151) showed no association between new LBBB and death, but led to an increase in

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Arrhythmia Mechanisms pacemaker insertion and failure of LVEF to improve at 1-year followup.20 In contrast, a Dutch registry (n=679) followed patients for a median of 450 days and showed that new LBBB was an independent predictor of all-cause mortality (37.8 % vs 24 % [no LBBB]; p=0.002). The authors postulate that LBBB-induced dyssynchrony and progression to higher degree heart block are two possible mechanisms behind the higher mortality rates.21 Smaller case series have demonstrated an increase in syncopal events and PPM insertion in patients with persistent LBBB and may be related to the progression of LBBB toward CHB described above.22,23 Previously, TAVR has been shown to improve or maintain left ventricular function (LVF), especially among patients with baseline depressed ejection fraction.24 In those with persistent LBBB, however, there is greater propensity for LV dyssynchrony and failure of LV ejection fraction to recover at one year.20 The effect that LBBB has on LV function may be akin to right ventricular (RV) pacing, which results in a similar pattern of electrical propagation. In both instances, the right ventricle is activated first and then crosses the interventricular septum via cell-to-cell conduction, bypassing physiological activation by the native His-Purkinje system. As a result of asynchronous conduction, abnormal septal wall motion and alterations in regional blood flow in the LV myocardium have been demonstrated.25 Clinically, several trials have highlighted the detrimental effects of long-term RV pacing on LV function. MOST (Mode Selection Trial) identified a significant correlation between frequency of RV pacing with the development of heart failure, noting that the lowest risk patients had a ventricular pacing burden <10 % (DDDR mode).26 These findings were validated by MADIT II (Multicentre Automatic Defibrillator Implantation Trial), which examined patients with prior MI (LVEF less than or equal to 30 %) who were randomised to receive an implantable cardiac defibrillator (ICD) or no device. Patients in the ICD group with high ventricular pacing burden had a significant rate of heart failure.27 Additionally, patients in the DAVID (Dual Chamber and VVI Implantable Defibrillator) trial who were continuously paced from the RV (DDDR with lower limit of 70 bpm) had a hazard ratio of 1.61 (95 % CI [1.06– 2.44]; p=0.03) with respect to the composite end-point of heart failure and death when compared with patients whose devices were set at a backup rate of VVIR 40 bpm.28 It remains to be seen if new, persistent LBBB after TAVR will duplicate these findings, as long-term follow-up data have yet to be collected, but the totality of current data support the idea that these concerns should be incorporated into current clinical practice in the post-TAVR population.

ventricular event). This algorithm will periodically check for intrinsic AV conduction, which if present, will revert back to AAI/R mode with ventricular monitoring. A crossover multicentre randomised trial compared this approach with standard DDD/R ICDs and found that the former resulted in significantly lower burden of RV pacing (4.1 +/- 16.3 vs 73.8 +/- 32.5, p<0.0001).29

Future considerations TAVR is a promising treatment strategy, which is likely to be expanded beyond its current indication for high- and extreme-risk surgical patients in the near future. SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation) is an ongoing trial randomising patients with intermediate operative risk to CoreValve versus SAVR.30 Moreover, in March 2015, the Food and Drug Administration (FDA) approved CoreValve for the treatment of bioprosthetic aortic valve failure via a valve-in-valve approach.31 With the expected increase in procedural volume, the concerns regarding management of conduction disorders will also increase. New iterations of CoreValve and SAPIEN valve continue to evolve, with novel designs already at varying stages of development. In addition, new generation TAVR systems have been designed with the ability to be retrieved and repositioned or having features that facilitate optimal device placement. These devices, all recently CE mark approved and currently being studied, include the Lotus valve (Boston Scientific), the Engager (Medtronic), the JenaValve (JenaValve Technology), the Acurate (Symetis), the Direct Flow Medical valve (Direct Flow Medical), and the Portico (St Jude Medical). Each of these releases will present a set of unique challenges, with varying effects on conduction disorder probabilities. In the case of the latest SAPIEN valve (SAPIEN 3; Edwards), a retrospective study (n=125) showed an impressive reduction in significant paravalvular regurgitation, but observed a PPM rate of 25.5 %, a similar rate to CoreValve.32 However, a study comparing the outcomes of TAVR with the Lotus valve versus the SAPIEN 3 valve showed a significantly higher need for pacemaker implantation in the former (27 % vs 4 %; p<0.003).33 The JenaValve device and Acurate valve also demonstrated relatively low pacemaker implantation rates (9.1 % and 10.0 %), though in a small prospective trial and in a short-term registry study.34,35 While the reduced profile and improved features of novel valve designs strive to minimise post-procedural conductional abnormalities, further study with larger datasets will be needed to determine if this is in fact the case.

Conclusion Pacing Modes The optimal pacing strategy is one that limits RV pacing and preserves native AV conduction. Novel algorithms have been developed to achieve these effects. AV search hysteresis (AVSH) is a feature in dual chamber (DDD) devices that enables temporary lengthening of the preset AV delay to see if native conduction occurs. If there is conduction with a long PR interval, AVSH will stretch the preset AV delay to the degree necessary to ensure physiologic conduction. There is a limit to the extent at which AV intervals can be set, so that AF detection and upper rate behavior in DDD devices can be optimised. A different approach that is also employed is to uncouple atrial activity altogether from ventricular pacing. This algorithm defaults DDD devices to AAI/R mode and the ventricle is monitored on a beat-to-beat basis, switching to DDD/R mode if loss of AV conduction is detected (defined as two out of four A–A intervals missing a

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The emergence of TAVR has provided inoperable patients with severe aortic stenosis a viable treatment option with meaningful survival benefit over medical therapy alone. However, the benefit of this procedure comes at the cost of a substantially increased risk of highgrade heart block that necessitates the placement of a permanent pacemaker. As the popularity of TAVR grows and the indications for its use widen, it has become increasingly important to identify patients at risk for the development of conduction abnormalities. A number of mechanical and clinical features have been implicated as risk factors for PPM placement after TAVR, including usage of the larger profile CoreValve device, deeper implantation within the LVOT (CoreValve), prosthesis to LVOT diameter ratio (SAPIEN valve), and pre-existing RBBB. These predictors are meaningful in this context, since it is wellestablished that the aortic root complex is intimately related to the AV node and its distal conduction fibres.

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Additional questions exist regarding the optimal timing of pacemaker placement following TAVR. Recent evidence – albeit from a few small trials – has raised the possibility that a substantial number of patients who receive permanent pacemakers after TAVR are not pacemaker-dependent during follow-up visits. These data emphasise the dynamic nature of post-procedural heart block and suggest that PPM implantation is perhaps occurring too early in a subset of patients who will ultimately regain full function of their conduction system. Conceivably pre-procedure risk (i.e. the presence of RBBB) can be used to predict those patients likely to require permanent pacing, and close follow-up of the clinical progress of patients

Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. 2. Nagaraja V, Raval J, Eslick GD, et al. Transcatheter versus surgical aortic valve replacement: a systematic review and meta-analysis of randomised and non-randomised trials. Open Heart 2014;1: e000013. 3. 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;159:497–503. 4. 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. 5. Kawashima T, Sato F. Visualising anatomical evidences on atrioventricular conduction system for TAVI. Int J Cardiol 2014;174:1–6. 6. Biondi-Zoccai G, Peruzzi M, Abbate A, et al. Network metaanalysis on the comparative effectiveness and safety of transcatheter aortic valve implantation with CoreValve or Sapien devices versus surgical replacement. Heart Lung Vessel 2014;6:232–43. 7. 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;8:60–9. 8. Ghadimi K, Patel PA, Gutsche JT, et al. Perioperative conduction disturbances after transcatheter aortic valve replacement. J Cardiothorac Vasc Anesth 2013;27:1414–20. 9. Khawaja MZ, et al. Permanent pacemaker insertion after CoreValve transcatheter aortic valve implantation: incidence and contributing factors (the UK CoreValve Collaborative). Circulation 2011;123:951–60. 10. Munoz-Garcia AJ, Hernández-García JM, Jiménez-Navarro MF, et al. Changes in atrioventricular conduction and predictors of pacemaker need after percutaneous implantation of the CoreValve(R). Aortic valve prosthesis. Rev Esp Cardiol 2010;63:1444–51. 11. MacDonald I, Pasupati S. Transcatheter aortic valve implantation: know the differences between the currently available technologies. Eur Heart J 2010;31:1663–5. 12. Murarka S, Lazkani M, Neihaus M, et al. Comparison of 30-Day outcomes of transfemoral versus transapical approach for transcatheter aortic valve replacement: a

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with persistent LBBB identify those patients likely to benefit from physiological pacing. While the prognostic implications of new conduction abnormalities following TAVR remain somewhat nebulous, it is evident that these obstacles will continue to present challenges for physicians and patients in the foreseeable future. By improving our ability to predict conduction disturbances and our understanding of the mechanism by which this occurs, we can improve on valve design, decrease the number of unnecessary devices implanted, optimise pacing modes when pacing is unavoidable, and improve overall outcomes following TAVR. n

single-centre US experience. Ann Thorac Surg 2015;99:1539–44. 13. Mautner RK, Phillips JH. Atrioventricular and intraventricular conduction disturbances in aortic valvular disease. South Med J 1980;73:572–8, 581. 14. Steinberg BA, Harrison JK, Frazier-Mills C, et al. Cardiac conduction system disease after transcatheter aortic valve replacement. Am Heart J 2012;164:664–71. 15. 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. JACC Cardiovasc Interv 2008;1:310–6. 16. Aktug Ö, Dohmen G, Brehmer K, et al. Incidence and predictors of left bundle branch block after transcatheter aortic valve implantation. Int J Cardiol 2012;160:26–30. 17. van der Boon RM, Van Mieghem NM, Theuns DA, et al. Pacemaker dependency after transcatheter aortic valve implantation with the self-expanding Medtronic CoreValve System. Int J Cardiol 2013:168:1269–73. 18. Urena M, Hayek S, Cheema AN, et al. Arrhythmia burden in elderly patients with severe aortic stenosis as determined by continuous electrocardiographic recording: toward a better understanding of arrhythmic events after transcatheter aortic valve replacement. Circulation 2015;131:469–77. 19. 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;129:1233–43. 20. 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;35:1599–607. 21. 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;126:720– 8. 22. Urena M, Mok M, Serra V, et al. Predictive factors and longterm clinical consequences of persistent left bundle branch block following transcatheter aortic valve implantation with a balloon-expandable valve. J Am Coll Cardiol 2012;60:1743–52. 23. 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;127:1300–7. 24. Clavel MA, Webb JG, Rodés-Cabau J, et al. Comparison between transcatheter and surgical prosthetic valve implantation in patients with severe aortic stenosis

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and reduced left ventricular ejection fraction. Circulation 2010;122:1928–36. Lee MY, Yeshwant SC, Lustgarten DL. Honing in on optimal ventricular pacing sites: an argument for His bundle pacing. Curr Treat Options Cardiovasc Med 2015;17:372. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003;107:2932–7. Steinberg JS, Fischer A, Wang P, et al. The clinical implications of cumulative right ventricular pacing in the multicentre automatic defibrillator trial II. J Cardiovasc Electrophysiol 2005;16:359–65. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002;288:3115–23. Sweeney MO, Ellenbogen KA, Casavant D, et al. Multicentre, prospective, randomised safety and efficacy study of a new atrial-based managed ventricular pacing mode (MVP) in dual chamber ICDs. J Cardiovasc Electrophysiol 2005;16:811–7. Cribier A, Durand E, Eltchaninoff H. Patient selection for TAVI in 2014: is it justified to treat low- or intermediate-risk patients? The cardiologist’s view. EuroIntervention 2014; 10 Suppl:U16–21. Tourmousoglou C, Rao V, Lalos S, Dougenis D. What is the best approach in a patient with a failed aortic bioprosthetic valve: transcatheter aortic valve replacement or redo aortic valve replacement? Interact Cardiovasc Thorac Surg 2015;20:837–43. Murray MI, Geis N, Pleger ST, et al. First experience with the new generation Edwards SAPIEN 3 aortic bioprosthesis: procedural results and short-term outcome. J Interv Cardiol 2015;28:109–16. Wöhrle J, Gonska B, Rodewald C, et al. Transfemoral aortic valve implantation with the repositionable Lotus valve compared with the balloon-expandable Edwards SAPIEN 3 valve. Int J Cardiol 2015;195:171–5. Treede H, Mohr FW, Baldus S, et al. 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:e131-8. Kempfert J, Holzhey D, Hofmann S, et al. First registry results from the newly approved ACURATE TA TAVI system. Eur J Cardiothorac Surg 2015;48:137–41.

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Clinical Arrhythmias

Arrhythmogenic Right Ventricular Cardiomyopathy – Antiarrhythmic Therapy Simo n E r m a k o v 1 a n d M e l v i n S c h e i n m a n 2 1. Stanford University Hospital and Clinics, California, US; 2. University of California‚ San Francisco, US

Abstract Arrhythmogenic right ventricular cardiomyopathy is an inherited disorder characterised by progressive replacement of ventricular myocardium by fibrofatty tissue that predisposes patients to ventricular arrhythmias, heart failure and sudden death. Treatment focuses on slowing disease progression, decreasing the burden of arrhythmias and preventing sudden cardiac death through placement of implantable cardioverter-defibrillators (ICDs), catheter ablation and the use of antiarrhythmic medication. Although only ICDs have been demonstrated to affect patient mortality, antiarrhythmic medications are important adjuncts in reducing patient morbidity and inappropriate ICD therapy. Of the individual antiarrhythmic agents available, sotalol, beta-blockers and amiodarone appear to be most effective in arrhythmia suppression. Calcium-channel blockers may be effective in selected patients. For patients who are refractory to single agent therapy, combination therapy may be considered with the most effective combinations being sotalol + flecainide and amiodarone + beta-blockers.

Keywords Arrhythmogenic right ventricular cardiomyopathy, right ventricular dysplasia, arrhythmia management, antiarrhythmic, medical therapy, sudden death Disclosure: Simon Ermakov has no conflicts of interest to declare. Melvin Scheinman has received lecture fees from Biotronic, Boston Scientific, Medtronic and St. Jude, as well as consultant fees from Janssen Inc. Acknowledgements: We thank Thomas Wichter for granting us permission to reproduce a figure from his prior publication. We additionally thank Wiley Publishing Company for copyright permission in the reproduction of the figure. Received: 2 June 2015 Accepted: 6 July 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(2):86–9 Access at: www.AERjournal.com Correspondence: Simon Ermakov, University of California‚ San Francisco, 350 Parnassus Ave # 300, San Francisco, CA 94117, US. E: Sermakov@stanford.edu

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterised by progressive replacement of the ventricular myocardium by fibrofatty tissue.1 Patients with the disease are predisposed to ventricular arrhythmias, heart failure and sudden cardiac death.

Pathophysiology ARVC has a strong genetic basis with most disease variants displaying an autosomal dominant mode of transmission.2 Several mutations have been discovered to be implicated in familial variants of ARVC many of which encode proteins involved in cell–cell adhesion such as plakoglobin,3 desmoplakin4 and plakophilin-2.5 These findings have led to the understanding that this disease fundamentally arises from defects in the cardiomyocyte junction.6 The dysregulation of the cell junction is thought in itself to predispose patients to cardiac arrhythmias as well as result in cell detachment, apoptosis and subsequent replacement of normal myocardium with fibrofatty tissue particularly in the setting of mechanical stress. Fibrofatty replacement further interferes with electrical impulse conduction creating a substrate for ventricular arrhythmias.7

Clinical Presentation Manifestations of ARVC vary widely with some patients being entirely asymptomatic while others experience debilitating arrhythmias, heart failure and sudden death. In patients with confirmed pathological mutations, the disease tends to manifest at an earlier age and follow a more aggressive trajectory.8

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Common arrhythmias in patients with ARVC include frequent premature ventricular complexes (PVCs), non-sustained ventricular tachycardia (VT) and sustained VT.9,10 In those who develop VT, the majority of events are monomorphic and commonly originate in the right ventricle.11 In patients presenting with RV arrhythmias as the sole manifestation, it is important to differentiate between relatively benign aetiologies such as RV outflow tract tachycardia and ARVC as the treatment and prognostic implications are significant. Careful analysis of the electrocardiographic characteristics of the arrhythmia as well as the patient’s baseline electrocardiogram may provide important clues to the diagnosis. A recently published algorithm provides guidance in terms of this differentiation with excellent sensitivity and specificity (see Table 1).12 Symptoms experienced by ARVC patients include palpitations, dizziness and syncope as well as characteristic symptoms of heart failure in patients with advanced or long-standing disease. Mortality rates associated with ARVC have been reported to be as high as 2–4 % per year resulting from fatal arrhythmias and heart failure.13,14 Rates of sudden cardiac death are particularly high in ARVC with reports of up to 10 % of all sudden death cases in patients under 30 being attributed to this condition.15 The risk of sudden death appears to be especially high in patients who are young and may be the first symptom of the disease.16

Preventive Measures Given the significant morbidity and mortality associated with ARVC, great effort has been expended to identify patients at particularly high risk for adverse outcomes and to develop therapies to improve

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their prognosis. In all patients with ARVC, primary intervention focuses on the prevention of disease progression. Patients are discouraged from participation in vigorous exercise as arrhythmias and sudden death events frequently occur at or around the time of exercise.17 Exercise additionally results in increased myocardial stress leading to the mechanical disruption of cell–cell junctions thus accelerating disease progression.18 For these reasons, many patients with ARVC are also prophylactically treated with beta-blockers, although no trial has demonstrated a significant mortality benefit for this therapy. Screening family members of patients with ARVC for clinical or genetic evidence of disease is highly encouraged as up to 50 % of relatives will test positive for the disease. Importantly, electrographic changes commonly precede structural changes, thus screening with an electrocardiogram may be effective in identifying early stages of the disease.19 In patients who develop symptoms, the mainstays of therapy have focused on antiarrhythmic medications, radiofrequency catheter ablation and the implantation of implantable cardioverter-defibrillators (ICDs).20

Risk Stratification and Therapeutic Options Several retrospective studies have been conducted to identify highrisk features of the disease in order to guide therapy. Established high-risk features include significant RV dysfunction, left ventricular involvement, history of syncope and development of sustained VT.20–22 Of the available treatment modalities, only ICDs have consistently been demonstrated to affect patient mortality. In one study, the survival benefit of ICD implantation was close to 25 % over a 4-year follow-up period.23 A recent meta-analysis estimated the annual mortality rate of patients with ARVC who underwent ICD implantation at 0.9 %, substantially lower than those without ICDs.24 For this reason, patients with high-risk features are recommended to undergo ICD implantation by the American College of Cardiology, American Heart Association and the European Society of Cardiology.25 ICD therapy, however, does not decrease the rate of ventricular arrhythmias or disease progression. Additionally, ICD implantation carries a risk of procedural complications, tricuspid regurgitation and inappropriate therapy, which may contribute to patient morbidity. The annual rate of inappropriate therapy in those with ICDs has been estimated to be as high as 4 %.24 Therefore, the concomitant utilisation of catheter ablation and antiarrhythmic therapy is often necessary with the goals of reducing arrhythmia recurrence, decreasing ICD therapy and improving patient symptoms. Catheter ablation has historically been effective in terminating malignant arrhythmias in the short term, but rates of VT recurrence following endocardial ablation are reported to be as high as 50–75 % within 3 years due to the progressive nature of the disease.26,27 Recognition of the larger role played by the epicardial arrhythmogenic substrate in ARVC has led to an increased focus on combined endocardial and epicardial ablation approaches. In a recent study comparing endocardial to endo+epicardial ablation, 83 % of patients treated with the combined approach remained arrhythmia free at 3 years compared with 52 % of patients treated with only endocardial ablation.27 Another study reported a similar success rate of 77 % with an endo+epicardial approach over an average follow-up of 18 months.28 While the results are very promising, it is important to recognise that epicardial ablation carries a substantial risk of complications such as epicardial bleeding and coronary stenosis occurring in approximately 5 % of cases.29 Nevertheless, catheter ablation remains an important therapeutic modality for decreasing patient morbidity in conjunction with ICD implantation and antiarrhythmic medication.

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Table 1: ARVC Risk Score for Differentiation of ARVC from Right Ventricular Outflow Tract Tachycardia Baseline Electrocardiogram Characteristic

Points

Anterior T-wave inversions (V1-V3) in sinus rhythm

VT/PVC Characteristics Lead I QRS duration >120 ms

QRS notching (multiple leads)

V5 transition or later

Maximum total points

Scores of ≥5 points are reported to have a sensitivity of 83.8 %, specificity of 100 %, positive predictive value of 100 % and negative predictive value of 91 % for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) in patients with ventricular arrhythmias of left-bundle-branch-block morphology with an inferior axis. (Adapted from Hoffmayer et al., 2013).12

Antiarrhythmic Therapy Individual Antiarrhythmic Therapy Overall data on the use of antiarrhythmic agents in ARVC are relatively limited as no randomised clinical trials have been conducted to compare the efficacy of agents in this condition. Early studies investigating the use of antiarrhythmics in ARVC were small, focused on inhomogeneous patient cohorts with variable follow-up periods, and evaluated largely empirical medication choice.30–34 The first study to systematically assess the efficacy of antiarrhythmic therapy in ARVC was published in 1992 by Wichter et al.35 The initial study focused on 81 patients with proven or highly probable ARVC, but was later expanded to 191 patients in 2000.36 All patients underwent electrophysiological study and were tested for the inducibility of ventricular arrhythmias with programmed ventricular stimulation as well as the use of intravenous isoproterenol. Patients with both inducible arrhythmias and those without were then treated with a number of antiarrhythmic agents and reassessed for arrhythmia control. Drug efficacy was defined as increased difficulty of arrhythmia induction for patients with initially inducible arrhythmias and suppression of ventricular arrhythmias on 48-hour Holter monitor and exercise tests for patients with non-inducible arrhythmias. The patients were then started on antiarrhythmic therapy guided by these studies and followed for a number of months with assessment of arrhythmia recurrence and adverse events. A total of 608 antiarrhythmic tests were conducted with various agents including beta-blockers, sodium channel blockers, verapamil, sotalol, amiodarone and combination therapy (see Figure 1). Sotalol, administered at a dosage of 320–640 mg/day, was determined to be the most effective therapy with approximately 68 % of patients achieving complete or partial arrhythmia suppression. Other therapies were less effective with Class I agents and amiodarone demonstrating only an 18 % and 26 % efficacy, respectively. Beta-blockers and verapamil proved to be most effective in patients with non-inducible arrhythmias on electrophysiology study and in patients thought to have triggered activity as the underlying mechanism of arrhythmia. In these patients, efficacy for these agents was 25 % and 44 %, respectively. Based upon these observations, several conclusions were reached by the authors. First, sotalol appeared to be the most effective antiarrhythmic agent in the treatment of ARVC-associated arrhythmias. Second, amiodarone use should be limited given significant long-term toxicity and questionable efficacy. Lastly, patients with arrhythmias presumed to be brought on by triggered activity as opposed to re-entry may benefit from beta-blockers and verapamil.

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Clinical Arrhythmias Figure 1: Efficacy of Antiarrhythmic Therapy in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy 80 68 %

Percentage of patients

70 60 50

44 %

33 %

26 %

25 % 18 %

20 10 0

to the more standardised method of serial programmed stimulation utilised in the Wichter et al. study. Despite the differences in their findings, these studies provide important guidance on the selection of antiarrhythmic therapy in ARVC. Both sotalol and amiodarone may represent effective antiarrhythmic choices in certain patients. Given the long-term toxicity associated with amiodarone its use should be limited in younger patients with a significant life expectancy; however, this risk should be balanced with the benefit of arrhythmia suppression. Beta-blockers and verapamil may be effective in patients with catecholamine-triggered arrhythmias although the efficacy of these agents in re-entrant arrhythmias appears to be limited.

Combination Antiarrhythmic Therapy Na+ blockers β-blockers 215 32

Sotalol 165

Amiodarone 31

Verapamil Combinations 45 119

Number of tests Complete suppression

Partial efficacy

Arrhythmogenic right ventricular cardiomyopathy = 191 patients Antiarrhythmic tests: n=608 In the 1992 Wichter et al. study, sotalol in doses of 320–480 mg/day showed the highest efficacy rates. Amiodarone monotherapy was less effective. Verapamil was tested only in patients with non-reentrant ventricular tachycardia (VT) but appears to be effective for such patients. ARVC = arrhythmogenic right ventricular cardiomyopathy. Wichter et al., 2000.36 Copyright @ 2000 Futura Publishing Company, Inc. Reprinted with permission from John Wiley & Sons, Inc.

These conclusions were further tested in a report from the North American ARVC Registry published in 2009 by Marcus et al.37 In this prospective cohort study, a group of 95 ARVC patients with implanted ICD devices were followed for 480 to 389 days. Patients were treated with a variety of antiarrhythmic medications selected at the discretion of their treating physicians. During the follow-up period, patients were contacted yearly for updates regarding changes in medications, symptoms, documented arrhythmias and ICD interrogations. The major antiarrhythmic agents investigated in this study were betablockers, sotalol and amiodarone. A total of 58 participants received beta-blockers during the follow-up period; however, no significant difference was found in rates of clinically relevant arrhythmias compared with participants not receiving beta-blockers. Thirty-eight patients received sotalol but, contrary to Wichter et al.’s findings, these patients had no statistically significant difference in the rate of clinically relevant arrhythmias and even demonstrated a tendency towards increased arrhythmia rates. Only 10 patients were treated with amiodarone but experienced the most effective arrhythmia control with 75 % of patients benefiting from lower arrhythmia rates. The disparate conclusions reached by Marcus et al. and Wichter et al. may be partially a result of significant differences in design of the two studies. First, the population in the Marcus et al. study may have been of higher risk given that all patients had definite ARVC with installed ICDs as opposed to Wichter et al.’s study in which none of the patients had ICDs. Second, the doses of sotalol used in the Wichter et al. study were on average much higher than in the Marcus et al. study (320–640 versus 160–320 mg/day). Likewise, the difference in the amiodarone results may have arisen from the fact that full amiodarone loading was not possible during the electrophysiology study period in the protocol utilised by Wichter et al. Third, the method of medication selection was less controlled in the Marcus et al. study relying on provider preference as opposed

Ermakov_FINAL.indd 88

In patients who demonstrate poor response to individual agents, therapy with multiple antiarrhythmic medications may be considered. However, even fewer data exist to guide the selection of agents for use in combination therapy. In the Wichter et al. study described above, a minority of patients were treated with combination therapy.35 In their cohort, the combination of Class I agents with amiodarone and sotalol were effective in a small number of patients in whom individual drug therapy had failed. Other reports indicate that the use of Class I agents combined with sotalol may be effective in controlling arrhythmias in those refractory to single agent therapy and failed endocardial ablation.38,39 One recent report demonstrated the effective addition of flecainide to patients receiving sotalol with resultant reduction in recurrent arrhythmias.38 Importantly, the addition of flecainide in this study was accomplished without significant adverse events despite a historic hesitation of using class Ic agents in patients with ventricular dysfunction stemming from experience with the post-myocardial infarction population. Since the publication of this report, an additional four patients in the authors’ cohort have been successfully treated with this combination and have likewise experienced excellent arrhythmia control without significant side-effects. Several other studies have reported that the combination of amiodarone and beta-blockers may be effective in patients unable to achieve arrhythmia suppression with amiodarone alone. In a report by Tonet et al. following 31 patients with ventricular tachycardia, addition of beta-blocker therapy to amiodarone resulted in improved VT control in all patients.40 Only four patients in the study had documented ARVC, however. In another small study by Leclercq et al. focused on ARVC patients, the combination of amiodarone and beta blockers was likewise shown to result in VT suppression in all patients treated.39 It has been postulated that this combination is particularly effective due to the Class III and II action of the agents, which may work especially well in the catechomaline dependent arrhythmias in ARVC. This mechanism may also partially explain the efficacy of sotalol demonstrated in the Wichter et al. study. Despite the promising results of several studies, much more research is necessary to establish the efficacy of combination therapy in treatment of ARVC. Additionally, toxicity of agents may increase when used in combination and thus such therapy should be used with caution. Nevertheless, in patients failing to achieve adequate arrhythmia control with an individual agent, combination therapy warrants consideration.

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Arrhythmogenic Right Ventricular Cardiomyopathy – Antiarrhythmic Therapy

Conclusion ARVC is a progressive disease that predisposes patients to ventricular arrhythmias, heart failure and sudden death. While no therapy exists to slow disease progression, treatment is aimed at reducing patient morbidity and mortality through the use of antiarrhythmic medications, catheter ablation and the implantation of ICDs. Only ICDs have been demonstrated to affect patient mortality, however antiarrhythmic medications are important in reducing patient arrhythmia burden and decreasing rates of inappropriate ICD therapy. Of the individual antiarrhythmics studied, sotalol and amiodarone appear to be the most effective in suppressing arrhythmias; however, the toxicities

1. 2.

10.

11.

12.

13.

14.

15.

Basso C, Corrado D, Marcus FI, et al. Arrhythmogenic right ventricular cardiomyopathy. Lancet 2009;373:1289–300. Nava A, Bauce B, Basso C, et al. Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 2000;36:2226–33. Asimaki A, Syrris P, Wichter T, et al. A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Am J Human Genetics 2007;81:964–73. Rampazzo A, Nava A, Malacrida S, et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2002;71:1200–6. Gerull B, Heuser A, Wichter T, et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 2004;36:1162–4. Sen-Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol 2007;50:1813–21. Corrado D, Basso C, Thiene G, et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol 1997;30:1512–20. Bhonsale A, Groeneweg JA, James CA, et al. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur Heart J 2015;36:847–55. Link MS, Laidlaw D, Polonsky B, et al. Ventricular arrhythmias in the North American multidisciplinary study of ARVC: predictors, characteristics, and treatment. J Am Coll Cardiol 2014;64:119–25. McKenna WJ, Thiene G, Nava A, et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J 1994;71:215–8. Cox MG, Nelen MR, Wilde AA, et al. Activation delay and VT parameters in arrhythmogenic right ventricular dysplasia/ cardiomyopathy: toward improvement of diagnostic ECG criteria. J Cardiovasc Electrophysiol 2008;19:775–81. Hoffmayer KS, Bhave PD, Marcus GM, et al. An electrocardiographic scoring system for distinguishing right ventricular outflow tract arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy from idiopathic ventricular tachycardia. Heart Rhythm 2013;10:477–82. Hulot JS, Jouven X, Empana JP, et al. Natural history and risk stratification of arrhythmogenic right ventricular dysplasia/ cardiomyopathy. Circulation 2004;110:1879–84. Lemola K, Brunckhorst C, Helfenstein U, et al., Predictors of adverse outcome in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy: Long term experience of a tertiary care centre. Heart 2005;91:1167–72. Tabib A, Loire R, Chalabreysse L, et al. Circumstances of

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16.

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24.

25.

26.

associated with long-term amiodarone use should be balanced against the benefit of arrhythmia reduction. Beta-blockers and calcium-channel blockers may be effective in catecholamine triggered arrhythmias but have limited efficacy in re-entrant rhythms. Monotherapy with Class I agents appears to be of likewise limited efficacy. In patients not achieving effective arrhythmia control with a single agent, combination antiarrhythmic therapy may result in improved outcomes. Particular combinations with demonstrated efficacy include Class I agents + amiodarone or sotalol as well as amiodarone + beta-blockers. Additional studies are necessary to provide further guidance regarding the use of antiarrhythmic agents in ARVC. n

death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. Circulation 2003;108:3000–5. Thiene G, Nava A, Corrado D, et al. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 1988;318:129–33. Kirchhof P, Fabritz L, Zwiener M, et al. Age- and trainingdependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice. Circulation 2006;114:1799–806. James CA, Bhonsale A, Tichnell C, et al. Exercise increases agerelated penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. J Am Coll Cardiol 2013;62:1290–7. te Riele AS, James CA, Rastegar N, et al. Yield of serial evaluation in at-risk family members of patients with ARVD/C. J Am Coll Cardiol 2014;64:293–301. Wichter T, Paul M, Eckardt L, et al. Arrhythmogenic right ventricular cardiomyopathy: Antiarrhythmic drugs, catheter ablation, or ICD. Herz – Cardiovasc Dis 2005;30:91–101. Peters S, Peters H, Thierfelder L. Risk stratification of sudden cardiac death and malignant ventricular arrhythmias in right ventricular dysplasia-cardiomyopathy. Int J Cardiol 1999;71:243–50. Lemola K, Brunckhorst C, Helfenstein U, et al. Predictors of adverse outcome in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy: Long term experience of a tertiary care centre. Heart 2005;91:1167–72. Corrado D, Leoni L, Link MS, et al. Implantable cardioverterdefibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation 2003;108:3084–91. Schinkel AF. Implantable cardioverter defibrillators in arrhythmogenic right ventricular dysplasia/cardiomyopathy: patient outcomes, incidence of appropriate and inappropriate interventions, and complications. Circ Arrhythm Electrophysiol 2013;6:562–8. Zipes DP, Camm AJ, Borggrefe M, et al. American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e385–484. Dalal D, Jain R, Tandri H, et al. Long-term efficacy of catheter ablation of ventricular tachycardia in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

J Am Coll Cardiol 2007;50:432–40. 27. Bai R, Di Biase L, Shivkumar K, et al. Ablation of ventricular arrhythmias in arrhythmogenic right ventricular dysplasia/ cardiomyopathy: arrhythmia-free survival after endoepicardial substrate based mapping and ablation. Circ Arrhythm Electrophysiol 2011;4:478–85. 28. Garcia FC, Bazan V, Zado ES, et al. Epicardial substrate and outcome with epicardial ablation of ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation 2009;120:366–75. 29. Sacher F, Roberts-Thomson K, Maury P, et al. Epicardial ventricular tachycardia ablation a multicenter safety study. J Am Coll Cardiol 2010;55:2366–72. 30. Borggrefe M, Breithardt G. Beneficial effects of sotalol in patients with right ventricular dysplasia and drug-refractory ventricular tachycardia. Circulation 1985;72(Suppl. II):III–1768. 31. Wichter T, Borggrefe M, Martinez-Rubio A, et al. Arrhythmogenic right ventricular disease: Antiarrhythmic drug therapy in patients with inducible and non-inducible ventriculartachycardia. Circulation 1990;82(Suppl. III):III–435. 32. Woelfel A, Foster JR, McAllister RG Jr, et al. Efficacy of verapamil in exercise-induced ventricular tachycardia. Am J Cardiol 1985;53:751–6. 33. Leclercq JF, Coumel P, Characteristics, prognosis and treatment of the ventricular arrhythmias of right ventricular dysplasia. Eur Heart J 1989;10(Suppl. D):61–7. 34. Lemery R, Brugada P, Della Bella P, et al. Nonischemic ventricular tachycardia: Clinical course and long-term followup in patients without clinically overt heart disease. Circulation 1989;79:990–9. 35. Wichter T, Borggrefe M, Haverkamp W, et al. Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disease. Results in patients with inducible and noninducible ventricular tachycardia. Circulation 1992;86:29–37. 36. Wichter T, Borggrefe M, Bocker D, et al. Prevention of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy. In: Aliot E, Clementy J, Prystowsky EN (eds). Fighting Sudden Cardiac Death: A Worldwide Challenge. New York: Futura Publishing Company, 2000; 275–95. 37. Marcus GM, Glidden DV, Polonsky B, et al. Multidisciplinary Study of Right Ventricular Dysplasia Investigators. Efficacy of antiarrhythmic drugs in arrhythmogenic right ventricular cardiomyopathy: a report from the North American ARVC Registry. J Am Coll Cardiol 2009;54:609–15. 38. Ermakov S, Hoffmayer KS, Gerstenfeld EP, et al. Combination drug therapy for patients with intractable ventricular tachycardia associated with right ventricular cardiomyopathy, Pacing Clin Electrophysiol 2014;37:90–4. 39. Leclercq JF, Coumel P. Characteristics, prognosis and treatment of the ventricular arrhythmias of right ventricular dysplasia. Eur Heart J 1989;10(Suppl. D):61–7. 40. Tonet J, Frank R, Fontaine G, et al. [Efficacy of the combination of low doses of beta-blockers and amiodarone in the treatment of refractory ventricular tachycardia]. Arch Mal Coeur Vaiss 1989;82:1511–7.

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Clinical Arrhythmias

Monitoring the Effects and Antidotes of the Non-vitamin K Oral Anticoagulants Nur A Rahmat 1 and Gregory Y H Lip 1,2 1. University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK; 2. Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

Abstract In the last decade, we have witnessed the emergence of the oral non-vitamin K oral anticoagulants (NOACs), which have numerous advantages compared with the vitamin K antagonists, particularly their lack of need for monitoring; as a result their use is increasing. Nonetheless, the NOACs face two major challenges: the need for reliable laboratory assays to assess their anticoagulation effect, and the lack of approved antidotes to reverse their action. This article provides an overview of monitoring the anticoagulant effect of NOACs and their potential specific antidotes in development.

Keywords Non-vitamin K oral anticoagulants (NOACs), monitoring, antidotes, anticoagulation, atrial fibrillation Disclosure: Dr Nur A Rahmat has no conflict of interest to declare. Prof. Gregory Lip is a consultant for Bayer, Medtronic, Sanofi, BMS/Pfizer, Daiichi-Sankyo and Boehringer Ingelheim and has been a speaker for Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo and Medtronic. Received: 4 March 2015 Accepted: 18 June 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(1):90–5 Access at: www.AERjournal.com Correspondence: Gregory YH Lip, University of Birmingham, Centre for Cardiovascular Sciences, City Hospital, Birmingham B18 7QH, UK. E: g.y.h.lip@bham.ac.uk

Until recently, the vitamin K antagonist (VKA, e.g. warfarin) class of drugs was the only oral anticoagulant in use. VKAs have important inter- and intra-patient variability, influenced by diet, alcohol and drugs; thus, regular anticoagulation monitoring is necessary. Indeed, VKAs offer their best efficacy and safety when the average time in therapeutic range (TTR) is >65–70 % in a particular individual.1,2

There is no role for routine monitoring to assess efficacy of NOACs. However, the ability to monitor the anticoagulant effect of NOACs can be helpful in selected situations including severe bleeding and thrombotic complications, urgent/emergent invasive procedure or surgery, suspected drug failure, overdose, treatment compliance and in special situations such as in individuals who are elderly, have renal/ liver dysfunction or extremes of body weight.14

In the last decade, we have witnessed the emergence of the oral non-vitamin K oral anticoagulants (NOACs). NOACs have numerous advantages compared with the VKAs, particularly their lack of need for monitoring; as a result their use is increasing. Nonetheless, the NOACs face two major challenges: the need for reliable laboratory assays to assess their anticoagulation effect and the lack of approved antidotes to reverse their action.

There are no validated quantitative assays or coagulation assays that are adequately sensitive to the NOACs. Current available laboratory tests are a practical selection as they are globally available and easily accessible. They measure the global status of the coagulation system in a patient, but not their precise plasma concentrations. Thus, these tests provide an indication of the anticoagulation effect rather than anticoagulation intensity.

This article provides an overview of monitoring the anticoagulant effect of NOACs and their potential specific antidotes in development.

Monitoring Assays for the NOACs and their Diagnostic Value

Significance of the NOACs NOACs have been introduced as alternatives to warfarin for various thromboembolic indications; including prevention and treatment of venous thromboembolism, stroke prevention in atrial fibrillation and secondary prevention in high-risk patients presenting with an acute coronary syndrome.3–7 The main advantage of the NOACs is their lack of need for routine blood monitoring. Furthermore, they have relatively few food–drug interactions. Other advantages of NOACs include predictable efficacy, rapid onset of action and fixed dosing.8 The large randomised trials with NOACs have now been complemented by large real-world observational data showing the relative efficacy and safety compared with warfarin.9–13

Lip-NOAC monitoring_FINAL.indd 90

To calculate and predict the anticoagulant activity, six key components need to be borne in mind: 1) choice of coagulation tests differ by clinical objective, 2) results often take >2 hours, 3) some tests may not be available in all institutions, 4) timing of the last dose is important, 5) quantitative or qualitative assays can be used and 6) kidney insufficiency. Cuker et al have systematically reviewed up to 17 articles on dabigatran, rivaroxaban and apixaban, which have demonstrated variable effects on coagulation assays.15

Direct Thrombin Inhibitor: Dabigatran Dabigatran prolongs most coagulation assays except prothrombin time (PT).16 The interpretation of these tests is highly dependent on the reagents used.

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NOACs: Monitoring their Anticoagulant Effects and Use of Antidotes

Activated Partial Thromboplastin Time (aPTT). Dabigatran prolongs the aPTT in a curvilinear relationship; dose response curve is linear up to a concentration of 200 to 300 ng/ml and then flattens out at higher drug levels.17 For this reason, aPTT is unsuitable for quantitative measurement.17–20 Commercial aPTT reagents differ widely in their sensitivity to dabigatran; thus, their calibration standards and interpretation should be communicated to clinicians. For qualitative measurement, especially during an emergency, the aPTT may help determine if dabigatran contributes to a haemorrhagic event. At trough (12–24 hours postdose), an aPTT level two times the upper limit of normal may indicate higher risk of bleeding.17

Table 1: Recommendations for NOACs Monitoring Assays Dabigatran

Rivaroxaban Apixaban

Edoxaban

Summary of

aPTT

Anti-FXa

potential

mPT

(few firm

laboratory tests

dTT

Recommended

1. dTT

Anti-FXa

2. ECT*

Anti-FXa (few firm data)

In an

aPTT

emergency

Thrombin Time (TT) is measured at 12–24 hour trough levels. The TT assay may serve as a sensitive method for determining the presence of dabigatran: a normal TT excludes a dabigatran-associated bleeding risk.17,18 However, TT is exquisitely sensitive to the presence of dabigatran and it may be too sensitive in the clinically relevant plasma concentration range.15 Depending on the reagent, TT frequently exceeds the maximum measurement time of the coagulometer.19,20

data)

ECT*

PT†

mPT*

(Sensitivity depends on reagent used)

Quantitative tests dTT

Anti-FXa

Interpretation:

(few firm

At trough, higher

data)

risk of bleeding if >65 s or 200 ng/ml ECT*

The Dilute Thrombin Time (dTT) displays a high degree of linearity with drug plasma concentration and thus is useful for quantitative measurement. A dTT overcomes the excessive sensitivity of the TT. A normal dTT indicates no clinically relevant anticoagulant effect of

At trough, higher risk of bleeding if level >3x ULN (directly measures

dabigatran. The dabigatran-calibrated Hemoclot thrombin inhibitor assay (a dTT) is commercially available for use to estimate drug level, although it is still not widely available.21,22 18

Interpretation:

The Ecarin-based Assays, ecarin clotting time (ECT) and ecarin chromogenic assay (ECA), show a high degree of linearity with drug plasma concentrations in the clinically relevant drug concentration range.15 They exhibit adequate sensitivity and precision. At trough, more than three times elevated ECT is associated with a higher risk of bleeding.23 However, ECT and ECA are not readily available in many clinical settings due to lack of standardisation, variability in sensitivity to dabigatran among different samples of ecarin, and limited availability.19,24

the activity of dabigatran) Qualitative

aPTT

tests

Interpretation:

At trough, higher Prolonged risk of bleeding if indicates

Direct Factor Xa Inhibitors: Rivaroxaban and Apixaban Specific Anti-factor Xa Chromogenic Assays, which are distinct from low molecular weight heparin (LMWH) testing, are the rational choice for measuring plasma concentrations of direct factor Xa inhibitors. They are calibrated individually for each drug (i.e. rivaroxaban, apixaban and likely edoxaban) and expressed in mass concentration (e.g. mg/l).26–28 In general, anti-factor Xa activity measurements demonstrate a strong linear relationship with rivaroxaban (up to a concentration of 500 ng/ml) and apixaban (at all concentrations).

excess

bleeding risk

Interpretation: At trough, no bleeding risk if normal level Not

The Prothrombin Time (PT), or international normalised ratio, is unsuitable for measuring the effects of dabigatran due to its low sensitivity and substantial variability.25

level >2x ULN

recommended

INR

aPTT

ECT

ECT PT

*not widely available; †sensitivity depends on reagent used; anti-FXa – anti-factor Xa chromogenic assays; aPTT – activated prothrombin time; dTT –diluted thrombin time assay Hemoclot®; ECT – ecarin clotting time; mPT– modified diluted PT; PT – prothrombin; TT – thrombin time; ULN – upper limit normal; Data pooled and adapted from references 18,23,60,61

of apixaban.18 Currently, there is still no validated coagulation assay available to measure the anticoagulant effect of apixaban.33

Expert Opinion: What Should We Use? 15,18

Prothrombin Time. Rivaroxaban has been shown to prolong the PT in a concentration-dependent and linear fashion.29–31 However, the results are significantly dependent on the PT-specific reagents used in the assay (e.g. neoplastine). A normal PT does not exclude clinically significant rivaroxaban concentrations; however, a prolonged PT qualitatively indicates the drug’s presence.32

• For dabigatran, the dTT and ecarin-based assays are preferred and may be used for drug concentration measurements. • For rivaroxaban and apixaban, anti-FXa activity is preferred for drug concentration measurements. • For rivaroxaban alone, PT is more sensitive than aPTT; however, it should not be used for drug concentration measurements. • For apixaban alone, both PT and aPTT are insensitive.

Apixaban has demonstrated less of an effect on the PT than rivaroxaban and it is not recommended to assess the pharmacodynamic effects

Recommendations for NOACs monitoring assays are summarised in Table 1.

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Clinical Arrhythmias Table 2: Indications and Clinical Pharmacology of Non-vitamin K Oral Anticoagulants Dabigatran (Pradaxa)

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Edoxaban (Savaysa)

Approved by EU and US

√

Approved Indications

a) Stroke/systemic embolism

a) Stroke/systemic

a) Stroke/systemic embolism

prevention in NVAF

embolism prevention in

prevention in NVAF

b) Prevention of recurrent VTE in

b) Treatment of DVT and PE

NVAF

b) DVT and PE treatment

patients who have previously

c) Prevention of recurrent DVT

b) VTE prevention in elective following 5–10 days of initial

been treated

and PE in adults

hip or knee replacement

therapy with a parenteral

c) DVT and PE treatment following

d) VTE prevention in elective hip

surgery

anticoagulant

5–10 days of initial therapy with a

or knee replacement surgery

√

Similar/better

Better

US and Japan only

parenteral anticoagulant d) VTE prevention in elective hip or knee replacement surgery Direct thrombin inhibitor

√

Direct factor Xa inhibitor NOAC compared with

Similar

warfarin in respect to major bleeding Increased risk of MI in

√

comparison with warfarin Increased risk of GI bleed

√

compared with warfarin Lower risk of stroke

√

and major bleeding Dyspepsia

√

Dosing

Twice daily

Once daily

Twice daily

Half-life

12–14 h

5–9 h (young) 11-13 h (elderly)

12 h

Renal clearance

80%

35%

27%

35–50%

Liver metabolism: CYP3A4 X

√

√ (minimal)

√

Unplanned surgery

Stop for at least 24 h

Minor bleed: stop for at

Stop for at least 12 h

Once daily

least 24 h; major bleed: stop for at least 48 h DVT – deep vein thrombosis; GI; gastrointestinal; h – hour; MI – myocardial infarction; NOAC – non-vitamin K oral anticoagulant; NVAF – non-valvular atrial fibrillation; PE – pulmonary embolism; VTE – venous thromboembolism. Data pooled from references 3,4,5,6.

Strategies for NOAC-related Bleeding and Reversal of NOACs Anticoagulant Effects NOACs pharmacokinetics/pharmacodynamics are important when challenged with a patient who may be bleeding in the setting of NOACs exposure. Table 2 shows the clinical pharmacology and indications of the NOACs; however, an in-depth discussion of their pharmacokinetics/pharmacodynamics is beyond the scope of this review. In view of the lack of readily available or reliable specific antidotes for the NOACs, institutional guidelines have provided general guidance to assist bleeding patients.18,23 These recommendations are often influenced by 1) the severity of the bleeding; 2) the pharmacology of the specific agent; 3) overdosing; 4) reversing the NOAC prior to an emergency surgery; and 5) renal function of the individual. The cornerstones in managing NOAC-related bleeding include: 1) withholding the specific NOAC; 2) resuscitation (e.g. intravenous access, mechanical compression, fluid administration, blood product transfusion, maintaining diuresis to clear drug); 3) proceduralist-led interventions and 4) consideration for non-specific procoagulant agents given the lack of specific reversal agents.34

Lip-NOAC monitoring_FINAL.indd 92

Non-specific reversal agents (e.g. prothrombin complex concentrates, activated prothrombin complex concentrates, recombinant factor VIIa [rFVIIa]) are considered for reversal of NOACS, however, there is no high-quality evidence to support their use. The use of these agents is also associated with small risk of thrombosis and it is recommended that they are reserved for severe and life-threatening bleeds. Prothrombin Complex Concentrates (PCCs) contain vitamin K-dependent coagulation factors II, IX, X, varying amounts of factor VII and proteins C and S. Three-factor PCCs contain factors II, IX, X and low levels of factor VII; while four-factor PCCs contain factors II, IX, X and higher levels of factor VII (see Table 3). PCCs have been shown to reduce bleeding in animal models with varying degree of success on haemostatic parameters.35–39 In human studies involving healthy volunteers, PCCs normalised PT in those receiving rivaroxaban.40–42 However, PCCs did not correct the aPTT, ECT or TT induced by dabigatran although PCCs enhanced the rate of thrombin generation.40,41,43 Activated Prothrombin Complex Concentrate (aPCC) contains factors II, VII, IX and X. In animal models, aPCC corrected the anticoagulant effect of high-dose rivaroxaban. 44,45 Siegal et al have

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NOACs: Monitoring their Anticoagulant Effects and Use of Antidotes

reviewed that in in vitro studies aPCC corrects some abnormal clot-based coagulation tests, thromboelastometry parameters and thrombin generation indices induced by dabigatran, rivaroxaban and apixaban. 34

Table 3: Prothrombin Complex Concentrate (PCCs) PCCs

• Derived from human plasma • Contain factors II, IX and X with or without significant levels of factor VII

rFVIIa. In in vitro studies, rFVIIa demonstrated variable effects on abnormal clot-based coagulation tests, thromboelastometry parameters and thrombin-generation indices induced by rivaroxaban and apixaban.34

• Also contains varying amounts of protein C and S PCCs products

of factor VII • Four-factor PCC: contain factors II, IX, X and higher levels of factor VII • Activated PCC: contains four coagulation factors (in

Antifibrinolytic Agents. Tranexamic acid interferes with fibrinolysis thus stabilisng fibrin clots. However, its prothrombic potential in NOAC-associated bleeding is unknown. Haemodialysis. Dabigatran may be removed from the circulation by haemodialysis in patients with major bleeding or surgical procedures. This approach takes 4–6 hours, and is more desirable in patients with end-stage renal disease and overdosing.46

• Three-factor PCC: contain factors II, IX, X and low levels

inactive and activated forms, e.g. factor VIII inhibitor bypassing activity)

Table 4: Management of NOAC-related Bleeding Bleeding severity Bleeding management Stop NOAC Resuscitation:

Expert Opinion: What Should We Use? 23,34

• Send bloods for FBC, group and save, renal and liver function, PT, aPTT, TT (anti-FXa level if

• It is important to inquire about the exact time of last NOAC intake. • Based on limited clinical data, PCC and aPCC can be administered in severe/life-threatening bleeding. • Haemodialysis may be useful for dabigatran removal. • Tranexamic acid may also be added. Table 4 shows a suggested algorithm for managing NOAC-related bleeding.

rivaroxaban/apixaban) • Inquire dose and timing of NOAC • Identify bleeding source • Maintain diuresis to aid drug clearance Mild

Mechanical compression

Moderate/major

Blood product replacement • Red blood cells/platelet transfusion or substitution Treat bleeding source (surgical or radiological intervention)

Significance of Antidotes for the NOACs Much promising research into antidotes for the NOACs is underway.47,48 Gomez-Outes et al. have reviewed recent antidotes patents and their ongoing clinical trials.49 Specific reversal agents that are being investigated as direct NOAC antidotes are summarised below.

Idarucizumab (aDabi-Fab, BI655075) Idarucizumab is a humanised monoclonal antibody fragment, or Fab, against dabigatran and its metabolites. It is generated from mouse monoclonal antibody, then humanised and reduced to a Fab fragment. Its structure is similar to thrombin, but with an affinity for dabigatran that is approximately 350 times higher than its affinity for thrombin.48 Dabigatran almost completely inhibits fibrinopeptide A (FPA) formation at the wound site, and idarucizumab is aimed at restoring systemic blood coagulation and re-enabling the formation of this fibrin.50 There have been at least three Phase I studies in healthy younger volunteers (clinicaltrials.gov identifiers NCT01688830, NCT01955720 and NCT02028780), which have demonstrated immediate, complete and sustained reversal of dabigatran-induced anticoagulation by idarucizumab. These randomised, double-blind, placebo-controlled studies showed that idarucizumab effectively restored wound-site formation of FPA, and did not cause any clinically relevant side-effects, no pro-thrombotic effect and no return of anticoagulant activity. Another important study has recently followed these three trials. It involved older volunteers/patients with mild or moderate renal impairment and demonstrated that a 5-minute infusion of idarucizumab was able to reverse the blood-thinning effects of dabigatran.51 Currently, a global Phase III study of patients on dabigatran with major bleeding or needing emergency surgery, is underway (REVERSE-AD,

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Dialysis for dabigatran-associated bleeding Life-threatening

aPCC or PCC Treat bleeding source

anti-FXa – anti-factor Xa; aPCC – activated prothrombin complex concentrate; aPTT – activated prothrombin time; FBC – full blood count; NOAC – non-vitamin K oral coagulant; PT – prothrombin; TT – thrombin time. Data pooled from references 18, 23, 34

NCT02104947). The study is open to eligible patients in more than 35 countries, expected to enrol 250 subjects and due to complete July 2017. The primary outcome of REVERSE-AD is the maximum reversal of dabigatran by intravenous administration of 5 g idarucizumab, based on dTT and ECT, at any time point from the end of the first infusion up to 4 hours after the last infusion.

Andexanet Alfa (r-Antidote,PRT064445, PRT4445) Developed by Portola, andexanet alfa is a universal antidote for factor Xa inhibitors. It is a small (39 kDa), catalytically inactive, human recombinant modified molecule that is similar to native factor Xa. Acting as a decoy receptor, it binds and sequesters direct factor Xa inhibitors, preventing them from inhibiting the activity of the native factor Xa, thus restoring normal haemostatic processes.47 In preclinical studies, a rivaroxaban-treated rabbit liver laceration model has shown andexanet alfa to restore haemostasis by sequestering the factor Xa inhibitor in a 1:1 molar ratio, reducing free fraction and anti-factor Xa activity of the factor Xa-inhibitor in plasma.47 A Phase I, first-in-man, randomised, double-blind, single-ascending dose safety and tolerability study conducted in 32 healthy volunteers has demonstrated that andexanet alfa reversed anti-FXa activity of rivaroxaban, with no thrombotic events or deaths reported.52

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Clinical Arrhythmias Table 5: Antidotes for NOACs Antidotes

bolus plus sustaining that effect through a continuous infusion. The latter is estimated to complete in 2022.

Idarucizumab

Andexanet alfa

PER977

(aDabi-Fab,

(r-Antidote,

(Aripazine,

PER977 (Ciraparantag, Aripazine)

BI655075)

PRT064445,

Ciraparantag)

Developed by Perosphere, this is a small (500 Da), synthetic, water soluble, thermally stable, cationic D-arginine compound that has broad activity against various old (heparin, LMWH) and newer oral anticoagulants (dabigatran, rivaroxaban, apixaban, edoxaban). For patients taking NOACs, PER977 re-establishes the normal blood coagulation state by directly binding to the factor Xa and IIa inhibitors through non-covalent hydrogen bonding. It has no pro-coagulant properties and does not bind to human plasma coagulation factors or albumin. Preclinical in vivo animal models (rat-tail injury model) have shown PER977 to reverse dabigatran, rivaroxaban and apixaban, as confirmed by >90% reduction in blood loss in bleeding model.56

PRT4445) Company Target NOACs

Boehringer

Portola

Perosphere Inc,

Ingelheim

Pharmaceutical

Daiichi Sankyo

Dabigatran

Direct factor Xa

Dabigatran,

inhibitor

direct factor Xa inhibitor

Dose used

IV 1–8 g (5-min

IV 200–800 mg

IV 100–300 mg (for

infusion)

bolus, followed by

bolus)

infusion Phase I

Immediate,

Reversed

Restored

(reference/

complete and

rivaroxaban in a

haemostasis

clinicaltrials.gov sustained reversal dose-dependent identifier)

(NCT01688830,

manner30

NCT01955720, and

(edoxaban; NCT01826266)35 Results unknown

NCT02028780)

(NCT02205905)

Phase II

Rapid (near

Ongoing for

(reference/

complete)

edoxaban

clinicaltrials.gov

and sustained

(NCT02207257)

identifier)

rivaroxaban/ pixaban reversal31–33 (NCT01758432) Ongoing

Ongoing for

(reference/

(REVERSE-AD/

apixaban

clinicaltrials.gov NCT02104947)

(ANNEXA-A/

identifier)

NCT02207725)

In November 2014, Perosphere published the results of first-in-human, 80-person, Phase I/II study.57 A single intravenous dose of PER977 (100–300 mg) was given 3 hours after edoxaban, and this restored blood clotting time to <10% above baseline within 10 minutes of administration, in comparison with placebo (12–15 h). These effects lasted for at least 24 hours. PER977 is currently in Phase II trials of patient receiving chronic edoxaban therapy. The advantages of PER977 compared with its rivals are that it is stable at room temperature and reverses the activity of all approved NOACs.

Results unknown Phase III

In human blood ex vivo, PER977 completely reverses rivaroxaban and apixaban in a dose-dependent fashion, as confirmed by aPTT and Xa assays.56

Ongoing for rivaroxaban (ANNEXA-R/ NCT02220725) Ongoing for factor Xa inhibitor (NCT02329327) Estimated

July 2017

Apixaban:

completion date

November 2014

for latest phase

Rivaroxaban:

January 2015

December 2014 Factor Xa inhibitors: November 2022 IV – intravenous; NOAC – non-vitamin K oral anticoagulant

Phase II proof-of-concept double-blind, placebo-controlled studies in healthy subjects examined the reversal of NOACs by andexanet alfa. A bolus of andexanet alfa 210–420 mg for rivaroxaban and apixaban, and 600–800 mg for edoxaban provided a rapid decreased (near complete) anticoagulant activity dose dependently. Continuation of the infusion regimen resulted in a sustained reversal of rivaroxaban, apixaban and edoxaban that could achieve complete reversal dose dependently. Andexanet alfa was well tolerated, with no thrombotic events or antibodies to factor Xa or factor X observed.53–55 At least three Phase III randomised, double-blind, placebo-controlled studies in older subjects are ongoing to assess safety, efficacy and the reversal of rivaroxaban (NCT02220725), apixaban (NCT02207725) and factor Xa inhibitors (NCT02329327) rapidly after an intravenous

Lip-NOAC monitoring_FINAL.indd 94

Table 5 summarises the antidotes for NOACs, currently in development. Gomez-Outes et al has also highlighted potential antidote reactions, which include hypersensitivity reactions (e.g. pyrexia), rebound anticoagulation and rebound hypercoagulation. To avoid rebound anticoagulation, the antidotes such as andexanet alfa is being administered as initial bolus injection followed by continuous infusion.49 Rebound hypercoagulation is the increase in thrombotic effect following cessation of antithrombotic medications, which has been previously observed after cessation of heparin and some thrombin inhibitors.58,59 Further studies will be needed to clarify these issues.

Conclusion NOACs are a new class of anticoagulants that have pharmacokinetic and pharmacodynamic advantages over warfarin. Their attractiveness is translated clinically into the greater convenience of no laboratory anticoagulation monitoring. However, as all anticoagulants can potentially cause bleeding, having access to laboratory assays is important to facilitate some clinical management decisions. From a clinical perspective, what is needed is a simple, rapid, reliable and global test that reflects and quantifies the anticoagulant effects of NOACs. The ideal antidote for NOACs would be a rapid universal with longer shelf-life, as it is unknown how often the use of an antidote is necessary in clinical practice. Specific antidotes for NOACs are not yet approved, although their development is at a fairly advanced stage. The development of specific antidotes to NOACs show promising results in neutralising the drugs. n

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19.

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21. Stangier J, Feuring M. Using HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012;23:138–43. 22. Baglin T, Hillarp A, Tripodi A et al. Measuring oral direct inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the Subcommittee on the Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 2013; doi: 10.1111/jth.12149 [Epub ahead of print]. 23. Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625–51. 24. Jones SD, Eaddy NS, Chan GT. Dabigatran: laboratory monitoring. Pathology 2012;44:578–80. 25. Lindahl TL, Baghaei F, Blixter IF, et al. Expert Group on Coagulation of the External Quality Assurance in Laboratory Medicine in Sweden. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost 2011;105:371–78. 26. Samama MM, Amiral J, Guinet C, et al. Monitoring plasma levels of factor Xa inhibitors: how, why and when? Expert Rev Hematol 2013;6:155–64. 27. Lindhoff-Last E, Ansell J, Spiro T, Samama MM. Laboratory testing of rivaroxaban in routine clinical practice: when, how, and which assays. Ann Med 2013;45:423–9. 28. Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct Factor Xa inhibitors: anti-Xa assay is preferable to prothrombin assay. Thromb Haemost 2010;104:1263–71. 29. Samama MM, Contant G, Spiro TE, et al. Laboratory assessment of rivaroxaban: a review. Thromb J 2013;11:11. 30. Douxfils J, Tamigniau A, Chatelain B et al. Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban. Thromb Haemost 203;110:723–31. 31. Hillarp A, baghaei F, Fagerberg Blixter I, et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. Thromb Haemost 2011;9:133–39. 32. Van Veen JJ, Smith J, Kitchen S, Makris M. Normal prothrombin time in the presence of therapeutic levels of rivaroxaban. Br J Haematol 2013;160:859–61. 33. Douxfils J, Chatelain B, Dogne J-M, Mullier F. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 2013;110:283–94. 34. Siegal DM, Garcia DA, Crowther MA. How I treat targetspecific oral anticoagulant-associated bleeding. Blood 2014;123:1152–8. 35. Pezborn E, Trabandt A, Selbach K, Tinel H. Prothrombin complex concentrate reverses the effects of high-dose rivaroxaban in rats (presented at the 21st International Congress on Thrombosis) (abstract). Pathophysiol Haemost Thromb 2010;37:A10–OC251. 36. Honickel M, Treutler S, van Ryn J, et al. Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab. Thromb Haemost 2015;113:728–40. 37. Pragst I, Zietler SH, Doerr B, et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. Thromb Haemost 2012;10:1841–8. 38. Godier A, Miclot A, Le Bonniec B, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012;116:94–102. 39. Martin A, Bonniec B, Fischer A, et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixabanin a rabbit model of bleeding and thrombosis. J Int Card 2013;168:4228–33. 40. Marlu R, Hoadaj E, Paris A, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomized crossover ex-vivo study in healthy volunteers. Thromb Haemost 2012;108:217–47. 41. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by protrombin complex concentrate. A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;24:1573–9.

42. Galan AM, Arellano-Rodrigo E, Sanz V, et al. Effects of rivaroxaban and dabigatran on haemostasis and reversion of their antithrombotic effects by different coagulation factors:evidence raised froma clinicalstudy in healthy volunteers (abstract). Thromb Haemost 2013;11(Suppl 2):418. 43. Hoffman MR, Volovyk Z, Monroe DM III. Partial reversal of dabigatran effect by a prothrombin complex concentrate in a modelof thrombin generation (abstract). Blood 2012;120:3420. 44. Gruber A, Marzek UM, Buetehorn U, et al. Potential of activated prothrombin complex concentrate and activated pactor VII to reverse the anticoagulant effects of rivaroxaban in primates (abstract). Blood 2008;112:1307. 45. Perzborn E, Gruber A, Tinel H, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost 2013;110:162–72. 46. Liesenfeld KH, Staab A, Hartter S, et al. Pharmacometric characterization of dabigatran haemodialysis. Clinical Pharmacokinet 2013;52:453–62. 47. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013;19:446–51. 48. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121:3554–62. 49. Gomez-Outes A, Suarez-Gea ML, Lecumberri R, et al. Specific antidotes in development for reversal of novel anticoagulants: a review. Rec Pat Cardiovasc Drug Discov 2014;9:2–10. 50. Van Ryn J, Schmol M, Pillu H, et al. Effect of dabigatran on the ability to generate fibrin at a wound site and its reversal by idarucizumab, the antidote to dabigatran, in healthy volunteers: an exploratory marker of blood loss (abstract 18403). Poster presentation at the American Heart Association’s Scientific Sessions, Chicago, 15–19 November 2014. 51. Glund S, Stangier J, Schmohl, et al. Idarucizumab, a specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. Presentation at the 56th Annual Meeting of the American Society for Haematology, San Francisco, 6–9 December 2014. Available at: https:// ash.confex.com/ash/2014/webprogram/Paper74960.html (accessed 30 July 2015). 52. Crowther MA, Kitt M, McClure M, et al. Randomized, double-blind, placebo-controlled single ascending dose pharmacokinetic and pharmacodynamic study of PRT064445, a universal antidote for factor Xa inhibitors (abstract). Arterioscler Thromb Vasc Biol 2013;33:A10. 53. Crowther M, Mathur V, Kitt M, et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for FXa inhibitors (abstract). Blood 2013;122:3636. 54. Crowther M, Lu G, Conley P, et al. Sustained reversal of apixaban anticoagulation with andexanet alfa using a bolus plus infusion regimen in a phase 2 placebo controlled trial. Eur Heart J 2014;35:P738 (abstract). 55. Crowther M, Levy G, Lu G, et al. A Phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. Presentation at the 56th Annual Meeting of the American Society for Haematology, San Francisco, December 6–9, 2014. Available at: https://ash.confex.com/ash/2014/ webprogram/Paper73672.html (accessed 30 July 2015). 56. Laulicht B, Bakhru S, Lee C, et al. Small molecule antidote for anticoagulants (abstract). Circulation 2012;126:A11395. 57. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014;371:2141–2. 58. Hermans C, Claeys D. Review of the rebound phenomenon in new anticoagulant treatments. Curr Med Res Opin 2006;22:471–81. 59. Cundiff D. Clinical evidence for rebound hypercoagulability after discontinuing oral anticoagulants for venous thromboembolism. Medscape J Med 2008;10:258. 60. Levy JH, Spyropoulos AC, Samama CM, Douketis J. Direct oral anticoagulants. JACC Cardiovascular Interventions 2014;7:1333–51. 61. Blann AD, Lip GYH. Laboratory monitoring of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:1140–2.

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Clinical Arrhythmias

Early Repolarisation – What Should the Clinician Do? Manoj N Obeyesekere 1 and Andrew D Krahn 2 1. Cabrini and Epworth Healthcare Groups, Victoria, Australia; 2. The Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada

Abstract The early repolarisation (ER) pattern is a common ECG finding. Most individuals with the ER pattern are at minimal risk for arrhythmic events. In others, ER increases the arrhythmic risk of underlying cardiac pathology. Rarely ER syndrome will manifest as a primary arrhythmogenic disorder causing ventricular fibrillation (VF). ER syndrome is defined as syncope attributed to ventricular arrhythmias or cardiac arrest attributed to ER following systematic exclusion of other etiologies. Some ECG features associated with ER portend a higher risk. However, clinically useful risk-stratifying tools to identify the asymptomatic patient at high risk are lacking. Patients with asymptomatic ER and no family history of malignant ER should be reassured. All patients with ER should continue to have modifiable cardiac risk factors addressed. Symptomatic patients should be systematically investigated, directed by symptoms.

Keywords Early repolarisation, idiopathic ventricular fibrillation Disclosure: The authors have no conflicts of interest to declare. Received: 28 March 2015 Accepted: 09 July 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(2):96–9 Access at: www.AERjournal.com Correspondence: Dr Manoj N Obeyesekere, The Northern Healthcare Group and Cabrini Health, Victoria, Australia. E: manojobey@yahoo.com

Early repolarisation (ER) is defined as J-point elevation of ≥0.1 mV in two adjacent leads with either a slurred or notched morphology (Figures 1 to 4).1,2 Numerous studies have established an association with ER and increased risk of death and idiopathic ventricular fibrillation (VF).1–5 Clinicians face questions such as patient and family counselling, quantitifying the risk of sudden cardiac death (SCD) associated with ER, inheritance/family screening and therapeutic strategies. This review emphasises that the arrhythmic risk in most individuals is minimal to none. In others ER may increase the arrhythmic risk of underlying cardiac pathology. Rarely ER syndrome will be diagnosed as a primary arrhythmogenic disorder, with a unique approach to managing associated ventricular arrhythmias.

Prevalence and Arrhythmic Risk Although the ER pattern on ECG has been reported to have a prevalence of between 1 % and 24 % in cohort studies, idiopathic VF is rare.2,5,6 The incidence of idiopathic VF due to ER in an individual younger than 45 years is estimated to be 3:100,000.4,7 A meta-analysis reporting the incidence of death reported events per 1,000 personyears of arrhythmia, cardiac and all-cause death of 1.68, 4.81 and 17.06 respectively in subjects with the ER pattern during follow-up. The ER pattern was associated with a higher risk for arrhythmia mortality (RR 1.70; 95 % CI [1.19–2.42]; p=0.003) but not cardiac mortality (RR 0.78; 95 % CI [0.27–2.21]; p=0.63) or all-cause mortality (RR 1.06; 95 % CI [0.85–1.31]; p=0.62).6 The data from this metaanalysis also revealed a low to intermediate absolute incidence rate of arrhythmia death (70 cases per 100,000 person-years of follow-up) in subjects with the ER pattern. ER >2.0 mm in the inferior leads was associated with the highest relative risk of 3.02 (95 % CI [1.84–4.96]; p<0.001). Additionally higher amplitude ER (>0.2 mV) in the inferior leads along with the horizontal/descending ST-segment variant, has

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been reported to have a hazard ratio of arrhythmic death of 3.14 (95 % CI [1.56–6.30]).8 Because the absolute risk remains very low, the incidental identification of the ER pattern should not be interpreted as a high-risk marker. Clinical decisions regarding ER are based on the presence and severity of symptoms and co-morbidities. The prevalence of ER is higher in athletes, reported to be between 22 % and 44 %,4,8 with the probability of arrhythmic death approximately 0.35:100,000 in competitive athletes.9 Still, the absolute risk remains very low and young, healthy athletes demonstrate an ST-segment morphology associated with ER that does not appear to be associated with an increased arrhythmic risk.8 One study reporting on the clinical significance of ER in 704 athletes (age 25±5 years, ER prevalence of 14 %) reported no cardiac events or ventricular arrhythmias during follow up (mean 6±4 years).10

Clinical Manifestations ER is most often an incidental benign finding. ER pattern may come to the attention of physicians caring for patients with concurrent cardiac disease. Although ER syndrome may rarely present as syncope,11 limited conflicting data report an association between ER and syncope.1,12 Although a classification system (types 1 to 4) based on arrhythmic risk associated with the spatial distribution of ER has been proposed,13,14 this classification is not universally accepted and has been criticised.15,16 In brief, type 1 ER is found in the lateral precordial leads. It is common among healthy male athletes and is thought to be largely benign. Type 2 ER is found in the inferior or inferolateral leads and is associated with a moderate level of risk. Type 3 ER, noted globally in the inferior, lateral and right precordial leads, appears to be associated with the highest risk.3 Brugada syndrome is classified as type 4, J-wave/point

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elevation in the right precordial leads. This approach assumes a common mechanistic link between these syndromes, with conflicting evidence to support this hypothesis. The above classification does not take into account the reported ST-segment characteristics associated with risk, with a clear higher risk being associated with the horizontal/ descending pattern.7,8 Additionally, the coexistence of non-type 1 anterior ER (without Brugada changes with and without provocative drug challenge) with inferolateral ER was a key predictor of poor outcome (VF recurrence) in patients with ER syndrome compared with the group with ER syndrome associated with only inferolateral ER.17 The prevalence of the higher risk patterns (e.g. global ER or inferior ER >2 mm with horizontal/descending ST-segment) is substantially lower than the low-risk patterns (lateral ER with ascending ST-segment or inferior ER <2 mm with ascending ST-segment).8,18 The risk has been estimated as low at 1:3,000 even for an adult with ER and horizontal ST-segment.7

Figure 1: Prominent early repolarisation manifest as inferior J-point slurring and lateral J-point notching each >2 mm in two contiguous leads.

Figure 2: Horizontal ST-segment following early repolarisation with prolonged QTc.

Diagnosis of Ventricular Fibrillation due to Early Repolarisation Syndrome Expert consensus recommendations have been reported for the diagnosis of ER syndrome (Table 1).19 Systematic assessment of survivors of SCD without evidence of infarction or left ventricular dysfunction establishes a causative diagnosis in approximately 50 % of cases.20 A systematic evaluation includes cardiac monitoring, echocardiogram, evaluation of coronary arteries, signal-averaged ECG, exercise testing, cardiac magnetic resonance imaging and intravenous epinephrine and sodium channel blocker challenge. The ER pattern can be intermittent, with 58 % of patients with ER-attributed cardiac arrest having at least one ECG that did not demonstrate the ER pattern during hospitalisation.20

Figure 3: Prominent lateral J-point notching >4 mm with ascending ST-segment and inferior J-point slurring with ascending ST-segment.

Although genotype data are emerging in case-report fashion, current guidelines do not recommend genetic testing. Even when a familial malignant phenotype is present, genetic testing has not been of assistance.21,22

Prognostic variables of the Early Repolarisation Pattern A number of variables have been suggested to modify the arrhythmic risk in ER. However, no risk stratifiers exist that allow for the identification of high-risk individuals who might be candidates for primary treatment. A horizontal/descending ST-segment following ER portends a higher risk in both the general population and in patients with idiopathic VF.2,5 The ST-segment pattern is defined as ascending when there is >0.1 mV elevation of the ST-segment within 100 ms after the J-point and the ST-segment merges gradually with the T wave or as horizontal/descending when the ST-segment elevation is ≤0.1 mV within 100 ms after the J-point and continues as a flat ST-segment until the onset of the T wave (Figure 1, 2, 3 and 4).7,8 Therefore the highest risk occurs with the combination of ER of high amplitude (≥0.2 mV) in the inferior limb leads and a horizontal or descending ST-segment. However the prevalence of the horizontal/descending ST-segment in controls (approximately 3 %) compared with the incidence of idiopathic VF renders this variable still devoid of meaningful clinical utility in the asymptomatic patient.7,8 Additionally, some individuals at risk demonstrate the up-sloping ST-segment pattern.4,7 The incidence of idiopathic VF due to ER with a horizontal ST-segment is estimated to be 0.03 % – 100-fold less than the prevalence.4,7 Thus

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Figure 4: Inferior J-point elevation with horizontal ST segment.

the absolute risk still remains extraordinarily low. Unless syncope or cardiac arrest are attributed to ER, the mere presence of these ECG features does not warrant intervention per se. Thus, ECG features lack the sensitivity, specificity and predictive accuracy necessary for any clinical utility at present. Although both slurring and notching type ER are observed and may exist in the same patient, the prognostic value of one compared with the other has not been clearly established (Figures 1 and 3).7,20,23

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Clinical Arrhythmias Table 1: Expert Recommendations for the Diagnosis of ER Pattern and Syndrome 19 1. ER syndrome is diagnosed in the presence of J-point elevation ≥1 mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead ECG in a patient resuscitated from otherwise unexplained VF/polymorphic VT. 2. ER syndrome can be diagnosed in an SCD victim with a negative autopsy and medical chart review, with a previous ECG demonstrating J-point elevation ≥1 mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead ECG.

study, lateral or inferior ER in non-African Americans was independently associated with cardiovascular death (HR 1.6; p=0.02), whereas it was not associated with cardiovascular death in African Americans (HR 0.75; p=0.50).26 This study also demonstrated that ER was more common in African Americans (HR 3.1; p<0.01). The hazard of the inferior-only ER could not be estimated because there were no African American deaths in this group. In contrast, in the non-African American cohort, there was a statistically significant association between cardiovascular death and the inferior ER pattern (HR 2.13; p<0.01).

3. ER pattern can be diagnosed in the presence of J-point elevation ≥1 mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead ECG.

Table 2: Expert Consensus Recommendations on Therapies in ER Syndrome 19 1. Class I ICD implantation is recommended in patients with a diagnosis of ER syndrome who have survived a cardiac arrest. 2. Class IIa Isoproterenol infusion can be useful in suppressing electrical storms in patients with a diagnosis of ER syndrome. 3. Class IIa Quinidine in addition to an ICD can be useful for secondary prevention of VF in patients with a diagnosis of ER syndrome. 4. Class IIb ICD implantation may be considered in symptomatic family members of ER syndrome patients with a history of syncope in the presence of ST-segment elevation >0.1 mm in two or more inferior or lateral leads. 5. Class IIb ICD implantation may be considered in asymptomatic individuals who demonstrate a high-risk ER ECG pattern (high J-wave amplitude, horizontal/descending ST-segment) in the presence of a strong family history of juvenile unexplained sudden death with or without a pathogenic mutation. 6. Class III ICD implantation is not recommended in asymptomatic patients with an isolated ER ECG pattern.

In addition to ECG markers, a number of demographic variables, including gender, family history and ethnicity have been reported to be associated with arrhythmic risk. A population-based study of central-European descent individuals demonstrated males with ER in the inferior leads had a hazard ratio of 4.32 (p<0.01) compared with the risk in women for cardiac mortality.5 However in a young biracial population (mean age 25, 40 % black) of 5,039 patients followed up for 23 years the presence of ER was not reported to confer an adverse outcome, with age, sex and race almost completely attenuating unadjusted associations of increased total and cardiovascular mortality.24 This study concluded the need for additional studies in patients whose ER pattern is maintained into and beyond middle age. A positive family history of sudden death has been reported to be significantly more common than in those without ER (16 % vs. 9 %; p=0.17),1 and another study reported a higher prevalence (23 %) of ER in family members of sudden arrhythmic death syndrome probands compared with matched unrelated healthy individuals from the general population (11 % ER).25 Rarely, familial ER has been reported to have an autosomal dominant inheritance pattern with incomplete penetrance. Further studies are required to illuminate inheritance and risk of familial ER. Although ER is more common in African Americans, there is no clear attributable risk associated with ethnicity and African Americans are not over-represented in idiopathic VF cohorts. In a large population

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In a multicentre study of patients with ER syndrome and aborted SCD/ VF involving 81 patients (age 36 ± 13 years, 60 males), inducability of sustained VF during electrophysiology study (22 %) did not predict subsequent arrhythmias followed up (7±4.9 years) by serial implantable cardioverter-defibrillator (ICD) interrogations.27

Autonomic Tone Bradycardia-dependent augmentation of ER is observed in both VF cases and healthy controls. However augmentation of the J-wave and the slope of the regression line (J-point elevation against heart rate) is greater in cases with VF compared with controls (p<0.01).28 Tachycardia, including exercise-testing-related ECG monitoring, tends to show normalisation of the ER pattern. VF often occurs at night when parasympathetic tone is augmented.28 Additionally, the amplitude of ER that may be unnoticeable during daytime in patients with idiopathic VF becomes progressively augmented immediately prior to VF, with bradycardia and an increase in vagal tone.1,29,30 Accentuation of ER due to compensatory pauses after extrasystoles along with the resultant short-long-short sequences may also contribute to VF3. In a preliminary report involving three French families with an apparent malignant familial ER pattern, the Valsalva manoeuvre was utilised to reveal ‘concealed’ ER.22 However, the relationship between ER manifested by Valsalva and the prognosis is not known.

Early Repolarisation Modifying Risk of Underlying Cardiac Pathology ER is a much more common modifier of cardiac risk of structural heart disease and primary electrical disorders. ER appears to be associated with an increased vulnerability to ventricular arrhythmias but not to non-arrhythmic cardiac events.31 Patients with J-waves appear to be at an increased risk of ischaemic VF in the event of a myocardial infarction/ischaemia.32,33 In an experimental animal model, the appearance of J-waves following left anterior descending artery occlusion demonstrated modest accuracy (positive predictive value 53 %) for predicting VF during myocardial infarction.34 ER in the inferior leads has also been demonstrated to be associated with increased risk of life-threatening ventricular arrhythmias in patients with chronic coronary artery disease, after adjustment for left ventricular ejection fraction.35 ER in the inferior leads is also reported to predict higher risk of sudden death in nonischaemic cardiomyopathy patients.36 Limited evidence suggests that the coexistence of ER with a Brugadapattern ECG is an incremental predictor of arrhythmic events and a more severe phenotype.37–39 Similar observations have been made in long QT syndrome, where major ER was a more potent predictor of symptoms than the QT interval (Figure 2).40 ER has also been demonstrated to be more prevalent in patients with arrhythmogenic right ventricular

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cardiomyopathy (31 %) compared with the general population, though this retrospective analysis identified no correlation with cardiac events.41 A high prevalence of ER in patients with short QT syndrome has been reported (65 %).42 Given the prevalence of the ER pattern, ER may be viewed as one of many arrhythmogenic factors that is rarely solely responsible for clinical events, but represents a risk ‘cofactor’.

Therapies for Early Repolarisation Syndrome Quinidine is effective for suppression of VF related to ER syndrome, with acute use of isoproterenol in patients who are unstable.43 In this study (n=122; 90 males; mean age 37±12 years), isoproterenol infusion immediately suppressed electrical storms in seven of seven patients. Quinidine decreased recurrent VF from an average of 33 episodes to none over more than two years of follow-up and restored a normal ECG. There was no suggestion of benefit from a number of other antiarrhythmic drugs (Table 1). An ICD is indicated following cardiac arrest. There is no current risk stratification strategy for asymptomatic patients with ER in the general population and within families with ER (Table 1).

ER demonstrates weak heritability in the general population.12,44 Familial ER appears to be transmitted as an autosomal dominant inheritance pattern with incomplete penetrance.25 Familial transmission has also been reported to be more frequent when the mother is affected.44 Potential explanations for unequal transmission include transmission through mitochondrial DNA, effects mediated via sex chromosomes

10.

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Haissaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarisation. N Engl J Med 2008;358:2016–23. Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early repolarisation on electrocardiography. N Engl J Med 2009;361:2529–37. Nam GB, Ko KH, Kim J, et al. Mode of onset of ventricular fibrillation in patients with early repolarisation pattern vs. Brugada syndrome. Eur Heart J 2010;31:330–9. Rosso R, Kogan E, Belhassen B, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance. J Am Coll Cardiol 2008;52:1231–8. Sinner MF, Reinhard W, Muller M, et al. Association of early repolarisation pattern on ECG with risk of cardiac and allcause mortality: a population-based prospective cohort study (MONICA/KORA). PLoS Med 2010;7:e1000314. Wu SH, Lin XX, Cheng YJ, Qiang CC, Zhang J. Early repolarisation pattern and risk for arrhythmia death: a metaanalysis. J Am Coll Cardiol 2013;61:645–50. Rosso R, Glikson E, Belhassen B, et al. Distinguishing ‘benign’ from ‘malignant’ early repolarisation: the value of the ST-segment morphology. Heart Rhythm 2012;9:225–9. Tikkanen JT, Junttila MJ, Anttonen O, et al. Early repolarisation: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011;123:2666–73. Cappato R, Furlanello F, Giovinazzo V, et al. J-wave, QRS slurring, and ST elevation in athletes with cardiac arrest in the absence of heart disease: marker of risk or innocent bystander? Circ Arrhythm Electrophysiol 2010;3:305–11. Quattrini FM, Pelliccia A, Assorgi R, et al. Benign clinical significance of J-wave pattern (early repolarisation) in highly trained athletes. Heart Rhythm 2014;11:1974–82. Maury P, Sacher F, Rollin A, et al. Ventricular fibrillation in loop recorder memories in a patient with early repolarisation syndrome. Europace 2012;14:148–9. Noseworthy PA, Tikkanen JT, Porthan K, et al. The early repolarisation pattern in the general population: clinical correlates and heritability. J Am Coll Cardiol 2011;57:2284–9. Antzelevitch C, Yan GX. J-wave syndromes. Heart Rhythm 2010;7:549–58. Antzelevitch C, Yan GX, Viskin S. Rationale for the use of the terms J-wave syndromes and early repolarisation. J Am Coll Cardiol 2011;57:1587–90. Surawicz B, Macfarlane PW. Inappropriate and confusing electrocardiographic terms: J-wave syndromes and early repolarisation. J Am Coll Cardiol 2011;57:1584–6. Wilde AA. J-wave syndromes bring the ATP-sensitive potassium channel back in the spotlight. Heart Rhythm 2012;9:556–7.

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Clinical Perspective • Early repolarisation (ER) syndrome is very rare. Patients with asymptomatic ER and no family history of malignant ER should be reassured that their ECG is a normal variant. • All patients with the ER pattern should continue to have modifiable cardiac risk factors addressed. • ER syndrome can be treated acutely with isoproterenol and chronically with ICD implantation and quinidine therapy.

Heritability and Family Screening

and parental imprinting of autosomal genes. Familial malignant forms of ER syndrome are exceptionally rare.21,22 Asymptomatic individuals with the ER pattern on ECG featuring a mutation considered pathogenic for ER, as well as family members of a patient diagnosed with ER syndrome who present with a diagnostic ECG, may be affected by familial ER syndrome. These families represent a unique cohort, and findings should not be extrapolated to the general population. Unlike these families with a malignant form of familial ER syndrome, the vast majority of familial ER per se is unlikely to portend a substantially increased risk compared with the general population. n

• Family screening and treatment of the asymptomatic individual continues to evolve. • High-risk family features, including extent of family history of SCD, arrhythmic syncope, and amplitude and morphology of the ER pattern, may lead to consideration of a prophylactic ICD in conjunction with review by an expert centre with a focus on inherited arrhythmias.

17. Kamakura T, Kawata H, Nakajima I, et al. Significance of non-type 1 anterior early repolarisation in patients with inferolateral early repolarisation syndrome. J Am Coll Cardiol 2013;62:1610–8. 18. Adler A, Rosso R, Viskin D, et al. What do we know about the ‘malignant form’ of early repolarisation? J Am Coll Cardiol 2013;62:863–8. 19. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS Expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932–63. 20. Derval N, Simpson CS, Birnie DH, et al. Prevalence and characteristics of early repolarisation in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry. J Am Coll Cardiol 2011;58:722–8. 21. Gourraud J, Chatel S, Le Scouarnec S, et al. Abstract 20987: Early repolarisation syndrome: autosomal dominant malignant form in large French families. Circulation 2010;122:A20987. 22. Gourraud J, Le-Scouarnec S, Sacher F, et al. Abstract 8808: Early repolarisation syndrome: Valsalva manoeuvre in familial screening. Circulation 2011;124:A8808. 23. Haruta D, Matsuo K, Tsuneto A, et al. Incidence and prognostic value of early repolarisation pattern in the 12-lead electrocardiogram. Circulation 2011;123:2931–7. 24. Ilkhanoff L, Soliman EZ, Prineas RJ, et al. Clinical characteristics and outcomes associated with the natural history of early repolarisation in a young, biracial cohort followed to middle age: the coronary artery risk development in young adults (CARDIA) study. Circ Arrhythm Electrophysiol 2014;7:392–9. 25. Nunn LM, Bhar-Amato J, Lowe MD, et al. Prevalence of J-point elevation in sudden arrhythmic death syndrome families. J Am Coll Cardiol 2011;58:286–90. 26. Perez MV, Uberoi A, Jain NA, et al. The prognostic value of early repolarisation with ST-segment elevation in African Americans. Heart Rhythm 2012;9:558–65. 27. Mahida S, Derval N, Sacher F, et al. Role of electrophysiological studies in predicting risk of ventricular arrhythmia in early repolarisation syndrome. J Am Coll Cardiol 2015;65:151–9. 28. Mizumaki K, Nishida K, Iwamoto J, et al. Vagal activity modulates spontaneous augmentation of J-wave elevation in patients with idiopathic ventricular fibrillation. Heart Rhythm 2012;9:249–55. 29. Kalla H, Yan GX, Marinchak R. Ventricular fibrillation in a patient with prominent J (Osborn)-waves and ST segment elevation in the inferior electrocardiographic leads: a Brugada syndrome variant? J Cardiovasc Electrophysiol 2000;11:95–8.

30. Shinohara T, Takahashi N, Saikawa T, Yoshimatsu H. Characterisation of J-wave in a patient with idiopathic ventricular fibrillation. Heart Rhythm 2006;3:1082–4. 31. Junttila MJ, Tikkanen JT, Kentta T, et al. Early repolarisation as a predictor of arrhythmic and nonarrhythmic cardiac events in middle-aged subjects. Heart Rhythm 2014;11:1701–6. 32. Viskin S, Rosso R, Halkin A. Making sense of early repolarisation. Heart Rhythm 2012;9:566–9. 33. Tikkanen JT, Wichmann V, Junttila MJ, et al. Association of early repolarisation and sudden cardiac death during an acute coronary event. Circ Arrhythm Electrophysiol 2012;5:714–8. 34. Demidova MM, Martin-Yebra A, van der Pals J, et al. Transient and rapid QRS-widening associated with a J-wave pattern predicts impending ventricular fibrillation in experimental myocardial infarction. Heart Rhythm 2014;11:1195–201. 35. Patel RB, Ng J, Reddy V, et al. Early repolarisation associated with ventricular arrhythmias in patients with chronic coronary artery disease. Circ Arrhythm Electrophysiol 2010;3:489–95. 36. Pei J, Li N, Gao Y, et al. The J-wave and fragmented QRS complexes in inferior leads associated with sudden cardiac death in patients with chronic heart failure. Europace 2012;14:1180–7. 37. Letsas KP, Sacher F, Probst V, et al. Prevalence of early repolarisation pattern in inferolateral leads in patients with Brugada syndrome. Heart Rhythm 2008;5:1685–9. 38. Sarkozy A, Chierchia GB, Paparella G, et al. Inferior and lateral electrocardiographic repolarisation abnormalities in Brugada syndrome. Circ Arrhythm Electrophysiol 2009;2:154–61. 39. Kamakura S, Ohe T, Nakazawa K, et al. Long-term prognosis of probands with Brugada-pattern ST-elevation in leads V1-V3. Circ Arrhythm Electrophysiol 2009;2:495–503. 40. Laksman ZW, Gula LJ, Saklani P, et al. Early repolarisation is associated with symptoms in patients with type 1 and type 2 long QT syndrome. Heart Rhythm 2014;11:1632–8. 41. Peters S, Selbig D. Early repolarisation phenomenon in arrhythmogenic right ventricular dysplasia-cardiomyopathy and sudden cardiac arrest due to ventricular fibrillation. Europace 2008;10:1447–9. 42. Watanabe H, Makiyama T, Koyama T, et al. High prevalence of early repolarisation in short QT syndrome. Heart Rhythm 2010;7:647–52. 43. Haissaguerre M, Sacher F, Nogami A, et al. Characteristics of recurrent ventricular fibrillation associated with inferolateral early repolarisation role of drug therapy. J Am Coll Cardiol 2009;53:612–9. 44. Reinhard W, Kaess BM, Debiec R, et al. Heritability of early repolarisation: a population-based study. Circ Cardiovasc Genet 2011;4:134–8.

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Clinical Arrhythmias

Anticoagulation in Atrial Fibrillation – Current Concepts Demosthenes G Ka t r i t s i s, 1 B e r n a r d J G e r s h 2 a n d A J o h n Ca m m 3 1. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, US; 2. Mayo Medical School, Rochester, Minnesota, USA; 3. St George’s University of London, UK

Abstract This article presents the current status of the use of anticoagulation for the treatment of AF, particularly with the use of non-vitamin K-dependent anticoagulants. Comparisons between these agents and warfarin are made and methods for assessment of anticoagulant activity and reversal are discussed.

Keywords Atrial fibrillation, guidelines, anticoagulants, thromboprophylaxis Disclosure: The authors have no conflicts of interest to declare Acknowledgements: Andrew Grace, Section Editor– Arrhythmia Mechanisms/Basic Science acted as Editor for this article. This article is adapted from Chapter 52: Atrial Fibrillation. In: Katritsis D, Camm AJ, Gersh BJ. Clinical Cardiology: Current Practice Guidelines. Oxford, UK: Oxford University Press, with kind permission. © Oxford University Press, 2013. Received: 11 May 2015 Accepted: 21 July 2015 Citation: Arrhythmia & Electrophysiology Review, 2015;4(2):100–7 Access at: www.AERjournal.com Correspondence: Dr D Katritsis, Division of Cardiology, Beth Israel Deaconess Medical Center, 185 Pilgrim Rd, Baker 4, Boston, MA 02215. E: dkatrits@bidmc.harvard.edu

Thrombotic material in atrial fibrillation (AF) usually develops in the left atrial appendage as a result of decreased flow and stasis, possible endothelial dysfunction and a hypercoagulable state as indicated by increased fibrinogen, D-dimer, thromboglobulin and platelet factor 4 levels.1 In the Framingham Heart Study, the percentage of strokes attributable to AF increases steeply from 1.5 % in patients aged 50–59 years to 23.5 % in those aged 80–89 years.2 In patients with a history of hypertension but no prior diagnosis of clinical AF, subclinical AF predisposes them to embolic events.3 Undiagnosed silent AF is a probable cause of cryptogenic strokes,4,5 and subclinical episodes of AF are associated with silent cerebral infarcts, particularly in patients with diabetes.6,7

1 and Table 1). In patients with CHA2DS2-VASc score of 1, anticoagulation should be individualised as the risk of stroke is low.13 However, patients aged >65 years, especially women, are at high risk of ischaemic stroke,14 and in these individuals anticoagulation reduces the rate of mortality.15,16 The risk of bleeding is assessed by schemes such as the HAS-BLED, ATRIA and HEMORR2HAGES scoring systems.17 A HAS-BLED score ≥3 indicates ‘high risk’. New oral anticoagulants are now recommended for nonvalvular AF as a potential alternative to warfarin. Nonsteroidal anti-inflammatory drugs increase the risk of both serious bleeding and thromboembolism in anticoagulated patients with AF.18

Aspirin The frequency of AF-related incident ischaemic strokes in patients aged ≥80 years have increased threefold over the last 25 years, despite the introduction of anticoagulants, and are projected to futher increase threefold by 2050.8 Among patients with AF who are at moderateto-high risk of stroke and are receiving anticoagulation, those with persistent AF have a higher risk of thromboembolic events and worse survival rates compared with those with paroxysmal AF.9 The risk of stroke is similar in patients with and without valvular disease.10 Serial ECGs, Holter monitoring mobile outpatient telemetry, external loop recorders and implantable loop recorders detect post-stroke AF in 23.7 % of patients.11 However, AF that occurs early after stroke can be caused by a transient neurogenic mechanism, and AF that occurs several months post-stroke can be an incidental finding; therefore, it cannot be concluded that the cause of cryptogenic stroke has been identified in all patients found to have post-stroke AF.11

Anticoagulation Adjusted-dose warfarin and antiplatelet agents reduce the risk of stroke by approximately 60 % and 20 %, respectively, in patients with AF.12 In general, oral anticoagulation is preferred in patients with CHA2DS2-VASc score ≥2, and no anticoagulation in patients with a score of 0 (see Figure

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The protective value of acetylsalicylic acid (aspirin) as monotherapy has come under question, and there are concerns that it may even increase risk of stroke in elderly patients (aged >75 years).19,20 Warfarin is superior to aspirin in patients aged >75 years, offering a 52 % reduction in yearly risk of a combined end-point of stroke, intracranial haemorrhage and peripheral embolism (1.8 % versus 3.8 %; Birmingham Atrial Fibrillation Treatment of the Aged Study [BAFTA]).15 Thus, the use of aspirin for stroke prevention in patients with AF should be limited to those who refuse any form of oral anticoagulation,21 or, perhaps, to those with a CHA2DS2-VASc score of 1.1

Aspirin and Clopidogrel The combination of aspirin and clopidogrel offers increased protection compared with aspirin alone, albeit at an increased risk of major bleeding,22 and is preferred when warfarin is contraindicated. However, aspirin and clopidogrel together offer less protection than warfarin alone (RR of 1.44 for stroke, peripheral embolism, MI and vascular death).22 In patients who sustain an ischaemic stroke despite international normalised ratio (INR) of 2.0–3.0, targeting a higher INR should be considered (3.0–3.5) rather than adding an antiplatelet agent, as major bleeding risk starts at INR >3.5.23

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Warfarin Warfarin is a racemic mixture of isomers that inhibits the synthesis of vitamin K-dependent coagulation factors. The effective dose of warfarin varies significantly among individuals, as a result of genetic variations in its receptor, metabolism via the cytochrome P450 (CYP) system and interactions with other drugs, vitamins and green vegetables.1 The risk of AF increases with INR >3.5–4.0. Recommended INR values for AF are 2–3. Pharmacogenetic testing for guiding doses, by means of genotyping for the variants CYP2C9 and VKORG1, which are associated with reduced clearance and thus a decrease in warfarin requirement, is not clinically useful.24 Patients initiating warfarin may be at an increased risk of stroke during the first 30 days of treatment, probably owing to rapid deactivation of proteins S and C, two endogenous anticoagulants.25 In high-risk cases, warfarin should be started with concomitant low molecular weight heparin administration for the initial 3–5 days of treatment. Increased levels of coronary calcification have been recently reported in patients on long‑term therapy with vitamin K antagonists.26

Figure 1: Choice of Anticoagulant for Atrial Fibrillation

Atrial fibrillation

No (i.e. non-valvular AF) Yes

<65 years and lone AF (including females) No Assess risk of stroke (CHA2DS2-VASc score)

Non-vitamin K Oral Anticoagulants

Direct Thrombin Inhibitors Dabigatran Dabigatran is preferred to warfarin for nonvalvular AF as recommended by the European Society of Cardiology 21 and the Canadian Cardiovascular Society.32 In 2010, the US Food and Drug Administration (FDA) approved dabigatran at a dose of 150 mg twice daily (CrCl >30 ml/min), or 75 mg twice daily (CrCl 15–30 ml/min) based on the results of the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.33 However, in the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial, during 2.3 years of continued treatment with dabigatran, there was a higher rate of major bleeding with dabigatran 150 mg twice daily

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≥2

Oral anticoagulant therapy

Non-vitamin K oral anticoagulants (NOACs) are direct thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban) inhibitors. Thrombin catalyses the final step in the coagulation cascade by converting fibrinogen to fibrin. Factor Xa, in conjuction with factor Va, mediates activation of prothrombin to thrombin. In patients with nonvalvular AF (ie not mechanical valves or mitral valve disease), they are associated with a relative 50 % reduction in the risk of intracranial haemorrhage and haemorrhagic stroke compared with warfarin that is also maintained in elderly patients. There is no need for frequent laboratory monitoring and dose adjustments.27,28 The main problems associated with NOACs are the lack of antidotes and specific assays to measure anticoagulant effect, and the considerably higher cost than warfarin.29 It should be also noted that all major clinical trials with warfarin have included patients without severe renal impairment (CrCl <25–30 ml/min), and renal function should always be considered, especially when treated with dabigatran (see Table 2). They are not indicated in patients on haemodialysis because they may precipitate inadvertent bleeding.30 NOACs do not interact with food but with inhibitors (or inducers) of P-glycoprotein transporters and CYP3A4. Caution is required when they are coadministered with drugs such as verapamil, amiodarone and dronedarone. In patients taking warfarin, switching to a new agent is appropriate when the INR is <2. The mode of action of novel oral anticoagulants in the coagulation cascade is presented in Figure 2. A comparison of new anticoagulants is presented in Tables 3 to 5. A practical guide by EHRA on the use of NOACs in patients with AF has been published (www.NOACforAF.eu).31

Yes

Valvular AFa

Assess bleeding risk (HAS-BLED score) Considered patient values and preferences

No antithrombotic therapy

NOAC

VKA

Antiplatelet therapy with aspirin plus clopidogrel, or – less effectively – aspirin only, should be considered in patients who refuse any OAC, or cannot tolerate anticoagulants for reasons unrelated to bleeding. If there are contraindications t o OAC or antiplatelet therapy, left atrial appendage occlusion, closure or e xcision may be considered. Colour: CHA2DS2-VASc; green= 0, blue = 1, red = ≥2. Line: solid = best option; dashed = alternative option. NOAC = novel oral anticoagulant; OAC = oral anticoagulant; VKA = vitamin K antagonist. a Includes rheumatic valvular disease and prosthetic valves. From: Camm et al, 2012.21 By permission of Oxford University Press on behalf of European Society of Cardiology. © ESC 2014. www.escardio.org

in comparison with 110 mg, and similar rates of stroke and death.34 The European Medicines Agency (EMA) has approved both the 110 mg twice-daily and 150 mg twice-daily doses for nonvalvular AF. Elective cardioversion may be performed in patients taking dabigatran for at least 3 weeks.21 Dabigatran is excreted through the kidneys and no dosing recommendation is given for clearance <15 ml/min. In elderly patients a reduced dose is reasonable (75 mg twice daily),35 especially for those aged >80 years. It can be used safely together with aspirin.33,36 A higher risk of major and gastrointestinal haemorrhage compared with warfarin has been seen in African Americans and patients with chronic kidney disease, but the risk of inrtracranial haemorrhage remains lower.37 Main side-effects of dabigatran are dyspepsia and stomach pain (11 %), and transaminase elevations 0.9–2.0 %, although with a frequency similar to that caused by warfarin. There is no evidence of liver toxicity as observed with ximelagatran. A trend in the RE-LY study towards more MIs in the dabigatran arm as compared with warfarin was not confirmed in a subsequent post-hoc analysis.38 A recent meta-analysis of seven trials including the RE-LY detected a higher risk of MI (1.19 % versus 0.79 %; p=0.03),39 and this was also observed in the recent Secondary Prevention of Venous Thromboembolism (RE-MEDY) trial.40 However, in the recent Danish Registry report (4,978 patients on dabigatran and 8,936 patients on

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Clinical Arrhythmias Table 1: Prevention of Thromboembolism ESC 2012 Guideline Update on Atrial Fibrillation: Prevention of Thromboembolism in Non-valvular Atrial Fibrillation General Antithrombotic therapy for all patients with AF, except in those at low risk (lone AF, aged <65 years, or with contraindications)

I-A

The choice of the antithrombotic therapy should be based upon the absolute risks of stroke/thromboembolism and bleeding

I-A

The CHA2DS2-VASc score is recommended as a means of assessing stroke risk in nonvalvular AF

I-A

In patients with a CHA2DS2-VASc score of 0 (i.e. aged <65 years with lone AF) who are at low risk, with none of the risk factors,

I-B

no antithrombotic therapy In patients with a CHA2DS2-VASc score of ≥2, OAC therapy with:

adjusted dose VKA (INR 2–3), or

a direct thrombin inhibitor (dabigatran), or

an oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)

I-A

unless contraindicated In patients with a CHA2DS2-VASc score of 1, OAC therapy wth:

adjusted dose VKA (INR 2–3), or

a direct thrombin inhibitor (dabigatran), or

an oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)

IIa-A

based on an assessment of the risk of bleeding complications and patient preferences No antithrombotic therapy for female patients who are aged <65 and have lone AF (but still have a CHA2DS2-VASc score of 1 by virtue of their gender)

IIa-B

When patients refuse the use of any oral anticoagulation (whether VKAs or NOACs), antiplatelet therapy should be considered, using combination

IIa-B

therapy with aspirin 75–100 mg plus clopidogrel 75 mg daily (where there is a low risk of bleeding) or – less effectively – aspirin 75–325 mg daily NOACs When adjusted-dose VKA (INR 2–3) cannot be used due to difficulties in keeping within therapeutic anticoagulation, experiencing

I-B

side-effects of VKAs, or inability to attend or undertake INR monitoring, one of the NOACs, either:

a direct thrombin inhibitor (dabigatran), or

an oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)

is recommended Where OAC is recommended, one of the NOACs, either:

a direct thrombin inhibitor (dabigatran), or

an oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)

IIa-A

should be considered rather than adjusted-dose VKA (INR 2–3) Where dabigatran is prescribed, a dosage of 150 mg twice daily is prefered to 110 mg twice daily, with the latter dosage recommended in:

elderly patients, age ≥80 years

concomitant use of interacting drugs (e.g. verapamil)

high bleeding risk (HAS-BLED score ≥3)

moderate renal impairment (CrCl 30–49 ml/min)

Where rivaroxaban is being considered, a dosage of 20 mg once daily is preferred to 15 mg once daily, with the latter dosage recommended in:

IIa-B

IIa-C

high bleeding risk (HAS-BLED score ≥3)

moderate renal impairment (CrCl 30–49 ml/min).

Annual baseline and subsequent regular assessment of renal function (by CrCl) in patients following initiation of any NOAC, but 2–3 times

IIa-B

per year in those with moderate renal impairment NOACs (dabigatran, rivaroxaban and apixaban) are not recommended in patients with severe renal impairment (CrCl<30 ml/min)

III-A

Bleeding Assessment of the risk of bleeding when prescribing antithrombotic therapy (whether with VKA, NOAC, aspirin/clopidogrel or aspirin)

I-A

The HAS-BLED score should be considered to assess bleeding risk. A score ≥3 indicates ‘high risk’ and some caution and regular review is

IIa-A

needed, following the initiation of antithrombotic therapy (with OAC or antiplatelet therapy) Correctable risk factors for bleeding (e.g. uncontrolled blood pressure, labile INRs if the patient was on a VKA, concomitant drugs

IIa-B

[aspirin, NSAIDs, etc.], alcohol, etc.) should be addressed Use of the HAS-BLED score should be used to identify modifiable bleeding risks, but should not be used on its own to exclude patients from

IIa-B

OAC therapy The risk of major bleeding with antiplatelet therapy (with aspirin–clopidogrel combination therapy and – especially in the elderly –

IIa-B

also with aspirin monotherapy) should be considered as being similar to OAC OAC: oral anticoagulation with VKA (vitamin K antagonists) or NOACs; NOACs: non-vitamin K oral anticoagulants, ie dabigatran, rivarixaban, apixaban. From: Camm et al, 2012.21 By permission of Oxford University Press on behalf of European Society of Cardiology. © ESC 2014. www.escardio.org

Additional Recommendations on the Prevention of Thromboembolism in Atrial Fibrillation (ESC, 2010) For patients with mechanical heart valves, the target intensity of anticoagulation with a VKA should be based on the type and position of the

I-B

prosthesis, maintaining an INR of ≥2.5 in the mitral position and ≥2.0 for an aortic valve Antithrombotic therapy for patients with atrial flutter as for those with AF

I-C

The selection of antithrombotic therapy should be considered using the same criteria irrespective of the pattern of AF (i.e. paroxysmal, persistent

IIa-A

or permanent) Interruption of VKA (with subtherapeutic anticoagulation for up to 48 h), without substituting heparin as‘bridging’ anticoagulation therapy in

IIa-C

patients without mechanical prosthetic heart valves or not at high risk for thromboembolism, and who are undergoing surgical or diagnostic procedures that carry a risk of bleeding

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Table 1 (cont.): Prevention of Thromboembolism Additional Recommendations on the Prevention of Thromboembolism in Atrial Fibrillation (ESC, 2010), cont. ‘Bridging’ anticoagulation with therapeutic doses of either LMWH or UFH during the temporary interruption of VKA therapy should be considered

IIa-C

in patients with a mechanical prosthetic heart valve or at high risk for thromboembolism who are undergoing surgical or diagnostic procedures Following surgical procedures, resumption of VKA therapy at the ‘usual’ maintenance dose (without a loading dose) on the evening of (or the next IIa-B morning after) surgery, assuming there is adequate haemostasis Re-evaluation at regular intervals of the benefits, risks and need for antithrombotic therapy should be considered

IIa-C

In patients with AF presenting with acute stroke or TIA, management of uncontrolled hypertension before antithrombotic treatment is started,

IIa-C

and cerebral imaging (CT or MRI) performed to exclude haemorrhage In the absence of haemorrhage, VKA should be considered ~2 weeks after stroke, but, in the presence of haemorrhage, anticoagulation should not be given

IIa-C

In the presence of a large cerebral infarction, delay the initiation of anticoagulation given the risk of haemorrhagic transformation

IIa-C

In patients with AF and an acute TIA, VKA as soon as possible in the absence of cerebral infarction or haemorrhage

IIa-C

UFH or subcutaneous LMWH when surgical procedures require interruption of VKA for longer than 48 h in high-risk patients

IIb-C

In patients who sustain ischaemic stroke or systemic embolism during treatment with usual intensity VKA (INR 2.0–3.0), raising the

IIb-C

intensity of the anticoagulation to a maximum target INR of 3.0–3.5, rather than adding an antiplatelet agent From: Camm et al., 2010.23 By permission of Oxford University Press on behalf of European Society of Cardiology. © ESC www.escardio.org

AHA/ACC/HRS 2014 Guideline on Atrial Fibrillation: Prevention of Thromboembolism Antithrombotic therapy based on shared decision-making, discussion of risks of stroke and bleeding, and patient’s preferences

I-C

Antithrombotic therapy selection based on risk of thromboembolism irrespective of paroxysmal, persistent or permanent AF

I-B

CHA2DS2-VASc score recommended to assess stroke risk

I-B

Warfarin recommended with mechanical heart valves. Target INR should be based on the type and location of prosthesis

I-B

With prior stroke, TIA, or CHA2DS2 -VASc score ≥ 2, oral anticoagulants recommended. Options include: · Warfarin

I-A

· Dabigatran, rivaroxaban, or apixaban

I-B

With warfarin, determine INR at least weekly during initiation and monthly when stable

I-A

Direct thrombin or factor Xa inhibitor recommended, if unable to maintain therapeutic INR

I-C

Re-evaluate the need for anticoagulation at periodic intervals

I-C

Bridging therapy with LMWH or UFH with a mechanical heart valve if warfarin is interrupted. Decisions regarding bridging therapy

I-C

should balance the risks of stroke and bleeding Without a mechanical heart valve, bridging therapy decisions should balance stroke and bleeding risks against the duration of time patient will

I-C

not be anticoagulated Evaluate renal function prior to initiation of direct thrombin or factor Xa inhibitors, and re-evaluate when clinically indicated and at least annually

I-B

For atrial flutter, antithrombotic therapy as for AF

I-C

With nonvalvular AF and CHA2DS2-VASc score of 0, omit antithrombotic therapy

IIa-B

With CHA2DS2-VASc score ≥ 2 and end-stage CKD (CrCl <15 mL/min) or on haemodialysis, prescribe warfarin for oral anticoagulation

IIa-B

With nonvalvular AF and a CHA2DS2-VASc score of 1, no antithrombotic therapy or treatment with an oral anticoagulant or aspirin

IIb-C

With moderate-to-severe CKD and CHA2DS2-VASc scores of ≥ 2, direct thrombin or factor Xa inhibitors at reduced doses

IIb-C

For PCI, BMS may be considered to minimise duration of DAPT

IIb-C

Following coronary revascularisation in patients with CHA2DS2-VASc score of ≥2, use clopidogrel concurrently with oral

IIb-B

anticoagulants, but without aspirin Direct thrombin inhibitor, dabigatran, and factor Xa inhibitor rivaroxaban are not recommended with AF and end-stage CKD or on

III-C

haemodialysis because of no benefit Direct thrombin inhibitor, dabigatran, should not be used with a mechanical heart valve

III-B (harm)

bd = twice daily; BMS = bare-metal stent; CKD = chronic kidney disease; CrCl = creatinine clearance; DAPT = dual antiplatelet therapy; INR = international normalised ratio; LMWH = low molecular weight heparin; NOAC = non-vitamin K oral anticoagulant; OAC = oral anticoagulant; PCI = percutaneous coronary intervention; TIA = transient ischaemic attack; UFH = unfractionated heparin; VKA = vitamin K antagonist. From: January et al., 2014.1 By permission of Elsevier on behalf of American College of Cardiology. © AHA/ACC/HRS 2014.

warfarin), rates of mortality, pulmonary embolism, and MI were lower with dabigatran compared with warfarin. Stroke/systemic embolism and major bleeding rates were similar in the two treatment groups.41 Thrombin time in diluted plasma (dilute TT using hemoclot direct thrombin inhibitor assay) and ecarin clotting time are precise methods to assess the anticoagulant effect of dabigatran. Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are prolonged by dabigatran but the correlation is not linear to guide dosage.42 However, in the presence of a normal aPTT dabigatran is unlikely to contribute to bleeding, and aPTT can be used in emergencies as a rough estimate.43

Antidotes For nonspecific and specific antidotes to direct thrombin inhibitors, please see the article by Rahmat and Lip, Monitoring the Effects and Antidotes of the Non-vitamin K Oral Anticoagulants, in this issue of the journal.

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Factor Xa Inhibitors Apixaban Apixaban, an oral factor Xa inhibitor, is approved in Europe and Canada, and by the FDA for nonvalvular AF, and may be the most cost-effective NOAC.29,44 Apixaban has demonstrated reduced risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial haemorrhage in patients with nonvalvular AF for whom vitamin K antagonist therapy was unsuitable (apixaban versus aspirin; AVERROES trial).45 In the Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE) trial, apixaban was found superior to warfarin in preventing embolic or haemorrhagic stroke, and resulted in less bleeding and lower mortality rates (11 % reduction; p=0.047).46 Benefits of apixaban have been seen in both paroxysmal and persistent/permanent AF.47 Rates of intracranial bleeding have been demonstrated to be significantly lower in patients treated with apixaban

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Clinical Arrhythmias Table 2: Oral Anticoagulants for AF Dose

Warfarin Dabigatran Variable od 150 or 110 bd

Rivaroxaban 20 mg od

75 mg bd if CrCl 15–30 ml/min 15 mg od if CrCl 15–30 ml/min

Apixaban 2.5–5 mg bd

Edoxaban 30–60 mg od

2.5 mg bd if

(no data in renal impairment)

Cr ≥1.5 mg/dl, ≥80 years

of age, body weight ≤60 kg

Target

Vitamin K-

dependent factors

Half life

40 h

Thrombin (factor II)

Factor Xa

12–14 h

9–13 h

8–11 h

8–10 h

Renal clearance 0

80 %

60 %

25 %

40 %

Onset of action 3–5 h

2 h

2.5–4.0 h

3 h

1–5 h

Not required

P-gp

P-gp; CYP3A4

inhibition Anticoagulation INR 2–3 monitoring Interactions

Multiple

Antidote

Vitamin K

P-gp; CYP3A4

3- and 4-factor prothrombin 4-factor prothrombin

4-factor prothrombin

complex concentrates

idarucizumab

andexanet alfa, aripazine

Dabigtatran is eliminated via the P-gp transporter, while the Xa inhibitors are eliminated via P-gp and cytochrome P450 (CYP)3A4 activity. Their dosage should be reduced with co-administration of P-gp or CYP3A4 inhibitors, and they should be used with caution or avoided with administration of P-gp or CYP3A4 inducers. P-gp inhibitors include verapamil, amiodarone, dronedarone, quinidine, erythromycin, clarithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, cyclosporin, grapefruit juice. P-gp inducers include rifampicin, St. John’s wort, carbamazepine, phenytoin, phenobarbital, trazodone. CYP3A4 inhibitors include ketoconazole, itraconazole, voriconazole, posaconazole, fluconazole, chloramphenicol, clarithromycin, HIV protease inhibitors (e.g., ritonavir, atanazavir). CYP3A4 inducers include phenytoin, carbamazepine, phenobarbital, rifampicin, and St. John’s wort (Hypericum perforatum). bd = twice daily; CrCl = creatine clearance; CYP = cytochrome P450; od = once daily; P-gp = P-glycoprotein.

Table 3: New Anticoagulants (NOACs) vs Warfarin in Nonvalvular AF Trial

Dose of NOAC

NOAC (%/y)

Warfarin (%/y)

Stroke/systemic embolism

RE-LY

Dabigatran 110 md bd

1.53

1.69

0.34

Dabigatran 150 mg bd

1.11

1.69

<0.001

ROCKET-AF

Rivaroxaban 15–20 mg oda 2.10

ARISTOTLE

Apixaban 2.5–5.0 mg bdb 1.27c 1.60c

0.01

ENGAGE-AF-TIMI 48

Edoxaban 60 mg od

1.57

1.80

0.08

Edoxaban 30 mg odd

2.04

1.80

0.10

2.40

0.12

Intracranial haemorrhage

RE-LY

Dabigatran 110 md bd

0.12

0.38

<0.001

Dabigatran 150 mg bd

0.10

0.38

<0.001

ROCKET-AF

Rivaroxaban 15–20 mg od

0.50

0.70

0.02

ARISTOTLE

Apixaban 2.5–5.0 mg bd

0.24

0.47

<0.001

ENGAGE-AF-TIMI 48

Edoxaban 60 mg od

0.26

0.47

<0.001

Edoxaban 30 mg od

0.47

<0.001

0.16

Major bleeding

RE-LY

Dabigatran 110 md bd

2.71

3.36

0.003

Dabigatran 150 mg bd

3.11

3.36

0.31

ROCKET-AF

Rivaroxaban 20 mg od

3.6

3.40

0.58

ARISTOTLE

Apixaban 2.5–5.0 mg bd

2.13

3.09

<0.001

ENGAGE-AF-TIMI 48

Edoxaban 60 mg od

2.75

3.43

<0.001

Edoxoban 30 mg od

1.61

3.43

<0.001

Total mortality

RE-LY

Dabigatran 110 md bd

3.75

4.13

0.13

Dabigatran 150 mg bd

3.64

4.13

0.051

ROCKET-AF

Rivaroxaban 20 mg od

4.50

4.90

0.15

ARISTOTLE

Apixaban 2.5–5.0 mg bd

3.52

3.94

0.047

ENGAGE-AF-TIMI 48

Edoxaban 60 mg od

3.99

4.35

0.08

Edoxaban 30 mg od

3.80

4.35

0.006

a15

mg od if CrCl 40-49 ml/min; b2.5 mg bd if ≥2 of the following: age ≥80 y BW<60 kg, creatinine ≥1.5 mg/dl; cThis number includes both embolic and haemorrhagic strokes; d30 mg od if CrCl 30-50 ml/min, BW<60 kg, concomitant verapamil or quinidine. bd = twice daily; BW = body weight; CrCl = creatinine clearance; od = once daily.

than with warfarin, regardless of renal function.48 Benefits of apixaban are irrespective of concomitant aspirin use49 or of patients’ age.50 A substudy of the ARISTOTLE trial has also shown that cardioversion of AF can be safely performed in apixaban-treated patients.51 The

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drug is metabolised in the liver via P450-dependent and -independent mechanisms and 25 % is excreted renally. It is not recommended for use in patients with severe hepatic impairment. Apixaban is also not recommended in patients receiving concomitant treatment with strong inhibitors of both CYP3A4 and P-glycoprotein, such as azole antimycotics

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Anticoagulation in Atrial Fibrillation – Current Concepts

Table 4: EHRA Practical Guide on the Use of New Oral Anticoagulants – Possible Measures in Case of Bleeding Direct thrombin inhibitors (dabigatran)

FXa inhibitors (apixaban, edoxaban, rivaroxaban)

Non life-threatening bleeding Inquire last intake + dosing regimen

Inquire last intake + dosing regimen

Estimate normalisation of haemostasis:

Normalisation of haemostasis: 12–24 h

Normal renal function: 12–24 h CrCl 50–80 ml/min: 24–36 h CrCl 30–50 ml/min: 36–48 h CrCl <30 ml/min: ≥48 h Maintain diuresis Local haemostatic measures

Local haemostatic measures

Fluid replacement (colloids if needed)

RBC substitution if necessary

Platelet substitution (in case of thrombocytopenia ≤60 × 109/l or thrombopathy)

Platelet substitution (in case of thrombocytopenia

≤60 × 109/l or thrombopathy)

Fresh frozen plasma as plasma expander (not as reversal agent)

Fresh frozen plasma as plasma expander (not as reversal

agent) Tranexamic acid can be considered as adjuvans

Tranexamic acid can be considered as adjuvans

Desmopressin can be considered in special cases (coagulopathy or thrombopathy)

Desmopressin can be considered in special cases

(coagulopathy or thrombopathy)

Consider dialysis (preliminary evidence: -65 % after 4 h)48 Charcoal haemoperfusion not recommended (no data) Life-threatening bleeding All of the above

All of the above

Prothrombin complex concentrate (PCC) 25 U/kg (may be repeated once or twice,

PCC 25 U/kg (may be repeated once or twice, but no

but no clinical evidence)

clinical evidence)

Activated PCC 50 IE/kg (max. 200 IE/kg/day): no strong data about additional benefit over PCC.

Activated PCC 50 IE/kg (max 200 IE/kg/day): no strong

Can be considered before PCC if available

data about additional benefit over PCC. Can be

considered before PCC if available

Activated factor VII (rFVIIa; 90 µg/kg) no data about additional benefit + expensive

Activated factor VII (rFVIIa; 90 µg/kg) no data about

(only animal evidence)

additional benefit + expensive (only animal evidence)

CrCl = creatine clearance; RBC = red blood cell. From: Heidbuchel et al., 2013.31 By permission of Oxford University Press on behalf of European Heart Rhythm Association. © EHRA 2013.

Table 5: EHRA 2013: Last Intake of NOAC before Elective Surgical Intervention No important bleeding risk and/or adequate local haemostasis possible: Perform 12–24 h after last intake Dabigatran Apixaban/Rivaroxaban

Low risk

High risk

Low risk

CrCl ≥80 ml/min

≥24

≥48

≥24

≥48

CrCl 50–80 ml/min

≥36

≥72

≥24

≥48

CrCl 30–50 ml/min

≥48

≥96

≥24

≥48

≥36

≥48

CrCl 15–30 ml/min

not indicated

High risk

CrCl = creatine clearance. From: Heidbuchel et al., 2013.31 By permission of Oxford University Press on behalf of European Heart Rhythm Association. © EHRA 2013.

and HIV protease inhibitors, and should be used with caution in patients taking rifampicin, phenytoin, carbamazepine and phenobarbital. There are limited clinical data on patients with a CrCl of 15–29 ml/min, and the drug is not recommended in patients with a CrCl of <15 ml/min. Antifactor Xa assays may be used to estimate the anticoagulant effect. APTT and PT are prolonged by apixaban but they cannot be used to guide dosage as the correlation is not linear, especially with PT.42 Concomitant use with diltiazem results in increased apixaban levels.

Rivaroxaban Rivaroxaban is an oral factor Xa inhibitor that has been approved by the FDA and EMA for nonvalvular AF. In the ROCKET-AF trial (Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation), rivaroxaban was not found to be inferior to warfarin (INR 2–3) in patients with nonvalvular

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AF for the prevention of stroke or systemic embolism, and offered a lower rate of intracranial bleeding, but a higher rate of gastrointestinal bleeding.52 In a substudy of this trial, rivaroxaban demonstrated equal safety and efficacy with warfarin in patients aged >75 years.53 The half-life of rivaroxaban is 7–11 hours, but factor Xa is inhibited for up to 24 hours, allowing once-daily dosage. Its bioavailability increases with food consumption. The drug is metabolised in the liver via P450dependent and -independent mechanisms, and is not recommended in patients receiving concomitant treatment with strong inhibitors of both CYP3A4 and P-glycoprotein inhibitors (see the apixaban section). The drug is not recommended in patients with a CrCl of <15 ml/min. Anti-factor Xa assays are used to estimate the anticoagulant effect.21 APTT and PT are prolonged by rivaroxaban but they cannot be used to guide dosage as the correlation is not linear.42 However, prolonged PT bleeding can be attributed to rivaroxaban, and PT can be used as a rough estimate in case of emergencies.43

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Clinical Arrhythmias Figure 3: Management of Bleeding in Patients Taking Nonvitamin K Oral Anticoagulants

Figure 2: Coagulation Cascade Intrinsic pathway (contact activation)

Patient on NOAC presenting with bleeding

XII

Extrinsic pathway (tissue factor)

Tissue factor

VIII

Check haemodynamic status, basic coagulation tests to assess antigoagulation effect (e.g. aPTT for dabigatran, PT or anti-Xa activity for rivaroxaban), renal function, etc.

VII

Delay next dose or discontinue treatment

Minor VKAs

Factors Xa inhibitors (-AT) Apixaban and Rivaroxaban

V II

Fibrinogen

Direct Thrombin inhibitors Dabigatran Fibrin clot

Moderate–severe

Symptomatic/ supportive treatment Mechanical compression Fluid replacement Blood transfusion Oral charcoal if recently ingesteda

AT = antithrombin; VKA = vitamin K antagonist. From: January et al, 2014.1 By permission of Elsevier on behalf of American College of Cardiology. © AHA/ACC/HRS 2014.

Edoxaban Edoxaban has been demonstrated as noninferior to warfarin with respect to prevention of stroke or systemic embolism and shown to be associated with significantly lower rates of bleeding and death from cardiovascular causes (ENGAGE AF-TIMI 48 trial), and it is approved by the FDA.54 Both the 30 and 60 mg doses were not inferior to warfarin, but in the intention-totreat analysis with the 60 mg dose there was a trend favoring edoxaban.

Betrixaban

Very severe

Consider rFVIIa or PCC Charcoal filtrationa/ haemodialysisa

aPTT = activated partial thromboplastin time; N OAC = novel oral anticoagulant; PCC = prothrombin complex concentrate; PT = prothrombin time; rFVIIa = activated a recombinant factor VII. With dabigatran. From: Camm et al, 2012.21 By permission of Oxford University Press on behalf of European Society of Cardiology. © ESC 2014. www.escardio.org

Betrixaban has also been found equivalent to warfarin.55

Antidotes For nonspecific and specific antidotes to factor Xa inhibitors, please see the article by Rahmat and Lip, Monitoring the Effects and Antidotes of the Non-vitamin K Oral Anticoagulants, in this issue of the journal. Although clinical experience is limited, antidotes for Xa inhibitors should be effective for all available agents.

Transition between NOACs/Warfarin Transitioning from one anticoagulant to another is a period of high risk for both strokes and bleeding. A reasonable strategy is to reduce

1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014:64:e1–76. 2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham study. Stroke 1991;22:983–8. 3. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012;366:120–9. 4. Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014;370:2467–77. 5. Sanna T, Diener H-C, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478–86.

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the NOAC dose by half, start warfarin and stop the NOAC when the INR is ≥2. When the patient is on warfarin, the NOAC is started after cessation of therapy and three-daily INR measurements to detect a value <2.56

Conclusion In conclusion, the new, non-vitamin K dependent oral anticoagulants, ie direct thrombin or Xa inhibitors, appear to be safer and more effective than warfarin in preventing thromboembolism in patients with non-valvular AF (ie absence of prosthetic valves or rheumatic mitral valve disease). n

6. Gaita F, Corsinovi L, Anselmino M, et al. Prevalence of silent cerebral ischemia in paroxysmal and persistent atrial fibrillation and correlation with cognitive function. J Am Coll Cardiol 2013:62:1990–7. 7. Marfella R, Sasso FC, Siniscalchi M, et al. Brief episodes of silent atrial fibrillation were associated with an increased risk of silent cerebral infarct and stroke in type 2 diabetic patients. J Am Coll Cardiol, 2013:62:525–30. 8. Yiin GS, Howard DP, Paul NL, et al, on behalf of the Oxford Vascular Study. Age-specific incidence, outcome, cost, and projected future burden of atrial fibrillation-related embolic vascular events: A population-based study. Circulation 2014;130:1236–44. 9. Steinberg BA, Hellkamp AS, Lokhnygina Y, et al. Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: Results from the ROCKET-AF trial. Eur Heart J

2015:36:288–96. 10. Breithardt G BH, Berkowitz SD, Hellkamp AS, et al, ROCKET AF Steering Committee & Investigators. Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET-AF trial. Eur Heart J 2014;35:3377–85. 11. Sposato LA, Cipriano LE, Saposnik G, et al. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: A systematic review and meta-analysis. Lancet Neurol 2015;14:377–87. 12. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67. 13. Friberg L, Skeppholm M, Terent A. Benefit of anticoagulation unlikely in patients with atrial fibrillation and a CHA2DS2-

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Vasc score of 1. J Am Coll Cardiol 2015;65:225–32. 14. Chao TF, Liu CJ, Wang KL, et al. Should atrial fibrillation patients with 1 additional risk factor of the CHA2DS2-Vasc score (beyond sex) receive oral anticoagulation? J Am Coll Cardiol 2015;65:635–42. 15. Mant J, Hobbs FD, Fletcher K, et al; BAFTA investigators, Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham atrial fibrillation treatment of the aged study, BAFTA): A randomised controlled trial. Lancet 2007;370:493–503. 16. Siu CW, Tse HF. Net clinical benefit of warfarin therapy in elderly Chinese patients with atrial fibrillation. Circ Arrhythm Electrophysiol 2014;7:300–6. 17. Roldan V Marín F, Fernández H, et al. Predictive value of the HAS-BLED and ATRIA bleeding scores for the risk of serious bleeding in a ‘real-world’ population with atrial fibrillation receiving anticoagulant therapy. Chest 2013;143:179–84. 18. Lamberts M, Lip GY, Hansen ML, et al. Relation of nonsteroidal anti-inflammatory drugs to serious bleeding and thromboembolism risk in patients with atrial fibrillation receiving antithrombotic therapy: A nationwide cohort study. Ann Intern Med 2014;161:690–8. 19. Själander S, SjälanderA, Svensson PJ, Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Europace 2013;15:1407–11. 20. Ben Freedman S, Gersh BJ, Lip GYH. Misperceptions of aspirin efficacy and safety may perpetuate anticoagulant underutilization in atrial fibrillation. Eur Heart J 2015:36:653–6 21. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: An update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–47. 22. Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE W): A randomised controlled trial. Lancet 2006;367:1903–12. 23. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: The task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Europace 2010;12:1360–420. 24. Furie B. Do pharmacogenetics have a role in the dosing of vitamin K antagonists? N Engl J Med 2013;369:2345–6. 25. Azoulay L, Dell’Aniello S, Simon TA, et al. Initiation of warfarin in patients with atrial fibrillation: Early effects on ischaemic strokes. Eur Heart J 2014;35:1881–7. 26. Weijs B, Blaauw Y, Rennenberg RJ, et al. Patients using vitamin K antagonists show increased levels of coronary calcification: An observational study in low-risk atrial fibrillation patients. Eur Heart J 2011;32:2555–62. 27. De Caterina R, Husted S, Wallentin L, et al. New oral anticoagulants in atrial fibrillation and acute coronary

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syndromes: ESC working group on thrombosis–task force on anticoagulants in heart disease position paper. J Am Coll Cardiol, 2012;59:1413–25 28. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials. Lancet 2013;383:955–62. 29. Canestaro WJ Patrick AR, Avorn J, et al. Cost-effectiveness of oral anticoagulants for treatment of atrial fibrillation. Circ Cardiovasc Qual Outcomes 2013;6:724–31. 30. Chan KE, Edelman ER, Wenger JB, et al. Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis, Circulation, 2015;131:972–9. 31. Heidbuchel H, Verhamme P, Alings M, et al; European Heart Rhythm Association. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625–51. 32. Gillis AM, Verma A, Talajic M, et al. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: Rate and rhythm management. Can J Cardiol 2011;27:47–59. 33. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. 34. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation 2013;128:237–43. 35. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015;131:157–64. 36. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study). Am J Cardiol 2007;100:1419–26. 37. Hernandez I, Baik SH, Piñera A, et al. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med 2014; 175:18–24. 38. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized evaluation of long-term anticoagulation therapy) trial. Circulation 2012;125:669–76. 39. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: Meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; 172:397–402. 40. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709–18. 41. Larsen TB, Rasmussen LH, Skjøth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in ‘real world’ patients with atrial fibrillation: A prospective nationwide cohort study. J Am Coll Cardiol 2013:61:2264–73. 42. Cuker AM, Siegal DM, Crowther MA, et al. Laboratory

measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:1128–39. 43. Blann AD, Lipp GY. Laboratory monitoring of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:1140–2. 44. Dorian P, Kongnakorn T, Phatak H, et al. Cost-effectiveness of apixaban vs. current standard of care for stroke prevention in patients with atrial fibrillation. Eur Heart J 2014;35:1897–906. 45. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. 46. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. 47. Al-Khatib SM, Thomas L, Wallentin L, et al. Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial. Eur Heart J 2013;34:2464–71. 48. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: Insights from the aristotle trial. Eur Heart J 2012;33:2821–30. 49. Alexander JH, Lopes RD, Thomas L, et al. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: Insights from the ARISTOTLE trial. Eur Heart J 2014;35:224–32. 50. Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: Observations from the ARISTOTLE trial. Eur Heart J 2014;35:1864–72. 51. Flaker G, Lopes RD, Al-Khatib SM, et al. Efficacy and safety of apixaban in patients following cardioversion for atrial fibrillation: Insights from the ARISTOTLE trial. J Am Coll Cardiol 2014;63:1082–7. 52. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. 53. Halperin JL Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014; 130:138–46. 54. Giugliano RP, Ruff CT, Braunwald E, for the ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. NEJM 2013;369:2093–104. 55. Connolly SJ Eikelboom J, Dorian P, et al. Betrixaban compared with warfarin in patients with atrial fibrillation: Results of a phase 2, randomized, dose-ranging study (EXPLORE-Xa). Eur Heart J 2013;34:1498–505. 56. Ruff CT, Giugliano RP, Braunwald E, et al. Transition of patients from blinded study drug to open-label anticoagulation: The ENGAGE AF-TIMI 48 trial. J Am Coll Cardiol 2014;64:576–84.

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Commentary

A Decade of CFAE Mapping: Still Seeking More Specific Tools to Identify Sources and Substrate of Persistent Atrial Fibrillation Amir S Jadidi and Thomas Arentz University Heart Centre Freiburg - Bad Krozingen, Germany

decade after its first description as ‘the electrophysiological substrate’ of atrial fibrillation,1 mapping complex fractionated atrial electrogram (CFAE) as an ablation target for atrial fibrillation (AF) remains highly controversial. Early high-density mapping studies of induced AF in humans revealed distinct mechanisms that underlie electrogram fractionation: collision areas of distinct wavefronts, sites of wavelet pivoting, anisotropic/slow conduction and conduction block.2 Further mapping studies revealed the functional nature of electrogram fractionation that implies important variations in distribution of fractionated activity within the same atria during different rhythms (AF versus sinus rhythm or paced rhythm).3

The recent multicentre randomised trial STAR-AF II failed to reveal any added benefit of CFAE ablation when performed in addition to pulmonary vein isolation in patients with persistent AF.4 Importantly, in that study only CFAE sites were targeted by ablation that were detected by the NavX ‘CFEmean’ algorithm (St Jude Medical). Previous studies have shown that the CFEmean algorithm detects fractionated activity at high voltage (>0.5 mV) – i.e. underdetecting CFAE within low voltage sites.3 Similarly, another randomised clinical study failed to show an added value of CFAE ablation when using the CFEmean algorithm.5 Multiple distinct types of CFAE may be observed during AF or regular rhythms. Although some CFAE patterns as continuous activity or presence of activation gradients between neighbouring bipoles6 have been described to have a greater impact with regard to AF termination or cycle length prolongation, their identification depends on the subjective judgment of the operator, because automatic CFAE algorithms fail to specifically differentiate these active CFAE types from passive ones. CFAE may be intermittent versus continuous versus high voltage (>0.5 mV) versus low voltage (<0.5 mV).7 Identification of the active CFAE sites that correspond to active AF driver sites remains a major challenge of future mapping techniques and developments. In this issue of the journal Sohal and colleagues8 give a comprehensive overview of the distinct CFAE types and difficulties in their distinction that depends on the electrode size, the mode of electrogram filtering/recording (unipolar vs bipolar) and the CFAE detection algorithm used. They provide a future perspective on a novel, promising non-invasive mapping tool enabling detection of sources and drivers of AF: the ECVUE Mapping System (CardioInsight Technologies).8,9 Recent clinical data have identified AF drivers to CFAE sites within low voltage areas that display prolonged electrical activity when using simultaneous regional mapping with multi-electrode catheters with smaller electrodes and higher local mapping resolution than a 4 mm tip ablation catheter.7,10 Future studies on persistent AF need to assess clinical efficacy of the novel AF mapping tools to identify the active CFAE sites from the passive ones, as well as impact of novel voltage-based substrate mapping/ablation strategies on rate of arrhythmia freedom.7,10,11n

Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044–53. Konings KT, Kirchhof CJ, Smeets JR, et al. High-density mapping of electrically induced atrial fibrillation in humans. Circulation 1994;89:1665–80. Jadidi AS, Duncan E, Miyazaki S, et al. Functional nature of electrogram fractionation demonstrated by left atrial highdensity mapping. Circ Arrhythm Electrophysiol 2012;5:32–42. Verma A, Jiang CY, Betts TR, et al; STAR AF II Investigators. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812–22.

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Dixit S, Marchlinski FE, Lin D, et al. Randomized ablation strategies for the treatment of persistent atrial fibrillation: RASTA study. Circ Arrhythm Electrophysiol 2012;5:287–94. Takahashi Y, O’Neill MD, Hocini M, et al. Characterization of electrograms associated with termination of chronic atrial fibrillation by catheter ablation. J Am Coll Cardiol 2008; 51:1003–10. Jadidi A, Lehrmann H, Sorrel J, et al. Rapid focal and reentrant activity localizes to atrial low voltage sites in human persistent atrial fibrillation. Heart Rhythm 2015;12 Suppl 5:S448–9.

Sohal M, Choudhury R, Taghji P, et al. Is CFAE mapping obsolete? Arhythm Electrophysiol Rev 2015;4: . 9. Haissaguerre M, Hocini M, Denis A, et al. Driver domains in persistent atrial fibrillation. Circulation 2014;130:530–8. 10. Arentz T, Lehrmann H, Sorrel J, et al. Selective substratebased ablation targeting low voltage areas compared to pulmonary vein isolation alone in patients with persistent atrial fibrillation. Heart Rhythm 2015;12 Suppl 5:S347–48. 11. Rolf S, Kircher S, Arya A, et al. Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2014;7:825–33.

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Diagnostic Electrophysiology & Ablation

Abstract Atrial fibrillation is the most common clinically encountered arrhythmia and catheter ablation has emerged as a viable treatment option in drug-refractory cases. Pulmonary vein isolation is widely regarded as the cornerstone for successful outcomes in paroxysmal AF given that the pulmonary veins are a frequent source of AF triggering. Ablation strategies for persistent AF are less well defined. Mapping and ablation of complex fractionated electrograms (CFAEs) is one strategy that has been proposed as a means of modifying the atrial substrate thought to be critical to the perpetuation of AF. Results of clinical studies have proved conflicting and there are now strong data to suggest that pulmonary vein isolation alone is associated with outcomes comparable to those of pulmonary vein isolation plus CFAE ablation. Several studies have demonstrated that the majority of CFAEs are passive phenomena and therefore not critical to the perpetuation of AF. Conventional mapping technologies (using a bipolar or circular mapping catheter) lack the spatiotemporal resolution to identify mechanisms of AF persistence. The development of wide-field mapping techniques allows simultaneous acquisition of activation data over large areas. This strategy has the potential to better identify regions critical to AF perpetuation, and preliminary data suggest that ablation outcomes are improved when guided by these techniques. While mapping and ablation of all CFAEs is almost certainly obsolete, better identification of regions responsible for AF persistence has the potential to improve outcomes in ablation of persistent AF.

Keywords Atrial fibrillation, complex fractionated electrogram, ECG imaging, phase mapping Disclosure: The authors have no conflicts of interest to declare. Received: 15 June 2015 Accepted: 12 August 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(2):109–15 Access at: www.AERjournal.com Correspondence: Dr Manav Sohal, Department of Cardiology, AZ Sint-Jan, Ruddershove 10, 8000 Bruges, Belgium. E: Manav.Sohal@gstt.nhs.uk

Ablative therapies for atrial fibrillation have gained popularity worldwide and prompted the development of new, and often complex, tools to achieve higher levels of success. Pulmonary vein (PV) isolation is widely considered as the cornerstone of successful catheter ablation based on seminal work by Haissaguerre et al.1 Successful isolation of the PVs is now the most commonly sought endpoint in paroxysmal AF, but the optimal strategy in persistent AF remains to be determined. Traditionally, the consensus has been that additional targeting of the atrial substrate responsible for perpetuation of AF is necessary to achieve better outcomes in persistent AF.2 Several strategies have been proposed including additional linear lesions as well as the ablation of complex fractionated electrograms (CFAEs).3,4 This approach has been questioned in light of the recent Substrate and Trigger Ablation for Reduction of AF 2 (STAR-AF 2) study.5 In this multicentre, randomised controlled trial of 589 patients with persistent AF, the addition of either linear ablation or CFAE ablation to PV isolation did not result in improved clinical outcomes. These findings justify a critical assessment of what role, if any, CFAE mapping has in the contemporary era, as CFAEs were traditionally thought to represent areas critical to the perpetuation of AF. This review will provide an overview of the association between CFAEs and underlying AF mechanisms and also the major clinical studies of CFAEs.

Electrophysiological Mechanisms Responsible for Complex Fractionated Electrograms Definitions To understand the relevance of CFAE mapping, a clear definition of the term is required. Various mechanisms are believed to contribute

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to the generation of CFAEs. The resulting complex signals are diverse and CFAE is therefore an umbrella term that describes electrograms with varying characteristics. CFAEs are generally thought to be present when any of the following criteria apply:6–10 • • • •

Continuous electrical activity At least two deflections Cycle length <120 ms Amplitude >0.05 mV (to distinguish genuine fractionation from low-level artefact).

Typical examples of CFAEs are shown in Figure 1. Given this heterogeneity, it is clear that a number of mechanisms are likely to be responsible for the genesis of CFAEs. The use of CFAE mapping as a strategy for AF ablation revolves around the association between CFAEs and AF mechanisms. An important question is whether CFAEs represent local (fixed) properties of the underlying tissue or functional phenomena that vary with time and patterns of activation. At this point it is instructive to refer to the prevailing hypotheses that explain the mechanisms thought to underlie the perpetuation of AF. These mechanisms are not absolutely defined but several hypotheses exist. The focal AF source theory was introduced by Thomas Lewis in 192011 before being superseded by the multiple wavelet hypothesis of Moe and Abildskov in 1959.12 In 1962, Moe hypothesised that a ‘grossly irregular wavefront becomes fractionated as it divides about islets or strands of refractory tissue, and each of the daughter wavelets may now be considered an independent offspring. Fully developed fibrillation would

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Diagnostic Electrophysiology & Ablation Figure 1: Examples of Frequently Encountered CFAE A

Panel A shows electrograms with continuous electrical activity recorded by the RF catheter. This is in contrast to the electrograms recorded from within the CS. Panel B shows complex electrograms with multiple deflections recorded by both the RF and CS catheters. Panel C demonstrates electrograms with a shorter cycle length at the RF catheter compared with those recorded by the CS catheter. CS = coronary sinus; RF = radiofrequency

then be a state in which many such randomly wandering wavelets coexistâ&#x20AC;&#x2122;.13 In this elegant description it is reasonable to make the link between the underlying AF process and the CFAE.

Experimental Support for the Link Between CFAEs and AF Mechanisms Experimental evidence for the hypothesis linking CFAEs wih AF mechanims was initially derived from animal studies in which excitation of the atria during AF was mapped.14 These studies showed multiple wavelets wandering around natural anatomical obstacles and functional arcs of conduction block. In some cases, the wavelets appeared to be offspring of a single reentrant circuit.14 In the specific example of AF, intraoperative observations have proved instructive in this regard. Konings et al. performed the first systematic mapping of AF in humans by inducing AF in patients undergoing surgery for Wolf-Parkinson White syndrome.15 The free wall of the right atrium was mapped using an electrode containing 244 unipolar electrodes. Regions of continuous electrical activity were most commonly characterised by initial activation by a single wave of leading circle reentry and subsequent collision with other wavefronts. It was inferred that areas of CFAEs during AF represent continuous reentry of fibrillation waves into the same area or overlap of different wavelets entering the same area at different times. Other studies have shown that wavefront collision, functional conduction block, wave break and wave fusion all contribute to the genesis of CFAEs.16,17

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The Possible Role of the Autonomic Nervous System The autonomic nervous system has also been implicated in the genesis of CFAEs. It is recognised that increased vagal tone is associated with easier induction of AF.18,19 Ganglionic plexi are found on the pericardial surface of the heart and provide extensive parasympathetic innervation to the atria. Lemery et al. mapped these plexi by using high-frequency stimulation and assessing for a vagal response.20 One of their main findings was that CFAEs were always reported at sites showing a positive autonomic response. Lin et al. studied a canine model of AF and found that CFAEs could be induced from a hyperactive state within the intrinsic cardiac autonomic nervous system.21 They applied acetylcholine to the atria in varying concentrations during AF and found that the incidence of inducing local CFAE was correlated with the concentration of acetylcholine applied. Injecting acetylcholine into the ganglionic plexi was also shown to induce CFAE. Importantly, CFAE occurring distal from the injected plexi could be attenuated or eliminated by ablation of the plexi thereby suggesting that the occurrence of CFAE did not solely result from a change in local electrophysiological properties, but involved the activation of the neural network within the intrinsic cardiac autonomic nervous system. The inference from these studies was that some, if not most, fractionated areas were the result of autonomic innervation. This link was further tested by Knecht et al. who used pharmacological blockade (using propranolol and atropine) of the autonomic nervous system to assess the effect on CFAE occurrence and distribution.22 They found that autonomic blockade resulted in only a small reduction in CFAE proportion and this phenomenon was seen only in paroxysmal and not persistent AF. The effect seemed to be mediated by a lengthening of AF cycle as patients with no cycle length change had no alteration in the proportion of electrograms that were fractionated. Interestingly, areas displaying CFAE were stable in two-thirds of cases, again suggesting that the impact of the autonomic nervous system on CFAE is minimal.

Rotors â&#x20AC;&#x201C; a Significant Step Forward in Understanding AF Mechanisms? Kalifa et al. provided new insights into the mechanistic basis of CFAEs during AF.23 They studied a healthy sheep model in which they induced sustained AF. Endocardial optical and electrical mapping of the posterior left atrium was performed to characterise dominant frequencies and the degree of regularity of recorded signals. The use of dominant frequency mapping during AF allows accurate identification of sites of periodic activity. The key findings described were: 1) the posterior left atrium is the site of regular, fast and spatiotemporally organised activity; and 2) highly periodic impulses propagate repetitively from inside to outside the posterior left atrium and fractionate close to the outer limit of the maximum dominant frequency domain, and this outer limit is the region where most fractionated activity surrounds the most regular activity. These apparently stable sources supported the notion of the mother rotor first suggested by Moe in 1962.13 These findings were confirmed by Umapathy et al., who used optical mapping of a murine atrial monolayer model to demonstrate that CFAEs occur at sites of migrating reentrant wavefronts and wavebreak or collision, but not at the core of a stable wavefront.24 The relevance of rotors will be discussed later in this review.

Alternative Sources of Electrogram Complexity and Fractionation It is important to recognise other potential causes of electrogram fractionation that may not be related to underlying AF processes. CFAEs may reflect purely local effects, but may also be caused by remote

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activity at the recording site where deflections that result from local and distant activity merge (e.g. the right superior pulmonary veins and the superior vena cava). It is important to recognise the latter point particularly if the identification of fractionated regions is to be used in guiding interventions. Adequate suppression of artefacts by means of efficient signal filtering is also mandatory. Tissue anisotropy may account for electrogram fractionation when activation proceeds in a direction perpendicular to fibre orientation. Finally, misinterpretation of the electrogram may also result from variations in contact between the mapping catheter and the atrial surface that are inevitable when mapping the beating heart. Similarly, electrogram resolution will be affected by differences in electrode characteristics. For example, the resolution afforded by a 4 mm electrode is greater than that provided by an 8 mm electrode. Thus, recognition of tissue and mapping characteristics that might affect electrogram interpretation is crucial when assessing for CFAEs.

CFAE Ablation in Clinical Studies Given the experimental evidence supporting a link between AF mechanisms and CFAEs, targeting of CFAEs for the purpose of improving AF ablation outcomes has become more prominent. A study by Nademanee et al. suggested that systematic ablation of these regions (as a sole ablation strategy for AF) was associated with excellent acute and chronic outcomes.7 In this study (n=121; 57 paroxysmal and 64 persistent), patients underwent biatrial electroanatomical mapping, and areas associated with CFAEs were identified and ablated with the aim of eliminating CFAE and/or converting to sinus rhythm. Two types of CFAE were described: fractionated electrograms with continuous prolonged activation and electrograms with a short cycle length compared with the rest of the atria. Ablation of CFAE regions (without concomitant PV isolation) resulted in AF termination without external cardioversion in 95 % of patients. One-year follow-up results were encouraging, with 91 % of patients free of arrhythmia or symptoms (the vast majority requiring only one procedure). Given the crucial role of the PVs as triggers of AF, CFAE ablation without concomitant PV isolation is not widely performed in patients with paroxysmal AF despite the findings of the Nademanee et al. study.7 In the contemporary era, PV isolation alone is widely regarded as the optimal lesion set in paroxysmal AF. Di Biase et al. randomised 103 consecutive patients with paroxysmal AF to one of three ablation strategies: PV isolation alone, PV isolation plus CFAE ablation or CFAE ablation alone.25 At 1-year follow-up after a single procedure, freedom from AF/atrial tachycardia was documented in 89 % of patients in the PV isolation group, 91 % in the PV isolation plus CFAE group and only 23 % in the CFAE group. This point was further emphasised in a meta-analysis of controlled trials comparing PV isolation plus CFAE ablation with PV isolation alone for the maintenance of sinus rhythm.26 Seven trials with a total of 622 participants (with paroxysmal or persistent AF) were included. In patients with persistent AF the addition of CFAE ablation was associated with significantly increased rates of sinus rhythm maintenance (RR 1.35; 95 % CI [1.04–1.75]; p=0.02) at 12 months’ follow-up but this was not the case in paroxysmal AF (RR 1.04; 95 % CI [0.92–1.18]; P=0.53). CFAE ablation therefore seemed better directed towards the treatment of non-paroxysmal AF, where mechanisms critical for the perpetuation of AF were thought to play a larger role. Whether CFAE ablation alone or with concomitant PV isolation was required remained to be determined. While Nademanee and co-workers demonstrated excellent results in both paroxysmal and persistent AF using a CFAE

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only ablation strategy,7 other investigators have been unable to replicate these findings. Oral et al. studied 100 patients with persistent AF and performed CFAE ablation within the left atrium and coronary sinus.9 During 14±7 months of follow-up after a single ablation procedure, 33 % of patients had sinus rhythm without receiving antiarrhythmic drugs (versus 77 % in the study by Nademanee et al.). A repeat ablation procedure was performed in 44 % of patients for recurrent AF and/or atrial tachycardia. A striking finding was that PV tachycardias in previously targeted or non-targeted PVs were found in all patients, underlining the importance of PV isolation in ablation of persistent AF. Other investigators have also demonstrated similar findings.4 The marked variation in outcomes between the Nademanee and Oral studies requires some explanation. The Nadamanee et al. study targeted CFAEs in the right atrium as well as left atrium and coronary sinus, whereas Oral et al. did not ablate within the right atrium. Additionally, Nademanee used a 4 mm ablation catheter, whereas Oral et al. used an 8 mm catheter. It is possible that the better resolution afforded by the 4 mm catheter allowed better identification of CFAEs. Furthermore, identification of CFAEs relied on subjective interpretation of the electrogram with obvious limitations.

Automatic CFAE Detection Algortihms Technical advancement has led to the production of automated algorithms that can be used to identify CFAEs using either the Carto (Biosense Webster) or NavX EnSite (St Jude Medical) electroanatomical mapping systems. One such algorithm embedded in Carto mapping systems identifies low-amplitude, high-frequency electrograms by tagging the peak voltage (positive or negative) exceeding a programmable low threshold (usually ± 0.05 mV) to exclude noise.27 Voltage peaks greater than this threshold, but less than a programmable upper threshold (usually ± 0.15 mV), are identified. The intervals between successive peaks falling within this window are measured. Intervals falling within a programmable duration (usually 60–120 ms) are identified and the number of such intervals during the entire 2.5 s sampling window calculated; this is designated the interval confidence level (ICL). Sites with a greater number of short intervals between low-amplitude multi-deflection complexes (higher ICL) reflect more frequent and repetitive CFAE and thus targets for ablation. Porter et al. found that targeting CFAEs identified using this algorithm resulted in a rate of 1-year freedom from recurrent atrial arrhythmias without antiarrhythmic therapy of 68 % in patients with persistent AF.28 The algorithm embedded in the NavX EnSite mapping system uses a different principle. It is based on two sequential steps: 1) activation events are recognised in the signal and 2) time intervals between subsequent activations are calculated and their average is denoted as CFAE mean. Locations with cycle length shorter than a pre-specified threshold (nominally 120 ms) are deemed to be ablation targets.29 Application of this more objective approach to CFAE identification was studied in the STAR AF study.4 In this study, 100 patients with high-burden paroxysmal or persistent AF were randomised to PV isolation alone, PV isolation plus adjunctive CFAE ablation (CFAEs identified using the NavX algorithm) or CFAE ablation alone. After one procedure, PV isolation plus CFAE ablation had a significantly higher rate of freedom from AF (74 %) compared with PV isolation (48%) and CFAE ablation (29 %). At this stage CFAE ablation seemed to have an adjunctive role in conjunction with PV isolation. Many of the early approaches to CFAE ablation required removal of large (bi)atrial regions; Figure 2 demonstrates a typical example. Several groups have proposed

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Diagnostic Electrophysiology & Ablation Figure 2: Intracardiac Electrograms and CFAE Map in a Patient with Persistent AF

The electrograms are recorded with a multi-electrode pentaray catheter positioned on the posterior left atrial wall (each spline labelled A through to E). Electrograms recorded from within the CS are also shown. Widespread fractionation can be appreciated, both in the CS and posterior left atrium. A CFAE map derived from the automated algorithm embedded in the NavX EnSite mapping system (St Jude Medical) is also shown. Areas colour coded white through to red are defined as areas exhibiting CFAEs and are therefore deemed potential targets for ablation. The widespread distribution can be appreciated by analysis of the electrograms and the CFAE map. CFAE = complex fractionated electrogram; CS = coronary sinus.

alternative algorithms as methods for reliably identifying CFAEs,30 but in an attempt to reduce the amount of atrial endocardium targeted for ablation, focus has turned towards the concept of a hierarchy of CFAE importance. The notion that some CFAE may represent sites of passive wavefront collision (and therefore not important to the maintenance of AF) is now the subject of much interest.

CFAEs – Active Versus Passive Phenomena Based on the early experimental data and the subsequent studies demonstrating the effect of distant autonomic effects on the generation of CFAE, the role of CFAEs in the perpetuation of AF has remained uncertain. Yamabe et al. used non-contact mapping to further examine the mechanisms of AF maintenance.17 Focal discharges were found at the pulmonary veins and sites characterised by CFAEs. In this study of 16 patients with paroxysmal AF, focal discharges were identified from the CFAE regions that generated a new wave of activation. Wavebreak and fusion associated with slow conduction and pivoting activation in the CFAE region sustained wave propagation, thereby resulting in the maintenance of AF. These data suggest that CFAEs represent active sources responsible for the perpetuation of AF. It should be noted that this analysis was based on virtual electrograms derived from non-contact mapping which may have made the findings more susceptible to noise and incorrect mathematical extrapolation of the acquired data. Rostock et al. used a custom-designed pentaray catheter (5 splines with a total of 20 equally distributed electrodes) to perform highdensity contact mapping of the left atrium in patients with paroxysmal AF during periods of sustained AF.8 They found that the occurrence of CFAE was significantly associated with a preceding acceleration of AF cycle length. Furthermore, local complex activation/reentry was only seen in 16 % of CFAE regions, with the remaining majority characterised by nearly simultaneous (within 40 ms) activation at all splines. These findings suggest that most CFAE sites are passive and the inverse relationship between CFAE and AF cycle length suggests that distinctive morphological and electrophysiological conditions

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predispose to the occurrence of fractionation. The same anatomic region may have short, non-fractionated electrograms during an episode with slow AF cycle length, whereas it could have a complex fractionated configuration when AF cycle length is shorter. The concept that many CFAE sites represent passive phenomena was supported by Jadidi et al. who performed high-density mapping of the left atrium in 18 patients (9 with persistent AF) during sinus rhythm, coronary sinus pacing and AF.31 Only a minority of sites exhibiting CFAE during AF displayed fractionation during sinus rhythm or coronary sinus pacing. Furthermore, there was no correlation between the distribution of fractionation during coronary sinus pacing and sinus rhythm. All sites exhibiting CFAE during AF had normal voltage during sinus rhythm, suggesting the absence of underlying scar. These findings support the notion that the majority of CFAEs are passive in nature and dependent on the direction and rate of activation (coronary sinus pacing versus sinus rhythm versus AF). The fact that most CFAEs do not occur at sites with underlying fibrosis was demonstrated by the same group who performed high-resolution delayed enhancement cardiac MRI to detect atrial fibrosis and compared this with the distribution of CFAE as determined by high-density contact mapping.32 Over 75 % of the regions characterised by dense late enhancement (i.e. fibrosis) did not display CFAE, but demonstrated low-voltage electrical activity. CFAEs were detected at atrial sites displaying voltages >0.5 mV using the EnSite algorithm. However, it is possible that this voltage threshold is too high and therefore may lack the sensitivity and specificity required to identify areas of fibrosis. With the range of electrograms falling under the umbrella term of CFAE and given that the majority of these appear to be passive phenomena, an important question is whether there is a type of CFAE that is more likely to represent an active participant in the AF process. Takahashi et al. studied 40 patients with persistent AF and performed PV isolation followed by a roof line.10 Electrogram-guided ablation was then performed in the left atrium and coronary sinus.Targeted electrograms were characterised and their association with favourable ablation regions, defined as those associated with slowing of AF cycle length (by ≥6 ms) or termination of AF, was assessed. The examined characteristics of targeted electrograms were: 1) percentage of continuous electrical activity during 4 s; 2) bipolar voltage; 3) dominant frequency; 4) fractionation index (defined as the number of deflections with an absolute value of >0.05 mV from baseline); 5) mean absolute dV/dt of electrograms; 6) local cycle length and 7) presence of a temporal gradient of activation such that there was a >70 ms gradient between activation recorded on the distal and proximal bipoles of the mapping catheter. AF was terminated by electrogram-guided ablation in 73 % of patients. The percentage of continuous electrical activity and the presence of a temporal gradient of activation were independent predictors of favourable ablation regions, and such electrograms may indicate regions that are more likely to be critical to the AF process and therefore good targets for ablation. This hypothesis was tested in the Selective Complex Fractionated Atrial Electrograms Targeting for Atrial Fibrillation Study (SELECT AF). Eighty-six patients with persistent/highburden paroxysmal AF were randomised to one of two arms: group I, in which all CFAE regions with an ICL >7 (using the Carto algorithm) were ablated, followed by PV isolation; group II, in which only CFAE sites with continuous electrical activity were ablated followed by PV isolation.33 More extensive CFAE ablation (group I) was associated with significantly higher rates of freedom from atrial arrhythmia recurrence at 1-year follow-up (50 % versus 28 %) after one procedure. There were

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also significantly fewer repeat procedures in this group (13 % versus 36 %, respectively). Adoption of the more generalised CFAE ablation approach targeted a mean left atrial surface area of 22±9 % versus only 3±2 % in the selective approach. In many cases of persistent AF, areas exhibiting complex fractionation are often widespread. While the SELECT AF study suggested that less selective CFAE ablation was associated with favourable outcomes, numerous mechanistic studies have demonstrated that many CFAEs are only passive participants in the AF process. The dichotomy is possibly explained by the fact that simply targeting continuous activity (as per SELECT AF) is not a specific enough approach for identifying critical CFAEs.

10 % of patients with paroxysmal AF 35 % of patients with persistent AF. Targeting ablation to these LVAs (after PV isolation) resulted in 12-month atrial tachycardia/AF-free survival of 70 % versus on 27 % in a control group of patients who had LVAs, but did not undergo targeted ablation. Atrial fibrosis is likely to be partly contributory to the mechanisms involved in AF persistence and this method may prove a useful means of targeting such areas.

The concept of more selective CFAE ablation based on electrogram interpretation derived from conventional contact mapping seems to lack supporting evidence. Until recently, the role of CFAE mapping in AF ablation was widely seen as an adjunct to PV isolation in cases of persistent AF. This view has come under considerable scrutiny with the publication of randomised studies calling the benefit of additional CFAE ablation into question. First, the Randomised Ablation Strategies for the Treatment of Persistent Atrial Fibrillation (RASTA) study compared two ablation strategies for persistent AF with PV isolation alone.34 In

While the PVs are undoubtedly crucial as trigger sites for AF, understanding of the mechanisms responsible for AF perpetuation remains incomplete and this is in part due to the limitations of conventional mapping strategies. Given that multiple atrial wavelets, macroreentries and localised (focal or reentrant) sources have been reported to contribute to the perpetuation of AF, a fundamental question is whether the many activation waves emanate from a small number of stable, periodic drivers or whether they are transient, widely distributed and self-perpetuating. Conventional mapping techniques lack the temporospatial resolution to determine this and, as already described, CFAE mapping lacks the required specificity. The limitations of conventional contact mapping with a single catheter are emphasised by Atienza et al.36 A high-density dominant frequency left atrium map was created by sequentially moving the ablation and/or circular mapping catheter throughout the entire left atrium. Sites with high-frequency atrial electrograms were identified by an automated

this single-centre study, patients were randomised to PV isolation alone, PV isolation plus empirical ablation of common non-PV trigger sites, or PV isolation plus CFAE ablation (detected by either the Carto or NavX systems). The primary endpoint of 1-year freedom from atrial arrhythmias without anti-arrhythmic drugs was achieved at a lower rate in the CFAE ablation arm (29 % versus 49 % with PV isolation alone).

algorithm designed to calculate the dominant frequency and depict local atrial activation frequency on the 3D left atrium shell. Targeting these sites for ablation (in addition to PV isolation) did not improve outcomes compared with PV isolation alone. This has led to the development of wide-field mapping tools that incorporate a balloon, multi-spline probes or electrode arrays enveloping the torso.37–40

A more comprehensive evaluation of the role of CFAE ablation for persistent AF has been provided by the multicentre STAR AF 2 study. In this study, 589 patients were randomised in a 1:4:4 fashion to PV isolation alone, PV isolation plus ablation of CFAEs or PV isolation plus linear ablation across the left atrial roof and mitral valve isthmus. CFAEs were detected using the NavX EnSite Velocity automated algorithm as described above. After 18 months of follow-up there was no significant difference between the three arms in terms of the rate of freedom from recurrent AF (PV isolation alone: 59 %; PV isolation + CFAE: 49 %; PV isolation + linear ablation: 46 %; p=0.15). These findings do not support contemporary guidelines, which suggest that patients with nonparoxysmal AF should have additional substrate ablation to improve outcome.2 The combination of PV isolation plus CFAE ablation plus linear ablation (the so-called ‘stepwise’ approach) was not tested in the STAR AF 2 study, but there are some single-centre data that suggest this may be associated with better outcomes.3 The STAR AF 2 study represents the most robust assessment of ablation strategies for persistent AF and the inference is that PV isolation alone is sufficient.

Narayan et al. hypothesised that AF is sustained by localised sources and that ablation of these sources would improve outcome following AF ablation.39 They developed a novel computational mapping approach to detect these sources and tested whether ablation of these patient-specific sources would modulate AF (termination or significant slowing). They termed this approach focal impulse and rotor modulation (FIRM). In short, a 64-pole basket catheter was used to map the left atrium (and the right atrium in later cases). AF signals were processed by linear detrending, removal of QRS artefact and spatial averaging. Sequences of activation at multiple electrodes in both atria were then used directly to create isochronal maps of AF. Algorithms and software were designed to continually associate electrogram sequences such that rotors or focal beat sources, when identified, could be tracked if they migrated. The electrograms were analysed in the context of rate-dependent repolarisation, that indicate the shortest physiological time between successive activations during AF, and ratedependent conduction slowing, used to identify mapped propagation paths that were physiologically possible. FIRM maps revealed electrical rotors, defined as sequential clockwise or counter-clockwise activation contours around a centre of rotation, or focal impulses, defined by centrifugal activation contours from an origin. Rotors and focal impulses were only considered AF sources if consistent in multiple recordings to eliminate transient AF patterns.

STAR AF 2 – The Last Call for CFAE Mapping?

Are There Better Ways of Assessing the Mechanisms of AF to Identify Critical Regions? The failure of additional CFAE mapping to improve outcomes in the STAR AF 2 study may in part be due to the CFAE mapping algorithm used. As discussed above, the threshold voltage of >0.5 mV may be too high for the purpose of detecting atrial regions with underlying fibrosis. Rolf et al. have explored this concept in a pilot study of 178 patients with paroxysmal or persistent AF.35 Patients underwent PV isolation and voltage maps of the left atrium were then constructed in sinus rhythm. Low voltage areas (LVAs; voltage <0.5 mV) were identified in

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A total of 92 patients, 76 of whom had non-paroxysmal AF, were studied over 107 procedures.39 Patients were enrolled in a two-arm 1:2 case cohort design and randomised to either ablation guided by FIRM plus conventional ablation or FIRM-blinded ablation (conventional ablation alone). The acute efficacy endpoint was AF termination or

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Diagnostic Electrophysiology & Ablation Figure 3: Phase Mapping Using ECG Imaging

B -π/2

Unipolar signal at epicardial surface Filtered electrogram - input to phase map calculation

π/2

-π/2

π/2

-π

Unipolar signals are assigned phase values, from –π to π Local Activation Time: Downward zero crossing

π/2

-π/2

-π

t=1

t=2

t=3

t=4

The 252-electrode torso vest records simultaneous unipolar signals from the epicardial surface of the heart (panel A). Electrode position is related to cardiac anatomy by means of a CT scan that is performed with the patient wearing the vest. Raw unipolar signals are filtered and input into a phase map calculation (panel B). Unipolar signals are assigned phase values from –π to π. The local activation time is taken at the point of downward zero crossing. The phases of wave propagation are then colour coded and related to biatrial geometry (panel C).

Figure 4: Correlation of Phase Map Data with Conventional Activation Time Mapping Phase Map

Activation Time Map

t=10 ms

t=15 ms

t=19 ms The phase map demonstrates a focal source of activation in the right atrial appendage with activation spreading centrifugally from this point. The locally recorded electrograms can be seen on the right. The high right atrial catheter (HRA) has been positioned in the right atrial appendage. The cycle length in this region is rapid and faster than the remainder of the atrium – a characteristic of potential trigger activity.

≥10 % reduction in AF cycle length. The primary long-term endpoint was defined as freedom from AF after a single procedure (median of 273-day follow-up). The mean number of AF sources detected per patient was 2.1±1.0, of which 70 % were rotors and 30 % focal impulses. Approximately three-quarters were found in the left atrium, with the remainder in the right atrium. The acute endpoint was achieved in 86 % of the FIRM-guided group versus 20 % in the FIRMblinded group. Total ablation time was similar between the two groups. The FIRM-guided group had a higher rate of freedom from AF (82 % versus 45 %). These findings therefore offer novel mechanistic insights

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into the perpetuation of AF and also offer a potentially useful treatment strategy. While these findings need to be confirmed in a randomised, multicentre setting, initial multicentre registry data (78 patients across 10 centres) are encouraging with approximately 80 % of patients being free from AF at 1 year.41 Biatrial AF mapping using activation or phase-based analysis of body surface potentials is another method that has recently been evaluated as a means of visualising the mechanisms responsible for perpetuation of AF.42 This technique takes advantage of the fact that phase parameters are not directly dependent on the amplitude of electrograms, which are often ambiguous during fibrillation. A vest containing 252-electrodes is placed on the torso of the subject and a non-contrast CT scan of the torso performed to derive cardiac geometry and relate this to the position of the electrodes, which record unipolar body surface potentials. This technique has been used to map the origin of cardiac arrhythmias with a localisation accuracy of 6 mm.43 The ECVUE non-invasive mapping system (CardioInsight) reconstructs biatrial unipolar electrograms from the torso potentials. Activation maps can be computed by marking local activation as the steepest –dV/dt of each electrogram. Multiple AF windows lasting >1 s are selected for analysis, and maps of each window are constructed using algorithms that combine signal filtering and phase mapping. A map of each window is displayed on individualised 3D biatrial geometry segmented from the CT scan. The phases of wave propagation are colour-coded. Surrogates of the depolarisation and repolarisation wavefronts are computed from the isophane values equal to π/2 and –π/2, respectively (Figure 3). The maps of each AF window are then combined to produce a composite map of all AF sources that are termed drivers. Figure 4

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Is Mapping of Complex Fractionated Electrograms Obsolete?

shows an example of a focal AF driver identified by phase mapping with the associated intracardiac electrograms. Active driver regions are differentiated from passive wave propagation to produce the final spatiotemporal density map.

compared with a matched (historical) control group. Ablation time to AF termination was 28±17 mins in the driver ablation group versus 65±33 mins in the control group.

Conclusion Haissaguerre et al. used this system to characterise AF mechanisms in patients with non-paroxysmal AF.42 Active driver regions were classified as either focal (centrifugal activation from a single point or area) or reentrant (at least one wave rotated fully around a centre on phase progression and confirmed by sequential activation of raw electrograms). Activity appearing more than once consecutively was considered repetitive. A total of 103 patients with non-paroxysmal AF were mapped. A median of four driver regions was mapped per patient. The number of drivers rose with increasing continuous duration of AF. The ablation strategy in this study was to target driver regions first. If drivers were identified in the PVs, circumferential ablation of ipsilateral PVs was undertaken. If AF still perisisted after all driver ablations had been ablated, linear lesions were undertaken (left atrial roof, mitral isthmus). The primary endpoint of acute AF termination was met in 82/103 patients. Ablation of the driver regions alone terminated AF in 65 patients. Of the 103 patients, 12-month follow-up data were available for 90, of whom 37 were not receiving anti-arrhythmic drugs, and 80% were free from AF (64 % sinus rhythm, 16 % atrial tachycardia). A key finding was the reduction in ablation time when

10.

11.

12.

13. 14.

15.

16.

Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. New Engl J Med 1998;339:659–66. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012;14:528–606. Knecht S, Hocini M, Wright M, et al. Left atrial linear lesions are required for successful treatment of persistent atrial fibrillation. Eur Heart J 2008;29:2359–66. Verma A, Mantovan R, Macle L, et al. Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): a randomized, multicentre, international trial. Eur Heart J 2010;31:1344–56. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. New Engl J Med 2015;372:1812–22. Jais P, Haissaguerre M, Shah DC, et al. Regional disparities of endocardial atrial activation in paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 1996;19:1998–2003. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044–53. Rostock T, Rotter M, Sanders P, et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrial fibrillation. Heart Rhythm 2006;3:27–34. Oral H, Chugh A, Good E, et al. Radiofrequency catheter ablation of chronic atrial fibrillation guided by complex electrograms. Circulation 2007;115:2606–12. Takahashi Y, O’Neill MD, Hocini M, et al. Characterization of electrograms associated with termination of chronic atrial fibrillation by catheter ablation. J Am Coll Cardiol 2008;51:1003–10. Lewis T. Observations upon flutter and fibrillation: part IV. Impure flutter: theory of circus movement. Heart 1920;7:293–331. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J 1959;58:59–70. Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn Ther 1962;140:183–8. Cox JL, Canavan TE, Schuessler RB, et al. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991;101:406–26. Konings KT, Kirchhof CJ, Smeets JR, et al. High-density mapping of electrically induced atrial fibrillation in humans. Circulation 1994;89:1665–80. Gerstenfeld EP, Lavi N, Bazan V, et al. Mechanism of complex fractionated electrograms recorded during atrial fibrillation in

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The role of CFAE mapping has reduced in stepwise fashion since its adoption as an ablation strategy for AF. Having initially been proposed as a standalone option in both paroxysmal and persistent AF, it became apparent that its role was perhaps best defined in persistent AF, as an adjunct to PV isolation. This approach has been recently questioned following publication of the STAR AF 2 study. What is clear is that a majority of CFAEs are not active participants in the AF process and as such are poor targets for ablation. The concept of drivers of AF represents a significant step forward in our understanding of the mechanisms responsible for perpetuation of AF and their relationship with electrogram fractionation. Newer widefield mapping techniques such as ECG imaging and the FIRM-guided approach may represent more optimal means of reliably mapping these active sources. Early data are encouraging but it is important that these are tested in appropriately powered multicentre, randomised controlled trials. Mapping of all CFAEs is almost certainly obsolete, but there undoubtedly remain some CFAEs that are critical sites for AF maintenance and better identification of these may result in better outcomes in persistent AF ablation. n

a canine model. Pacing Clin Electrophysiol 2011;34:844–57. 17. Yamabe H, Morihisa K, Tanaka Y, et al. Mechanisms of the maintenance of atrial fibrillation: role of the complex fractionated atrial electrogram assessed by noncontact mapping. Heart Rhythm 2009;6:1120–8. 18. Fedorov VV, Sharifov OF, Beloshapko GG, Yet al. Effects of a new class III antiarrhythmic drug nibentan in a canine model of vagally mediated atrial fibrillation. J Cardiovasc Pharmacol 2000;36:77–89. 19. Schuessler RB, Grayson TM, Bromberg BI, et al. Cholinergically mediated tachyarrhythmias induced by a single extrastimulus in the isolated canine right atrium. Circ Res 1992;71:1254–67. 20. Lemery R, Birnie D, Tang AS, et al. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhythm 2006;3:387–96. 21. Lin J, Scherlag BJ, Zhou J, et al. Autonomic mechanism to explain complex fractionated atrial electrograms (CFAE). J Cardiovasc Electrophysiol 2007;18:1197–205. 22. Knecht S, Wright M, Matsuo S, et al. Impact of pharmacological autonomic blockade on complex fractionated atrial electrograms. J Cardiovasc Electrophysiol 2010;21:766–72. 23. Kalifa J, Tanaka K, Zaitsev AV, et al. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation 2006;113:626–33. 24. Umapathy K, Masse S, Kolodziejska K, et al. Electrogram fractionation in murine HL-1 atrial monolayer model. Heart Rhythm 2008;5:1029–35. 25. Di Biase L, Elayi CS, Fahmy TS, et al. Atrial fibrillation ablation strategies for paroxysmal patients: randomized comparison between different techniques. Circ Arrhythm Electrophysiol 2009;2:113–9. 26. Li WJ, Bai YY, Zhang HY, et al. Additional ablation of complex fractionated atrial electrograms after pulmonary vein isolation in patients with atrial fibrillation: a meta-analysis. Circ Arrhythm Electrophysiol 2011;4:143–8. 27. Scherr D, Dalal D, Cheema A, et al. Automated detection and characterization of complex fractionated atrial electrograms in human left atrium during atrial fibrillation. Heart Rhythm 2007;4:1013–20. 28. Porter M, Spear W, Akar JG, et al. Prospective study of atrial fibrillation termination during ablation guided by automated detection of fractionated electrograms. J Cardiovasc Electrophysiol 2008;19:613–20. 29. Verma A, Novak P, Macle L, et al. A prospective, multicenter evaluation of ablating complex fractionated electrograms (CFEs) during atrial fibrillation (AF) identified by an automated mapping algorithm: acute effects on AF and efficacy as an adjuvant strategy. Heart Rhythm 2008;5:198–205.

30. El Haddad M, Houben R, Claessens T, et al. Histogram analysis: a novel method to detect and differentiate fractionated electrograms during atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:781–90. 31. Jadidi AS, Duncan E, Miyazaki S, et al. Functional nature of electrogram fractionation demonstrated by left atrial highdensity mapping. Circ Arrhythm Electrophysiol 2012;5:32–42. 32. Jadidi AS, Cochet H, Shah AJ, et al. Inverse relationship between fractionated electrograms and atrial fibrosis in persistent atrial fibrillation: combined magnetic resonance imaging and high-density mapping. J Circulation Arrhythmia and Electrophysiology Am Coll Cardiol 2013;62:802–12. 33. Verma A, Sanders P, Champagne J, et al. Selective complex fractionated atrial electrograms targeting for atrial fibrillation study (SELECT AF): a multicenter, randomized trial. Circ Arrhythm Electrophysiol 2014;7:55–62. 34. Dixit S, Marchlinski FE, Lin D, et al. Randomized ablation strategies for the treatment of persistent atrial fibrillation: RASTA study. Circ Arrhythm Electrophysiol 2012;5:287–94. 35. Rolf S, Kircher S, Arya A, et al. Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2014;7:825–33. 36. Atienza F, Almendral J, Ormaexe JM, et al. Comparison of radiofrequency catheter ablation of drivers and circumferential pulmonary vein isolation in atrial fibrillation. J Am Coll Cardiol 2014;64:455–67. 37. Haissaguerre M, Hocini M, Shah AJ, et al. Noninvasive panoramic mapping of human atrial fibrillation mechanisms: a feasibility report. J Cardiovasc Electrophysiol 2013;24:711–7. 38. Haissaguerre M, Hocini M, Sanders P, et al. Localized sources maintaining atrial fibrillation organized by prior ablation. Circulation 2006;113:616–25. 39. Narayan SM, Baykaner T, Clopton P, et al. Ablation of rotor and focal sources reduces late recurrence of atrial fibrillation compared with trigger ablation alone: extended follow-up of the CONFIRM trial (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation). J Am Coll Cardiol 2014;63:1761–8. 40. Ramanathan C, Ghanem RN, Jia P, et al. Noninvasive electrocardiographic imaging for cardiac electrophysiology and arrhythmia. Nature Med 2004;10:422–8. 41. Miller JM, Kowal RC, Swarup V, et al. Initial independent outcomes from focal impulse and rotor modulation ablation for atrial fibrillation: multicenter FIRM registry. J Cardiovasc Electrophysiol 2014;25:921–9. 42. Haissaguerre M, Hocini M, Denis A, et al. Driver domains in persistent atrial fibrillation. Circulation 2014;130:530–8. 43. Cuculich PS, Wang Y, Lindsay BD, et al. Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns. Circulation 2010;122:1364–72.

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Device Therapy

The Entirely Subcutaneous Defibrillator – A New Generation and Future Expectations Hussa m A l i , P i e r p a o l o L u p o a n d R i c c a r d o Ca p p a t o Arrhythmia & Electrophysiology Research Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy; Arrhythmia & Electrophysiology Unit II, Humanitas Gavazzeni Clinics, Bergamo, Italy

Abstract Although conventional implantable cardioverter-defibrillators (ICDs) have proved effective in the prevention of sudden cardiac death (SCD), they still appear to be limited by non-trivial acute and long-term complications. The recent advent of an entirely subcutaneous ICD (S-ICD) represents a further step in the evolution of defibrillation technology towards a less-invasive approach. This review highlights some historical and current issues concerning the S-ICD that may offer a viable therapeutic option in selected patients at high risk of SCD and in whom pacing is not required. After the CE Mark and US Food and Drug Administration (FDA) approvals, the S-ICD is being implanted worldwide with growing clinical data regarding its safety and efficacy (the EFFORTLESS Registry). The recently developed new generation of S-ICD (EMBLEM, Boston Scientific) demonstrates favourable features including a smaller device, longer longevity and remote-monitoring compatibility. Further innovations in the S-ICD system and potential integration with leadless pacing may play an important role in defibrillation therapy and prevention of SCD in the near future.

Keywords Defibrillation technology, subcutaneous ICD, transvenous leads, sudden cardiac death, inappropriate shock Disclosure: Riccardo Cappato has equity and intellectual property rights with Cameron Health, San Clemente, California, US. The other authors have no conflicts of interest to declare. Received: 04 June 2015 Accepted: 03 August 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(2):116–21 Access at: www.AERjournal.com Correspondence: Riccardo Cappato, Arrhythmia & Electrophysiology Research Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy. E: riccardo.cappato@humanitas.it

Numerous large clinical trials have demonstrated the benefit of implantable cardioverter-defibrillators (ICDs) to prevent sudden cardiac death (SCD) in selected populations.1,2 These results and advances in defibrillation therapies have led to an impressive expansion of ICD implants and indications in recent decades. Although initially focusing on secondary prevention, current ICD indications have expanded to include prophylactic implantation in individuals at high risk of SCD (primary prevention), increasing the potentially eligible ICD candidates.2–4 The introduction of transvenous ICDs (TV-ICDs) was a paradigm shift in ICD therapy by avoiding the surgical approach and its associated risks and comorbidities.5,6 Nevertheless, TV-ICDs are still associated with considerable morbidity (1.5 % major complications)7 and acute and longterm procedural risks.8–10 Late infections including endocarditis, vessel occlusion, lead dislodgment, valvular dysfunction and intrinsic lead defects with consequent inappropriate/ineffective therapies are also observed with endocardial leads.11 Notably, the TV leads have been considered the weakest link in the TV-ICD with up to 20 % annual lead failure rates for 8-year-old systems.12–14 Moreover, lead extraction of failed/infected chronic TV leads is a complex procedure requiring special skills and equipment, and it is also associated with substantial comorbidity and mortality.15,16 An ICD system residing only in the subcutaneous space, without touching the heart or its vessels, may further simplify the implant procedure and minimise the shortcomings related to the TV leads.

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Conceptualisation of the Subcutaneous Defibrillation and Early Clinical Studies The concept of a subcutaneous ICD (S-ICD) is not new. As early as in 1970, Schuder et al.17 reported on an implantable system provided with subcutaneous transthoracic electrodes in a canine model. In the successive decades, this concept was overlooked with the expanding use of epicardial, and subsequently, TV-ICD systems. In the early 2000s, a few cases of subcutaneous defibrillation were reported in children with venous access issues, but without applying a dedicated functional S-ICD.18–20 At the beginning of this century, growing knowledge and evidence of the shortcomings/risks related to the TV leads stimulated the investigators to conceive an entirely S-ICD system without touching the heart or its vessels. The initial challenge was to find out the optimal shock configuration regarding the positions of the subcutaneous lead and pulse generator (PG). The first short-term defibrillation trial was conducted in 78 patients to assess defibrillation threshold, according to different configurations of a temporary S-ICD system.21 The results led to the selection of the S-ICD shock configuration currently available for clinical use, consisting of a left lateral PG positioned at the fifth intercostal space between the mid and anterior axillary lines, and an 8 cm coil electrode positioned parallel to the left parasternal margin. Throughout 2004 and 2005, a second trial was conducted in 49 patients, with the aim of comparing the efficacy

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The Entirely Subcutaneous Defibrillator – A New Generation and Future Expectations

Figure 1: The Subcutaneous ICD

con

Alternate (a-b) b

Primary

(a-

(b-Can)

CAN

Simultaneous 3-lead ECG

14 cm

LEA

D II LL

LEAD

Incorrect profile

Correct profile

Unacceptable lead

Acceptable lead

Peak zones

RA LEAD I

of an S-ICD shock configuration with that of a conventional TV-ICD system. Both subcutaneous and TV systems effectively defibrillated induced ventricular fibrillation (VF) in all but one patient, with a mean threshold of 37±20 J and 11±9 J, respectively. From late 2008 to early 2009, a multicentre clinical trial of permanent S-ICD implantation was conducted in New Zealand and Europe, involving 55 patients with class I, IIa or IIb indications for ICD therapy. Exclusion criteria included a clinical indication for antibradycardia pacing, severe renal insufficiency and a history of slow (<170 bpm), or pace-terminable ventricular tachycardia (VT). The S-ICD successfully detected and defibrillated (at 65 J) the induced VF in 100 % and 98 % of patients, respectively. The mean time to shock delivery was 14.0±2.5 seconds, whereas the mean procedure duration was 67±33 minutes. After 10±1 months of follow-up, a total of 12 episodes of clinical ventricular arrhythmia were detected and terminated effectively by the S-ICD. Minor complications were observed in five patients (pocket infection in two patients, parasternal subcutaneous lead dislodgement in three patients). Oversensing and inappropriate sensing were rare (double counting, muscle noise) and were managed by device reprogramming.

III

1. RECORD: Supine + standing 25 mm/s, 5–20 mm/mV

2. SELECT: the coloured profile. The largest QRS peak must be within a Peak Zone.

3. Verify at least one lead is acceptable in all postures.

The S-ICD System

A) The standard position of the subcutaneous lead and PG in the left thorax with the available sensing vectors. B) S-ICD components: The programmer, tunneling tool and the PG connected to the subcutaneous lead. C) The screening tool guide to verify patients’ eligibility prior to S-ICD Implantation. PG = pulse generator.

The system consists of a subcutaneous PG and a subcutaneous lead placed along the left side of the sternum. The first PG generation (model SQ-RX 1010, Cameron Health, Inc.) has a volume of ~70 cc, a weight of

oversensing. 3) Decision phase: after excluding suspected events, only certified events are continuously analysed to calculate a running four

145 g and a projected longevity of 5 years. The subcutaneous lead is provided with two sensing electrodes separated by an 8 cm shock coil. Using these sensing electrodes and the generator itself as the third one, three sensing vectors are available to detect the subcutaneous signals. The best vector is automatically selected by the system in order to avoid double QRS counting and T-wave oversensing. In this regard, a screening tool is used before implantation to confirm patients’ eligibility to the S-ICD by analysing the surface electrocardiogram (ECG) signals in both supine and standing positions (see Figure 1). The implantation procedure is basically guided by anatomical landmarks with the option of fluoroscopy check to confirm optimal shock vector crossing the heart silhouette. At the end of the procedure, VF is induced using 50 Hz to assess correct detection and defibrillation (at 65 J) of the arrhythmia. Unlike the TV-ICD, the defibrillation test is still mandatory in the S-ICD since defibrillation threshold may be more dependent on the system positioning with fewer available long-term follow-up data.

Sensing the Subcutaneous Signals and Tachyarrhythmia Detection Three sensing vectors are available in the S-ICD (see Figure 1); primary: sensing from the proximal electrode ring on the subcutaneous lead to the active surface of the PG; secondary: sensing from the distal sensing electrode ring on the subcutaneous lead to the active surface of the PG; and alternate: sensing from the distal sensing electrode ring to the proximal sensing electrode ring on the subcutaneous lead. Based on signal/noise and QRS/T ratios, the system automatically selects the best sensing vector to provide appropriate detection. Automatic analysis of sensed signals basically includes three consecutive phases to avoid inappropriate sensing. 1) Detection phase: the device uses a detection threshold that is automatically adjusted continuously using amplitudes of recently detected events. 2) Certification phase during which the system excludes suspected events such as noise/artifacts, double QRS counting or T wave

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R–R interval average, which is the indicator of heart rate. In the shock zone (programmable between 170 and 250 bpm), rate is the only criterion used to determine if a rhythm will be treated with a shock. On the other hand, the optional conditional shock zone (programmable between 170 and 240 bpm) has additional discriminators used to differentiate supraventricular from ventricular tachyarrhythmias avoiding inappropriate therapies of the former. The discrimination algorithm in the conditional shock zone is based on the following sequential analysis: 1) correlation waveform analysis of each tachycardia beat with the stored baseline template. More than 50 % of correlation is considered normal activity suggesting supraventricular tachyarrhythmia; 2) beat-to-beat analysis, which considers polymorphic relationship as ventricular tachyarrhythmia, while in the case of monomorphic relationship the algorithm continues to the next analysis step; (3) QRS width analysis that indicates ventricular tachycardia if the QRS complex is wider than the baseline QRS template. When 18 out of 24 consecutive tachy beats exceed the pre-determined therapy zone the device charges its capacitor to deliver an 80-J (nonprogrammable) biphasic shock, with shock polarity being automatically inverted after an initial unsuccessful therapy. Spontaneous termination of the arrhythmia during capacitor charging leads to shock abortion in order to avoid treating non-sustained episodes. The system is capable of delivering only 30 seconds of post-shock transcutaneous pacing if bradycardia is detected. Telemetric control of the S-ICD is provided by a small-size portable programmer allowing review and/or programming of all device diagnostics/settings including battery status, shock impedance, therapy and post-shock pacing activation, conditional shock VT and shock VF detection zones and stored arrhythmic events.

Commercial Phase and Clinical Data Regarding the S-ICD Performance After preclinical and clinical research, the S-ICD received CE mark and US Food and Drug Administration (FDA) approval in June 2009 and September 2012, respectively. Several clinical studies have reported

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Device Therapy Table 1: Summary of Available Data from Clinical Trials/Registries Regarding the Performance of the Subcutaneous ICD in Different Patient Cohorts S-ICD Cohorts/

Patient

Mean

Primary

EF %

Ischaemic Follow-up

Successful

Inappropriate Infection

Trials Number Age Prevention % (Month) (Years) % CE Trial21 55 56 78 34 67 10±1

Termination of Termination of Shocks % Induced VF % Clinical VT/VF % 98 100 9

3.6

UK Cohort22

111 33 50

– 14

100

9.9

Dutch Cohort23

118 50 60

41 38

100

5.9

German I Cohort24

42 42.5

47 22.5 7.6

97.5

100

–

German II Cohort25

45 59.4

46 15.9 7.2

95.5

100

7.2

1.4

Pooled data

882

~40

98.6

98.2

13.1 at

11.1 at

3 years

~70

37.8

21.7±11.5

(EFFORTLESS + IDE)26

Rate %

EF = ejection fraction; S-ICD = subcutaneous implantable cardioverter-defibrillator; VF = ventricular fibrillation; VT = ventricular tachycardia.

on the safety and efficacy of the S-ICD in primary and secondary prevention of SCD, and in different cardiac etiologies (see Table 1).21–26

appropriate therapies by treating potentially non-sustained episodes ‘unnecessary therapies’.

The most available data on the S-ICD performance were obtained through pooled data from two large registries: IDE (S-ICD System IDE Clinical investigation) and EFFORTLESS (Boston Scientific Post Market S-ICD Registry).26 Data from these registries were recently published analysing S-ICD performance in 882 patients followed for 21.7±11.5 months.

Notably, in the S-ICD pooled data about 36 % of detected VT/VF episodes were self-terminated, reflecting a deliberate time-delay strategy and a longer time-to-therapy (~20 seconds).26

The incidence of appropriate shock was 5.3 % over 1 year in this pooled cohort of S-ICD patients, which is relatively low compared with what has been reported with the conventional ICD. The annual incidence of appropriate ICD therapy (shock or antitachycardia pacing [ATP]) varied widely in the TV-ICD trials ranging from about 5 % (SCDHeft) to 21 % (AVID).1,27 This is mainly due to different inclusion criteria enrolling patients with secondary prevention (Antiarrhythmics Versus Implantable Defibrillators Trial [AVID]), non-sustained/inducible VT (Multicentre Unsustained Tachycardia Trial [MUSTT], Amiodarone Versus Implantable Cardioverter-defibrillator Randomised Trial [AMIOVIRT]) or severely reduced EF (<30 %; Multicentre Automatic Defibrillator Implantation Trial II [MADIT II]).3,4,27 The pooled S-ICD cohort included relatively younger patients (~50 years), mainly with primary prevention indication (~70 %), and more than 20 % prevalence of channelopathies, electrical and genetic heart disease.26 Another important factor to be considered is the setting of ICD therapies. The incidence of appropriate therapy in the S-ICD was somewhat similar to that in the Sudden Cardiac Death in Heart Failure Trial (SCD-Heft) trial.1 The latter trial was conducted in patients with primary prevention indication (ejection fraction [EF] <35 %) and the ICD therapy consisted of a single-lead, single-shock zone (>187 bpm) device with no ATP being programmed.1 This ICD setting mimics the S-ICD design, which aims to treat fast ventricular tachyarrhythmias and has no ATP capability. Indeed, in the pooled S-ICD data the lowest-therapy zone was usually set at 200 bpm, with dual shock zone being activated in about 80 % of patients.26 The Multicentre Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADITRIT) trial addressed how the ICD programming may affect the incidence of appropriate therapies.28 Appropriate ATP therapy occurred in 22 % of patients in the conventional programming arm compared with 8 % and 4 % in the high rate and delayed therapy arms, respectively. However, there was no difference in appropriate shock (5 % with conventional programming or high rate programming, and 4 % with delayed therapy over 1.4 years). This study highlights the fact that conventional ‘aggressive’ ICD programming may overestimate the real incidence of

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About 90 % of spontaneous VT/VF events were terminated with first shock, and 98.2 % were terminated within the five available shocks. The estimated 3-year device-related complications and allcause mortality were 11.1 % and 4.7 %, respectively. Importantly, no lead failures nor S-ICD related endocarditis/bacteraemia were reported. Inappropriate shock rate was 13.1 % at 3 years, mostly secondary to T-wave oversensing (about 40 % of inappropriate therapies). In patients with dual-zone programming at the index procedure, the incidence of inappropriate shocks at 3 years was significantly lower (11.7 %) compared with those with single-zone programming (20.5 %). These data further confirm the START (Subcutaneous versus Transvenous Arrhythmia Recognition Testing) study results, which highlighted the accuracy of S-ICD detection algorithms to discriminate supraventricular from ventricular tachyarrhythmia.29 Although current guidelines 30 do not include the S-ICD as an alternative therapy, the available clinical data outline the potential benefit of this technology in selected patients at high risk of SCD. However, huge amounts of clinical data are available regarding the safety and efficacy of the TV-ICD while long-term data concerning the S-ICD performance are still lacking and need further research. The Prospective, Randomised Comparison of Subcutaneous and Transvenous Implantable Cardioverter-defibrillator Therapy (PRAETORIAN) trial, which is a randomised, controlled, multicentre, prospective double-arm trial, including 700 patients randomised (1:1) to subcutaneous versus transvenous ICD therapy, should provide further data in terms of safety and efficacy comparing both technologies. 31 The S-ICD System Post Approval Study (ClinicalTrials.gov identifier: NCT01736618) is a non-randomised registry targeting to enroll more than 1,600 subjects at up to 150 investigational sites to analyse the long-term (5-year) performance of the S-ICD system. Another ongoing clinical trial is the Understanding Outcomes With the EMBLEM S-ICD in Primary Prevention Patients With Low Ejection Fraction (UNTOUCHED) Study (ClinicalTrials.gov Identifier: NCT02433379), which will assess the 18-month incidence of all-cause shocks in patients implanted with the new-generation S-ICD for primary prevention of SCD. Devices are to be programmed with zone cutoffs at 200 bpm and 250 bmp in order to mimic the programming settings for TV-ICDs in the MADIT-RIT study.28

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The Entirely Subcutaneous Defibrillator – A New Generation and Future Expectations

Figure 2: Clinical Features/Data that may Favour Subcutaneous ICD or Transvenous ICD Indications

S-ICD

Clinical evaluation

TV-ICD

– Young patients (<40 years) – Channelopathies (BS, LQTS, CPVT, SQTS), idiopathic VF – Non-obstructive HCM – Patients with venous anomaly/occlusion – Congenital heart disease * No venous access to the heart (extracardiac Fontan) Primary and * Intracardiac shunts secondary – Patients at high risk of infection: * Immunosuppressive therapy prevention * Patients on haemodialysis of SCD * HIV positive – Patients with prior complications due to TV leads: * Endocarditis * Venous thrombosis * Multiple TV lead failures/extractions – Bridge therapy: * Prior to heart transplant * Acute phase of MI/cardiomyopathy Patient preference

EPS – Slow sustained <170 bpm – Indication for antibrady pacing – Indication for CRT – Recurrent pace-terminable VT (ATP) Screening – Inadequate transcutaneous signals tool – Unipolar PM – High probability of developing pacing indication: * PQ >300 ms, bi-/tri-fascicular block * LBBB ± low EF % * LQTS3 ECG, * Marked sinus bradycardia with beta-blocker Holter therapy is still to be optimised * Specific heart conditions: sarcoidosis, amyloidosis, OHCM * Very old patients (>75 years) – Inadequate Patient Stature: * Very young children (<8–10 years) * Extremely low bodyweight (<35 kg) Cardiac – Contraindication to ICD testing imaging

ATP = antitachycardia pacing; BS= Brugada syndrome; CPVT = cathecolaminergic polymorphic ventricular tachycardia (VT); ECG = electrocardiogram; EF = ejection fraction; EPS = electrophysiology study; HCM = hypertrophic cardiomyopathy; LBBB = left bundle branch block; LQTS and SQTS = long and short QT syndromes, respectively; MI = myocardial infarction; OHCM = obstructive HCM.

S-ICD – In Which Patients? In general terms, all patients with an ICD indication may find in the S-ICD an alternative therapeutic option if pacing is not required. Those who have pacing indications (i.e. antibrady, cardiac resynchronisation therapy [CRT] or ATP) are not eligible for the S-ICD. In addition to the general ICD population, specific patient cohorts seem to benefit more from an S-ICD. TV-ICDs are often problematic in young patients (i.e. <40 years) who have long life expectancy and an active lifestyle making them more prone to lead failures, thus requiring multiple lead revision/ extraction procedures. Particularly, young patients with electrical heart disease/channelopathies (e.g. long and short QT syndromes, catecholaminergic polymorphic VT, Brugada syndrome and idiopathic VF) may benefit more from an S-ICD since their index arrhythmia is usually VF or polymorphic VT unresponsive to ATP. Moreover, patients who had already experienced serious complications related to TV leads (endocarditis, lead failures and inappropriate shocks, venous occlusion/thrombosis) should be considered for S-ICD if pacing is not indicated. Due to its subcutaneous nature, the risk of serious infections (bacteraemia, endocarditis) is extremely low with the S-ICD, making it a favoured option in patients at high risk of infection, such as those on immunosuppressive therapy, HIV patients or patients on haemodialysis who also often have vascular access concerns. Furthermore, TV-ICDs are problematic or unfeasible in some patients with congenital heart diseases (intracardiac shunts, venous occlusion/anomaly, extracardiac Fontan), in whom the S-ICD technology may offer a practical alternative to the more complex surgical approach.32,33 Considering the simplicity of its implantation and extraction, the S-ICD may also play a role in patients with a temporary risk for ventricular arrhythmias, such as prior to cardiac transplantation, the acute phase post-myocardial infarction/ myocarditis or recent onset of dilated cardiomyopathy. Additionally, some women may prefer the S-ICD for cosmetic factors as the PG pocket could be performed and hidden under the left breast.

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Figure 3: Features of the Second Generation Subcutaneous ICD (EMBLEM) Compared with the First Generation (SQ-RX 1010) First-generation S-ICD SQ-RX 1010 (Cameron Health)

15.7 mm 69.9 cc 145 gram 5.1 years Not available

Second-generation S-ICD EMBLEM (Boston Scientific)

Thickness Volume Weight Longevity Remote monitoring

12.7 mm 59.5 cc 130 gram 7.3 years LATTITUDE

S-ICD = subcutaneous implantable cardioverter-defibrillator. Modified from Boston Scientific data.

On the other hand, caution should be taken before considering the S-ICD in patients with a higher probability of developing pacing indications in the near future. These may include patients with significant brady-arrhythmias/conduction defects, and specific cardiomyopathies known to be associated with monomorphic VT which may be pace-terminable. Detailed discussion with patients and families is required to address this issue with a potential future shift to a conventional TV-ICD. The role of an electrophysiology study to evaluate the propensity to a pace-terminable VT, favouring TV-ICD, is still to be determined. Figure 2 highlights the clinical features that may help to select the appropriate ICD technology for each patient.

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Device Therapy How to Reduce Inappropriate Shocks in S-ICD Patients Inappropriate shocks are a major concern in all ICD systems and are associated with increased mortality and reduced quality of life.34 Regarding the S-ICD a few considerations should be followed in order to minimise these undesired therapies: • Prior to implantation: patient screening to ensure adequate transcutaneous signals (pre-operating screening tool) and to exclude those with high probability of double QRS counting/Twave oversensing, which presents the most common cause of inappropriate shocks in S-ICD patients. In one study about 8 % of S-ICD candidates had inadequate transcutaneous signals that were mostly predicted by negative T-waves in lead I and the inferior leads of the surface ECG.35 • After implantation, sensing optimisation to select the best sensing vector (supine/standing positions). • Dual zone programming is preferred (e.g. conditional shock zone 190– 220 bpm, shock zone >220 bpm) as it was significantly associated with inappropriate shocks reduction in the EFFORTLESS registry.26 • Exercise test may be helpful to evaluate the occurrence of myopotential oversensing/functional bundle branch block during exercise, with the possibility of selecting the best sensing vector and/or to update the QRS template.36 Developments in detection algorithms, such as the T-wave oversensing (TWOS) algorithm, may further optimise S-ICD functioning and reduce the incidence of inappropriate therapies.37

The EMBLEM S-ICD – A New Generation and Future Expectations

the determinant factor to reduce replacement interventions that are associated with significant costs and infection risk. • The new device generation is compatible with remote monitoring (LATTITUDE). This feature might be particularly useful in the S-ICD since there are only a few parameters to be controlled/ programmed allowing the majority of patients to be followed, unless a thorough clinical assessment is required. • Other technical improvements including the ability to store and print VF induction (defibrillation testing), and Bluetooth pairing/transfer. Even after 15 years of continuous research and studies, the S-ICD technology is still evolving and the EMBLEM S-ICD represents one of its most recent advances. However, future research and design improvements are still required to address various aspects. For example, a paediatric model of the S-ICD to be used in small children (e.g., < 8 years, < 30 kg) may be an alternative option in the future. At least theoretically, subcutaneous defibrillation would require lower energies in these subjects due to their small cardiac mass and transthoracic impedance, and thus, a smaller paediatric model of the S-ICD with lower-energy might be feasible. Ongoing improvements in detection algorithms, as with the recent algorithm to avoid TWOS, should further improve S-ICD performance and reduce inappropriate therapies. The possibility of simultaneously analysing three, rather than one, available sensing vectors to define the rhythm status might be an advantageous feature to be considered and developed in the future. Finally, the integration of the S-ICD system with leadless pacing, if proved feasible, could play an important role in defibrillation technology enabling the expansion of the less invasive S-ICD therapy to a larger cohort of ICD population. n

Since March 2015, a new generation of the S-ICD device, EMBLEM, has been developed and launched commercially by Boston Scientific. The EMBLEM S-ICD has several favourable features (see Figure 3) compared with the first S-ICD generation (SQ-RX 1010, Cameron Health):

Clinical Perspective

• S maller PG size: with a substantial reduction in volume (i15 %, from ~70 to ~60 cc), thickness (3mm less, i20 % from 15.7 to 12.7 mm) and weight (i10 %, from 145 to 130 g). • Device shape: the edges of the new PG are more rounded and smoother to make its placement in the pocket easier and more comfortable. Furthermore, the header is centred to facilitate the subcutaneous electrode-wrap. These modified physical features of the new generation might be important to reduce patients’ discomfort, and importantly, the mechanical stress/skin erosions and thus pocket complications, including haematoma and infections. • Another important feature of the EMBLEM S-ICD is the longer expected battery longevity (h40 % from 5.1 to 7.3 years). Battery longevity is

• Growing clinical data are available regarding the safety and efficacy of this defibrillation therapy (EFFORTLESS registry).

Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–83. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933–40. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341:1882–90. Anvari A, Stix G, Grabenwoger M, et al. Comparison of three cardioverter defibrillator implantation techniques: initial

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• The S-ICD system represents a viable alternative to TV-ICD for primary and secondary prevention of SCD unless pacing is required. • Its implantation is less invasive, does not require fluoroscopy and avoids the shortcomings related to TV leads.

• Careful patients selection and efforts to minimise inappropriate shocks are essential to optimise the clinical outcome of the S-ICD. • Those who may particularly benefit from this technology are young patients, those with channelopathies or patients who have already experienced TV lead complications. • The second-generation S-ICD (EMBLEM) has several favoured features including a smaller PG, longer longevity and remote-monitoring compatibility. • Further innovations in the S-ICD system, detection algorithms and potential integration with leadless pacing in the future, may make this therapy suitable for a larger cohort of patients at high risk of SCD.

results with transvenous pectoral implantation. Pacing Clin Electrophysiol 1996;19:1061–9. 6. Saksena S. Defibrillation thresholds and perioperative mortality associated with endocardial and epicardial defibrillation lead systems. Pacing Clin Electrophysiol 1993;16:202–7. 7. Curtis JP, Luebbert JJ, Wang Y, et al. Association of physician certification and outcomes among patients receiving an implantable cardioverter-defibrillator. JAMA 2009;310:1661–70. 8. Kleemann T, Becker T, Doenges K, et al. Annual rate of transvenous defibrillation lead defects in implantable cardioverter-defibrillators over a period of 10 years. Circulation 2007;115:2474–80. 9. Alter P, Waldhans S, Plachta E, et al. Complications of implantable cardioverter defibrillator therapy in 440 consecutive patients. Pacing Clin Electrophysiol 2005;28:926–32. 10. Kron J, Herre J, Renfroe EG, et al. Lead- and device-related

11.

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complications in the antiarrhythmics versus implantable defibrillatorstrial. Am Heart J 2001;141:92–8. Gold MR, Peters RW, Johnson JW, et al. Complications associated with pectoral implantation of cardioverter defibrillators. Pacing Clin Electrophysiol 1997;28:208–11. Kleemann T, Becker T, Doenges K, et al. Annual rate of transvenous defibrillation lead defects in implantable cardioverter-defibrillators over a period of N 10 years. Circulation 2007;115:2474–80. Eckstein J, Koller MT, Zabel M, et al. Necessity for surgical revision of defibrillator leads implanted long-term: causes and management. Circulation 2008;117:2727–33. Maisel WH, Kramer DB. Implantable cardioverter-defibrillator lead performance. Circulation 2008;117:2721–3. Buiten MS, van der Heijden AC, Schalij MJ, et al. How adequate are the current methods of lead extraction? A review of the efficiency and safety of transvenous lead

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The Entirely Subcutaneous Defibrillator – A New Generation and Future Expectations

extraction methods. Europace 2015;17:689–700. 16. Birgersdotter-Green UM, Pretorius VG. Lead extractions: indications, procedural aspects, and outcomes. Cardiol Clin 2014;32:201–10. 17. Schuder JC, Stoeckle H, Gold JH, et al. Experimental ventricular defibrillation with an automatic and completely implanted system. Trans Am Soc Artif Intern Organs 1970;16:207–12. 18. Berul CI, Triedman JK, Forbess J, et al. Minimally invasive cardioverter defibrillator implantation for children: an animal model and pediatric case report. Pacing Clin Electrophysiol 2001;24:1789–94. 19. Luedemann M, Hund K, Stertmann W, et al. Implantable cardioverter defibrillator in a child using a single subcutaneous array lead and an abdominal active can. Pacing Clin Electrophysiol 2004;27:117–9. 20. Madan N, Gaynor JW, Tanel R, et al. Single-finger subcutaneous defibrillation lead and “active can”: a novel minimally invasive defibrillation configuration for implantable cardioverter-defibrillator implantation in a young child. J Thorac Cardiovasc Surg 2003;126:1657–9. 21. Bardy GH, Smith WM, Hood MA, et al. An entirely subcutaneous implantable cardioverter-defibrillator. N Engl J Med 2010;363:36–44. 22. Jarman JW, Todd DM. United Kingdom national experience of entirely subcutaneous implantable cardioverterdefibrillator technology: important lessons to learn. Europace 2013;15:1158–65. 23. Olde Nordkamp LR, Dabiri Abkenari L, Boersma LV, et al. The entirely subcutaneous implantable cardioverter-defibrillator: initial clinical experience in a large Dutch cohort. J Am Coll Cardiol 2012;60:1933–9.

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24. Aydin A , Hartel F, Schlüter M, et al. Shock efficacy of subcutaneous implantable cardioverter-defibrillator for prevention of sudden cardiac death: initial multicenter experience. Circ Arrhythm Electrophysiol 2012;5:913–9. 25. Köbe J, Reinke F, Meyer C, et al. Implantation and follow-up of totally subcutaneous versus conventional implantable cardioverter-defibrillators: a multicenter case-control study. Heart Rhythm 2013;10:29–36. 26. Burke MC, Gold MR, Knight BP, et al. Safety and efficacy of the totally subcutaneous implantable defibrillator: 2-year results from a pooled analysis of the IDE study and EFFORTLESS registry. J Am Coll Cardiol 2015;65:1605–15. 27. Germano JJ, Reynolds M, Essebag V, et al. Frequency and causes of implantable cardioverter-defibrillator therapies: is device therapy proarrhythmic? Am J Cardiol 2006;97:1255–61. 28. Ruwald AC, Schuger C, Moss AJ, et al. Mortality reduction in relation to implantable cardioverter defibrillator programming in the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT). Circ Arrhythm Electrophysiol 2014;7:785–92. 29. Gold MR, Theuns DA, Knight BP, et al. Head-to-head comparison of arrhythmia discrimination performance of subcutaneous and transvenous ICD arrhythmia detection algorithms: the START study. J Cardiovasc Electrophysiol 2012;23:359–66. 30. Epstein AE, Di Marco JP, Ellenbogen KA, et al. American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Heart Rhythm Society.2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the

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American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2013;127:e283–352. Olde Nordkamp LR, Knops RE, Bardy GH, et al. Rationale and design of the PRAETORIAN trial: a Prospective, RAndomizEd comparison of subcuTaneOus and tRansvenous ImplANtable cardioverter-defibrillator therapy. Am Heart J 2012;163:753–60. Mondésert B, Khairy P. Implantable cardioverter-defibrillators in congenital heart disease. Curr Opin Cardiol 2014;29:45–52. Radbill AE, Triedman JK, Berul CH, et al. System survival of nontransvenous implantable cardioverter-defibrillators compared to transvenous implantable cardioverterdefibrillators in pediatric and congenital heart disease patients. Heart Rhythm 2010;7:193–8. Proietti R, Labos C, Davis M, et al. A systematic review and meta-analysis of the association between implantable cardioverter-defibrillator shocks and long-term mortality. Can J Cardiol 2015;31:270–7. Groh CA, Sharma S, Pelchovitz DJ, et al. Use of an electrocardiographic screening tool to determine candidacy for a subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2014;11:1361–6. Kooiman KM, Knops RE, Olde Nordkamp L, et al. Inappropriate subcutaneous implantable cardioverterdefibrillator shocks due to T-wave oversensing can be prevented: implications for management. Heart Rhythm 2014;11:426–34. Brisben AJ, Burke MC, Knight BP, et al. A new algorithm to reduce inappropriate therapy in the S-ICD system. J Cardiovasc Electrophysiol 2015;26:417–23.

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Device Therapy

Developments in Cardiac Resynchronisation Therapy Ge o f f r e y F L e w i s a n d M i c h a e l R G o l d Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, US

Abstract Cardiac resynchronisation therapy (CRT) is an important therapy for patients with heart failure with a reduced ejection fraction and interventricular conduction delay. Large trials have established the role of CRT in reducing heart failure hospitalisations and improving symptoms, left ventricular (LV) function and mortality. Guidelines from major medical societies are consistent in support of CRT for patients with New York Health Association (NYHA) class II, III and ambulatory class IV heart failure, reduced LV ejection fraction and QRS prolongation, particularly left bundle branch block. The current challenge facing practitioners is to maximise the rate of patients who respond to CRT and the magnitude of that response. Current areas of interest for achieving these goals include tailoring patient selection, individualising LV lead placement and application of new technologies and techniques for CRT delivery.

Keywords Cardiac resynchronisation therapy, heart failure, cardiac pacemaker, implantable cardioverter/defibrillator, left ventricular function, LV reverse remodelling, left bundle branch block, device programming, LV lead delivery Disclosure: Geoffrey F Lewis has no conflicts of interest to declare. Michael R Gold has received consulting fees and has performed clinical trials with Boston Scientific, Medtronic and St Jude. Received: 29 May 2015 Accepted: 10 August 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(2):122–8 Access at: www.AERjournal.com Correspondence: Michael R Gold, 114 Doughty Street, MSC 592, Charleston, SC 29425-5920, US. E: goldmr@musc.edu

Since the introduction of CRT more than 20 years ago, its role in mild to severe systolic heart failure has become well established. CRT has been shown to decrease mortality, reduce heart failure hospitalisations and improve functional status in patients with NYHA class II–IV heart failure and QRS prolongation, most commonly with LBBB pattern.1 One of the major limitations of CRT implementation is the significant number of ‘appropriate’ candidates, as determined by guidelines, who fail to respond with clinical, functional or structural endpoints. The rate of non-responders has been estimated between 20 % and 40 %. 2 Efforts to predict those patients who will respond to CRT and to optimise the magnitude of response have been important areas of focus with regard to the future of CRT. This article will present recent considerations and advances, both technical and theoretical, in CRT.

Background Efficacy of CRT therapy in select patient populations has been demonstrated in multiple large, randomised clinical trials (RCTs). The first multi-centre, randomised trial to demonstrate clinical benefits of CRT was the Multisite Stimulation in Cardiomyopathy (MUSTIC) trial published in 2001.3 This trial examined 67 patients with LV ejection fraction (LVEF) ≤35 %, NYHA class III heart failure symptoms, sinus rhythm and QRS duration >150 ms who had biventricular pacemakers placed. The devices were initially programmed to ventricular back-up pacing for rates <40 beats per minute for a period of 3 months followed by reprogramming to encourage biventricular pacing. CRT resulted in significant improvement in 6-minute walk distance, quality of life and peak oxygen uptake as well as decreased hospitalisations. Eighty-five per cent of the study patients reported that they felt better during the period with biventricular pacing programmed on.

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The Multicentre InSync Randomised Clinical Evaluation (MIRACLE) trial evaluated a similar but much larger patient population.4 There were 453 patients with NYHA class III–IV heart failure, LVEF ≤35 % and QRS duration ≥130 ms randomised to biventricular or no pacing. Over 6 months of follow-up, significant improvements were noted in 6-minute walk distance, NYHA class and quality of life. Additionally, CRT was an effective adjunct to optimal medical therapy in reducing the secondary combined endpoint of heart failure hospitalisation or death. Although the results of MUSTIC and MIRACLE were encouraging in terms of the clinical benefits of CRT, reduced mortality had not yet been proved. The Comparison of Medical Therapy, Pacing and Defibrillation (COMPANION) trial used a combined primary endpoint of hospitalisation or death from any cause.5 Enrolling 1,520 patients with LVEF ≤35 %, NYHA class III–IV heart failure and QRS duration >120 ms, this trial randomised subjects to optimal medical therapy, medical therapy with a CRT pacemaker (CRT-P) or medical therapy with a CRT defibrillator (CRT-D). At 1 year of follow-up, the CRT-D group showed significant reduction in overall mortality versus medical therapy alone, and the CRT-P group had showed a strong trend for reduced mortality (p=0.059). These results suggested a mortality benefit from CRT even in the absence of defibrillator capabilities. Several studies have since examined the effects of biventricular pacing alone (i.e. CRT-P) on heart failure. The Cardiac Resynchronisation in Heart Failure (CARE-HF)6 trial utilised a composite primary endpoint of all-cause mortality or hospitalisation for a major cardiac event and a secondary endpoint of all-cause mortality. A total of 813 patients were randomised to optimal medical therapy or CRT. All patients had LVEF ≤35 %, NYHA class III–IV heart failure, QRS duration ≥120 ms

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Developments in Cardiac Resynchronisation Therapy

and echocardiographic evidence of ventricular dyssynchrony. CRT-P was associated with a statistically significant 26 % reduction in the composite primary endpoint after 29 months as well as significant reduction in the secondary endpoint. CARE-HF was thus the first trial to demonstrate a mortality benefit with CRT even in the absence of defibrillator therapy. Expanding the findings of these trials, the Resynchronisation-Defibrillation for Ambulatory Heart Failure (RAFT) trial randomised 1,798 patients with LVEF ≤30 %, NYHA class II–III heart failure and QRS duration ≥120 ms to CRT-D or implantable cardioverterdefibrillator (ICD) without CRT.7 RAFT showed an absolute 7 % reduction in all-cause mortality or heart failure hospitalisation in the CRT-D group, confirming benefit of CRT over traditional ICD therapy. Another patient group of interest were those with only mildly reduced LVEF, also at times referred to as the mid-EF population. It was previously shown in the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial8 that chronic right ventricular (RV) pacing worsens long-term ventricular function and patient outcomes. The Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK-HF) trial9 evaluated patients with NYHA class I–III heart failure but required LVEF only ≤50 %. CRT-D was utilised only if an indication for defibrillation existed, otherwise CRT-P devices were implanted. Patients were randomised to standard RV or biventricular pacing. The major finding of the BLOCK-HF study was that over 37 months of follow-up, patients assigned to biventricular pacing had a significantly lower rate of the combined endpoint of death from any cause, urgent visits for heart failure and increase in LV end-systolic volume index, demonstrating the negative effects of chronic RV-only pacing. These results were similar in both CRT-D and CRT-P groups. The inclusion of an LV remodelling measure in the composite primary endpoint was controversial, but statistically significant reductions in the other clinical components were also observed. Published in 2009, the Multicentre Automatic Defibrillator Implantation Trial – Cardiac Resynchronisation Therapy (MADIT-CRT) was the largest CRT trial to date and evaluated subjects with milder (NYHA class I–II) heart failure with a reduced EF.10 Among 1,820 patients with LVEF ≤30 % and QRS duration ≥130 ms, randomisation to biventricular pacing with a CRT-D device reduced the combined endpoint of mortality and heart failure events (defined as need for intravenous diuresis) by 29 % versus no pacing but ICD backup. Although the majority of the benefit was in reducing heart failure events, this trial showed that NYHA class I–II patients could also derive benefit from CRT. The Resynchronisation Reverses Remodelling in Systolic Left Ventricular Dysfunction (REVERSE) study was performed concomitantly with MADIT CRT. This was a double-blind, multinational, randomised trial that enrolled patients with an LVEF <40 % and NYHA I–II CHF. All subjects received either a CRT-P or CRT-D depending on the local guidelines at the time. The primary endpoint was the clinical composite response (CCS) measured at 1 year of follow-up. The overall distribution was improved with CRT ON, although the proportion of patients who worsened with CRT did not differ.11 The pre-planned 5-year follow-up of the REVERSE study showed a survival benefit of CRT-D compared with CRT-P,12 extending earlier observations noted previously from the COMPANION study.

Guidelines The results of the aforementioned trials, among others, led to publication of guideline recommendations on CRT by the major scientific societies.13,14 A consensus statement endorsed by the European Heart

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Table 1: Summary of CRT Recommendations from the ACC/AHA/HRS and ESC/EHRA Guidelines ACC/AHA/HRS

ESC/EHRA

Class I, LOE A

NYHA III and ambulatory IV • LVEF ≤35 % • Sinus rhythm • QRS ≥150 ms • LBBB

NYHA II, III, ambulatory IV • LVEF ≤35 % • QRS≥150 ms • LBBB

Class I, LOE B

NYHA II • LVEF ≤35 % • Sinus rhythm • QRS ≥150 ms • LBBB

NYHA II, III and ambulatory IV • LVEF≤35% • Sinus rhythm • QRS 120–150 ms • LBBB NYHA III, ambulatory IV • LVEF ≤35 % • Upgrade from existing device • High percentage of ventricular pacing

Class IIa, NYHA III, ambulatory IV LOE A • LVEF ≤35 % • Sinus rhythm • QRS ≥150 ms • Non-LBBB morphology Class IIa, NYHA II–ambulatory IV LOE B • LVEF ≤35% • Sinus rhythm • QRS 120–149 ms NYHA III and ambulatory IV • LVEF ≤35 % • Atrial fibrillation • Requires ventricular pacing close to 100 % due to AV node ablation or pharmacological therapy

NYHA II–ambulatory class IV • LVEF ≤35 % • QRS ≥150 ms • Non-LBBB morphology NYHA II–IV • LVEF ≤35 % • Permanent atrial fibrillation • QRS ≥120 ms • Biventricular pacing close to 100 % should be achieved Any NYHA Class • LVEF ≤35% • Indication for pulse generator change or ICD therapy with high percentage of ventricular pacing expected Any NHYA Class–LVEF ≤35 % • Permanent atrial fibrillation • Uncontrolled heart rate • Planned AV node ablation

Class IIa, NYHA III–ambulatory IV LOE C • Indication for pacing and expected pacing >40 % Class IIB, NYHA ambulatory IV LOE B • LVEF ≤30 % • Sinus rhythm • QRS 120-149ms • Non-LBBB morphology

NYHA II–ambulatory IV • LVEF ≤35 % • Sinus rhythm • QRS 120–150 ms • Non-LBBB morphology

NYHA II–ambulatory IV • LVEF ≤35 % • Sinus rhythm • QRS 120–150 ms • Non-LBBB morphology Class IIb, NYHA I LOE C • LVEF ≤30 % • Sinus rhythm • QRS ≥150 ms • LBBB • Ischaemic aetiology Class III

NYHA I–II • Non-LBBB morphology • QRS <150 ms

Any NYHA class • Sinus rhythm • QRS <120 ms

ACC = American College of Cardiology; AHA = American Heart Association; AV = atrioventricular; CRT = cardiac resynchronisation therapy; EHRA = European Heart Rhythm Association; ESC = European Society of Cardiology; HRS = Heart Rhythm Society; ICD = implantable cardioverter-defibrillator; LBBB = left bundle branch block; LOE = level of evidence; LVEF = left ventricular ejection fraction. Source: Brignole et al., 2013 and Tracy et al., 2012.13,14

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Device Therapy Figure 1: Models Showing Hazard Ratios and their 95 % Confidence Intervals for the Effects of Cardiac Resynchronisation Therapy vs Control A

Mortality endpoint

Hazard ratio for CRT

2.5

Smoothed estimate 95 % bootstrap confidence bounds

2.0 1.5 1.00 0.5 00 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 QRS duration

Mortality/HFH endpoint

Hazard ratio for CRT

2.5

Smoothed estimate 95 % bootstrap confidence bounds

2.0 1.5 1.00

prolonged QRS duration (> 150 ms) and LBBB. However, guidelines recommend less strongly expansion of CRT to include patients with less severe heart failure and some QRS morphologies other than LBBB. Both MADIT-CRT10 and the REVERSE trial11 included low percentages of patients with NYHA class I heart failure (15 % and 18 %, respectively). Neither of these trials demonstrated a significant advantage in terms of patient outcomes in this population, although REVERSE did show improved ventricular size and function in CRT patients. Solomon et al., also as part of the MADIT-CRT trial, did show evidence of LV reverse remodelling in these patients.16 A later post hoc analysis of MADIT-CRT was able to demonstrate the NYHA class I patients with ischaemic aetiology and LVEF ≤30 % had a 53 % relative risk reduction in heart failure events or death versus ICD only.17 No benefit was observed in non-LBBB patients. This finding prompted the ACC/AHA/HRS guidelines to add a class IIb recommendation for CRT-D in patients with NYHA class I heart failure, QRS duration ≥150 ms, LBBB and ischaemic aetiology.14 Currently, this is the only indication for CRT in NYHA class I patients; however, with expanding utilisation in this patient population other subgroups who might benefit are likely to emerge. CRT therapy has been suggested for patients with QRS prolongation and non-LBBB morphologies, but trial data are mixed in this regard. An analysis of data from the MIRACLE and Contak-CD trials showed

0.5 00 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 QRS duration

A. The relationship between the effect of cardiac resynchronisation therapy on all-cause mortality and QRS. B. The corresponding relationship for heart failure hospitalisation (HFH) or death. The intersection of the 95 % confidence interval and the line indicating a hazard ratio of 1.0 (no effect) indicates the QRS duration above which there is a high certainty of response. From: Cleland JG, et al. Eur Heart J 2013;34:3547–56.21

Rhythm Association (EHRA), Heart Rhythm Society (HRS), American College of Cardiology (ACC), American Heart Association (AHA), European Society of Cardiology (ESC) and Heart Failure Society of America (HFSA) was published in 2012 regarding preoperative evaluation and operative management.2 All patients considered for CRT are recommended to undergo careful pre-implant screening including comorbidities, routine labs, functional assessment, qualityof-life measurement, echocardiogram for quantification of LVEF and cardiac size, and electrocardiogram (ECG) to document QRS duration and morphology. Additionally, optimal medical therapy per current guidelines should be instituted and stable. Both the ESC/EHRA13 and ACC/AHA/HRS14 guidelines have class I recommendations for CRT-D in patients with NYHA II, III and ambulatory class IV heart failure with LVEF ≤35 %, sinus rhythm, QRS duration ≥150 ms and LBBB. Chronic RV pacing has also become an accepted indication for CRT. Additional recommendations are summarised in Table 1.

New Developments in Cardiac Resynchronisation Therapy As both CRT-D and CRT-P have become broadly accepted, attention is now turning to improving rates of response and how this goal can be achieved. Ideally CRT patients will have ventricular pacing as close to 100 % of the time as possible.15 Recent areas of interest for maximising CRT response include patient selection, optimised and individualised lead placement, device programming and new technologies for delivering CRT.

Patient Selection As demonstrated by subgroup analyses of the studies reviewed above, the best outcomes with CRT were observed among patients with very

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no improvement in symptoms, 6-minute walk distance or quality of life scores after 6 months of follow-up in RBBB patients.18 Both MADITCRT and RAFT increased heart failure event-free survival rates in LBBB patients but not those with right bundle branch block (RBBB) or intraventricular conduction delay (IVCD).16,19 However, the REVERSE trial showed a benefit of CRT among patients with RBBB and mild HF.20 In addition, a large individual patient meta-analysis of multiple randomised trials showed that QRS duration was the best predictor of clinical response with CRT independent of QRS morphology (see Figure 1).21 Given these conflicting results, interest remains to better identify nonLBBB heart failure patients who will best benefit from CRT. In this regard, pacing at sites of late mechanical or electrical delay may be particularly important for these lower response candidates as discussed below. QRS duration that best predicts CRT response also remains an active area of interest. Randomised trials have consistently shown maximum benefit from CRT in those with QRS duration ≥150 ms.11,16,19 More recently the trend has been to apply the ≥150 ms cutoff more strictly for patients with lesser degrees of heart failure (NYHA class I/II) and non-LBBB QRS morphologies, while pursuing CRT for patients with QRS duration >120 ms for patients who are more ill (NYHA class III/ambulatory class IV).22

Individualising Lead Placement LV lead implantation via the coronary sinus (CS) is the established technique for transvenous implementation of CRT. Lateral or posterolateral LV position has long been preferred; the results of large multicentre studies have shown that apical positions are the anatomic site associated with worst outcomes.23,24 This technique for CRT delivery has been limited by individual patients’ unique anatomic variations with regard to distribution and size of CS branch vessels. The only alternative to transvenous CS cannulation has been surgical placement of epicardial LV leads, an approach with significantly increased risk due to the invasive nature of the procedure. Recently, an endocardial approach using a transseptal puncture and with a lead crossing the mitral valve has been explored (Alternate Site

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Cardiac Resynchronisation [ALSYNC] trial), but this is still considered investigational (see Figure 2).

Figure 2: Endocardial Atrial Transseptal Approach

In addition to the use of multipolar leads, attention has been turned towards optimising traditional lead placement. Several approaches have been explored, including identifying areas of LV scar, assessing the latest mechanical or electrical LV activation and new techniques for delivery, including multi-site LV pacing.

Mechanical Synchrony Despite general assumptions regarding LV lead placement on the lateral/posterolateral wall, optimal placement in fact varies between patients due to differences in underlying heart disease and site of maximal electrical and/or mechanical delay.25 Echocardiographic imaging, most recently using speckle tracking, has been used to identify sites of latest LV mechanical activation. In the Targeted Left Ventricular Lead Placement to Guide Resynchronisation Therapy (TARGET) trial, Khan et al. performed speckle tracking radial strain imaging on 220 patients prior to undergoing CRT implant.26 Patients were then randomised to standard LV lead placement or implant at the latest site of mechanical activation as identified by echocardiogram. The latter group demonstrated a significantly greater response rate at 6 months (70 % versus 55 %; p=0.031) as defined by reduction of ≥15 % in LV end-systolic volume and greater reduction in NYHA class. The Speckle Tracking Assisted Resynchronisation Therapy for Electrode Region (STARTER) trial used similar techniques to optimise LV lead placement and demonstrated a greater event-free survival (hazard ratio 0.48; p=0.006).27 Although these trials demonstrate the promise of this approach to CRT delivery, the increased time associated with screening in this manner and the percentage of patients who cannot undergoing speckle-tracking imaging due to inadequate image quality (11 % in TARGET)26 have limited its utility. Additionally controversy exists regarding whether speckle tracking is the ideal measure of latest site of mechanical contraction. Thus, although promising as a means to increase CRT response rates, this technique requires further study.

Scar Imaging Imaging, to identify both location and extent of transmural scar, has been suggested as a means to predict clinical response and guide lead placement. Those with greater scar burden are less likely to show a clinical response to CRT28 and patients with non-ischaemic aetiology of heart failure show greater degrees of improvement in LVEF and reverse remodelling compared with ischaemic cardiomyopathy.4 Both single-photon emission CT and, more recently, contrast-enhanced MRI have been used to identify areas of transmural scar. Presence of scar in the posterior–lateral LV, the region typically targeted for LV lead placement, was shown to reduce rates of clinical response and reverse remodelling of the LV in several trials.29–32 An LV lead with its tip in such an area of scar is less likely to effectively pace the LV.33 Despite these findings, pre-implant cardiac MRI remains uncommon practice due to expense, inconvenience and inability to perform in patients with an existing pacemaker or defibrillator.

Electrical Dyssynchrony Another recent area of study is targeting the area of latest electrical activation, most commonly assessed by the QLV interval. Defined as the time from onset of QRS on surface ECG to the first large peak of the LV electrogram (EGM),34 this measurement is obtained at time of CRT implant. Among 426 patients, Gold et al. observed that lead placement in the highest quartile of QLV measurement (QLV ≥120 ms)

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The left ventricle lead was inserted through an atrial transseptal puncture and located in the medial lateral region of the left ventricle. AP = anteroposterior projection; LAO = left anterior oblique projection; LV = left ventricle lead; RA = right atrium lead; RV: right ventricle lead.

Figure 3: Changes in Left Ventricular End-systolic Volume, Left Ventricular End-diastolic Volume, Ejection Fraction and Quality of Life from Implant Baseline to 6 Months for the QLV Quartiles LVESV

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The data were presented as median ± interquartile range (box). QOL = quality of life; LVEDV = left ventricular end-diastolic volume; LVESV = left ventricular end-systolic volume. From: Gold MR et al. Eur Heart J 2011;32:2516–24.34

was strongly associated with both echocardiographic improvement (reduction in LV end-systolic volume) and improved clinical outcomes as measured by quality-of-life questionnaires (see Figure 3). These results were confirmed by a substudy of the SmartDelay Determined AV Optimisation (SmartAV) trial, which showed longer QLV durations were strongly associated with positive reverse remodelling response to CRT (≥15 % reduction in LV end-systolic volume)35 and even greater improvement was observed with long QLV and optimised AV delays. Other recent trials have shown that the longest QLV intervals (>95 ms) are associated with greater acute haemodynamic improvements (LV dP/dt max).36 Thus targeting the site of latest electrical activation, as defined by a QLV interval greater than the median of 95 ms, can improve patient response to CRT. Subgroup analyses from these trials show that this is a robust predictor of response, even among subjects with non-LBBB, ischaemic aetiology or QRS duration <150 ms. The ratio of QLV to QRS duration has also been used as a measure of LV electrical delay and this predicts CRT outcomes.37

Multi-site Left Ventricular Pacing Conventional delivery of CRT involves pacing the LV from a single site. Small trials have suggested that CRT nonresponders might benefit from placement of an additional LV lead to achieve multi-site

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Device Therapy LV pacing. So-called triventricular pacing, referring to the number of sites of stimulation, may be useful, especially in those with enlarged left ventricles and intraventricular conduction delay.22 A small randomised trial of 54 patients with conventional indications for CRT performed by Lenarczyk et al. showed significant improvements in NYHA class, VO2 max and 6-minute walk distance and response rate in triventricular versus standard CRT groups.38 Another small trial demonstrated benefit of the triventricular strategy in patients with permanent atrial fibrillation.39 These studies did not observe significant increases in procedural time, fluoroscopy exposure or complications associated with implantation of an additional LV lead. In 2012, Ginks et al. examined LV endocardial and multi-site pacing in 10 patients with standard indications for CRT.40 The patients first underwent complete electrophysiology study including non-contact mapping of LV endocardium for areas of scar. Response to conventional CRT pacing was then compared with LV endocardial and multi-site pacing. Acute haemodynamic improvement, as measured by change in LV dP/ dt, showed a 26 % increase from baseline with standard biventricular pacing, 37 % increase with LV endocardial pacing (p<0.0005 compared with standard biventricular pacing) and 47 % increase with triventricular pacing (p=0.08 compared with LV endocardial pacing). Thus, there was a statistically significant improvement with LV endocardial pacing and a trend towards even further improvement with multi-site pacing. Although this study was too small to identify differences between patient groups, the authors do note that those patients with myocardial scar and less QRS prolongation responded better to LV endocardial and triventricular pacing. This study did not utilise clinical endpoints and was also limited by the requirement for invasive testing prior to device implant. Pappone et al. found improvement in LV dP/dt and reduction of QRS duration by 22 % with multi-site LV pacing in 2000,41 and more recently has shown that multiple other haemodynamic metrics also improve.42 Generally lacking in the studies of triventricular pacing, however, is proof of clinical benefit. Based on these promising pre-clinical results there are two ongoing randomised trials, Triple-Site versus Standard Cardiac Resychronisation Therapy (TRUST CRT)43 and Dual Site Left Ventricular Pacing (DIVA), for which results are not available. As yet there are no results from a large RCT that prove the benefit of this approach. The Dual Site LV Pacing in CRT Non-Responders (V3) trial currently underway will enrol 84 patients at multiple French hospitals classified as non-responders to CRT and randomise to implant of an additional LV lead or continuing standard CRT.44 The primary endpoint of this study will be heart failure clinical composite score at follow-up. Moreover, it will also be important to compare these results with the simpler approach of multi-point pacing from a quadripolar lead as described below.

Technological Advances After appropriate patient selection, the other major area of focus for decreasing CRT non-responder rates is optimal lead placement, including the use of novel technologies to improve CRT delivery. These new techniques represent hope for the effective delivery of CRT in the 5–8 % of patients in whom a LV lead cannot be delivered and the 15–20 % in whom the lead position is suboptimal.45 Several exciting new technologies have recently become available commercially or are being studied with promising results and these will be reviewed briefly here.

Leadless Left Ventricular Pacing Although not yet introduced commercially, a system for leadless LV endocardial pacing is being developed and studied. The WiCS-LV system (EBR Systems, Inc.) is currently undergoing safety and feasibility trials.

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This system uses ultrasound waves to pace the LV endocardium using acoustic energy. A small electrode is implanted in the LV endocardial wall via a retrograde aortic approach and a pulse generator is implanted subcutaneously in an overlying intracostal space.46 The system senses the RV pacing from a concurrently implanted traditional dual chamber pacemaker or defibrillator and triggers LV stimulation from the RV pacing spike. Ultrasound pulses delivered from the pulse generator to the endocardial electrode to induce LV contraction. In the Wireless Stimulation Endocardially for CRT (WiSE-CRT) trial, Aurrichio et al. reported 1- and 6-month results after implanting this device in 17 heart failure patients of three types: those with failed traditional LV lead implantation via the CS, non-responders with a functional LV lead and patients with a dual-chamber device, but no previous attempt at LV lead placement.47 System implant was successful in 13 (76.5 %); complications included failure of LV capture in one (5.8 %) and pericardial effusion in three (17.6 %). The authors report a significant increase in LVEF at 6-month follow-up, shortened QRS duration at 1 and 6 months and improvement of at least one NYHA functional class in twothirds of patients. Although the results of this small trial are promising as an alternative to traditional LV lead placement, they also demonstrate safety and efficacy concerns of a new device that require further study before widespread utilisation can be considered.

Alternate Approaches to Left Ventricular Lead Placement Other techniques for LV endocardial pacing have also been studied. As discussed above, the ALSYNC trial is the first large prospective multicentre trial of LV endocardial pacing. However, earlier pilot studies were performed. Betts et al. describe a series of 10 patients with either failed CS lead placement or nonresponders due to suboptimal lead positioning in whom LV endocardial leads were placed using transseptal puncture of the interventricular septum.48 This technique, performed via the subclavian vein, required coronary angiography and ventriculography prior to the procedure. An active fixation lead was then delivered to the LV lateral endocardial wall successfully in nine of 10 patients reported. This technique has the obvious disadvantage of requiring lifelong anticoagulation to avoid thrombus formation on the LV lead. Response to LV pacing was generally good with eight out of nine patients improving at least one NYHA functional class and five out of nine showing decrease in LV end-systolic volume and increase in LVEF. Complications included failure to capture at 3-month follow-up, VT during procedure requiring external cardioversion and VT storm necessitating emergency cardiac transplant. This technique is undergoing further study in the Interventricular Septal Puncture for Cardiac Resynchronisation Therapy to Treat Heart Failure (LV-CONSEPT) trial. The atrial transseptal approach has also been reported;49–51 however, this technique has been limited by technical difficulties with the procedure. Overall, although LV endocardial pacing is promising for those with those patients in whom LV lead placement is not possible or CS anatomy does not provide an optimal branch location there has not yet been a system or technique for delivery that can allow its widespread utilisation.

Quadripolar Pacing Leads A significant development in delivery of CRT that is commercially available in the US is the quadripolar LV lead. Utility of traditional bipolar LV leads has been limited by high pacing thresholds and phrenic nerve stimulation resulting from limited potential pacing vectors. Quadripolar LV pacing leads have now been introduced by St Jude Medical, Medtronic and Boston Scientific. These leads expand

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pacing options relative to bipolar leads by providing between 10 and 17 potential vectors.52–54 Increasing options for pacing vectors creates greater ability to achieve LV capture at lower threshold and to avoid phrenic nerve stimulation by ‘programming around’ these complications. An additional advantage of quadripolar LV leads is their availability with several lead tip shapes (straight, straight with tines and fixed ‘S’ or hook-type curves) for greater lead stability and reduced chance of lead dislodgement. Phrenic nerve stimulation has been reported in up to 20 % of CRT patients with bipolar leads,55 a complication that frequently results in the LV lead being programmed ‘off’, thus eliminating potential for CRT delivery. A multi-centre registry of quadripolar LV leads published in 2014 found that among 721 patients receiving LV leads (347 quadripolar; 364 bipolar), more patients experienced phrenic nerve stimulation with quadripolar (16 %) versus bipolar (11.6 %) leads.56 Device reprogramming using alternate pacing vectors, however, eliminated phrenic nerve stimulation in all patients with quadripolar leads but only 60 % (24/40) with bipolar leads. Lead repositioning was necessitated in those with bipolar leads in whom phrenic nerve stimulation was not remedied by device reprogramming, thus exposing them to the inherent dangers of repeat invasive procedures. This registry also demonstrated lower rates of lead dislodgement with quadripolar (1.7 %) compared with bipolar (4.6 %) leads. Finally, the pacing threshold at implant was significantly lower with quadripolar leads, potentially prolonging pulse generator

region of the LV.63 QuickOpt uses the duration of right atrial contraction to set AV delay such that ventricular contraction occurs fully after atrial depolarisation and contraction are complete, setting the paced AV delay as sensed AV delay plus 50 ms.61 AdaptiveCRT calculates AV delay from intracardiac EGMs to fuse LV pacing with intrinsic contraction.62 An active trial evaluating a novel pacing algorithm designed to optimise haemodynamic function weekly is underway.64 Compared with echocardiographic optimisation or fixed AV delays, neither QuickOpt (in the Frequent Optimisation Study Using the QuickOpt Method [FREEDOM]) nor Smart AV Delay (in the SMART-AV trial) improved heart failure measures (reverse remodelling and symptoms). AdaptiveCRT was found to have non-inferior outcomes compared with echocardiography-based optimisation of CRT,62 although this trial does not necessarily present a ‘real world’ comparison as echocardiographic CRT optimisation is uncommon in practice. Although as a whole these trials have not shown significant improvement in heart failure outcomes compared with standard device programming this remains an area of active research. The ongoing Clinical Trial of the SonRtip Lead and Automatic AV–VV Optimisation Algorithm in the PARADYM RF SonR CRT-D (RESPONDCRT) randomises patients to the Sorin SonR CRT optimisation algorithm or the control arm (echocardiographic optimisation).19,64 The primary effectiveness endpoint is based on proportion of responders to CRT therapy at 12 months. Secondary endpoints include freedom from death or heart failure hospitalisation, worsened NYHA class and lead

battery life. Although this study did not find a significant difference in successful implant rates, the relative larger size of quadripolar leads means not all CRT patients will have CS branch vessel anatomy suitable for delivery. Recent observational data have suggested a mortality benefit from the use of quadripolar leads, although the mechanism of this benefit is not yet defined.56

electrical performance. The Adaptive CRT algorithm is also being tested in a prospective study of LBBB and normal AV conduction time, which is the group that benefited most from this therapy.35 Finally, patients with a prolonged QLV interval were shown to benefit from the SMART Delay algorithm.62 Thus, although currently available evidence does not suggest benefit from routine AV and VV optimisation there may remain a role for this practice in select patients.

Device Programming Improved algorithms for device programming demonstrates promise in improving CRT delivery. In addition to increasing the percentage of paced beats, these algorithms have focused on atrioventricular (AV) and interventricular (VV) interval optimisation, which have the potential to improve CRT response rates and possibly increase the magnitude of response.28 AV optimisation aims to ensure complete LV filling prior to contraction; VV optimisation attempts to minimise ventricular mechanical dyssnchrony.57 AV and VV optimisation is speculated as having a particularly important role in improving haemodynamic response when LV lead positioning is not considered optimal.58 Techniques for AV optimisation traditionally have used echocardiographic parameters, including measuring aortic and mitral velocity-time integral with multiple AV intervals,59 but these methods are costly and time consuming. Greater attention is now being paid to automatic AV and VV optimisation through device-based algorithms. Device manufacturers have developed proprietary algorithms, including Smart AV Delay (Boston Scientific),60 QuickOpt (St Jude Medical)61 and AdaptiveCRT (Medtronic).62 Smart AV Delay considers intrinsic AV intervals, intraventricular timing and LV lead location, and it is designed to achieve fusion between intrinsic conduction through the interventricular septum and paced activation of the latest activated

Prinzen FW, Vernooy K, Auricchio A, Cardiac resynchronization therapy: state-of-the-art of current applications, guidelines, ongoing trials, and areas of controversy. Circulation 2013;128:2407–18. Daubert JC, Saxon L, Adamson PB, et al. 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. Europace 2012;14:1236–86.

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Conclusion CRT is an important and well-proven procedure for the management of patients with heart failure and QRS prolongation. The impact of CRT, however, has been limited by inadequate delivery of and unpredictable response to therapy. Recent efforts have focused on patient selection, individualising LV lead placement and novel technologies to improve therapy response rates. Ongoing research and development efforts hope to broaden indications for CRT by improving prediction algorithms for CRT response and by delivering therapy in optimal fashion. n

Clinical Perspective • C ardiac resynchronisation therapy (CRT) is an important management strategy for patients with New York Health Association (NYHA) class II–IV heart failure and left bundle branch block (LBBB) whose indications are expanding. • New technologies, including leadless and multi-site pacing, offer hope for reducing the high (20–40 %) rate of non-responders to CRT. • Individualised left ventricular (LV) lead placement to reduce mechanical and/or electrical dyssynchrony may also have a role in optimising delivery of CRT.

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defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–50. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–49. Birnie DH, Ha A, Higginson L, et al. Impact of QRS morphology and duration on outcomes after cardiac resynchronization therapy: Results from the Resynchronization-Defibrillation

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Electrophysiol 2014;7:968–77. 26. Khan FZ, Virdee MS, Palmer CR, et al. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial. J Am Coll Cardiol 2012;59:1509–18. 27. Saba S, Marek J, Schwartzman D, et al. Echocardiographyguided left ventricular lead placement for cardiac resynchronization therapy: results of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region trial. Circ Heart Fail 2013;6:427–34. 28. Pastromas S, Manolis AS, Cardiac resynchronization therapy: Dire need for targeted left ventricular lead placement and optimal device programming. World J Cardiol 2014;6:1270–7. 29. Bleeker GB, Kaandorp TA, Lamb HJ, et al. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation 2006;113:969–76. 30. White JA, Yee R, Yuan X, et al. Delayed enhancement magnetic resonance imaging predicts response to cardiac resynchronization therapy in patients with intraventricular dyssynchrony. J Am Coll Cardiol 2006;48:1953–60. 31. Rodriguez LM, Timmermans C, Nabar A, et al. Variable patterns of septal activation in patients with left bundle branch block and heart failure. J Cardiovasc Electrophysiol 2003;14:133–41. 32. Adelstein EC, Saba S, Scar burden by myocardial perfusion imaging predicts echocardiographic response to cardiac resynchronization therapy in ischemic cardiomyopathy. Am Heart J 2007;153:105–12. 33. Jaffe LM, Morin DP. Cardiac resynchronization therapy: history, present status, and future directions. Ochsner J 2014;14:596–607. 34. Gold MR, Birgersdotter-Green U, Singh JP, et al. The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy. Eur Heart J 2011;32:2516–24. 35. Gold MR, Yu Y, Singh JP, et al. The effect of left ventricular electrical delay on AV optimization for cardiac resynchronization therapy. Heart Rhythm 2013;10:988–93. 36. Zanon F, Baracca E, Pastore G et al. Determination of the longest intrapatient left ventricular electrical delay may predict acute hemodynamic improvement in patients after cardiac resynchronization therapy. Circ Arrhythm Electrophysiol 2014;7:377–83. 37. Kandala J, Upadhyay GA, Altman RK, et al. Electrical delay in apically positioned left ventricular leads and clinical outcome after cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2013;24:182–7. 38. Lenarczyk R, Kowalski O, Kukulski T, et al. Mid-term outcomes of triple-site vs. conventional cardiac resynchronization therapy: a preliminary study. Int J Cardiol 2009;133:87–94. 39. Leclercq C, Gadler F, Kranig W, et al. A randomized comparison of triple-site versus dual-site ventricular stimulation in patients with congestive heart failure. J Am Coll Cardiol 2008;51:1455–62. 40. Ginks MR, Shetty AK, Lambiase PD, et al. Benefits of endocardial and multisite pacing are dependent on the type of left ventricular electric activation pattern and presence of ischemic heart disease: insights from electroanatomic mapping. Circ Arrhythm Electrophysiol 2012;5:889–97. 41. Pappone C, Rosanio S, Oreto G, et al. Cardiac pacing in heart failure patients with left bundle branch block: impact of pacing site for optimizing left ventricular resynchronization. Ital Heart J 2000;1:464–9. 42. Pappone C, Ćalović Ž, Vicedomini G, et al. Multipoint left ventricular pacing improves acute hemodynamic response assessed with pressure-volume loops in cardiac resynchronization therapy patients. Heart Rhythm 2014;11:394–401. 43. Lenarczyk R, Kowalski O, Sredniawa B, et al. Triple-site versus standard cardiac resynchronization therapy study (TRUST CRT): clinical rationale, design, and implementation. J Cardiovasc Electrophysiol 2009;20:658–62. 44. Bordachar P, Alonso C, Anselme F, et al. Addition of a second LV pacing site in CRT nonresponders rationale and design of the multicenter randomized V(3) trial. J Card Fail 2010;16:709–13. 45. Gamble JH, Bashir Y, Rajappan K, Betts TR, Left ventricular endocardial pacing via the interventricular septum for cardiac resynchronization therapy: first report. Heart Rhythm

2013;10:1812–4. 46. Auricchio A, Delnoy PP, Regoli F, et al. First-in-man implantation of leadless ultrasound-based cardiac stimulation pacing system: novel endocardial left ventricular resynchronization therapy in heart failure patients. Europace 2013;15:1191–7. 47. Auricchio A, Delnoy PP, Butter C, et al. Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the wireless stimulation endocardially for CRT (WiSE-CRT) study. Europace 2014;16:681–8 48. Betts TR, Gamble JH, Khiani R, et al. Development of a technique for left ventricular endocardial pacing via puncture of the interventricular septum. Circ Arrhythm Electrophysiol 2014;7:17–22. 49. Nuta B, Lines I, MacIntyre I, Haywood GA. Biventricular ICD implant using endocardial LV lead placement from the left subclavian vein approach and transseptal puncture via the transfemoral route. Europace 2007;9:1038–40. 50. Bordachar, , et al. Left ventricular endocardial stimulation for severe heart failure. J Am Coll Cardiol 2010.56(10):747–53. 51. Bordachar P, Derval N, Ploux S, et al. The Jurdham procedure: endocardial left ventricular lead insertion via a femoral transseptal sheath for cardiac resynchronization therapy pectoral device implantation. Heart Rhythm 2012;9:1798–804. 52. Shetty AK, Duckett SG, Bostock J, et al. Initial single-center experience of a quadripolar pacing lead for cardiac resynchronization therapy. Pacing and Clinical Electrophysiology 2011;34:484–9. 53. Biffi M, Foerster L, Eastman W, et al. Effect of bipolar electrode spacing on phrenic nerve stimulation and left ventricular pacing thresholds: an acute canine study. Circ Arrhythm Electrophysiol 2012;5:815–20. 54. Attain Performa Product Information, Medtronic, Editor. 2013;1–2. 55. Biffi M, Moschini C, Bertini M, et al. Phrenic stimulation: a challenge for cardiac resynchronization therapy. Circ Arrhythm Electrophysiol 2009;2:402–10. 56. Behar JM, Bostock J, Zhu Li AP, et al. Cardiac resynchronization therapy delivered via a multipolar left ventricular lead is associated with reduced mortality and elimination of phrenic nerve stimulation: long-term followup from a multicenter registry. J Cardiovasc Electrophysiol 2015;26:540–6. 57. Chandraprakasam S, Mentzer GG. Recent advances in the optimization of cardiac resynchronization therapy. Curr Heart Fail Rep 2015;12:48–60. 58. Bogaard MD, Doevendans PA, Leenders GE, et al. Can optimization of pacing settings compensate for a nonoptimal left ventricular pacing site? Europace 2010;12:1262–9. 59. Jansen AH, Bracke FA, van Dantzig JM, et al. Correlation of echo-Doppler optimization of atrioventricular delay in cardiac resynchronization therapy with invasive hemodynamics in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2006;97:552–7. 60. Ellenbogen KA, Gold MR, Meyer TE, et al. Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation 2010;122:2660–8. 61. Abraham WT, Gras D, Yu CM, et al. Rationale and design of a randomized clinical trial to assess the safety and efficacy of frequent optimization of cardiac resynchronization therapy: the Frequent Optimization Study Using the QuickOpt Method (FREEDOM) trial. Am Heart J 2010;159:944–8.e1. 62. Birnie D1, Lemke B, Aonuma K, et al. Clinical outcomes with synchronized left ventricular pacing: analysis of the adaptive CRT trial. Heart Rhythm 2013;10:1368–74. 63. Stein KM, Ellenbogen KA, Gold MR, et al. SmartDelay determined AV optimization: a comparison of AV delay methods used in cardiac resynchronization therapy (SMART-AV): rationale and design. Pacing Clin Electrophysiol 2010;33:54–63. 64. Brugada J, Brachmann J, Delnoy PP, et al. Automatic optimization of cardiac resynchronization therapy using SonR-rationale and design of the clinical trial of the SonRtip lead and automatic AV-VV optimization algorithm in the paradym RF SonR CRT-D (RESPOND CRT) trial. Am Heart J 2014;167:429–36.

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Device Therapy

Sex Differences in Utilisation and Response to Implantable Device Therapy Deepika Narasimha and Anne B Curtis Department of Medicine, University at Buffalo, Buffalo, New York, US

Abstract Multiple studies have demonstrated that implantable cardioverter-defibrillators (ICDs) and cardiac resynchronisation therapy (CRT) provide significant mortality and morbidity benefits to eligible patients irrespective of gender. However, female patients are less likely to receive this life-saving therapy and are significantly under-represented in cardiac device trials. Various performance improvement programmes have proved that this gender disparity can be reduced and these therapies should be offered to all eligible patients regardless of sex. Efforts should be made to enrol more women in clinical trials and sex-specific analysis in medical device clinical studies should be encouraged. In this article we review the data on sex differences in clinical outcomes with ICDs and CRT and explore the reasons for this sex-based disparity.

Keywords Implantable cardioverter-defibrillator, cardiac resynchronisation therapy, sudden cardiac death, gender differences in cardiac device utilisation Disclosure: Professor Curtis has received consulting fees and honoraria for lectures from Medtronic Inc. and advisory board fees and honoraria for lectures from St Jude Medical. Dr Narasimha has no conflicts of interest to declare. Received: 29 June 2015 Accepted: 12 August 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(2):129–35 Access at: www.AERjournal.com Correspondence: Anne B Curtis, Charles and Mary Bauer Professor and Chair, UB Distinguished Professor, Department of Medicine, University at Buffalo, Buffalo General Hospital, D2-76, 100 High Street, Buffalo, NY 14203, US. E: abcurtis@buffalo.edu

Implantable cardiac devices such as implantable cardioverterdefibrillators (ICDs) and cardiac resynchronisation therapy (CRT) devices lead to improved survival and better clinical outcomes in appropriately selected patients with heart failure (HF) with a reduced ejection fraction (EF). Although there are significant sex differences in the aetiology, pathophysiology and clinical course of HF, clinical practice guidelines for cardiac device therapy are not sex-specific and are based on clinical trials where the majority of patients enrolled were men. In this review, we explore sex differences in clinical outcomes and utilisation of ICDs and CRT and explore the reasons for these disparities.

and at least New York Heart Association (NYHA) class II HF had better survival with ICDs compared with medical therapy plus amiodarone or medical therapy alone.5 The SCD-HeFT trial included patients with non-ischaemic cardiomyopathy, which further expanded the patient population eligible for ICD therapy. Table 1 lists the major ICD clinical trials. Of note, in all of these trials, less than 25 % of the total population enrolled were women.

Implantable Cardioverter-Defibrillators

Curtis et al.6 analysed a 5 % national sample of patients from the US Centers for Medicare & Medicaid Services eligible for ICD therapy and found that, in the secondary prevention ICD cohort, there was a statistically significant mortality benefit for both sexes even after adjustment for other factors.

The annual incidence of sudden cardiac death (SCD) in the US is estimated to be 300,000 to 450,000.1 A major risk factor for SCD is HF with reduced EF. There have been several large randomised controlled studies that have demonstrated a mortality benefit from ICDs in eligible patients for both primary and secondary prevention of SCD. However, under-representation of women in these trials has made it somewhat difficult to determine the sex-specific survival benefit of ICD therapy.

Evidence for the Use of ICD Therapy for Primary and Secondary Prevention of SCD The Antiarrhythmics versus Implantable Defibrillators trial (AVID), Cardiac Arrest Study Hamburg (CASH) trial and the Canadian Implantable Defibrillator Study (CIDS) all showed a survival benefit from ICDs in patients who had already survived a potentially life-threatening ventricular arrhythmia. Multiple primary prevention trials (the Multicentre Automatic Defibrillator Implantation Trial [MADIT I], the Multicentre Unsustained Tachycardia Trial [MUSTT] and MADIT II) all showed improved outcomes with ICD therapy in patients with a history of myocardial infarction (MI) and significant left ventricular (LV) dysfunction.2–4 Similarly, in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), patients with LVEF <35 %

Curtis-FINAL.indd 129

Sex Differences in Outcomes with ICD Therapy Sex Differences in ICD Therapy for Secondary Prevention of SCD

Sex Differences in Primary Prevention ICDs In the MUSTT trial,3 a total of 301 women were enrolled, and they constituted 10 % (68) of the randomised patients and 16 % (233) of those followed in the registry. Overall, there was no statistically significant difference in mortality between men and women in the electrophysiology (EP)-guided therapy group (21 % versus 32 %; p=0.13) or in the registry (20 % versus 27 %; p=0.15). However, there was a trend towards increased mortality in women, although the trial did not have sufficient power to detect gender differences due to the small number of women enrolled. In MADIT-II, 1,232 patients with ischaemic cardiomyopathy were enrolled of which 192 (16 %) were women.4 Patients received ICDs versus standard medical therapy, with a total of 119 women receiving ICD therapy. Women were noted to have more advanced HF, as well as

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Device Therapy Table 1: Major Implantable Cardioverter-Defibrillator Trials and their Outcomes Study

Total

Indication

% Women Groups

Mortality

Population MADIT I2

196

Primary prevention 8

Antiarrhythmic drug therapy versus ICD

of SCD MADIT II4

1,232

not stratified by sex

Primary prevention 16

ICD versus medical therapy

of SCD SCD-HeFT5

2,521

MUSTT3

704

DEFINITE7

458 1,885

Men: HR 0.66; p=0.011 Women: HR 0.57; p=0.132

Primary prevention 23

ICD versus medical therapy + amiodarone

Men: HR 0.73; CI [0.57–0.93]

of SCD

versus medical therapy alone

Women: HR 0.96; CI [0.58–1.61]

Primary prevention 10

Standard medical therapy versus

Mortality in EP-guided therapy group – men: 21 %

of SCD

medical therapy plus EP-guided therapy

women: 32 % (p=0.13)

Primary prevention 29

Medical therapy versus ICD

Men: HR 0.49; CI [0.27–0.90]; p=0.019

of SCD AVID6

54 % relative reduction in mortality in ICD group;

Women: HR 1.14; CI [0.50–2.64]; p=0.754

Secondary

Antiarrhythmic drug therapy versus ICD

prevention of SCD

Mortality in women – 15.5 %, men: 14.4 % compared with 24.5 % in patients without ICD

AVID = Antiarrhythmics Versus Implantable Defibrillators; DEFINITE = Defibrillators in Non-Ischaemic Cardiomyopathy Treatment Evaluation ; EP = electrophysiology; ICD = implantable cardioverter-defibrillator; MADIT = Multicentre Automatic Defibrillator Implantation Trial; MUSTT = Multicentre Unsustained Tachycardia Trial; SCD = sudden cardiac death; SCD-HeFT = Sudden Cardiac Death in Heart Failure Trial.

Figure 1: Adjusted Mortality Rates for Women with and without an ICD

of women enrolled was so low. Similarly, the Defibrillators in NonIschaemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial reported a mortality benefit for men in the ICD group but not women (men: HR 0.49; 95 % CI [0.27–0.90]; p=0.019; women: HR 1.14; 95 %

0.80

CI [0.50–2.64]; p=0.754).7 The study was not powered to detect sex differences, and only 63 women were randomised to an ICD (total number of patients in the study was 458, including 132 women).

0.70 0.60 0.50

No ICD

Adjusted mortality 0.40 rate

ICD

0.30 0.20 0.10 0.00 Number at risk No ICD ICD

84 182

44 62

Years of follow-up 490 490

327 352

244 283

154 232

The cumulative risk of death in women with an implantable cardioverter-defibrillator (ICD) was less than that of women without an ICD. At 1 year, mortality was 21.7 % in women with an ICD and 28.3 % in women without an ICD. At 3 years, adjusted mortality was 44.3 % in women with an ICD and 54.5 % in women without an ICD. Reproduced with permission from Zeitler et al.10

a higher incidence of hypertension, diabetes and left bundle branch block (LBBB). The 2-year overall mortality rate as well as the rates for SCD were similar between men and women in the medical therapy arm of the trial. The hazard ratios for ICD effectiveness after adjusting for clinical covariates were similar for men and women (men: HR 0.66; p=0.011; women: HR 0.57; p=0.132). The interaction between gender, mortality and ICD therapy was not significant (p=0.72). SCD-HeFT enrolled a total of 2,521 HF patients (588 [23 %] women) and included patients with both ischaemic and non-ischaemic cardiomyopathy.5 Patients were randomised to amiodarone, placebo or ICD in a 1:1:1 manner, with 185 women receiving an ICD. A post-hoc analysis of the trial revealed a mortality benefit for men but not for women for the primary prevention of SCD. However, it was noted that women had a much lower overall mortality risk compared with men (HR 0.68; 95 % CI [0.55–0.84]; p=0.001). In addition, the trial was not adequately powered to detect sex differences, as the number

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MacFadden et al.8 followed 5,213 Canadian HF patients who received primary and secondary prevention ICDs for up to 1 year. Of the 921 women who received ICDs for primary prophylaxis and 367 who received ICDs for secondary prophylaxis, they found no difference in mortality between men and women. However, women were less likely to receive appropriate ICD shocks. Another observational study of 582 patients (291 men and 291 women propensity matched based on age, EF, indication for ICD therapy and ischaemic versus nonischaemic cardiomyopathy) found no difference in mortality rates between men and women.9 Zeitler et al.10 analysed data from the National Cardiovascular Data Registry (NCDR) ICD Registry, the Get With The Guidelines-HF [GWTG-HF] database, and the Centers for Medicare & Medicaid Services on women eligible for a primary prevention ICD. There were 490 women with primary prevention ICDs who were matched with 490 women without an ICD but who were eligible for a primary prevention ICD. After a median follow-up of 4.6 years, women with ICDs had better survival than women without ICDs (HR: 0.79; 95 % CI [0.66–0.95]; p<0.013) (see Figure 1). Further statistical analyses revealed that the clinical effectiveness of ICD therapy did not vary by sex. Similarly, the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF) study found that ICD and CRT therapy was associated with a similar mortality benefit in both men and women with HF eligible for device therapy.11 Curtis et al.6 analysed a 5 % national sample of patients from the US Centers for Medicare & Medicaid Services eligible for ICD therapy and found that unadjusted analyses showed a significant survival benefit for women in the primary prevention ICD cohort. However, this finding was no longer significant after adjustment for confounding factors. Several meta-analyses have attempted to look into sex-specific outcomes with ICDs, especially for primary prevention of SCD, with

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Sex Differences in Utilisation and Response to Implantable Device Therapy

Table 2: Outcomes of CRT-defibrillator Clinical Trials by Sex Study/Design

Number of Subjects

Enrolment Criteria

Randomisation

HR for Events (95 %; p Value)

COMPANION22

Men: 1,025 (67 %)

LVEF ≤35 %

OMT versus OMT

HR for death – men: 0.63 (0.4–0.9)

Women: 495 (33 %)

NYHA class III–IV

+ CRT-D

women: 0.58 (0.25–1.13)

OMT versus OMT + CRT

HR for death or cardiac hospitalisation –

QRS ≥120 ms CARE-HF23

Men: 597 (73 %)

LVEF ≤35 %

Women: 216 (27 %)

NYHA class III–IV

men: 0.62 (0.49–0.79)

QRS ≥120 ms

women: 0.64 (0.42–0.97)

LVEDD ≥30 mm MADIT CRT27

RAFT28

REVERSE30

Men: 1,367 (75 %)

LVEF ≤30 %

Women: 453 (25 %)

NYHA class I–II

ICD versus CRT-D

men: 0.76 (0.59–0.97)

QRS ≥130 ms

women: 0.37 (0.22–0.61)

Men: 1,490 (83 %)

LVEF ≤30 %

Women: 308 (17 %)

NYHA class II–III

men: 0.82 (0.7–0.95)

QRS ≥120 ms

women: 0.52 (0.35–0.85)

Men: 479 (78.5 %)

LVEF <40 %

Women: 131 (21.5 %)

NYHA class I–II

ICD versus CRT-D

CRT-ON versus CRT-OFF

HR death or HF admission –

HF clinical composite end-point – men: 0.69 (0.43–1.11)

QRS >120 ms MIRACLE24

HR for HF event or death –

women: 0.75 (0.26–2.19)

Men: 216 (67 %)

LVEF <35 %

CRT-ON versus CRT-OFF

Women: 107 (33 %)

NYHA class III–IV

NYHA class, quality of life, exercise capacity: women but not men with CRT experienced longer times to

QRS >130 ms

first HF hospitalisation or death (p=0.157)

CARE-HF = cardiac resynchronisation-heart failure; CRT-D = cardiac resynchronisation therapy with defibrillator; COMPANION = Comparison Of Medical Therapy, Pacing And Defibrillation in Heart Failure; HF = heart failure; ICD = implantable cardioverter-defibrillator; LVEDD = left ventricular end-diastolic dimension; LVEF = left ventricular ejection fraction; MADIT CRT = Multicentre Automatic Defibrillator Implantation Trial with Cardiac Resynchronisation Therapy; MIRACLE = Multicentre InSync Randomised Clinical Evaluation; NYHA = New York Heart Association; OMT = optimal medical therapy; RAFT = Resynchronisation for Ambulatory Heart Failure; REVERSE = Resynchronisation Reverses Remodeling in Systolic Left Ventricular Dysfunction. Reproduced and modified with permission from Tompkins et al.28

conflicting results. In a recent meta-analysis, Ghanbari et al.12 combined data from five major primary prevention trials including MUSTT, MADIT II, SCD-HeFT, DEFINITE and the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT) trial. A total of 3,810 men and 934 women were included in the analysis. A mortality benefit was seen in men receiving ICD therapy compared with medical treatment (HR 0.78; 95 % CI [0.70–0.87]; p<0.001) but not in women (HR 1.01; 95 % CI [0.76–1.33]; p=0.95). Another recent meta-analysis by Santangeli et al.13 analysed data from five major trials (MUSTT, MADIT-II, SCD-HeFT, DEFINITE and the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure [COMPANION] trial, the last of which was a CRT trial). These trials enrolled 7,229 patients of which 23 % (1,630) were women. Women had a similar overall mortality rate, although only men had a statistically significant mortality benefit with prophylactic ICD therapy (men: HR 0.67; 95 % CI [0.58–0.78]; p<0.001; women: HR 0.78, 95 % CI [0.57–1.05]; p=0.1). Women also experienced lower rates of appropriate ICD interventions (HR=0.63; 95 % CI [0.49–0.82]; p<0.001). Under-representation of women in cardiac device trials is a significant problem, with women constituting <25 % of the total enrolled population. The resulting HRs for mortality benefit with ICD therapy in women have wide confidence limits, indicating that the studies were underpowered to detect a significant mortality benefit with ICD therapy in women. There are other differences in outcomes with ICD therapy between men and women beyond mortality. Men with coronary artery disease (CAD) in whom ICDs have been implanted have more ventricular tachycardia/ventricular fibrillation (VT/VF) events as well as more ICD shocks and electrical storms than women.14 Lampert et al.15 reviewed the records of 340 men and 59 women with CAD who received an ICD and followed them for 30±22 months. They found that 52 % of the men experienced sustained VT or VF requiring ICD therapy (p<0.01)

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compared with 34 % of the women. Overall, men also experienced more VT/VF events than the women in the study. Myocardial scarring post-infarction is more often seen in men, and ischaemic scars are frequently the substrate for sustained monomorphic VT. Other studies have demonstrated that men presenting with out-ofhospital sudden cardiac arrest are more likely to have VT/VF versus women (41 % versus 30 %). Women are more likely to have asystole (8.8 versus 7 %) or pulseless electrical activity (24 versus 18 %) than men.16 These findings from various studies could suggest that SCD in women is more often due to non-shockable arrhythmias compared with men. No significant difference has been found in the incidence of VT among men and women with non-ischaemic dilated cardiomyopathy.17 There have also been studies looking at sex differences in complications following cardiac device implantation. Peterson et al.18 identified 161,470 patients from the NCDR ICD Registry, of which women constituted around 27 % (43,655) of the cohort. Women were more likely to have HF, non-ischaemic cardiomyopathy, advanced NYHA class and were more likely to receive CRT-defibrillators (CRT-D) compared with men. Women had a higher in-hospital adverse event rate after ICD implantation than men (4.4 versus 3.3 %; p<0.001). In particular, peri-procedural complications were more common in women, although there was no difference in in-hospital mortality between men and women.

Sex Disparities in ICD Utilisation Hernandez et al.19 analysed data from the GWTG-HF programme and studied 13,034 patients with HF who were eligible for ICD therapy. The study revealed that while around 44 % of eligible (white) men received ICDs, only around 28 % of eligible women received ICD therapy. In addition, after adjustment for patient-related factors, the odds ratios for ICD use were 0.73 for African-American men, 0.62 for Caucasian women and 0.56 for African-American women compared with white

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Device Therapy Figure 2: Kaplan-Meier Survival Curves for Time-to-first Heart Failure Hospitalisation or Death in (A) women and (B) Men Treated with Cardiac Resynchronisation Therapy versus Control 100

% surviving

90 80 70 60 50 Number at risk Control Treatment

72 72

68 71

63 71

60 71

153 156

146 147

141 142

3 4 5 Months since enrolment 58 70

54 69

25 33

100

% surviving

90 80 70 60 50 Number at risk Control Treatment

4 5 Months since enrolment 137 138

134 134

127 132

49 66

Reproduced with permission from Woo et al.24

Cumulative probability of VT/VF/death

Figure 3: Cumulative Probability of VT/VF or Death in Subjects with LBBB who Received CRT-D Based on CRT Response 0.35

Female resp Male resp Female non-resp Male non-resp

0.30

Iog rank p<0.001

Over the past few years there have been ongoing efforts to improve utilisation of implantable cardiac device therapy in eligible female patients. The IMPROVE HF20 study evaluated whether a programme to provide clinical decision-making support tools and educational materials to healthcare providers would lead to similar improvements in adherence to clinical practice guidelines for both male and female patients. This was a prospective study where high-risk patients with HF with reduced EF (<35 %) eligible for treatment with an ICD, CRT or several other guideline-recommended therapies were identified and hospitals were provided with clinical algorithms, pocket cards, patient educational materials and patient assessment forms and were followed for 24 months. The study included a total of 15,170 patients of whom 4,383 (28.9 %) were women. At the end of 2 years, rates of ICD use went up from 40–50 % to 75–80 % and CRT use from 35–40 % to 65–75 % in both men and women. Thus, providing clinical decision-making support and education can lead to better ICD therapy utilisation in eligible patients irrespective of sex. Similarly, Al-Khatib et al. analysed 11,880 patients enrolled in the GWTG-HF program for trends in ICD implantation rates over the past decade and found that with the implementation of the GWTG-HF program, rates of ICD implantation went up overall (around 30 % in 2005 to 42 % in 2007). The greatest increase in ICD use was seen in African–American women (23.3% increase), a group in whom the use of implantable cardiac devices has been extremely low compared with white men.21

Cardiac Resynchronisation Therapy Several studies, including COMPANION and the Cardiac ResynchronisationHeart Failure (CARE-HF) study, have demonstrated a significant mortality benefit with CRT in eligible patients.22,23 In addition to these studies, trials such as the Multicentre InSync Randomised Clinical Evaluation (MIRACLE), Pacing Therapies in Congestive Heart Failure (PATH-CHF), and Multisite Stimulation in Cardiomyopathies (MUSTIC) showed that CRT therapy in HF patients led to significant improvements in clinical symptoms, NYHA class and quality of life.24–26 Table 2 lists the major CRT trials and the percentage of women enrolled in each trial.

Sex Differences in Outcomes with CRT Therapy

0.25

Compared with the ICD trials, CRT trials have had a higher number of female patients (around 30 %). However, considering that in the US the prevalence of HF is similar in both sexes,1 women have still been significantly underrepresented in CRT trials.

0.20 0.15 0.10 0.05

CRT-D = cardiac resynchronisation therapy with defibrillator; LBBB = left bundle branch block; VT = ventricular tachycardia; VF = ventricular fibrillation. Reproduced with permission from Tompkins et al.28

The MIRACLE trial enrolled 453 patients with HF with reduced EF (<35 %), NYHA class III or IV and QRS >130 ms and randomised them to CRT or the control group. Women constituted 36 % of the total enrolment (144/453). Improvements in both clinical status and cardiac function were seen in the CRT group. Woo et al.24 analysed eight pre-specified subgroups in the MIRACLE study, including sex, for differences in response to CRT. They found that compared with control subjects, women but not men with CRT experienced longer times to first HF hospitalisation or death (see Figure 2).

men. These differences were not attributable to the proportions of women and African–American patients at participating hospitals or to differences in the reporting of LVEF. The study by Curtis et al. mentioned previously showed that only 8.6 per 1,000 women received an ICD compared with 32.3 per 1,000 men within 1 year of known eligibility for a primary prevention ICD. The rates of ICD implantation for secondary prevention of SCD were also equally disproportionate in women (38.4 per 1,000) compared to men (102.2 per 1,000).

The Multicentre Automatic Defibrillator Implantation Trial with Cardiac Resynchronisation Therapy (MADIT-CRT) enrolled 1,820 patients with NYHA class I and II symptoms, LVEF <30 % and QRS >130 ms, of whom 453 were women.27 Patients were randomly assigned to CRT-D or ICD alone. Patients in the CRT-D arm experienced a 34 % reduction in the combined endpoint of HF or death. The study pre-specified an analysis by sex and found that the primary outcome of HF or death was seen in 29 % of the women with ICDs and 11 % of those with CRT-D compared

0.00 0.0

0.5

Female resp Male resp Female non-resp Male non-resp

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Curtis-FINAL.indd 132

129 262 31 112

1.0

1.5

2.0

2.5

78 (0.07) 141 (0.12) 17 (0.21) 58 (0.27)

48 (0.08) 82 (0.14) 12 (0.25) 36 (0.32)

Years of follow-up

Number of patients at risk 127 (0.02) 255 (0.02) 30 (0.03) 101 (0.10)

123 (0.02) 242 (0.05) 28 (0.10) 94 (0.14)

104 (0.03) 193 (0.08) 26 (0.10) 73 (0.25)

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The COMPANION and CARE-HF trials both demonstrated improvements in time-to-first hospitalisation or death in patients with advanced HF with CRT.22,23 The COMPANION trial enrolled 1,520 patients with NYHA class III or IV HF and compared CRT with either a pacemaker (CRT-P) or a defibrillator (CRT-D) to optimal medical therapy. Women constituted around 30 % of the total population, and there was a statistically significant reduction in the risk of the combined primary endpoint of death or hospitalisation for both men and women. The Resynchronisation Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial evaluated the effects of CRT on the clinical course and LV function in patients with mild HF.30 There were 684 patients enrolled in the trial, with women constituting 20 % of the total enrolment. Patients were randomised to CRT or the control group and a pre-specified analysis of 419 patients with CRT devices turned on was performed. Patients in the CRT-ON group were followed for an additional 5 years, and on multivariable analysis it was found that there was a significant survival benefit for patients with CRT-D devices compared with the control group, with the mortality benefit being larger for women than men. Xu et al.31 retrospectively evaluated 728 patients who received CRT with the aim of detecting sex differences in CRT effectiveness. Women constituted 22.8 % (166) of the total sample and had a statistically significant improvement in NYHA class that was not seen in men (p=0.009). A greater improvement in LVEF was also seen in women compared with men. Other prospective studies have demonstrated that women experience better survival, longer event-free survival from death/HF hospitalisation as well as significantly better improvements in NYHA class, LVEF and LV reverse remodelling with CRT compared to men.32 Using a Cox proportional hazards model, it was also shown in the above-mentioned study that female sex was an independent predictor of survival regardless of age, LVEF, QRS duration, type of CRT device and NYHA class. Loring et al. also showed that LBBB was associated with a significantly better survival rate in women compared with men treated with CRT.33 In this study of 144,642 CRT recipients, women with LBBB experienced a 26 % reduction in mortality (HR 0.74; 95 % CI [0.71–0.77]), while men experienced a reduction of 15 % (HR 0.85; 95 % CI [0.83–0.87]) after adjusting for confounding factors. An improvement in echocardiographic parameters in women with CRT was also observed in a study by Lilli et al. They followed 195 patients for 12 months after they received CRT and found that women showed a greater benefit with CRT in the form of decreased LV end diastolic volumes and higher LVEF compared with men.34 More recently, the IMPROVE

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Probability of heart failure or death, %

Figure 4: Kaplan-Meier Estimates of Outcomes in LBBB and QRS of 130 to 149 Milliseconds Stratified by Sex

Outcome of heart failure or death Women Log rank p<0.001

40 ICD 30 20 10

CRT-D

0 0 12 24 36 Time to first heart failure event or death, mo

Probability of heart failure or death, %

with 25 % of men with ICDs and 20 % with CRT-D (women: HR 0.31; p<0.001; men: HR 0.72; p<0.01). The short-term sex-specific outcomes demonstrated a statistically significant reduction in mortality in women (HR 0.28; 95 % CI [0.10–0.79]; p<0.02) but not in men (HR 1.05; 95 % CI [0.70–1.57]; p=0.83). Furthermore, this mortality benefit was seen in women with a QRS duration >150 ms and in women with LBBB but not in men (see Figure 3).28 More recently, Biton et al.29 presented the results of long-term sex-specific outcomes in the MADIT-CRT population with LBBB. A total of 1,281 patients were included in this analysis, including 394 women and 887 men. Both men and women experienced a significant mortality benefit with CRT-D versus ICD only. However women had a significantly greater reduction in HF only and HF or death with CRT-D compared with men.

Outcome of heart failure or death Men Log rank p<0.38

40 ICD 30

CRT-D

20 10 0 0 12 24 36 Time to first heart failure event or death, mo

CRT-D = cardiac resynchronisation therapy with defibrillator; ICD = implantable cardioverterdefibrillator; LBBB = left bundle branch block. Reproduced with permission from Zusterzeel et al.35

HF trial showed that both men and women with ICD/CRT-D derived a significant mortality benefit (men OR, 0.67; 95 % CI [0.49–0.92]; p=0.0133; women OR 0.53; 95 % CI [0.31–0.91]; p=0.0227), and this benefit persisted after adjusting for age.11 Zusterzeel et al.35 combined patient data from three major CRT-D versus ICD trials (MADIT-CRT, Resynchronisation for Ambulatory Heart Failure Trial [RAFT] and REVERSE) to conduct a post-hoc meta-analysis evaluating sex-specific outcomes with CRT. The final analysis included 4,076 patients, of which 22 % were women. Women with mild HF, LBBB and a QRS duration of 130–149 ms showed a 76 % reduction in mortality with CRT-D (HR 0.24; 95 % CI [0.06–0.89]), with no similar benefit in men with similar findings (see Figure 4). The relationship between sex and response to CRT with varying QRS durations in patients with LBBB was further studied by Varma et al.36 Patients with NYHA class III/IV HF, non-ischaemic cardiomyopathy and LBBB with a CRT device were followed for a period of 2 years. A total of 212 patients were enrolled of which 49.5 % (104) were women. The overall positive response rate in both sexes was 76 % in those with a QRS >150 ms, and 58 % in those with a QRS <150 ms. However, women had a higher response rate than men at a QRS <150 ms (86 % in women versus 36 % in men; p<0.001). These studies indicate that the relationship between QRS duration and response to CRT is different between men and women. One reason why women might benefit more from CRT than men at shorter QRS durations may be that women normally have shorter QRS durations than men. Thus, any particular degree of QRS prolongation is

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Device Therapy relatively longer in women compared with men and may indicate greater dyssynchrony. By not considering sex-related differences in response to CRT, there is a possibility that practice guidelines might exclude female patients with shorter QRS durations who would benefit from CRT.

Sex Disparities in Cardiac Resynchronisation Therapy Utilisation Women with HF are usually older than men, and they are more likely to have HF with preserved EF compared with men. They are also more likely to have non-ischaemic cardiomyopathy and are more often diabetic and hypertensive. As eligibility for CRT is based on EF (EF <35 %), many women with HF with preserved EF will not be candidates for CRT despite having a worse NYHA class.

Despite a clear mortality benefit seen with CRT in women, this lifesaving therapy is still significantly underutilised in women as noted above. As demonstrated in the IMPROVE HF study, a significant improvement in CRT utilisation was seen in both men and women when clinical decision-making support and information were provided to physicians and patients.

Conclusion

Despite the overall prevalence of HF in women being slightly less than that of men, a study sponsored by the Agency for Healthcare Research and Quality revealed that hospital admissions for HF exacerbations or HF-related complications have been higher among female HF patients than male patients. This trend has been consistent over the past three decades.37 Data on new CRT implantations from 2002 to 2004 extracted from the Healthcare Cost and Utilisation Project showed that the total number of CRTs implanted increased significantly (2,590 CRT devices implanted in 2002 and 34,803 in 2004). An increase in the use of CRT was seen both in women and men; however, the increase

There is ample evidence that ICDs and CRT provide significant benefit in terms of mortality and other important clinical outcomes in patients eligible for these devices. However, the majority of patients enrolled in these trials have been men. Thus, determination of sex-specific mortality and clinical outcomes has often not been possible owing to the low numbers of women enrolled. There are differences in cellular electrophysiological properties, autonomic modulation and hormonal effects on the expression of ion channels as well as the arrhythmogenic substrate between men and women that may explain the lower incidence of life-threatening arrhythmias in women compared with men. However, there is enough evidence regarding the survival benefit with ICD therapy in both sexes that recommendations as to which patients should receive ICD therapy do not vary by sex. With CRT, women benefit more than men in general, likely because of both a higher incidence of non-ischaemic cardiomyopathy and relatively greater dyssynchrony for any particular QRS duration. Thus, the rate of CRT use in women should be at least

was significantly less in women compared with men (women: 659 in 2002 versus 11,286 in 2004; men: 1,931 in 2002 versus 42,196 in 2004). This disparity remained even after adjusting for the lower incidence of CHF in women.

equal to that in men. In fact, current practice guidelines may be too restrictive in their recommendations as to the QRS duration that warrants consideration of CRT in women, given that the recommendations were based largely on outcomes in men in the clinical trials.

Various studies have identified female sex as a positive predictor of response to CRT. Leyva et al.38 studied long-term clinical outcomes after CRT implantation in 550 patients, of which 122 (22 %) were women. A Cox proportional hazards analysis showed that women had better survival from death due to any cause as well as cardiovascular death. They also had a lower incidence of the combined endpoint of cardiovascular death/HF hospitalisations. A greater increase in LVEF and a greater reduction in LV end-systolic volume were seen in women compared with men. These benefits were independent of QRS duration, NYHA class, LVEF, age and other comorbidities.

Eligible female patients are less likely to receive both ICD and CRT therapy, although the guidelines clearly state that these life-saving therapies should be offered to all patients irrespective of sex. It has also been demonstrated in multiple performance improvement initiatives that this sex-based disparity can be significantly reduced with favourable outcomes for both sexes. There is still a large gap between the number of patients who are eligible for implantable cardiac devices and those who receive it, and this gap is especially wide in women. A concerted effort to enroll more women in cardiac device trials and offer eligible patients implantable cardiac devices regardless of sex is necessary. n

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