AER 3.1

Arrhythmia & Electrophysiology Review Volume 3 • Issue 1 • Spring 2014

www.AERjournal.com

Volume 3 • Issue 1 • Spring 2014

Ablation of Arrhythmias in Patients with Adult Congenital Heart Disease Rodrigo Gallardo Lobo, Michael Griffith and Joseph De Bono

Left Atrial Appendage Closure Devices for Stroke Prevention Sunil Kapur and Moussa Mansour

Endurance Sport Activity and Risk of Atrial Fibrillation – Epidemiology, Proposed Mechanisms and Management Nikolaos Fragakis, Gabriele Vicedomini and Carlo Pappone

Device-based Approaches to Modulate the Autonomic Nervous System and Cardiac Electrophysiology William J Hucker, Jagmeet P Singh, Kimberly Parks and Antonis A Armoundas A

Cavotricuspid Isthmus Ablation in a Patient with Previous Senning Intervention

B

Positioning of Leadless Cardiac Pacemaker in the Myocardium

SVC

MA IVC TA TA IVC

Left Atrial Appendage Closure Device

Cardiovascular Autonomic Control

ISSN - 2050-3369

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Reduce Stroke Risk Protect Your AF Patients One tablet, once daily for 24-hour stroke prevention2-4

ESC Guidelines recommend novel OACs for non-valvular AF5 Xarelto® is indicated for the prevention of stroke and systemic embolism in eligible adult patients with non-valvular AF with one or more risk factors1

Simple Protection for More Patients

AF: Atrial Fibrillation, OACs: oral anticoagulants ▼ This medicinal product is subject to additional monitoring Xarelto® 10, 15 and 20 mg film-coated tablets (rivaroxaban) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing) Presentation: 10mg/15mg/20mg rivaroxaban tablet Indication(s): 10mg Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.

15mg/20mg - 1. Prevention of stroke & systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors such as congestive heart failure, hypertension, age ≥ 75, diabetes mellitus, prior stroke or transient ischaemic attack (SPAF). 2. Treatment of deep vein thrombosis (DVT) & pulmonary embolism (PE), & prevention of recurrent DVT & PE in adults (see W&P for haemodynamically unstable PE patients).

Posology & method of administration: 10mg - Dosage 10 mg rivaroxaban orally once daily; initial dose should be taken 6 to 10 hours after surgery provided haemostasis established.

Recommended treatment duration: Dependent on individual risk of patient for VTE determined by type of orthopaedic surgery: for major hip surgery 5 weeks; for major knee surgery 2 weeks. 15mg/20mg - SPAF: 20 mg orally o.d. with food. DVT & PE: 15 mg b.i.d. for 3 weeks followed by 20 mg o.d. for continued treatment & prevention of recurrent DVT & PE; take with food.

10mg/15mg/20mg - Refer to SmPC for full information on duration of therapy & converting to/from Vitamin K antagonists (VKA) or parenteral anticoagulants. For patients who are unable to swallow whole tablets, refer to SmPC for alternative methods of oral administration. Renal impairment: mild (creatinine clearance 50-80 ml/min) - no dose adjustment; 10mg - moderate (creatinine clearance 30-49 ml/min) – no dose adjustment. Severe (creatinine clearance 15-29ml/min) - limited data indicate rivaroxaban concentrations are significantly increased, use with caution. 15mg/20mg - moderate & severe renal impairement limited data indicates rivaroxaban plasma concentrations are significantly increased, use with caution – SPAF: reduce dose to 15mg o.d., DVT & PE: 15 mg b.i.d. for 3 weeks, thereafter 20mg o.d. Consider reduction from 20mg to 15mg o.d. if patient’s bleeding risk outweighs risk for recurrent DVT & PE; 10mg/15mg/20mg - Creatinine clearance <15 ml/min - not recommended. Hepatic impairment: Do not use in patients with coagulopathy & clinically relevant bleeding risk including cirrhotic patients with Child Pugh B & C patients. Paediatrics: Not recommended. Contra-indications: Hypersensitivity to active substance or any excipient; active clinically significant bleeding; lesion or condition considered to confer a significant risk for major bleeding (refer to SmPC); concomitant treatment with any other anticoagulants except when switching therapy to or from rivaroxaban or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter; hepatic disease associated with coagulopathy & clinically relevant bleeding risk including cirrhotic patients with Child Pugh B & C; pregnancy & breast feeding. Warnings & precautions: 10mg - Not recommended in patients: undergoing hip fracture surgery; receiving concomitant systemic treatment with strong CYP3A4 and P-gp inhibitors, i.e. azole-antimycotics

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or HIV protease inhibitors; with creatinine clearance <15 ml/min.

Please note - Increased risk of bleeding, therefore careful monitoring for signs/ symptoms of bleeding complications & anaemia required after treatment initiation in patients: with severe renal impairment, with moderate renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations; treated concomitantly with medicinal products affecting haemostasis; with congenital or acquired bleeding disorders, uncontrolled severe arterial hypertension, active ulcerative gastrointestinal disease (consider appropriate prophylactic treatment for at risk patients), vascular retinopathy, bronchiectasis or history of pulmonary bleeding.

Take special care when neuraxial anaesthesia or spinal/ epidural puncture is employed due to risk of epidural or spinal haematoma with potential neurologic complications.

15mg/20mg - Clinical surveillance in line with anticoagulant practice is recommended throughout the treatment period.

Discontinue if severe haemorrhage occurs. In studies mucosal bleedings & anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment – haemoglobin/haematocrit testing may be of value to detect occult bleeding. The following sub-groups of patients are at increased risk of bleeding & should be carefully monitored after treatment initiation so use with caution: in patients with severe renal impairment or with renal impairment concomitantly receiving medicinal products which increase rivaroxaban plasma concentrations; in patients treated concomitantly with medicines affecting haemostasis. Not recommended in patients: with creatinine clearance <15 ml/min; with an increased bleeding risk (refer to SmPC); receiving concomitant systemic treatment with azole-antimycotics or HIV protease inhibitors; with prosthetic heart valves; with PE who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy. If invasive procedures or surgical intervention are required stop Xarelto use at least 24 hours beforehand. Restart use as soon as possible provided adequate haemostasis has been established. See SmPC for full details. 10mg/15mg/20mg - There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-Factor Xa tests. Elderly population – Increasing age may increase haemorrhagic risk. Xarelto contains lactose. Interactions: Concomitant use with strong inhibitors of both CYP3A4 & P-gp not recommended as clinically relevant increased rivaroxaban plasma concentrations are observed. Avoid coadministration with dronedarone. Use with caution in patients concomitantly receiving NSAIDs, acetylsalicylic acid (ASA) or platelet aggregation inhibitors due to the increased bleeding risk.

Concomitant use of strong CYP3A4 inducers should be avoided unless patient is closely observed for signs and symptoms of thrombosis. Pregnancy & breast feeding: Contra-indicated.

Effects on ability to drive and use machines: syncope (uncommon) & dizziness (common) were reported. Patients experiencing these effects should not drive or use machines.

Undesirable effects: Common: anaemia, dizziness, headache,

eye haemorrhage, hypotension, haematoma, epistaxis, haemoptysis, gingival bleeding, GI tract haemorrhage, GI & abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, pruritus, rash, ecchymosis, cutaneous & subcutaneous haemorrhage, pain in extremity, urogenital tract haemorrhage, renal impairment, fever, peripheral oedema, decreased general strength & energy, increase in transaminases, post-procedural haemorrhage, contusion, wound secretion. Serious: cf. CI/ Warnings and Precautions – in addition: thrombocythemia, angioedema and allergic oedema, occult bleeding/haemorrhage from any tissue (e.g. cerebral & intracranial, haemarthrosis, muscle) which may lead to complications (incl. compartment syndrome, renal failure, fatal outcome), syncope, tachycardia, abnormal hepatic function, hyperbilirubinaemia, jaundice, vascular pseudoaneurysm following percutaneous vascular intervention. Prescribers should consult SmPC in relation to full side effect information. Overdose: No specific antidote is available. Legal Category: POM. Package Quantities and Basic NHS Costs: 10mg - 10 tablets: £21.00, 30 tablets: £63.00 and 100 tablets: £210.00. 15mg – 14 tablets: £29.40, 28 tablets: £58.80, 42 tablets: £88.20, 100 tablets: £210.00; 20mg – 28 tablets: £58.80, 100 tablets £210.00 MA Number(s): 10mg - EU/1/08/472/001-10, 15mg/20mg - EU/1/08/472/011-21 Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, U.K. Telephone: 01635 563000. Date of preparation: January 2014.

Xarelto® is a trademark of the Bayer Group.

References: 1. Xarelto® 15mg and 20mg Summary of Product Characteristics. United Kingdom: Bayer HealthCare AG. http:// www.medicines.org.uk/emc/medicine/25586/SPC 2. Patel MR, Mahaffey KW, Garg J, et al.; ROCKET AF Investigators. Xarelto versus warfarin in non-valvular atrial fibrillation. N Engl J Med 2011; 365(10): 883-891. 3. Kubitza D, Becka M, Roth A, Mueck W. The Influence of Age and Gender on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban-An Oral, Direct Factor Xa Inhibitor. J Clin Pharmacol. 2013 Mar; 53(3):249-55. 4. Kubitza D, Becka M, Roth A, et al. The influence of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban-an oral, direct factor xa inhibitor. J Clin Pharmacol. 2013; 53(3):249255. 5. Camm AJ et al. Eur Heart J. 2012; 33(21):2719–2747.

Adverse events should be reported.

Reporting forms and information can be found at www.mhra.gov.uk/yellowcard.

Adverse events should also be reported to Bayer plc. Tel.: 01635 563500, Fax.: 01635 563703, Email: phdsguk@bayer.co.uk April 2014

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Volume 3 • Issue 1 • Spring 2014

Editor-in-Chief Demosthenes Katritsis Athens Euroclinic, Greece

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

Antonio Raviele

University Hospital of Nancy, France

University of Oklahoma Health Sciences Center, Oklahoma City, US

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

University Hospital Uppsal, Sweden

Mark Josephson

Frédéric Sacher

Johannes Brachmann

Beth Israel Deaconess Medical Center, Boston, US

Klinikum Coburg, II Med Klinik, Germany

Josef Kautzner

Bordeaux University Hospital / LIRYC / INSERM 1045

Pedro Brugada

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

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 Policlinico San Donato, Milan, Italy

Alessandro Capucci Università Politecnica delle Marche, Ancona, Italy

Ken Ellenbogen Virginia Commonwealth University School of Medicine, US

Samuel Lévy Aix-Marseille Université, France

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

Antonis Manolis Athens University School of Medicine, Greece

Francis Marchlinski University of Pennsylvania Health System, Philadelphia, US

Jose Merino

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

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

Jesper Hastrup Svendsen Rigshospitalet, Copenhagen University Hospital, Denmark

Juan Luis Tamargo University Complutense, Madrid, Spain

Sotirios Tsimikas

Hospital Universitario La Paz, Spain

University of California San Diego, US

Sanjiv M Narayan

Panos Vardas

University of California San Diego, US

Heraklion University Hospital, Greece

Mark O’Neill

Marc A Vos

St Vincenz-Hospital Paderborn and University Hospital Magdeburg, Germany

King’s College, London, UK

University Medical Center Utrecht, The Netherlands

Hein Heidbuchel

Maria Cecilia Hospital, Italy

Katja Zeppenfeld

University Hospital Leuven, Belgium

Sunny Po

Gerhard Hindricks

Leiden University Medical Center, The Netherlands

University of Leipzig, Germany

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

Carsten W Israel

Christopher Piorkowski

JW Goethe University, Germany

University of Dresden, Germany

Sabine Ernst Royal Brompton and Harefield NHS Foundation Trust, UK

Andreas Götte

Carlo Pappone

Managing Editor Becki Davies • Design Manager Tatiana Losinska Publisher David Ramsey • Publication Manager Liam O’Neill •

•

Douglas P Zipes Krannert Institute of Cardiology, Indianapolis, US

In partnership with

•

Editorial Contact Becki Davies | managingeditor@radcliffecardiology.com Circulation Contact David Ramsey | david.ramsey@radcliffecardiology.com Commercial Contact Liam O’Neill | liam.oneill@radcliffecardiology.com Lifelong Learning for Cardiovascular Professionals Cover image © | shutterstock.com

Radcliffe Cardiology Radcliffe Cardiology

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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. © 2014 All rights reserved © RADCLIFFE CARDIOLOGY 2014

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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: Spring 2014

• 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, which comprises experts appointed for their experience and knowledge of a specific topic.

• An experienced team of Editors and Technical Editors.

From 2014 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 Deputy Editor to determine their suitability for inclusion.

• The Editorial Manager, following consultation with the Editor-in-Chief, Deputy Editor, 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 manuscripts from other journals within Radcliffe cardiovascular portfolio – namely, Interventional Cardiology Review and European Cardiology Review. n

Radcliffe Cardiology

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Radcliffe Cardiology

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Contents

Foreword

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Arrhythmia & Electrophysiology Review – Great Expectations

Demosthenes Katritsis, Editor-in-Chief

Director, Department of Cardiology, Athens Euroclinic, Greece and Honorary Consultant Cardiologist, St Thomas’ Hospital, London, UK

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Clinical Arrhythmias

Current Evidence and Recommendations for Cardiac Resynchronisation Therapy

Matthew J Dewhurst 1 and Nicholas J Linker 2

1. Cardiology Specialist Registrar, 2. Consultant Cardiologist, The James Cook University Hospital, Middlesbrough, UK

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Endurance Sport Activity and Risk of Atrial Fibrillation – Epidemiology, Proposed Mechanisms and Management , , Nikolaos Fragakis, 1 2 Gabriele Vicedomini 2 and Carlo Pappone 2 3

1. Assistant Professor in Cardiology, Aristotle University of Thessaloniki, Greece;

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2. Department of Arrhythmology, Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy

Use of Cardiac Resynchronisation Therapy – Change of Clinical Settings , , Khang-Li Looi, 1 Anthony SL Tang 2 3 and Sharad Agarwal 2 3

1. Cardiac Electrophysiology Fellow, 2. Consultant Cardiologist and Electrophysiologist,

Papworth Hospital NHS Foundation Trust, Cambridge, UK; 3. Consultant Cardiologist and Electrophysiologist,

London Health Science Centre, London, Ontario, Canada

Device Therapy

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Left Atrial Appendage Closure Devices For Stroke Prevention

Sunil Kapur 1 and Moussa Mansour 2

1. Fellow in Cardiovascular Medicine, Brigham and Women’s Hospital; 2. Associate Professor in Medicine, Harvard Medical School; Director, Cardiac Electrophysiology Laboratory; Director, Atrial Fibrillation Program, Massachussets General Hospital, US

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Device-based Approaches to Modulate the Autonomic Nervous System and Cardiac Electrophysiology

William J Hucker, 1 Jagmeet P Singh, 2 Kimberly Parks, 3 Antonis A Armoundas

1. Fellow in Cardiovascular Medicine, Division of Cardiology, Massachusetts General Hospital, US; 2. Associate Professor of Medicine, Harvard Medical School, Director, Resynchronization and Advanced Cardiac Therapeutics Program, Massachusetts General Hospital, US; 3. Instructor in Medicine, Harvard Medical School, Advanced Heart Failure and Transplantation, Massachusetts General Hospital, US ; 4. Assistant Professor of Medicine, Harvard Medical School Cardiovascular Research Center, Massachusetts General Hospital, US

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POWERFUL CARDIAC MONITORING

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Contents

Diagnostic Electrophysiology & Ablation 36

Ablation of Arrhythmias in Patients with Adult Congenital Heart Disease Rodrigo Gallardo Lobo, 1 Michael Griffith 2 and Joseph De Bono 2

1. Senior Fellow in Electrophysiology , 2. Consultant Cardiologist, Queen Elizabeth Hospital,

Birmingham, UK

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Supported Contributions

The Potential Role of Edoxaban in Stroke Prevention Guidelines

Oliver Plunkett 1 and Gregory Y H Lip 2

1. Research Fellow, 2. Professor of Cardiovascular Medicine, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK

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T hermo C ool ® S mart T ouch ® C atheter – The Evidence So Far for Contact Force Technology and the Role of V isi T ag ™ M odule

4 ,4 Tina Lin, 1 Feifan Ouyang, 2 Karl-Heinz Kuck 3 and Roland Tilz

1. Electrophysiology Fellow, 2. Electrophysiologist, 3. Director of Cardiology, 4. Electrophysiologist, Department of Cardiology, Asklepios Klinik St Georg, Hamburg, Germany

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The Role of Continuous Monitoring in Atrial Fibrillation Management

A John Camm

Professor of Clinical Cardiology, Cardiac and Vascular Sciences, St. George’s University of London, London, UK

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The Promise of Leadless Pacing Katrina Mountfort, Medical Writer, Radcliffe Cardiology Reviewed for accuracy by: Reinoud Knops, 1 Johannes Sperzel 2 and Petr Neuzil 3

1. Electrophysiologist, Academic Medical Centre, University of Amsterdam, The Netherlands;

2. Director, Department of Cardiology, Kerckhoff Heart Centre, Bad Nauheim, Germany; 3. Chairman,

Department of Cardiology, Homolka Hospital, Prague, Czech Republic

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Foreword

Arrhythmia & Electrophysiology Review – Great Expectations

T

he pace at which Arrhythmia & Electrophysiology Review is maturing is really impressive. We are now preparing our fourth issue and the volume of manuscripts considered, the quality of accepted papers, and the names behind them, are really amazing. It is obvious that the electrophysiology community is

convinced about the need for regular reviews and summary articles on our ever-evolving and intellectually demanding discipline. Apart from submitting their excellent papers, our colleagues have also wholeheartedly responded towards supporting the reviewing and editing process of our journal. I am proud to announce that Karl-Heinz Kuck has joined us as Section Editor on Clinical Electrophysiology and Ablation, and Angelo Auricchio as Section Editor on Implantable Devices. Together with Andrew Grace, our Section Editor on Arrhythmia Mechanisms and Basic Science, they comprise a very promising team indeed. I am also very glad to welcome Sonny Jackman, Bill Stevenson, Sunny Po and Frank Marchlinski onto our editorial board. I am sure none of them needs any introduction.

Please continue to support Arrhythmia & Electrophysiology Review with your high-quality contributions.

We have already initiated the process of getting the journal into PubMed and Medline, and we can all be assured that our papers will not only be valuable tools for clinicians and scientists; they will also be properly identifiable and contribute to the recognition of our efforts. This will be the epitome of our success. n

Demosthenes Katritsis, Editor-in-Chief Director, Department of Cardiology, Athens Euroclinic, Greece and Honorary Consultant Cardiologist, St Thomas’ Hospital, London, UK

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Clinical Arrhythmias

Current Evidence and Recommendations for Cardiac Resynchronisation Therapy Ma t th e w J D e w h u r s t 1 a n d N i c h o l a s J L i n k e r 2 1. Cardiology Specialist Registrar, 2. Consultant Cardiologist, The James Cook University Hospital, Middlesbrough, UK

Abstract The number of people in Europe living with symptomatic heart failure is increasing. Since its advent in the 1990s, cardiac resynchronisation therapy (CRT) has proven beneficial in terms of morbidity and mortality in selected heart failure (HF) patient populations, when combined with optimal pharmacological therapy. We review the evidence for CRT and the populations of HF patients it is currently shown to benefit, and those in which more research needs to be performed.

Keywords Cardiac resynchronisation therapy, complex devices, heart failure, guidelines, recommendations Disclosure: The authors have no conflicts of interest to declare.

Received: 5 October 2013 Accepted: 13 March 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(1):9–14 Access at: www.AERjournal.com Correspondence: Dr NJ Linker, The James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UK. E: nick.linker@nhs.net

Approximately 2 % of the adult population in high-income countries has clinical heart failure (HF),1 and almost the same percentage again has impaired left ventricular (LV) function without symptoms.2 The incidence and prevalence of HF rises steeply with age; the mean age at first diagnosis being 76 years,3 with about half of these patients having a left ventricular ejection fraction (LVEF) of <50 %.1 The prevalence of HF is expected to rise because of an ageing population, improved survival of patients with ischaemic heart disease and more effective pharmacological treatments for HF.4 Prognosis from HF is poor, with a one-year mortality rate in those admitted to hospital with clinical HF of up to 40 % in those aged >75 years.5 However, there is already evidence of increased survival of HF patients, with one study showing a reduction in six month mortality over the 10 years between 1995 and 2005 from 26 % to 14 %.6 This has coincided with improved medical therapies and co-ordinated multidisciplinary care, but is likely to improve further since the advent of widespread use of cardiac resynchronisation therapy (CRT). Based on current guideline criteria from the European Society of Cardiology (ESC),7 CRT is only indicated in 5–10 % of HF patients, but this is still a large number of patients. It has been estimated that up to 400 patients per million population per year in Europe may be suitable for CRT;8 but even in Italy and Germany where the highest number of implants takes place, the implant rate is currently just over 200 per million.9 Cazeau and Bakker published the first case reports on LV pacing in 1994.10,11 They described the beneficial effects of biventricular pacing for New York Heart Association (NYHA) III/IV HF patients with a prolonged QRS, describing case series of thoracoscopically placed epicardial LV leads. The feasibility of biventricular pacing was furthered in 1998 when Daubert published the results of a fully transvenous permanent biventricular pacing system using a unipolar Medtronic lead.12 Since then, there have been several large international multicentre studies extolling the virtues of CRT, which

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this article will review. We will suggest populations where we know the evidence to be strong for being a CRT ‘responder’, other populations where the data are not so strong, and unresolved issues with regard to who may benefit from CRT and what decision tools are available to clinicians in order to decide who will be most likely to benefit.

Patients in Sinus Rhythm and New York Heart Association III-IV The evidence is fairly convincing for the benefits of CRT in patients who are in sinus rhythm with severely impaired LV function, who have NYHA class III HF symptoms. Earlier studies suggested a benefit in terms of symptoms, exercise capacity and LV function.13–17 More recently, two large randomised controlled trials have shown benefit in terms of all-cause mortality and HF hospitalisations.18,19 The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial18 showed statistically significant reductions in the combined primary endpoint of death or hospitalisation from HF by 34 % in the cardiac resynchronisation therapy with pacemaker (CRT-P) arm and 40 % in the cardiac resynchronisation therapy with pacemaker-defibrillator (CRT-D) arm, versus optimal pharmacological therapy. It also showed reduction in all-cause mortality by 24 % (p=0.059) in the CRT-P group and by 36 % (p=0.003) in the CRT-D arm. The Cardiac Resynchronization – Heart Failure (CARE-HF) study19 reported a hazard ratio (HR) of 0.63 (p<0.001) for the primary combined endpoint of time to death from any cause or hospitalisation for any cardiovascular cause for CRT-P versus medical therapy. The HR for all-cause mortality was 0.64 (p<0.001) in the CRT-P group.

The evidence for patients in NYHA class IV is more limited. A substudy of COMPANION 20 suggested benefit in so-called ‘ambulatory class IV’ patients (i.e. those without a HF hospitalisation in the preceding month) in terms of a significant reduction in the primary endpoint

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Clinical Arrhythmias as above, and a trend towards reduction in all-cause mortality and HF deaths.

Patients in Sinus Rhythm and New York Heart Association I-II The Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy (MADIT-CRT)21 looked at 1,820 patients with predominantly NYHA class II HF symptoms randomised 1:1 to either CRT-D or implantable cardioverter defibrillator (ICD). There was a statistically significant 34 % (p=0.001) reduction in the combined primary endpoint of all-cause mortality or any HF event in the CRT-D group versus the ICD group. However, the endpoint was driven by a 41 % reduction in HF events, and the annual mortality rate of 3 % did not differ between the two groups. The Resynchronization Defibrillation for Ambulatory Heart Failure Trial (RAFT)22 took 1,798 predominantly NYHA class II patients and showed a HR of 0.75 for the primary outcome of death from any cause or HF hospitalisation with CRT-D versus ICD. This time the result was not driven by just HF; a statistically significant reduction in all-cause mortality alone was shown (HR 0.75, p=0.003). Two other smaller randomised trials confirm the benefit in NYHA II patients.23,24 CRT does not seem to reduce mortality or HF events in NYHA class I patients, according to subgroup analyses of the small percentage of NYHA I Reverses Remodeling (REVERSE)24 (15 %) and NYHA class I patients is

patients making up the Resynchronization In Systolic Left Ventricular Dysfunction MADIT-CRT21 (18 %) trials, and thus CRT in currently not recommended.

QRS Duration and Morphology HF patients with a broad QRS have a worse prognosis than those with a narrow QRS, with three-year mortality rates in the MADIT-CRT trial for inter-ventricular conduction delay, right bundle branch block (RBBB) and left bundle branch block (LBBB) being 4, 7 and 8 %, respectively.25 Meta-analyses suggest that the most benefit from CRT is gained, regardless of NYHA class (II-IV), if the QRS duration is ≥150 ms26 and in patients with complete LBBB.27 This benefit was a composite of all-cause mortality and HF hospitalisations, and it remains unclear as to whether there is benefit on all-cause mortality alone.

Furthermore, in MADIT-CRT, those patients with non-LBBB had a 24 % (non-significant) increased risk of the primary outcome with CRT.25

Atrial Fibrillation It is apparent, despite how common atrial fibrillation (AF) is in HF patients, that there is a paucity of randomised controlled trial data in patients with a CRT indication and persistent or permanent AF. The evidence of benefit is small, and restricted to those in NYHA class III-IV in whom biventricular pacing can be maximised. The Multisite Stimulation in Cardiomyopathy – Atrial Fibrillation (MUSTICAF) trial28 looked at CRT in patients with severe left ventricular systolic dysfunction (LVSD), NYHA III-IV and permanent AF. In those achieving >85 % biventricular pacing, there was a small but statistically significant improvement in functional status at six and 12 months.

In the subgroup of 229 AF patients in the RAFT study,29 there were no significant differences shown in patients treated with CRT-D versus ICD, with only trends towards reduced HF hospitalisations and improvements in Minnesota Living with HF Score found. However, results are slightly more encouraging in trials including patients undergoing atrioventricular (AV) node ablation. Both the Ablation for Paroxysmal Atrial Fibrillation (APAF)30 and Post AV Nodal Ablation

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Evaluation (PAVE)31 trial showed, in patients with AF undergoing AV node ablation and concurrent CRT implant with severe LVSD, NYHA III-IV and QRS ≥120 ms, a significant reduction in the primary composite endpoint of death from, or hospitalisation for, or worsening of, HF. One of the most important factors determining the response to CRT is maximisation of biventricular pacing, and AF has been shown to be a major determinant in loss of biventricular pacing in large registries.32–34 Competing AF rhythm, be that by spontaneous conduction or fusion and pseudofusion beats, reduces biventricular pacing. Holter monitoring may be required to detect fusion and pseudofusion, as this will often be registered as biventricular pacing by device algorithms.35 Biventricular pacing between 93 and 100 % has been shown to reduce all-cause mortality and HF hospitalisation by 44 % compared with 0–92 %,32 with the greatest magnitude of mortality reduction in patients achieving >98 % biventricular pacing.33 In AF patients who cannot achieve this with AV nodal blocking agents alone, AV node ablation is the next appropriate step.

Ischaemic Versus Non-ischaemic Cardiomyopathy A substudy of MADIT-CRT36 has suggested that in mildly symptomatic patients (predominantly NYHA II), those with non-ischaemic cardiomyopathy tend to derive more benefit than those with ischaemic cardiomyopathy. CRT-D versus ICD therapy was associated with a 34 % and 44 % reduction in risk of HF or death in ischaemic and non-ischaemic patients, respectively. There was also greater benefit derived in terms of reduction in end-systolic and diastolic volumes of the left ventricle in non-ischaemic patients versus ischaemic patients.

Patients in the ischaemic cardiomyopathy group were also noted to have greater benefit if they had a QRS ≥150 ms, systolic blood pressure <115 mmHg or LBBB, and likewise in the non-ischaemic group if they were female, diabetic or had LBBB. For those with more significant symptoms (predominantly NYHA III), the same appears to be true in terms of non-ischaemic patients deriving greater benefit. In fact, in the COMPANION trial,18 the HR for all-cause mortality was 0.50, which was significant (p=0.015) for CRT-D versus ICD in non-ischaemic cardiomyopathy patients, while in those with ischaemic cardiomyopathy there was a trend to reduced mortality (HR 0.73), but this reduction was non-significant (p=0.082).

Cardiac Resynchronisation Therapy Pacemaker Device or Cardiac Resynchronisation Therapy Defibrillator Device?

Data from the Contak Italian Registry on 620 patients with an ESC IA recommendation for CRT randomised to either CRT-P or CRT-D suggests that there is a significant mortality benefit with CRT-D, and is the first randomised controlled trial to do so.37 After a median follow-up of 55 months, mortality rates were significantly lower in the CRT-D group (6.6 % per year) versus the CRT-P group (10.4 % per year) (p=0.020). Following adjustment for the fact that the CRT-P group were predominantly older, female, had no history of life-threatening ventricular arrhythmias, had longer QRS durations and worse renal function, the only independent predictor of death from any cause was the use of CRT-P (HR 1.97, p=0.007). This data confers with observational data from other large trials not powered to look specifically at differences between CRT-P and CRT-D. Data from the three groups in COMPANION (optimal medical therapy, CRT-P and CRT-D)18 suggested that at one-year, only the CRT-D group had a significant reduction in all-cause mortality (p=0.003). While the CRT-P

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Figure 1: Decision Aid Flowchart for Selecting Patients Suitable for Cardiac Resynchronisation Therapy EF ≤35 %

AF

Uncontrolled rate

NYHA I/II

CRT + AVN Ablation

No CRT

SR

NYHA III/IV

QRS<120 ms

CHB

Significant AV Block

NYHA I

CRT

CRT

No CRT

NYHA II-IV

QRS<120 ms ±dyssynchrony

No CRT

No CRT

QRS 120–149 ms

QRS 120–149 ms

RBBB/ NSIVCD

LBBB

RBBB/ NSIVCD

LBBB

No CRT

CRT

CRT

CRT

BiV >90 %

BiV <90 %

No AVN ablation

AVN ablation

QRS ≥150 ms

QRS ≥150ms

RBBB/ NSIVCD

LBBB

CRT

CRT

BiV >90 %

BiV <90 %

BiV >90 %

BiV <90 %

No AVN ablation

AVN ablation

No AVN ablation

AVN ablation

RBBB/ NSIVCD

LBBB

CRT

CRT

Pink = strong evidence-based recommendation likely to gain benefit; Purple = evidence present that may gain benefit, but not strong; Green = little/no evidence of benefit and/or potential for harm. AF = atrial fibrillation; AV = atrioventricular; AVN = atrioventricular node; BiV = biventricular pacing; CHB = complete heart block; CRT = cardiac resynchronisation therapy; EF = ejection fraction; LBBB = left bundle branch block; NSIVCD = non-specific interventricular conduction delay; NYHA = New York Heart Association Class; RBBB = right bundle branch block; SR = sinus rhythm.

group also showed a reduction, this was not significant (p=0.059).

It took 16 months of follow-up for the reduction in sudden cardiac death with the CRT-D arm to become significant, hence suggestions in the current guidelines that the patient should be expected to live

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for at least a year from time of implant to benefit.8 CARE-HF was the first trial to show a reduction in all-cause mortality for CRT-P, but did not initially show a reduction in the risk of sudden cardiac death.19 However, the extension study with a mean of 37.4 months follow-up

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Clinical Arrhythmias showed a significant 5.6 % reduction in sudden cardiac death.38 These data suggest that the reduction in death seen initially with CRT-P is likely due to a reduction in HF-related deaths, and that only with the beneficial effects of CRT on LV reverse remodelling over time does one get a reduction in sudden cardiac death. Therefore, the argument is made that to help prevent sudden death in the initial period, CRT-D is the better modality. A recent meta-analysis of 12 randomised controlled trials showed no significant difference in survival between CRT-D and CRT-P (odds ratio [OR] 0.85, 95 % confidence interval [CI] 0.60–1.22) or CRT-D and ICD (OR 0.82, 95 % CI 0.57–1.18), but also looked at ‘probabilities’ of best therapy, finding a 75 % chance that CRT-D was the best therapy to reduce overall mortality (versus CRT-P 14 % and ICD 10 %).39

Heart Failure Patients with Atrioventricular Block

Role of Imaging and Evidence of Mechanical Dyssynchrony

Long-term right ventricular pacing is documented as causing adverse remodelling and deterioration in LV function. Up until recently, only small randomised trials suggested the benefit of de novo CRT implants versus standard RV pacing in patients with moderate-tosevere LV dysfunction and a bradycardia pacing indication. However, the Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK-HF) study,56 randomised 691 patients with an ejection fraction (EF) ≤50 % (mean EF 40 %) and a pacing indication with AV block to either CRT or RV pacing. The primary outcome was a composite of death from any cause, an urgent care visit for HF requiring intravenous therapy, or ≥15 % increase in LV end-systolic volume index. The study reported a significantly lower incidence of the primary outcome in the CRT group versus RV pacing group (HR 0.74, 95 % CI 0.6–0.9), and this benefit persisted when excluding LV end-systolic volume index from analysis (HR 0.73, 95 % CI 0.57–0.92). However, the Kaplan–Meier curve suggests all the benefit appears to be in the first 12 months, with the lines running fairly parallel following that. In addition, there was the 6.4 % complication rate associated with LV lead placement. At this point in time, decisions regarding de novo CRT implants for patients with a reduced LV function and AV block should be individualised.

The benefit of imaging to help decide which patients will benefit from CRT remains uncertain. A subanalysis of CARE-HF data suggested an

In terms of upgrading devices to CRT from the conventional

While CRT-D may show a trend towards being the optimum therapy to reduce risk of death, this must be countered by the appropriateness of defibrillator therapy, as well as taking into account the physical and psychological effects of appropriate and inappropriate shock therapy, and potential problems with lead longevity.

echocardiographic interventricular conduction delay of ≥49.2 ms was an independent predictor of CRT response.40 Other imaging techniques have shown several measures of mechanical dyssynchrony to be predictive of response.41–45 However, The Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) trial,46 which was a large multicentre study, showed only modest ability of dyssynchrony measures to predict response to CRT. The large differences in sensitivity, and specificity and heterogeneity in results between centres has in some areas been criticised, and further studies are needed in this area.

Left Ventricular Lead Position and Multi-site Pacing The posterolateral position is the current recommended area for LV lead placement as it is often associated in patients with LBBB with the latest mechanical contraction. Data from REVERSE47 and COMPANION48 support this in terms of improvement in survival and clinical status, but the COMPANION data also suggest no difference in benefit between posterior, lateral and anterior lead placement. MADIT-CRT data show that basal or mid-ventricular positions of the LV lead are superior to apical placements,49 as the closer to the apex the lead is, the closer to the right ventricular (RV) lead it is likely to be. Data are emerging suggesting benefit of a more technical approach in terms of placing the LV lead in positions of latest activated areas measured by speckle tracking echocardiography,50 or by haemodynamic response of rate of rise of LV pressures (dP/dt) measured invasively by a pressure wire in the LV.51 While this may be an optimal solution, often the implanter is faced with limited options in terms of coronary venous anatomy and target veins.

With regard to multi-site LV pacing, there is a paucity of data at the current time. Most of the studies are small, but do show promise for multi-site pacing in terms of haemodynamic52 and functional53,54 benefit, or in patients with significant posterolateral scar.55 Further study is needed to confirm the benefit, and it is important to balance this out with the potential complications associated with leaving an extra LV lead in situ.

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pacemaker or the defibrillator, the evidence is encouraging but restricted to small trials57–60 and observational data.61–67 Reasons for upgrading are likely to be moderate-to-severe LV dysfunction combined with significant HF symptoms. This is reflected in the studies to date that have mainly been in NYHA III-IV patients, and have reported reductions in hospitalisations for HF. The decision to upgrade should not be taken lightly given a recently reported 18.7 % peri-procedural complication rate.68

Patients with a Narrow QRS While up to 50 % of patients with HF and a narrow QRS show evidence of echocardiographic dyssynchrony69 the Echocardiography Guided Cardiac Resynchronization Therapy (Echo-CRT) study 70 showed no benefit to CRT-D over ICD in 809 patients with an EF <35 %, narrow QRS and evidence of mechanical dyssynchrony, in terms of death or hospitalisation, and may actually increase mortality. This serves as a reminder that CRT is not without its challenges.

Cardiac Resynchronisation Therapy Complications When considering CRT in a patient, complication rates are significantly higher than with simple pacemaker implants. Complication rates are higher in low volume centres, with a relative risk of complications of 1.6 for operators with fewer than 25 CRT implants. Lead complications are the most common reason for re-operation, with the presence of a CRT device being an important factor (OR 3.3) in re-intervention, with 4.3 % of LV leads needing to be re-operated on.71 A meta-analysis of 25 CRT trials (9,082 patients) suggested peri-procedural complications of mechanical complications (such as coronary sinus dissection, pneumothorax, haemothorax) in 3.2 %, lead problems in 6.2 % and infections in 1.4 %. The same study reported success in LV lead placement of 94.4 % and peri-implant deaths at 0.3 %.72 Haematomas are common, and are usually managed conservatively.

Evacuation is required in 0.3–2.0 % of implants and associated with a 15 times higher infection rate compared with the original implant. Aspirin doubles haematoma risk, and dual antiplatelet therapy quadruples

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it.73 Heparin bridging has also been shown to increase bleeding risk, with recent data suggesting that continuing warfarin therapy peri-procedurally is a safer option (OR of clinically significant haematoma 0.19).74 No data are currently available with respect to bleeding risk with the novel oral anticoagulants.

Infection remains one of the most worrying post-operative complications. In one study looking at CRT infections, the prevalence was 4.3 % overall, with risk factors for infection being increased procedure time, requirement of re-intervention, haematoma, lead dislodgement, patient on dialysis and type of device (CRT-D devices being more likely to get infected than CRT-P).75

Patient Selection Criteria for Cardiac Resynchronisation Therapy Clearly, selection for CRT and certainly CRT-D therapy, should be made on an individual basis based on a number of clinical, physical and psychological factors. From the evidence presented, electrocardiographic criteria are still the most useful in deciding whether a patient is likely to benefit from CRT. It seems that

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11. Bakker P, Meiburg H, de Jonge N, et al. Beneficial effects of biventricular pacing in congestive heart failure (Abstr). PACE 1994;17:820.

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13. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–53.

14. Auricchio A, Stellbrink C, Butter C, et al. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am Coll Cardiol 2003;42:2109–16.

15. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873–80.

16. Higgins SL, Hummel JD, Niazi IK, et al. Cardiac resynchronization therapy for the treatment of heart failure in

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the presence of LBBB and QRS duration of ≥150 ms remain the strongest predictors of response to CRT. Patients with non-ischaemic cardiomyopathy and females are the next most likely to benefit, with men and those with ischaemic cardiomyopathies slightly less likely to benefit, with narrower QRS durations and non-LBBB pattern patients the least likely to derive benefit. Figure 1 details a decision aid to decide whether an individual patient may be suitable for CRT, and the likelihood of them benefitting from CRT.

Conclusions Certain subgroups have been delineated as likely to respond, and other subgroups await more evidence from larger randomised controlled trials. The decision to implant CRT should not be taken lightly given the complication rates, but neither should it be denied patients solely based on these concerns. CRT has been shown to reduce mortality and morbidity in several populations of HF patients. The most favourable outcomes with CRT require astute patient selection, effective LV lead placement, optimisation of device programming and active ongoing medical management of HF with optimal pharmacological therapy. n

patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol 2003;42:1454–9.

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19. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure.

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22. Tang AS, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010;363:2385–95.

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24. Linde C, Abraham WT, Gold MR, et al. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol 2008;52:1834–43.

25. Zareba W, Klein H, Cygankiewicz I, et al. Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation TrialCardiac Resynchronization Therapy (MADIT-CRT). Circulation 2011;123:1061–72.

26. Sipahi I, Carrigan TP, Rowland DY, et al. Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. Arch Intern Med 2011;171:1454–62.

27. Sipahi I, Chou JC, Hyden M, et al. Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. Am Heart J 2012;163:260–7.e3.

28. Leclercq C, Walker S, Linde C, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J 2002;23:1780–7.

29. Healey JS, Hohnloser SH, Exner DV, et al. Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail 2012;5:566–70.

30. Brignole M, Botto G, Mont L, et al. Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial.

Eur Heart J 2011;32:2420–9.

31. Doshi RN, Daoud EG, Fellows C, et al. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol 2005;16:1160–5.

32. Koplan BA, Kaplan AJ, Weiner S, et al. Heart failure decompensation and all-cause mortality in relation to

percent biventricular pacing in patients with heart failure: is a goal of 100% biventricular pacing necessary? J Am Coll Cardiol 2009;53:355–60.

33. Hayes DL, Boehmer JP, Day JD, et al. Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival. Heart Rhythm 2011;8:1469–75.

34. Cheng A, Landman SR, Stadler RW. Reasons for loss of cardiac resynchronization therapy pacing: insights from 32 844 patients. Circ Arrhythm Electrophysiol 2012;5:884–8.

35. Kamath GS, Cotiga D, Koneru JN, et al. The utility of 12-lead Holter monitoring in patients with permanent atrial fibrillation for the identification of nonresponders after cardiac resynchronization therapy. J Am Coll Cardiol 2009;53:1050–5.

36. Barsheshet A, Goldenberg I, Moss AJ, et al. Response to preventive cardiac resynchronization therapy in patients with ischaemic and non-ischaemic cardiomyopathy in MADIT-CRT. Eur Heart J 2011;32:1622–30.

37. Morani G, Gasparinin M, Zanon F, et al. Cardiac resynchronization therapy-defibrillator improves long-term survival compared with cardiac resynchronization therapypacemaker in patients with a class IA indication for cardiac resynchronization therapy: data from the Contak Italian Registry. Europace 2013;15:1273–9.

38. Cleland JG, Freemantle N, Erdmann E, et al. Long-term mortality with cardiac resynchronization therapy in the Cardiac Resynchronization-Heart Failure (CARE-HF) trial. Eur J Heart Fail 2012;14:628–34.

39. Lam SK, Owen A. Combined resynchronisation and implantable defibrillator therapy in left ventricular dysfunction: Bayesian network meta-analysis of randomised controlled trials. BMJ 2007;335:925.

40. Richardson M, Freemantle N, Calvert MJ, et al. Predictors and treatment response with cardiac resynchronization therapy in patients with heart failure characterized by dyssynchrony: a pre-defined analysis from the CARE-HF trial. Eur Heart J 2007;28:1827–34.

41. Bilchick KC, Dimaano V, Wu KC, et al. Cardiac magnetic resonance assessment of dyssynchrony and myocardial scar predicts function class improvement following cardiac resynchronization therapy. JACC Cardiovasc Imaging 2008;1:561–8.

42. Boogers MM, Van Kriekinge SD, Henneman MM, et al.

Quantitative gated SPECT-derived phase analysis on gated myocardial perfusion SPECT detects left ventricular dyssynchrony and predicts response to cardiac resynchronization therapy. J Nucl Med 2009;50:718–25.

43. Delgado V, van Bommel RJ, Bertini M, et al. Relative merits of left ventricular dyssynchrony, left ventricular lead position, and myocardial scar to predict long-term survival of ischemic heart failure patients undergoing cardiac resynchronization therapy. Circulation 2011;123:70–8.

44. Gorcsan J 3rd, Oyenuga O, Habib PJ, et al. Relationship of echocardiographic dyssynchrony to longterm survival after cardiac resynchronization therapy. Circulation 2010;122:1910–8.

45. Hara H, Oyenuga OA, Tanaka H, et al. The relationship of QRS morphology and mechanical dyssynchrony to long-term outcome following cardiac resynchronization therapy. Eur Heart J 2012;33:2680–91.

46. Chung ES, Leon AR, Tavazzi L, et al. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation 2008;117:2608–16.

47. Thébault C, Donal E, Meunier C, et al. Sites of left and right ventricular lead implantation and response to cardiac

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Clinical Arrhythmias resynchronization therapy observations from the REVERSE trial. Eur Heart J 2012;33:2662–71.

48. Saxon LA, Olshansky B, Volosin K, et al. Influence of left ventricular lead location on outcomes in the COMPANION study. J Cardiovasc Electrophysiol 2009;20:764–8.

49. Singh JP, Klein HU, Huang DT, et al. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial. Circulation 2011;123:1159–66.

50. 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.

51. Duckett SG, Ginks M, Shetty AK, et al. Invasive acute hemodynamic response to guide left ventricular lead implantation predicts chronic remodeling in patients undergoing cardiac resynchronization therapy. J Am Coll Cardiol 2011;58:1128–36.

52. 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.

53. 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.

54. 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.

55. Ginks MR, Duckett SG, Kapetanakis S, et al. Multi-site left ventricular pacing as a potential treatment for patients with postero-lateral scar: insights from cardiac magnetic resonance imaging and invasive haemodynamic assessment.

Europace 2012;14:373–9.

56. Curtis AB, Worley S Adamson PB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. New Engl J Med 2013;368:1585–93.

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57. Leclercq C, Cazeau S, Lellouche D, et al. Upgrading from single chamber right ventricular to biventricular pacing in permanently paced patients with worsening heart failure: The RD-CHF Study. Pacing Clin Electrophysiol 2007;30 Suppl 1:S23–30.

58. Delnoy PP, Ottervanger JP, Vos DH, et al. Upgrading to biventricular pacing guided by pressure-volume loop analysis during implantation. J Cardiovasc Electrophysiol 2011;22:677–83.

59. Höijer CJ, Meurling C, Brandt J. Upgrade to biventricular pacing in patients with conventional pacemakers and heart failure: a double-blind, randomized crossover study. Europace 2006;8:51–5.

60. van Geldorp IE, Vernooy K, Delhaas T, et al. Beneficial effects of biventricular pacing in chronically right ventricular paced patients with mild cardiomyopathy. Europace 2010;12:223–9.

61. Baker CM, Christopher TJ, Smith PF, et al. Addition of a left ventricular lead to conventional pacing systems in patients with congestive heart failure: feasibility, safety, and early results in 60 consecutive patients. Pacing Clin Electrophysiol 2002;25:1166–71.

62. Eldadah ZA, Rosen B, Hay I, et al. The benefit of upgrading chronically right ventricle-paced heart failure patients to resynchronization therapy demonstrated by strain rate imaging. Heart Rhythm 2006;3:435–42.

63. Laurenzi F, Achilli A, Avella A, et al. Biventricular upgrading in patients with conventional pacing system and congestive heart failure: results and response predictors. Pacing Clin Electrophysiol 2007;30:1096–104.

64. Leon AR, Greenberg JM, Kanuru N, et al. Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing.

J Am Coll Cardiol 2002;39:1258–63.

65. Shimano M, Tsuji Y, Yoshida Y, et al. Acute and chronic effects of cardiac resynchronization in patients developing heart failure with longterm pacemaker therapy for acquired complete atrioventricular block. Europace 2007;9:869–74.

66. Valls-Bertault V, Fatemi M, Gilard M, et al. Assessment of

upgrading to biventricular pacing in patients with right ventricular pacing and congestive heart failure after atrioventricular junctional ablation for chronic atrial fibrillation. Europace 2004;6:438–43.

67. Vatankulu MA, Goktekin O, Kaya MG, et al. Effect of long-term resynchronization therapy on left ventricular remodelling in pacemaker patients upgraded to biventricular devices. Am J Cardiol 2009;103:1280–4.

68. Poole JE, Gleva MJ, Mela T, et al. Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures: results from the REPLACE registry. Circulation 2010;122:1553–61.

69. Yu CM, Lin H, Zhang Q, Sanderson JE. High prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal QRS duration. Heart 2003;89:54–60.

70. Ruschitzka F, Abraham WT, Singh J, et al. CardiacResynchronization Therapy in Heart Failure with a Narrow QRS Complex. N Engl J Med 2013;369:1395–405.

71. Kirkfeldt RE, Johansen JB, Nohr EA, et al. Risk factors for lead complications in cardiac pacing: a population-based cohort study of 28,860 Danish patients. Heart Rhythm 2011;8:1622–8.

72. Al-Majed NS, McAlister FA, Bakal JA, Ezekowitz JA. Metaanalysis: cardiac resynchronization therapy for patients with less symptomatic heart failure. Ann Intern Med 2011;154:401–12.

73. Tompkins C, Cheng A, Dalal D, et al. Dual antiplatelet therapy and heparin “bridging” significantly increase the risk of bleeding complications after pacemaker or implantable cardioverter-defibrillator device implantation. J Am Coll Cardiol 2010;55:2376–82.

74. Birnie DH, Healey JH, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation.

N Engl J Med 2013;368:2084–93.

75. Romeyer-Bouchard C, Da Costa A, Dauphinot V, et al. Prevalence and risk factors related to infections of cardiac resynchronization therapy devices. Eur Heart J 2010;31:203–10.

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Clinical Arrhythmias

Endurance Sport Activity and Risk of Atrial Fibrillation – Epidemiology, Proposed Mechanisms and Management Nik ola os Fra g ak i s ,

1,2

G a b r i e l e V i c e d o m i n i 2 a n d Ca r l o Pa p p o n e

2

1. Assistant Professor in Cardiology, Aristotle University of Thessaloniki, Greece; 2. Department of Arrhythmology, Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy

Abstract There is evidence for a higher prevalence of atrial fibrillation (AF) in athletes engaged in long-term endurance sports training compared with the general population. Although atrial anatomic adaptations, alterations in autonomic nervous system, chronic systemic inflammation and fibrosis have been proposed as potential mechanisms, they remain speculative. Medical therapy with long-term antiarrhythmic agents or ‘pill in the pocket’ medications is hampered by limitations, such as sports eligibility and interference with exercise tolerance. AF ablation represents a valid therapeutic option with results similar to these achieved in other patients. Nevertheless, further clinical trials are needed to confirm whether endurance sport practice affects the maintenance of sinus rhythm following catheter ablation of AF.

Keywords Athletes, atrial fibrillation, atrial flutter, endurance sport activity, epidemiology, management Disclosure: The authors have no conflicts of interest to declare.

Received: 16 December 2013 Accepted: 11 March 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(1):15–9 Access at: www.AERjournal.com Correspondence: Nikolaos Fragakis, Department of Arrhythmology, Maria Cecilia Hospital, Cotignola, Via Corriera, 1 – 20132 Contignola (RA), Italy.

E: fragakis.nikos@gmail.com

Although atrial fibrillation (AF) is considered the most common arrhythmia in clinical practice, its prevalence is relatively low in the young and middle-aged, ranging from 0.5 % in men below 40 years to 1 % by 60 years.1,2 Regular exercise is proposed as a powerful tool for the primary and secondary prevention of cardiovascular disease, reducing most of the risk factors that predispose to AF, such as hypertension, diabetes mellitus, coronary artery disease and obesity.3,4 However, there is growing evidence that long-term endurance exercise may increase the risk of developing AF, with a reported 2–10 times greater prevalence in athletes and those who are involved in long-term sport participation.5

Prevalence and Incidence of Atrial Fibrillation in Endurance Sport Practice and in Vigorous Physical Activity

Why athletes should be susceptible to AF is an issue of ongoing debate. Several mechanisms underlying the association between exercise and AF have been proposed but they remain speculative.

It is of interest that adaptations such as sinus bradycardia and atrioventricular node disturbances, which are generally considered benign and reversible after a short period of detraining, have been considered by some investigators as a reason for AF development in elderly athletes. 6 It is clear that AF in athletes has some differences in cause, clinical presentation and treatment strategies compared with the general population.7

Furlanello et al.16 and Pelliccia et al.17 reported a low rate of AF (0.2 % and 0.3 %, respectively), no different from that observed in the general population. However, both studies included exclusively young athletes with relatively fewer years of training. In contrast, several other studies of middle-aged athletes, who were engaged in sport training for many years, demonstrated an increased prevalence of AF compared with the rest of the population (see Table 1). A common characteristic among all these studies was that the participating athletes were predominately male and they were involved in endurance sports. The prevailing pattern of AF was the so-called vagal lone AF, as it was usually encountered in relatively young individuals (<60 years old) without clinical or echocardiographic evidence of cardiopulmonary disease, and appeared predominantly in vagal circumstances, such as the postprandial period.18 Atrial flutter (AFL) was also frequently reported, implying that endurance sport may contribute to the development of both arrhythmias.6,19

The aim of this short review is to present the existing data about the epidemiology of AF in athletes and those engaged in long-term endurance sport practice, to analyse the pathophysiological mechanisms that connect AF with exercise, and finally to discuss the existing treatment options.

© RADCLIFFE CARDIOLOGY 2014

Fragakis_edited.indd 15

The prevalence of AF in the athletic community varies considerably dependent on the age and the number of years of training of the subjects. It is essential to make a distinction between studies including young athletes with only a few years of training and those with middle-aged or older individuals practising sports for many years.

Whereas the incidence of AF in young athletes appears similar to that observed in the general population, in older athletes an increased incidence of AF is reported.6,8–15

15

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Clinical Arrhythmias Table 1: Studies Demonstrating an Increased Risk of Atrial Fibrillation in Long-lasting Endurance Sport Activity Studies Type of Studies Men % Age Type of Activity Cases/Controls

Karjalainen et al.8 Longitudinal case/controls 100 47 ± 5/49 ± 5 Orienteers 262/373

Relative Risk or Prevalence % Atrial Fibrillation for Athletes 5.5 (95 % CI 1.3–24.4)

Baldesberger et al.6

Longitudinal case/controls

100

66 ± 7/66 ± 6

Cycling

134/62

10 %/0 % (p=0.028)

Grimsmo et al.9

Observational prospective

100

group I 54–62

Cross-country

group I 33

12.8 % of LAF

cohort study

group II 72–80

skiers

group II 37

group III 87–92

GIRAFA study10

Prospective case/controls

69

48 ± 11

Endurance sports

107/107

7.31 (95 % CI 2.33–22.9)

Mont et al.11

Retrospective/general

100

44 ± 13/49 ± 11

Endurance sports

70 LAF

63 %/15 % (p=0.05)

population (subgroup

analysis of lone AF population)

Elosua et al.12

Retrospective case/controls

51/109

2.87 (95 % CI 1.20–6.91)

100

41 ± 13/44 ± 11

group III 8

(>3 hours/week) Current practice

and >1,500

cumulated hours

of practice

Molina et al.13

Retrospective

100

39 ± 9/50 ± 13

Marathon running

252/305

8.80 (95 % CI 1.2–61.2)

Winhelm et al.14

Retrospective

100

42 ± 7

Running

60 cases, stratified

6.7 %

according to lifetime

training hours

<1,500 h: 17

1,500–4,500 h: 21

>4,500 h: 22

Andersen et al.15

Prospective

90

57.0 ± 13.5

Cross-country

681 cases stratified

HR 1.29; 95 % CI 1.04–1.61;

skiers

according to the

for ≥5 versus 1 completed races

number of races and

HR 1.20; CI 0.93–1.55; for

faster finishing times

100–160 % versus 240 % of

winning time

CI = confidence interval; HR = hazard ratio; LAF = lone atrial fibrillation.

Karjalainen and colleagues8 were the first to establish a relationship between endurance sport practice and AF, reporting a 5.5 odds ratio for AF associated with vigorous exercise, in a series of middle-aged endurance cross-country runners. Elousa et al.12 showed analogous results, with three times higher prevalence of lone AF and five times higher prevalence of vagal AF, indicating a threshold limit of 1,500 lifetime hours of intense endurance practice in order to attain this association. A following meta-analysis of six case-control studies including 655 athletes and 895 controls verified the aforementioned increased overall risk of AF for athletes compared with controls, demonstrating a high odds ratio of 5.29.5 Other studies with longer follow-up not only confirmed the association between endurance sport practice and AF but revealed an even higher prevalence, suggesting that the incidence of AF further increases with ageing in athletes. Indeed, Grimsmo et al.9 showed a 12.8 % prevalence of lone AF after 28–30 years of follow-up in a prospective study of high-performance male participants in endurance cross-country ski competitions, while Baldesberger et al.6 reported a 10 % versus 0 % prevalence of AF and AFL in a comparison of former professional cyclists (mean age 66 ± 7 years) with a control group of male golfers who had never performed high-endurance training. A less pronounced incidence of AF (hazard ratio [HR] 1.29) was reported in a recent large prospective study following athletes who completed long-distance cross-country ski races over a period of 10 years.

Nevertheless, the incidence of AF and AFL remained higher in the older group of athletes (55–64 years old).15 According to some reports, not only athletic activity but also vigorous physical activity associated with occupational activities

16

Fragakis_edited.indd 16

may pose a similar risk for AF. The Girafa study10 showed that the moderate and heavy physical activity, whether sport or jobrelated, increased the risk of AF. Aizer et al.,20 in line with the previous study, found that middle-aged subjects who took moderate exercise (5–7 times a week) had a significant risk (relative risk 1.53, 95 % confidence interval [CI] 1.12–2.09) for developing AF at three-year follow-up compared with controls. On the other hand, the Cardiovascular Health Study,21 which investigated the association between habitual physical activity and AF among 5,446 adults ≥65 years of age over a 12-year period showed that, unlike high intensity exercise, light to moderate physical activity is associated with a lower incidence of AF. A recent meta-analysis,22 including 95,526 subjects, confirmed that regular physical activity is not associated with a higher risk of AF compared with sedentary lifestyle, providing additional strength to the already known beneficial effects of regular exercise on cardiovascular risks.4,23 The concept of a U-shaped pattern relationship between exercise dose and relative risk of developing AF may better explain these apparently contradictory data. According to this theory, regular mild to moderate exercise21,22 may provide a degree of protection from AF, while more sustained vigorous exertion could promote AF.10,15,20 In summary, previous studies indicate a higher incidence of AF among athletes and former competitive athletes compared with the general population. However, this occurs predominately in middle-aged athletes engaged in sport activities over a long time period, which supports the concept that years of endurance training may be necessary before the development of AF. The lack of prospective studies where the exercise dose was accurately

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Endurance Sport Activity and Risk of Atrial Fibrillation

measured and the athletes were followed over many years does not allow at present the establishment of a threshold of lifetime hours of sport practice for AF development.

Figure 1: Factors Influencing the Development of Atrial Fibrillation in Athletes Increased Atrial Ectopies

Pathophysiology of Atrial Fibrillation in Athletes A multifactorial mechanism concerning the role of intense and long-term exercise in the development of AF has been proposed (see Figure 1). Atrial anatomic adaptations due to chronic volume or pressure overload, alterations in autonomic nervous system, chronic systemic inflammation and fibrosis have been suggested as potential mechanisms. However, all these associations still remain speculative.24,25 Fluid shifts and electrolyte abnormalities occurring during vigorous exercise may also trigger AF,26 whereas the use of illicit drugs may be associated with the arrhythmia.27 Nevertheless, it is essential in the work-up of the arrhythmia to exclude any underlying structural (hypertension, cardiomyopathy, myocarditis) or electrical (Wolff-Parkinson-White syndrome [WPW], concealed pathways, channelopathies) substrate for AF as well as extracardiac causes like thyrotoxicosis, as a considerable percentage of athletes with AF may have underlying pathologies.

Atrial Anatomic Adaptation Even though AF in athletes is considered predominately lone,10,12 evidence of atrium structural alterations, such as enlarged left atrial dimension,17 put this definition into question, raising additional concerns as to whether exercise-induced atrial remodelling is necessarily a benign adaptation to exercise conditioning.

Endurance exercise training is associated with increased left and right atrial size, probably due to long-standing volume and/or pressure overload. Although these conditions can precipitate AF, either by shortening atrial effective refractory period28 and/or eliciting more atrial ectopics, this has yet to be proved in clinical studies. Indeed, Pelliccia et al.17 showed that athletes involved in regular endurance practice have a larger atrium when compared with sedentary controls without this increased size predisposing per se to AF. Furthermore, Baldesberger et al.6 did not find an increased prevalence of atrial ectopy in former professional cyclists in contrast with older studies connecting atrial ectopic activity and physical activity.29 The concept of atrium fibrosis as consequence of long-term intensive exercise training derives exclusively from animal models, while data from athletes’ hearts are non-existent. An increase in mRNA and protein expression of a series of fibrotic markers in the right ventricle and both atria was found in rats exercised for 16 weeks compared with sedentary rats.30 In contrast, histological remodelling in athletes’ ventricles was reported by few clinical studies supporting the concept of fibrosis in humans following long-term engagement in exercise.31,32

Inflammation The hypothesis that inflammation may play a significant role for AF in athletes derives from many studies that have demonstrated an increase in inflammatory markers such as cytokines interleukin 1 (IL-1), IL-6 and C-reactive protein (CRP) in response to intensive or prolonged endurance exercise.25,33,34 The relationship between elevated inflammatory markers and the risk for developing AF has also been proved.35,36 Nonetheless, this concept remains speculative since no data concerning the association between exercise intensity, amount of inflammation and risk for AF in athletes exist so far.

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Fluids Shifts Electrolyte Abnormalities Atrial Enlargement

Adrenergic Stimulation Increased Vagal Tone

Mechanisms of AF in Athletes Atrial Fibrosis

Inflammation

Illicit Drugs

Erythropoiesis-stimulating agents, growth hormone, stimulants, β2 agonists, alcohol, cannabinoids, etc.

AF = Atrial fibrillation.

Autonomic Nervous System Vagal AF is the prevailing type of AF in athletes.10 A recent study confirmed the relationship between increased vagal tone and AF in middle-aged healthy men.37 The hyperactivity of vagal tone in athletes acting synergistically with a high level of sympathetic activation during training, produce significant shortening of atrial refractory period and increase dispersion of repolarisation, creating the proper conditions for initiation and perpetuation of AF.38–41

Management of Atrial Fibrillation in Athletes The natural course of AF has not been well-documented in athletes. A study by Hoogsteen et al. showed that lone AF did not demonstrate a severe evolution and is well-tolerated in most athletes.42 It is also essential, before proceeding to specific therapies for AF, to exclude and treat appropriately other possible causes of the arrhythmia, such as hyperthyroidism, myocarditis, pericarditis, WPW syndrome, channelopathies and hypertrophic cardiomyopathy, as well as alcohol consumption and use of illicit sympathomimetic substances.

Although few data support the concept that limitation of sports activities can have favourable outcomes in athletes with AF,16,42 it is advisable to look for cases where arrhythmia may be a manifestation of excessive engagement in sports training. In these cases, a period of detraining for three months to achieve and maintain sinus rhythm is advocated, while the degree of improvement during this resting period will determine whether athletes are allowed to resume their training.43

Pharmacological Therapy Few data on pharmacological treatment for athletes with AF are available. Even though antiarrhythmic agents used to treat AF in athletes are no different than those used in non-athletes, some issues need specific attention. Beta-blockers, further to their limited efficacy in preventing AF recurrences, are often not well tolerated due to the prevalence of increased vagal tone among athletes.

Another limitation to the use of beta-blockers is their inclusion in the World Anti-Doping Agency prohibited list for specific sports.44 Class IC antiarrhythmic agents, and in particular flecainide, may be useful in preventing AF. However, concomitant use of beta-blocker or calcium channel antagonists is strongly recommended due to the risk of 1:1 conduction to the ventricles if AFL occurs under conditions of sympathetic overactivation. The ‘pill in the pocket’ approach with IC drugs45 may be suitable in some athletes. Sport cessation should be considered for as long as the arrhythmia persists, and until one or

17

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Clinical Arrhythmias two half-lives of the antiarrhythmic drug used have elapsed, according to the current guidelines (Class IIA,C).46 Amiodarone, while being efficient, is not recommended due to its side-effects. Dronedarone has yet to prove its efficacy in athletes.

Pulmonary Vein Ablation Radiofrequency (RF) ablation of AF emerges as a particularly attractive option for athletes with AF, who would otherwise face a lifetime need for medical therapy, possibly interfering with exercise eligibility or tolerance, aside from the documented proarrhythmic tendency of most of them. The interaction between high levels of sympathetic and parasympathetic activity, increased pulmonary vein (PV) ectopic activity and atrial remodelling in trained athletes comprise a milieu that is highly conducive to promotion of AF. This may render AF more refractory to ablation or it may demand a more extensive approach involving also the ganglionated plexi,47–49 given the pivotal role of the autonomic system in the mechanism of AF in this specific population.

There are few data confirming the efficacy of catheter ablation in athletes. Furlanello et al.50 described a highly successful ablation procedure of PV isolation, with 90 % success after a mean of two ablation procedures in a series of 20 symptomatic elite athletes.

Calvo et al.51 reported high efficacy of circumferential PV isolation in endurance athletes with lone AF, proving also that the probability in athletes of remaining free of AF recurrences after a single procedure was similar to the general population. Finally, Koopman et al.52 showed in a series of 59 endurance athletes suffering from paroxysmal focally induced AF, that PV isolation was as effective in athletes as in other patients after three years follow-up. The aforementioned studies, although not allowing for clear conclusions to be made (due to the small number of subjects and the relatively limited follow-up period), suggest that exercise continuation does not appear to act as a trigger for AF evolution after PV isolation. According to the current guidelines, AF ablation in athletes is a Class IIA with level of evidence C indication, which should be considered to prevent recurrent AF when appropriate.46

Cavotricuspid Isthmus Ablation Long-term endurance exercise may cause right ventricle enlargement usually in parallel with left ventricle dilatation aiming to augment cardiac output and meet the increased metabolic demands during rigorous activity. This remodelling process occasionally leads to structural alterations facilitating electrical instability as well as initiation and maintenance of macro re-entry tachycardias such as typical AFL.53,54 Cavotricuspid isthmus ablation should be considered

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Heeringa J, van der Kuip DA, Hofman A, et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 2006;27:949–53.

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Abdulla J, Nielsen JR. Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis. Europace 2009;11:1156–9.

Baldesberger S, Bauersfeld U, Candinas R, et al. Sinus node disease and arrhythmias in the long term follow-up of former professional cyclists. Eur Heart J 2008;29:71–8.

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as first-line therapy in this case, given its high success rate and low incidence of complications.55 According to the recent guidelines, isthmus ablation is a Class IIA-C indication, especially when therapy with flecainide or propafenone is intended.46 A history of endurance sports has been identified as an independent predictor of AF development after AFL ablation, while the continuation of endurance sports activity after ablation showed a trend for increased risk of developing AF.19

Anticoagulation Indications for oral anticoagulation are the same as in non-athletes.

Since most treated athletes present a zero CHADS2 score, aspirin or no-drug can be prescribed.46 Anticoagulation therapy excludes these individuals from participation in close contact sports.

Sports Eligibility Athletes with asymptomatic AF in the absence of structural heart disease who have an appropriate ventricular response to exercise are eligible for all types of competitive sports. In the presence of structural heart disease, participation in competitive sports should be consistent with the limitations imposed by their disease.56–58 A three-month interruption of sports participation, from the time when stable sinus rhythm was restored, is recommended for athletes with paroxysmal, persistent or even first-onset AF, providing that no major cardiac disease exists. Finally, athletes without structural heart disease whose arrhythmia was eliminated by means of ablation may resume all sports activity at least three months after the procedure, provided that there are no subsequent recurrences. It is essential, however, that these athletes are followed up closely (i.e. every six months).43

Conclusions There is growing evidence that long-term endurance exercise may increase the risk of AF. However, the bulk of reported data supports the concept that years of endurance training may be necessary before this arrhythmia occurs. Several proposed factors contributing to the mechanism of AF in athletes, such as atrial dilatation, increased atrial ectopic activity, inflammatory changes, fibrosis, and above all the strong influence of vagal tone, remain unproven. Treatment of AF in athletes can be challenging because of limitations in the usage of common antiarrhythmic agents and also due to the lack of randomised studies from which clear guidelines may be produced.

Pulmonary vein ablation represents an attractive therapeutic option yet few data are available. Finally, further studies on the intensity and duration of exercise are needed in order to clarify whether a threshold limit for AF development exists. n

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Alboni P, Botto GL, Baldi N, et al. Outpatient treatment of recent-onset atrial fibrillation with the “pill-in-the-pocket” approach. N Engl J Med 2004;351:2384–91.

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). Eur Heart J 2010;31:2369–429.

47. Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm 2005;2:624–31.

48. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 2004;109:327–34.

49. Katritsis D, Pokushalov E, Romanov A, et al. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial. J Am Coll Cardiol 2013;62:2318–25.

50. Furlanello F, Lupo P, Pittalis M, et al. Radiofrequency catheter ablation of atrial fibrillation in athletes referred for disabling symptoms preventing usual training schedule and sport competition. J Cardiovasc Electrophysiol 2008;19:457–62.

51. Calvo N, Mont L, Tamborero D, et al. Efficacy of circumferential pulmonary vein ablation of atrial fibrillation in endurance athletes. Europace 2010;12:30–6.

52. Koopman P, Nuyens D, Garweg C, et al. Efficacy of radiofrequency catheter ablation in athletes with atrial fibrillation. Europace 2011;13:1386–93.

53. Claessen G, Colyn E, La Gerche A, et al. Long-term endurance sport is a risk factor for development of lone atrial flutter. Heart 2011;97:918–22.

54. Ector J, Ganame J, van der Merwe N, et al. Reduced right ventricular ejection fraction in endurance athletes presenting with ventricular arrhythmias: a quantitative angiographic assessment. Eur Heart J 2007;28:345–53.

55. Schmieder S, Ndrepepa G, Dong J, et al. Acute and long-term results of radiofrequency ablation of common atrial flutter and the influence of the right atrial isthmus ablation on the occurrence of atrial fibrillation. Eur Heart J 2003;24:956–62.

56. Zipes DP, Ackerman MJ, Estes NA 3rd, et al. Task Force 7: arrhythmias. J Am Coll Cardiol 2005;45:1354–63.

57. Pelliccia A, Fagard R, Bjørnstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: A consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005;26:1422–45.

58. Fragakis N, Pagourelias ED, Koskinas KC, Vassilikos V. Arrhythmias in athletes: evidence-based strategies and challenges for diagnosis, management, and sports eligibility.

Cardiol Rev 2013;21:229–38.

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Use of Cardiac Resynchronisation Therapy – Change of Clinical Settings K ha ng - Li Lo o i , 1 A n t h o n y S L Ta n g 3 a n d S h a r a d A g a r w a l 2 1. Cardiac Electrophysiology Fellow, 2. Consultant Cardiologist and Electrophysiologist, Papworth Hospital NHS Foundation Trust, Cambridge, UK; 3. Consultant Cardiologist and Electrophysiologist, London Health Science Centre, London, Ontario, Canada

Abstract Current guidelines recommend cardiac resynchronisation therapy (CRT) for patients with severe left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤35 %), QRS duration of ≥120–150 ms (Class IA and IB indications) on surface electrocardiogram (ECG) and New York Heart Association (NYHA) class III or IV heart failure (HF) symptoms. Ongoing studies aim to expand the use of CRT in patients with asymptomatic or minimal symptoms left ventricular dysfunction. There have been studies that have shown benefit of CRT extended to this group of patients. There have also been different implications of the role of CRT in patients with atrial fibrillation (AF), patients with narrow QRS duration or with right bundle branch block (RBBB) on surface ECG, as well as patients with end-stage renal failure on dialysis therapy. This article aims to review the current body of evidence of expanding use of CRT in these populations.

Keywords Cardiac resynchronisation therapy, left ventricular ejection fraction, New York Heart Association (NYHA) class, heart failure Disclosure: The authors have no conflicts of interest to declare Received: 23 February 2014 Accepted: 24 March 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(1):20–4 Access at: www.AERjournal.com Correspondence: Khang-Li Looi, Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, CB23 3RE, UK. E: khangli@hotmail.com

Heart failure (HF) is a growing and major health burden in western countries. The prevalence of HF is estimated at 1–2 % in the western world, and the incidence approaches 5–10 per 1,000 persons per year.1 Cardiac resynchronisation therapy (CRT) has been shown in multiple studies to improve HF symptoms, quality of life and improve survivals.2–6 The two landmark studies, Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) and Cardiac ResynchronizationHeart Failure (CARE-HF), established the clinical indications for CRT, which form the basis for consensus international guidelines.5–7 These two trials randomised 2,333 patients in sinus rhythm (SR) with QRS prolongation on surface electrocardiogram (ECG) (≥120 ms), New York Heart Association (NYHA) functional class III and ambulatory class IV HF and a persistently reduced left ventricular ejection fraction (LVEF), despite optimal medical treatment. The trials showed that CRT reduced the risk of death from any cause and hospital admission for worsening HF.5,6 The effect of left ventricular reverse remodelling from CRT was sustained over time.8 This has significant clinical implications and has led to the development of the hypothesis that implanting CRT in patients at an earlier stage of HF and different characteristics of patients with HF may prevent disease progression and lead to improved clinical outcomes. This article reviews the use of CRT in the changing and new clinical setting and the implications for daily clinical practice.

Cardiac Resynchronisation Therapy in Patients with Mild Heart Failure – The Evidence The earliest evidence of CRT in NYHA class I–II patients came from CONTAK CD and Multicenter InSync ICD Randomized Clinical Evaluation II (MIRACLE ICD) trials.4,9 In CONTAK CD, 490 patients with implantable cardioverter defibrillators (ICDs) were randomised to either CRT-on or no CRT.4 All patients

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were in NYHA class II–IV at the time of entry into the study. However, many patients demonstrated significant symptomatic improvement with medical treatment during this period. Thus, 227 patients were in NYHA class III/IV and 263 were in NYHA class I/II when the randomised therapy was initiated. At six months, CRT was linked to a significant reduction in left ventricular dimensions (p<0.001) and improvement in LVEF (5.1 versus 2.8 %, p=0.020).4 However, the reduction in HF progression and changes in NYHA class as well as quality of life were not statistically significant. Many patients responded positively once medical treatment was optimised before randomisation. This improvement in clinical status made it more difficult to show the benefit in healthier patients. Importantly, this trial showed that CRT improves left ventricular reverse remodelling.

Likewise, in the MIRACLE ICD trial all of the 186 patients with secondary indication for ICD were randomised either to CRT-on or CRT-off.9 CRT resulted in significant improvement in cardiac structure and function, and clinical HF composite endpoint over six months, but did not alter exercise capacity. It appeared that CRT offered important benefits to optimally medically managed, mildly symptomatic NYHA class II HF patients with ventricular dyssynchrony and an indication for an ICD. The study showed the potential of CRT to limit disease progression even in patients with mild HF symptoms.

These studies provided a preview of the much larger trials such as the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE), the Multicenter Automatic Defibrillator Implantation with Cardiac Resynchronization Therapy (MADIT-CRT) and the Resynchronization/Defibrillator for Ambulatory Heart Failure Trial (RAFT) studies in this group of patients with asymptomatic or mildly symptomatic HF.

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The REVERSE trial was the first large randomised controlled trial that included 610 patients with NYHA class I and II symptoms, QRS ≥120 ms and LVEF ≤40 %.10 At 12 months of follow-up, only 16 % of patients with a CRT device turned on worsened compared with 21 % of those with CRT-off (p=0.10).10 However, CRT was associated with a significant improvement in left ventricular dimensions (p<0.0001). The reduction of left ventricular dimensions was particularly prominent in those patients with non-ischaemic cardiomyopathy, those with larger left ventricular end-systolic volumes and those with a broader QRS on surface ECG (≥152 ms). The time to the first HF hospitalisation was also significantly delayed in those with CRT-on (hazard ratio [HR] 0.47, p=0.03).10 Although CRT appeared to slow the HF disease progression in this study, the impact of clinical outcome was only modest. It is worth noting that the patients in the REVERSE trial were on optimal medical treatment. This might be a potential explanation for these ‘negative’ results. Also, this trial has a short follow-up of one year. The treatment effect of CRT might require a prolonged period, and therefore, it might not be surprising that a one-year trial of CRT including asymptomatic patients with HF was too short to demonstrate the efficacy of CRT. The sub-analysis of the European data of the REVERSE trial provided further insights into the role of CRT in 262 mildly symptomatic HF patients. Over the 24 month period, 19 % of those patients with CRT-on versus 34 % of those with CRT-off worsened (p=0.01).11 Furthermore, CRT was associated with a significant reduction in the left ventricular end-systolic volume index (p<0.0001). The time to first HF hospitalisation was significantly delayed in those with CRT-on (p=0.03).11 These results provided additional data to support the use of CRT in delaying HF progression.

The MADIT-CRT study demonstrated a 34 % reduction in the risk of death or non-fatal HF among the mild HF patients with CRT defibrillators (CRT-D) as compared with those in the ICD only group (p=0.001).12 This benefit was mainly driven by the 41 % reduction in the risk of HF events, and there was no difference between the patients with ischaemic or non-ischaemic cardiomyopathy. Furthermore, there were clear improvements in the left ventricular mechanical indexes, with reduction in the left ventricular volumes (p<0.001) and increase in LVEF (p<0.001), reiterating the reverse remodelling effect of CRT that was observed in the REVERSE study.

Another large study that compared ICD with CRT-D in patients with mildly symptomatic HF was the RAFT study. Among the 1,798 patients with LVEF ≤30 %, QRS durations ≥120 ms and NYHA class II or III HF, the primary outcome of death or hospitalisation for HF occurred in 33.2 % of those with CRT-D, compared with 40.3 % in those with ICD only (p<0.001).13 The time to the occurrence of the primary outcome was significantly delayed in the CRT-D group (HR 0.75, p<0.001). The time to death was also significantly prolonged in the CRT-D group (HR 0.75, p=0.003).13 A recent meta-analysis of the above five randomised trials was performed. At pooled analysis there was a significant decrease in mortality with CRT (odds ratio [OR] 0.78, p=0.024) and this benefit was largely driven by the RAFT study. CRT was shown to reduce HF events (OR 0.63, p<0.001) and induced significant left ventricular reverse remodelling (p<0.001).14 The analysis also showed that CRT was associated with a delay progression of HF symptoms (OR 0.54, p=0.026) and a significant improvement in exercise tolerance (p<0.001).14

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With the additional findings from the above trials, the relative magnitude of the benefits of CRT in patients with NYHA class II symptoms is similar to those observed in patients with NYHA class III symptoms. Therefore, the European Society of Cardiology (ESC) Task Force agreed to give a new recommendation for patients with NYHA class II HF. In the 2013 ESC Guidelines on cardiac pacing and cardiac resynchronisation therapy, CRT (preferably a CRT-D) is a class IA indication for NYHA class II HF patients with LVEF ≤35 % and QRS duration ≥150 ms.7 However, the evidence for recommending CRT in patients with NYHA class I remains inconclusive due to the low number of patients enrolled in randomised trials.

Special Considerations and New/Future Indications of Cardiac Resynchronisation Therapy Cardiac Resynchronisation Therapy and Patients with Atrial Fibrillation Atrial fibrillation (AF) is a common arrhythmia, and its prevalence increases in the presence of HF. The development of AF in HF patients may significantly affect the outcomes. Population data from the Framingham Study suggest that new-onset AF after a diagnosis of HF conferred a hazard ratio (HR) for death of 1.6 in men and 2.7 in women.15 The role of CRT in patients with AF is less well established.

The evidence of CRT in patients with AF predominantly came from observational case studies.16–18 The first prospective, randomised trial that evaluated the role of CRT in patients with permanent AF and severe HF is the Multisite Stimulation In Cardiomyopathies (MUSTIC) AF trial, which included 131 patients, at least half of whom were in permanent AF and in need of ventricular pacing. However, only patients with a biventricular pacing rate >85 % showed a slight but significant improvement in functional status at one-year followup.19 In the RAFT study, 229 patients (12.7 %) had permanent AF at baseline. There was no clear reduction in clinical events and patients with permanent AF appeared to gain minimal benefit from CRT-D compared with a standard ICD.20 Despite apparently good rate control of AF before randomisation, the delivery of CRT remained suboptimal because of a low percentage of biventricular pacing. A recent metaanalysis including 23 observational studies followed a total of 7,495 CRT patients, 25.5 % with AF, for a mean of 33 months and found that AF was associated with an increased risk of non-response to CRT (34.5 versus 26.7 %; pooled relative risk [RR] 1.32; p=0.001) and all-cause mortality (10.8 versus 7.1 % per year, pooled RR 1.50; p=0.015).21 The benefits of CRT appear to be attenuated in patients with AF. Indeed, the presence of AF affects the effective delivery of biventricular pacing. In patients with AF, phases of effective biventricular capture alternate with phases of competing AF rhythm, which causes spontaneous, fusion or pseudofusion beats.22 This suggests that the global effective that CRT delivery has may be markedly reduced compared with atrial synchronous rhythm with a short atrioventricular (AV) interval as is achieved during SR. Moreover, in AF patients during exertion, spontaneous ventricular rate tends to override biventricular pacing rates, resulting in further reduction of paced beats precisely when patients are most in need of having biventricular capture, thus greatly limiting exercise tolerance. For this aspect, the indication of CRT for patients in AF with NYHA class III or IV, QRS duration ≥130 ms and LVEF ≤35 % remains Class IIA in the recent 2013 ESC Guidelines.7 In most patients with AF with intact intrinsic conduction, adequate biventricular pacing could only be achieved with AV nodal ablation. The use of AV nodal ablation was highly variable in majority of CRT trials.

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Clinical Arrhythmias In RAFT, AV nodal ablation was only used in one patient.20 A recent meta-analysis of six studies that enrolled 768 CRT-AF patients, including 339 patients who underwent AV nodal ablation, showed that AV nodal ablation conferred a RR of 0.42 and 0.44 for overall mortality and for cardiovascular mortality, respectively.23 AV nodal ablation was also shown to improve NYHA functional class in patients with AF. The current 2013 ESC Guidelines recommend a Class IIA indication for CRT in patients with AF, QRS duration ≥120 ms and LVEF ≤35 %, provided that AV nodal ablation is added to these patients with incomplete (<99 %) biventricular capture and those who are candidates for AV nodal ablation for rate control. A randomised controlled trial, Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation Patients (CAAN-AF) (www.clinicaltrials.gov/ct2/show/NCT01522898) is currently enrolling and its aim is to determine if AV nodal ablation combined with CRT in CRT-eligible AF patients will result in significant reductions in mortality and HF events compared with patients treated with CRT alone.

Cardiac Resynchronisation Therapy and Patients with Chronic Kidney Disease Renal impairment is common in patients with HF. In a systematic review of a HF population, a total of 63 % of the patients had any renal impairment, and 29 % had moderate to severe impairment.24 Adjusted all-cause mortality was increased for patients with any renal impairment (HR 1.56; p<0.001) and moderate to severe impairment

depressed left ventricular systolic function and exhibit left ventricular mechanical dyssynchrony as assessed by echocardiography.28,29 Several small studies have reported that HF patients with narrow QRS have demonstrated a substantial echocardiographic and clinical improvement following CRT.30–32 Based on these encouraging outcomes of the smaller observational studies, the Cardiac Resynchronization Therapy with Heart Failure and Narrow QRS (RethinQ) study was conducted to evaluate the efficacy of CRT in patients with standard indication for ICD, NYHA class III HF, a QRS duration <130 ms and evidence of mechanical dyssynchrony on echocardiography.33 At the end of follow-up, there was no difference between those with narrow and wide QRS patients. However, this study was of too short a duration to observe any effects on morbidity and mortality.

Recently, the Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial that assessed whether CRT improves exercise capacity and left ventricular reverse remodelling outcomes in patients with LVEF ≤35 %, symptoms of HF and a QRS duration <120 ms was interrupted prematurely after 85 patients were randomised. The trial showed that CRT did not improve clinical outcomes or left ventricular reverse remodelling in those with a narrow QRS duration <120 ms.34 In fact, there was an associated with a non-significant trend toward an increase in HF-related hospitalisation.

(HR 2.31; p<0.001).24 The effect of CRT on renal function has not been studied in large randomised trials. A retrospective study showed the survival rate among those with standard ICD alone (88 patients) and CRT-D patients (787 patients) within glomerular filtration rate (GFR) <30 mL/min/1.73 m2 and GFR ≥60 mL/min/1.73 m2 groups was similar, whereas CRT-D patients with GFR 30–59 mL/min/1.73 m2 (moderate renal impairment) had significantly better survival compared with those with ICD alone (HR 2.23, p=0.002).25 This survival benefit was associated with improved renal and cardiac function. However, among patients with a baseline GFR <30 mL/min/1.73 m2, a group largely ignored in most CRT trials, survival was limited.25 It might imply that the CRT implantation procedure itself had no lasting impact on renal function.

Many patients with chronic kidney disease (CKD) have concomitant cardiac disease with indications for device therapy, but the majority of trials have excluded this group of patients. Recently, a study of 482 CKD patients treated by CRT reported higher survival in those with normal or mild renal impairment than in those with CKD (defined as a GFR of ≤60 mL/min/1.73 m2) (72 versus 57 % at three years, p<0.01).26 This study excluded patients on dialysis.

There is also a paucity of data on the role of CRT in patients with CKD on dialysis therapy. Based on current limited data, the benefits and risks should be taken into consideration when considering the implantation of a CRT device in a dialysis patient. More research in this field is warranted to guide appropriate clinical decisions in this group of patients.

Cardiac Resynchronisation Therapy and Patients with Heart Failure but with Narrow QRS Complex Previous studies have shown that approximately 30 % of HF patients have narrow QRS duration <120 ms and thus these patients will not qualify for CRT according to current guidelines.27 Yet these patients have

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Similarly, the Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) study was recently terminated early due to the futility of CRT in this population. The mean QRS duration was 105 ms for the CRT group. The primary outcome, death from any cause or hospitalisation for worsening HF, occurred in 28.7 % in the CRT group, compared with 25.2 % in the control group (HR with CRT, 1.20; p=0.15).35 There was an excess of deaths due to cardiovascular causes in patients randomly assigned to CRT (37 deaths versus 17 in the control group; p=0.004). There was also a non-significant trend towards an increase in mortality related to HF.35 Despite the hypothesis that CRT might be beneficial to those with HF but narrow QRS duration, the current published studies have consistently failed to demonstrate a benefit in this group of patients.

The current guidelines do not recommend CRT in patients with chronic HF with QRS duration <120 ms (Class IIIB evidence).

Cardiac Resynchronisation Therapy and Patients with Right Bundle Branch Block Left bundle branch block (LBBB) has been shown to have a detrimental effect in patients with HF. Short-term mortality rates for the subgroups of patients with decompensated HF with QRS <120 ms, right bundle branch block (RBBB) and LBBB were 46.1 %, 56.8 % and 57.7 %, respectively (p<0.0001).36 Another population-based study of HF patients showed that those with LBBB had features consistent with more severely decompensated HF. Furthermore, even after accounting for these baseline factors and validated predictors of mortality, a LBBB on the presentation ECG conferred a 10 % increased risk of death and a 32 % increase in HF rehospitalisation in long-term follow-up.37 In patients with LBBB, the normal sequence of electrical activation is reversed leading to significant electromechanical coupling delay.

On the other hand, patients with RBBB might have minimal electrical or electromechanical coupling delay unless left fascicular hemiblock

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is present.38 A study using a three-dimensional non-fluoroscopic electroanatomic contact mapping system (3D-Map) showed that patients with RBBB, compared with LBBB, have a greater right-sided conduction delay, while the degree of left ventricular delay is not significantly different between the two groups.39 These findings seem to suggest that in HF patients with RBBB, CRT should benefit those in whom an underlying left-sided intraventricular conduction delay is masked by RBBB.

current guideline criteria, irrespective of echocardiographically measured dyssynchrony.

Safety and Cost-effectiveness Issues With the current progress in research, the clinical applications for CRT are expanding. However, the cost, invasiveness and morbidity (e.g. infection) of CRT needs to be considered carefully.

Cost-effectiveness The number of patients with RBBB included in large randomised controlled trials of CRT was low. A single-centre registry of 636 CRT patients with only 59 patients with RBBB (9.3 %) found that the composite endpoint of death, heart transplantation or ventricular assist device implantation occurred in 147 patients (23.0 %) – most frequently in the RBBB group (p=0.004).40 The highest symptomatic NYHA response rate was observed in those with LBBB, whereas few patients with RBBB responded (p<0.001). This differential response remained significant after controlling for baseline differences among groups (p=0.02).40 Similarly, pooled data from the MIRACLE and CONTAK-CD trials showed that patients with RBBB had no evidence of improvement in symptoms, six-minute walk test or quality of life scores at six months.41 A meta-analysis of four publications from five studies reported that data on patients with RBBB showed no favourable outcomes of CRT in patients with RBBB.42 In a recent post hoc analysis of the MADIT-CRT trial, patients with RBBB and a non-left anterior fascicular block showed improvement in left ventricular volumes and function. However, there was no difference in the three-year probability of death or HF admissions among those with RBBB or ICD only (p=0.962 and p=0.374).43 At present, for those with non-LBBB with QRS >150 ms the indication remains as Class IIB for CRT device.7 Physicians and patients should be aware of the likely reduced benefit from CRT in patients with RBBB, and this should be factored into decision making. However, until more data are available it is too early to change guidelines.

Cardiac Resynchronisation Therapy and Patients with Mechanical Dyssynchrony The hypothesis of CRT in narrow QRS with ventricular dyssynchrony cannot be neglected, albeit the evidence remains weak so far. Similar questions remained for patients with mechanical dyssynchrony and wide QRS – how do we select the right patients for CRT? Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT), a prospective, multicentre, non-randomised study was unable to find a single echocardiographic measure of dyssynchrony through which patient selection for CRT could be improved, even though up to 12 echocardiographic parameters had been used.44 The recent study using apical rocking (ApRock) as a surrogate marker for left ventricular (LV) dyssynchrony in patients with wide QRS implies that patients with an increase in myocardial contractile reserve resulting in more dyssynchrony may derive a greater benefit from CRT. The Prospective Comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection Fraction (PARAMOUNT) trial suggested that dyssynchrony may play a pathophysiological role in HF patients with preserved LVEF.45 However, strong evidence for the usefulness of echocardiography for patient selection in CRT is still lacking. Despite these well-presented and convincing data, the answer at this point in time is clearly that physicians will only implant CRT in those meeting

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The cost-effectiveness study from the European cohort of REVERSE indicated that CRT in mildly symptomatic HF has a similar cost-effectiveness ratio as in moderate to severe HF. Compared with CRT-off, 0.94 life years or 0.80 quality-adjusted life years (QALYs) were gained in the CRT-on group at an additional cost of €11,455, yielding an incremental cost-effectiveness ratio of €14.278 per QALY gained.46 The 2007 Health Technology Assessment found that CRT pacemakers (CRT-P) and CRT-D devices reduce mortality and hospitalisations due to HF, improve quality of life and reduce sudden cardiac death in those with NYHA classes III and IV, and evidence of dyssynchrony.

Compared with optimal medical treatment, the devices are estimated to be cost-effective at a willingness-to-pay (WTP) threshold of £30,000 per QALY; CRT-P is cost-effective at a WTP threshold of £20,000 per QALY.47 However, the estimated net benefit from CRT-D is less than with the other two strategies, until the WTP threshold exceeds £40,160 per QALY.47 The cost of CRT-P devices is already substantial; the addition of ICD will be more expensive since the latter technology involved will be more sophisticated. The hypothesised incremental benefits in survival from CRT-D would need to be balanced by possible increases in morbidity owing to, for example, device-related complications and inappropriate shocks.

Safety CRT implantation is an invasive procedure and the implant often takes considerably longer than other pacemaker and ICD procedures, and is undertaken in a patient group at increased risk of haemodynamic compromise because of the underlying HF and poor LVEF. Overall peri-operative complication rates range from 4 % in more recent trials to as high as 28 % in earlier CRT trials.10,48 The success rate of LV lead implantation in the REVERSE trial was 97 %, which is higher than those reported in previous studies.10 The rate of LV lead dislodgement was 8 % at one year. However, all the centres that participated in the REVERSE trial had a long experience with CRT implantations, suggesting that these procedures should be limited to centres with high volumes and excellence.

In the MADIT-CRT trial, serious device-related adverse events occurred with a frequency of 4.5 per 100 device-months in the CRT–D group and 5.2 per 100 device-months in the ICD-only group.12 Although the adverse events were infrequent in both groups, they could not be completely ignored.

The rate of adverse events within 30 days after device implantation was significantly higher among patients in the CRT-D group than among those in the ICD group, in the RAFT study. There were 118 device- or implantation-related complications among the 888 patients receiving CRT-D, as compared with 61 of 899 patients in the ICD group (p<0.001).13 The adverse events reported were consistent with

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Clinical Arrhythmias the rates in other studies.48,49 LV lead dislodgement and an increased rate of infection remain significant problems. Although many of these adverse events did not have substantial long-term consequences, they may prolong hospitalisation.

With the increasing number of CRT device implantations, infection becomes a major challenge that an implanting physician has to face. The first large prospective study analysing both incidence and prevalence of CRT device-related infection showed that the risk of CRT infection is twice that of a standard pacemaker implant risk. The prevalence was close to 4.3 % at 2.6 years, an incidence of 1.7 % per annum.50 Four independent predictive factors were identified: • procedure time (p=0.002); • dialysis (p=0.0001);

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• re-intervention (p=0.006); and • procedure type (CRT-D versus other procedures; p=0.01).50 These factors should be considered carefully in the evaluation of patients selected for CRT implantation.

Conclusion CRT has demonstrated favourable survival and symptom benefits in prior trials, especially those with highly symptomatic HF, LVEF ≤35 % and QRS ≥120 ms. The issue of whether CRT might be extended to other patient populations has been raised. Ongoing clinical randomised trials will provide stronger evidence for any potentially new indications. Considering the cost and safety issues of CRT, one has to be cautious of translating all the trial findings into the wider and routine use of CRT. n

of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol 2006;48(4):734–43.

18. Gasparini M, Auricchio A, Metra M, et al. Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation. Eur Heart J 2008;29(13):1644–52.

19. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study.

J Am Coll Cardiol 2002;40(1):111–8.

20. Healey JS, Hohnloser SH, Exner DV, et al. Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail 2012;5(5):566–70.

21. Wilton SB, Leung AA, Ghali WA, et al. Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and metaanalysis. Heart Rhythm 2011;8(7):1088–94.

22. Gasparini M, Regoli F, Galimberti P, et al. Cardiac resynchronization therapy in heart failure patients with atrial fibrillation. Europace 2009;11(suppl 5):v82–6.

23. Ganesan AN, Brooks AG, Roberts-Thomson KC, et al.

Role of AV nodal ablation in cardiac resynchronization in patients with coexistent atrial fibrillation and heart failure a systematic review. J Am Coll Cardiol 2012;59(8):719–26.

24. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: systematic review and metaanalysis. J Am Coll Cardiol 2006;47(10):1987–96.

25. Adelstein EC, Shalaby A, Saba S. Response to cardiac resynchronization therapy in patients with heart failure and renal insufficiency. Pacing Clin Electrophysiol 2010;33(7):850–9.

26. Lin G, Gersh BJ, Greene EL, et al. Renal function and mortality following cardiac resynchronization therapy. Eur Heart J 2011;32(2):184–90.

27. Bleeker GB, Schalij MJ, Molhoek SG, et al. Relationship between QRS duration and left ventricular dyssynchrony in patients with end-stage heart failure. J Cardiovasc Electrophysiol 2004;15(5):544–9.

28. Bleeker GB, Schalij MJ, Molhoek SG, et al. Frequency of left ventricular dyssynchrony in patients with heart failure and a narrow QRS complex. Am J Cardiol 2005;95(1):140–2.

29. Ghio S, Constantin C, Klersy C, et al. Interventricular and intraventricular dyssynchrony are common in heart failure patients, regardless of QRS duration. Eur Heart J 2004;25(7):571–8.

30. Achilli A, Sassara M, Ficili S, et al. Long-term effectiveness of cardiac resynchronization therapy in patients with refractory heart failure and “narrow” QRS. J Am Coll Cardiol 2003;42(12):2117–24.

31. Bleeker GB, Holman ER, Steendijk P, et al. Cardiac Resynchronization Therapy in Patients With a Narrow QRS Complex. J Am Coll Cardiol 2006;48(11):2243–50.

32. Yu CM, Chan YS, Zhang Q, et al. Benefits of cardiac resynchronization therapy for heart failure patients with narrow QRS complexes and coexisting systolic asynchrony by echocardiography. J Am Coll Cardiol 2006;48(11):2251–7.

33. Beshai JF, Grimm RA, Nagueh SF, et al. Cardiacresynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med 2007;357(24):2461–71.

34. Thibault B, Harel F, Ducharme A, et al. Cardiac resynchronization therapy in patients with heart failure and a QRS complex <120 milliseconds: the Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial. Circulation 2013;127(8):873–81.

35. Ruschitzka F, Abraham WT, Singh JP, et al. Cardiac-

resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013;369(15):1395–405.

36. McCullough PA, Hassan SA, Pallekonda V, et al. Bundle branch block patterns, age, renal dysfunction, and heart failure mortality. Int J Cardiol 2005;102(2):303–8.

37. Abdel-Qadir HM, Tu JV, Austin PC, et al. Bundle branch block patterns and long-term outcomes in heart failure. Int J Cardiol 2011;146(2):213–8.

38. Haghjoo M, Bagherzadeh A, Farahani MM, et al.

Significance of QRS morphology in determining the prevalence of mechanical dyssynchrony in heart failure patients eligible for cardiac resynchronization: particular focus on patients with right bundle branch block with and without coexistent left-sided conduction defects. Europace 2008;10(5):566–71.

39. Fantoni C, Kawabata M, Massaro R, et al. Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: a detailed analysis using three-dimensional non-fluoroscopic electroanatomic mapping system. J Cardiovasc Electrophysiol 2005;16(2):112–9.

40. Adelstein EC, Saba S. Usefulness of baseline electrocardiographic QRS complex pattern to predict response to cardiac resynchronization. Am J Cardiol 2009;103(2):238–42.

41. Egoavil CA, Ho RT, Greenspon AJ, Pavri BB. Cardiac resynchronization therapy in patients with right bundle branch block: analysis of pooled data from the MIRACLE and Contak CD trials. Heart Rhythm 2005;2(6):611–5.

42. Nery PB, Ha AC, Keren A, Birnie DH. Cardiac resynchronization therapy in patients with left ventricular systolic dysfunction and right bundle branch block: a systematic review. Heart Rhythm 2011;8(7):1083–7.

43. Tompkins C, Kutyifa V, McNitt S, et al. Effect on cardiac function of cardiac resynchronization therapy in patients with right bundle branch block (from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT] trial). Am J Cardiol 2013;112(4):525–9.

44. Chung ES, Leon AR, Tavazzi L, et al. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation 2008;117(20):2608–16.

45. Santos AB, Kraigher-Krainer E, Bello N, et al. Left ventricular dyssynchrony in patients with heart failure and preserved ejection fraction. Eur Heart J 2014;35(1):42–7.

46. Linde C, Mealing S, Hawkins N, et al. Cost-effectiveness of cardiac resynchronization therapy in patients with asymptomatic to mild heart failure: insights from the European cohort of the REVERSE (Resynchronization Reverses remodeling in Systolic Left Ventricular Dysfunction).

Eur Heart J 2011;32(13):1631–9.

47. Fox M, Mealing S, Anderson R, et al. The clinical effectiveness and cost-effectiveness of cardiac resynchronisation (biventricular pacing) for heart failure: systematic review and economic model. Health Technol Assess 2007;11(47):iii–iv, ix–248.

48. León AR, Abraham WT, Curtis AB, et al. Safety of transvenous cardiac resynchronization system implantation in patients with chronic heart failure: combined results of over 2,000 patients from a multicenter study program. J Am Coll Cardiol 2005;46(12):2348–56.

49. Duray GZ, Schmitt J, Cicek-Hartvig S, et al. Complications leading to surgical revision in implantable cardioverter defibrillator patients: comparison of patients with singlechamber, dual-chamber, and biventricular devices. Europace 2009;11(3):297–302.

50. Romeyer-Bouchard C, Da Costa A, Dauphinot V, et al.

Prevalence and risk factors related to infections of cardiac resynchronization therapy devices. Eur Heart J 2010;31(2):203–10.

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Device Therapy

Left Atrial Appendage Closure Devices For Stroke Prevention Sunil Kapur1 and Moussa Mansour2 1. Fellow in Cardiovascular Medicine, Brigham and Women’s Hospital; 2. Associate Professor in Medicine, Harvard Medical School; Director, Cardiac Electrophysiology Laboratory; Director, Atrial Fibrillation Program, Massachussets General Hospital, US

Abstract Cardioembolic stroke is a major cause of morbidity and mortality in patients with atrial fibrillation (AF). The left atrial appendage (LAA) is the prominent source of clot formation. While systemic anticoagulation is the current standard of care, anticoagulants carry many contraindications and possible complications. Techniques for elimination of the LAA are in various stages of development and early clinical use. In the coming years, accumulating data will help guide the management of AF patients at risk of bleeding as well as potentially become first-line therapy to reduce the risk of thromboembolic stroke. The purpose of this article is to review current endovascular and epicardial catheter-based LAA occlusion devices and the clinical data supporting their use.

Keywords Atrial fibrillation, left atrial appendage, Amplatzer , Watchman, PLAATO, LARIAT, AEGIS Disclosure: Sunil Kapur has no conflicts of interest to declare. Moussa Mansour is a consultant at St Jude Medical.

Received: 17 February 2014 Accepted: 2 April 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(1):25–9 Access at: www.AERjournal.com Correspondence: Moussa Mansour, Brigham and Women’s Hospital and Massachusetts General Hospital, 55 Fruit Street, GRB-109, Boston, MA 02114, US. E: mmansour@partners.org

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting more than three million Americans.1 The management of AF revolves around the alleviation of symptoms related to an accelerated and irregular ventricular response, and the prevention of cardioembolism, notably stroke. In patients with AF, there is a fivefold increased incidence of embolic stroke.2 The prevention of systemic embolism has seen significant progression with the recent development of novel oral anticoagulants. However, these medications are associated with poor compliance leaving many patients with AF without systemic anticoagulation. A recent meta-analysis highlighted the current issues with pharmacological prophylaxis in AF.3 Of the 29,272 participants who received warfarin as part of a randomised, phase III trial, the median time in therapeutic ranged from 58 % to 68 %. The event of stroke or systemic embolisation with all-comers on warfarin occurred in 1,107 out of 29,229 patients or 3.8 %. Even with all novel oral anticoagulants, this outcome occurred in 911 out of 29,312 patients or 3.1 %. Even more concerning, major bleeding occurred in 1,541 and 1,802 patients on novel anticoagulants and warfarin, respectively.

These are discouraging data, as the devastating side effect of major bleeding outpaces the outcome (stroke or systemic embolisation) we are primarily trying to prevent. Ideally, prophylaxis would effectively limit the embolisation risk without the glaring side effect of bleeding complications. It is for this reason that non-pharmacological prevention of embolism has garnered interest. Among patients with non-valvular AF, the majority of thrombi are located within the left atrial appendage (LAA). As such, non-pharmacological therapy has centred on occlusion, obliteration or removal of the LAA.

The Left Atrial Appendage The LAA empties into the left atrium through an orifice located between the left upper pulmonary vein and the left ventricle.4 Its unique

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anatomy, often multilobulated and trabeculated, allows predisposition to in situ thrombus formation. Studies using various imaging modalities demonstrate significant heterogeneity in LAA morphology,5–7 which complicates mechanical occlusion of the appendage. The physiological role of the LAA is incompletely understood, but is likely important in natriuresis and volume regulation.8 However, pathophysiological descriptions of the LAA, is a source of embolism in AF, are well described and date back to the 1940s.9 Review of human data has suggested that at least 90 % of left atrial thrombi are found within the LAA.10 As such, the concept of LAA modification as a method to reduce thromboembolism has arisen. A variety of surgical techniques have been described to close the LAA, with various degrees of efficacy.11 In the 1990s, interest was increased with the inclusion of atrial appendage removal at the time of Maze procedure.12 A retrospective study of 205 patients who underwent mitral valve replacement, analysed a group of 58 patients in which LAA ligation was performed. After almost six years, the incidence of an embolic event in those with LAA ligation was significantly lower than in those without this procedure (3 versus 17 %).13 The Left Atrial Appendage Occlusion Study (LAAOS), the first randomised trial of surgical LAA occlusion, in patients referred for coronary bypass surgery at risk for AF or ischaemic stroke, concluded that surgical exclusion of the LAA was safe and did not increase operative time or peri-operative bleeding.14 However, oversewing the appendage without amputation produced successful exclusion in only 45 % of patients. This rate only increased to 72 % if a stapler device was used. In recent years, Interest in the LAA has been driven by the development in percutaneous occlusion devices. The lack of efficacy of open exclusion underlies the significant difficulty that percutaneous exclusion devices will also face.

The percutaneous devices are divided into two fundamental delivery techniques – endocardial and epicardial approaches.

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Device Therapy Figure 1: Four Devices Currently in Evolution for Left Atrial Appendage Closure A

C

not feasible for the presence of a multilobed LAA. In one patient, the procedure was complicated by cardiac perforation with pericardial effusion, treated with pericardiocentesis. At a mean follow-up of 40 ± 10 months, no embolic events occurred.

B

A larger series of patients treated with the PLAATO device was in a single German centre. Percutaneous LAA closure was performed in 71 patients with a contraindication to anticoagulation or history of stroke under anticoagulant therapy.18 In a mean follow-up of 24 months, one minor stroke was reported (1.4 %), a lower rate than the 5.0 % predicted on the basis of a mean CHADS2 score of 2.5. One device embolisation occurred, occluding the left ventricular outflow tract, resulting in the patient’s death, and there was one case of device instability requiring removal by open surgery.

D

Later trials with the device showed similar success. A European study reported on 180 patients with non-rheumatic AF and a contraindication to warfarin, who were treated with the device.19 Placement was successful in 90 % of patients. Two patients died within 24 hours of the procedure (1.1 %) and six patients had cardiac tamponade (3.3 %), with two requiring surgical drainage. During a follow-up of 129 patient-years, there were three strokes, for a rate of 2.3 % per year.

The five-year North American results consisted of 64 patients who were similarly at high-risk of stroke (mean congestive heart

(A) the WATCHMAN device; (B) the ACP device; (C) the WaveCrest device; (D) the LARIAT.

Percutaneous Left Atrial Appendage Endocardial Occlusion Three devices have been investigated: the Percutaneous Atrial Appendage Transcatheter Occlusion (PLAATO) system, Amplatzer™ Cardiac Plug and the WATCHMAN™ device. All delivered percutaneously through transseptal access to the atrium (LA).

Left the are left

Percutaneous Left Atrial Appendage Transcatheter Occlusion In 2001 the PLAATO system was the first device of its kind used in humans. It was withdrawn by the manufacture for commercial reasons.

Its details highlight the evolution of the LAA occlusion technology.

The PLAATO system was a self-expandable nitinol cage with a polytetrafluoroethylene membrane. The purpose of the membrane is both to occlude the orifice of the LAA and to allow tissue incorporation into the device. Small anchors along the struts and passing through the occlusive membrane assist with device anchoring and encourage healing response. The device is delivered through a custom 14 French (Fr) transseptal sheath curved to point at the LAA. PLAATO implantation was described in 15 patients with persistent AF and contraindications to oral anticoagulant therapy in 2002.15 Subsequently, an international multicentre registry of 111 patients with contraindication to oral anticoagulation was published.16 In this cohort, device implantation was 97 % successful, and LAA occlusion was documented in 98 % of patients at the six-month follow-up transoesophageal echocardiogram (TOE). There were seven major adverse events, including one death and two strokes, at a mean follow-up of 9.8 months. The stroke rate of 2.2 % per year compared with the estimated annual stroke rate of 6.3 % for this population, representing a 65.0 % relative reduction in stroke.

Another small series 17 of 20 patients with non-valvular AF documented LAA closure using the PLAATO system. All patients had contraindications to anticoagulant therapy and were at high-risk for cardioembolic stroke (mean CHADS2 score 3.0 ± 1.2). Eighteen patients had successful implant, while in two patients closure was

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failure, hypertension, age, diabetes mellitus, prior stroke or transient ischaemic attack [CHADS2] score 2.6) and were not oral anticoagulation candidates.20 Device implantation success was 98 % by core laboratory TOE. In comparison with historical controls, with an expected 6.6 % stroke rate, the PLAATO device in this trial showed a 3.8 % stroke rate or a 42.0 % relative risk reduction.

The PLAATO experience demonstrated that in a non-randomised cohort, device implantation is feasible. When compared with the stroke risk estimated using the CHADS2 score, the device reduced the stroke rate from 40 % to 65 % in higher risk AF patients with contraindications to anticoagulation.

WATCHMAN The WATCHMAN LAA closure device began its use in humans after the PLAATO device. The WATCHMAN LAA system is a self-expanding nickel titanium (nitinol) device (see Figure 1A). It contains a polyester covering and fixation barbs for attachment. Like the PLAATO system, implantation is performed percutaneously through venous access and transseptal puncture. In the initial clinical experience, following implantation, patients are anticoagulated with warfarin or alternate agents for approximately 45 days, as the fabric requires time for sealing. After this period, patients are maintained on antiplatelet agents indefinitely. The WATCHMAN device is the only LAA closure device studied in randomised clinical studies.

Data in Patients with No Contraindications to Anticoagulation Given the need for anticoagulation peri-implantation, data for the WATCHMAN device consist of trials with patients that have no contraindications to anticoagulation. This is thought provoking, as it may suggest a future role for first-line therapy in AF patients as opposed to lifelong anticoagulation.

The seminal clinical trial with the WATCHMAN device is the Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation (PROTECT-AF) trial.21 The population was at somewhat

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lower cardioembolic risk, with a mean CHADS2 mean score of 2.17.

The study had a non-inferiority design and randomised 707 patients with non-valvular AF worldwide to the WATCHMAN device or warfarin therapy in a 2:1 fashion. A primary composite endpoint consisted of stroke, cardiovascular death and systemic embolism. If the TOE at 45 days showed minimal flow in the LAA and no thrombus or clinical endpoints, then warfarin was discontinued with aspirin/ clopidogrel to six-months, followed by aspirin alone. At 45 days, 86 % of the WATCHMAN device patients had documented closure and were able to stop warfarin. This increased to 92 % at six months. In the WATCHMAN group, there was a 38 % reduction in primary efficacy, 29 % in stroke and 38 % in death compared with the warfarin control group. Meanwhile, there was a 77 % increase in primary safety events in the WATCHMAN group. Procedural complications occurred in a relatively high percentage – 49 of 453 (10.6 %) of the device cohort. The control group had a 6.6 % (16 of 244) adverse event rate, which consisted of major bleeding (4.3 %) and haemorrhagic stroke (2.5 %). The PROTECT-AF trial demonstrated the non-inferiority of the WATCHMAN device compared with standard therapy with warfarin, but concerns of safety of implantation remained.

Subsequent analysis comparing the PROTECT AF trial with the Continued Access Protocol (CAP) Registry, 22 demonstrated that procedure-related and device-related adverse events were greater in the first half of PROTECT AF trial than in the second half. In the four-year follow-up, the primary efficacy event rate per 100 patient-years was lower with the WATCHMAN device compared with controls (2.3 versus 3.8 %), demonstrating a 40 % relative risk reduction. In addition, in an intention-to-treat analysis, patients who received the WATCHMAN device were at reduced risk compared with warfarin-treated patients for both all-cause mortality (3.2 versus 4.8 %; hazard ratio [HR] 0.66; 95 % confidence interval [CI] 0.45–0.98; P=0.0379) and cardiovascular mortality (1.0 versus 2.4 %; HR 0.40; 95 % CI 0.23–0.82; P=0.0045). These data suggest that the WATCHMAN device may actually confer superior outcomes as compared with the previously published non-inferiority.23 The Prospective Randomized Evaluation of the Watchman LAA Closure Device in Patients with Atrial Fibrillation Version Long Term Warfarin Therapy (PREVAIL) study is a more recent evaluation of patients with no contraindications to anticoagulation.24 While still awaiting formal publication, data from the trial have been released. The PREVAIL trial enrolled 407 patients, again randomised in a 2:1 fashion to the device or warfarin. As a result of procedural refinements, the implant success rate in the PREVAIL study was 95.1 %, significantly better than the 90.9 % rate in the PROTECT AF trial. The main safety endpoint – acute (seven-day) occurrence of death, ischaemic stroke, systemic embolism and procedure, or device-related complications requiring major cardiovascular or endovascular intervention – occurred in six out of 269 patients (2.2 %) who received the device. A second, broader, safety endpoint, including cardiac perforation, pericardial effusion with tamponade, ischaemic stroke, device embolisation and other vascular complications, occurred in 4.4 % of patients receiving the WATCHMAN device in the PREVAIL study, compared with 8.7 % in the PROTECT AF study. The observed adverse event rate at 18 months for both the WATCHMAN device and the control was 0.064, resulting in a rate ratio of 1.07, device versus control. The PREVAIL trial also met its pre-specified endpoint for the third co-primary endpoint occurrence of late ischaemic stroke and systemic embolism (>7 days post-randomisation) at 18 months. The observed adverse event rate

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was 0.0253 per 100 patient-years, resulting in an observed difference between the device and control group of 0.0051 per 100 patient-years.

Data in Patients with Contraindications to Anticoagulation The PROTECT AF and PREVAIL trials demonstrated that LAA closure with the WATCHMAN device was non-inferior to warfarin therapy. However, the PROTECT AF study only included patients that were candidates for warfarin.

The ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology (ASAP) registry,25 a non-randomised feasibility study, was designed to assess the safety and efficacy of LAA closure in AF patients ineligible for warfarin therapy. The regimen after implant was clopidogrel through six months and aspirin indefinitely. The mean CHADS2 score in the ASAP population was 2.8, which equates to a predicted ischaemic stroke rate of 7.4 % (although assuming no aspirin use). If this expected stroke rate of 7.4 % per year is averaged with data in which aspirin was used, the expected ischaemic stroke of the ASAP population is approximately 7.3 %. The ASAP registry demonstrated that the WATCHMAN device recipients had a 77 % reduction in ischaemic stroke versus aspirin alone, and a 64 % reduction versus aspirin and clopidogrel.

It is important to note that incomplete LAA closure is a complication of the device (as with any of the devices). In fact, residual peri-device flow into the LAA after percutaneous closure with the WATCHMAN device was common (~32 % of patients with at least some degree of peri-device flow at 12 months) in the PROTECT AF study.26 Other studies have replicated this experience.27 The cardioembolic significance of this remains unclear, as the event rate was exceedingly low in the PROTECT AF study population.

The WATCHMAN device has been considered for Food and Drug Administration (FDA) approval based on the results accumulating data. While FDA advisory panels for this topic have voted in favour of approval, the FDA has yet to grant approval at the time of this writing.

Amplatzer Occlusion Device The Amplatzer septal occluder has been in use for over 15 years, with extensive success in patent foramen ovale and atrial septal defect closure, and is FDA approved for this latter indication. The first human clinical application in LAA occlusion was in 2002. In a series of 16 patients, LAA occlusion was successful in 15, with one instance of device embolisation requiring surgical intervention.28 Subsequently, the Amplatzer Cardiac Plug was developed specifically for LAA occlusion (see Figure 1B). It consists of a self-expanding flexible nitinol mesh with a distal lobe with retaining hooks, a proximal disk, each containing central polyester patch. The mechanism of the lobe and disk for sealing the LAA orifice is termed the ‘pacifier principle’.

The device has been used extensively outside the US, with reports of great efficacy.29 In the initial European experience, the device was successfully implanted in 96 % (137 of 143) of patients.30 This retrospective data did not specify ability to tolerate anticoagulation.

There were serious complications in 10 (7.0 %) patients (three patients with ischaemic stroke; two patients experienced device embolisation, both percutaneously recaptured; and five patients with clinically significant pericardial effusions). Minor complications were insignificant pericardial effusions in four patients, transient myocardial ischaemia in two patients and loss of the implant in the venous system in one patient. The registry did not aim to assess indications for LAA closure or the effectiveness of the procedure – Asia Pacific experience was similar.31

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Device Therapy Few data exist regarding the formation of thrombi on the Amplatzer cardiac plug (ACP), but reports of this exist. In one case, a patient with chronic AF underwent successful percutaneous LAA exclusion and was prescribed clopidogrel for one month and aspirin indefinitely, but TOE at three-month follow-up revealed a thrombus adhering to the device. This resolved with enoxaparin 60 mg twice-daily for six months.32 In January 2011 the manufacturer (at that time AGA Medical) published a Field Safety Notice for all centres implanting the ACP, updating the instructions for use, stating that the most likely cause for thrombus formation on the device was excessively deep implantation.

They recommended aspirin for six months post-implant.

Data also exist on the late outcomes after LAA closure in patients with absolute contraindications to warfarin. A recently published small trial followed a total of 52 patients who underwent Amplatzer LAA closure.33 Most patients received short-term (1–3 months) dual antiplatelet therapy after the procedure and single antiplatelet therapy thereafter. The procedure was successful in 98.1 % of the patients, and the main complications were device embolisation (1.9 %) and pericardial effusion (1.9 %), with no cases of peri-procedural stroke. At a mean follow-up of 20 ± 5 months, the rates of death, stroke, systemic embolism, pericardial effusion and major bleeding were 5.8 %, 1.9 %, 0.0 %, 1.9 % and 1.9 %, respectively. The presence of mild peri-device leak was observed in 16.2 % of patients at the six-month follow-up as evaluated by TOE. There were no cases of device thrombosis.

These data suggest that the Amplatzer device followed by dual/single antiplatelet therapy may be associated with a low rate of embolic and bleeding events in intermediate length follow-up.

Observational data regarding cardioembolic effects are limited. One prospective observational report followed a total of 197 patients who were not candidates for anticoagulation and underwent ACP implantation at one of 15 investigative centres in Europe in 2009 to 2011.34 The stroke rate was 1.98 % at 101 patient-years compared with a CHADS2 prediction of 5.60 %.

The Amplatzer device does not have FDA approval for LAA closure.

Recent variations on the device have been made to help with implantation, now known as the AMPLATZER™ Amulet™ Left Atrial Appendage Occluder.35 A randomised clinical study comparing the efficacy of the ACP device versus warfarin enrolled its first patient in March 2013. The Amulet device is not approved for use in the US. In Europe the use of the device has been temporarily suspended.

Developing Endocardial Occlusion Devices The Coherex WaveCrest36 is a developing device (see Figure 1C).

Purportedly, the WaveCrest device is designed to improve confidence in clinical outcomes through an ability to better control placement with retractable anchors, better visualise closure, position and stability as well as material that allows for rapid endothelization. This highlights the potential areas for advancement in endocardial LAA occlusion. Coherex has received CE Mark approval for the WaveCrest and expects to begin commercialisation outside the US. The Cardia Ultrasept,37 Lifetech LAmbre™38 and Occlutech®39 devices are also in varying stages of development in this rich space.

Epicardial Left Atrial Appendage Occlusion Two devices in various stages of development involve a transcatheter transpericardial technique – the LARIAT® Suture Delivery Device and the Aegis electrocardiogram-guided LAA capture and ligation system.

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LARIAT The LARIAT Suture Delivery Device uses transseptal placement of a temporary balloon in the LAA, two magnet-tipped guidewires inserted endocardialy into the LAA and the pericardial space, and a closure snare device (see Figure 1D). A radiopaque suture loop captures the LAA. Due to the need for pericardial access, patients with potential adhesions such as those with a history of cardiac surgery or pericarditis are not ideal candidates for the procedure. However, the LARIAT procedure does not require the use of peri-procedural anticoagulation therapy.

This device demonstrated successful LAA closure in a canine model, with 100 % successful deployment.40 Early data showed the feasibility of the procedure in 13 human patients.41 In 2011, a total of 13 patients undergoing either mitral valve surgery (n=2) or electrophysiological study and radiofrequency catheter ablation for AF (n=11) underwent ligation of the LAA with the LARIAT device. Both mitral valve patients had complete closure by visual inspection; 10 of 11 patients having ablation underwent a successful LAA ligation.

Subsequently, larger series have shown further positive results.42 Eighty-five (96 %) of 89 patients underwent successful LAA ligation.

Eighty-one of 85 patients had complete closure immediately. Three of 85 patients had a ≤2 mm residual LAA leak, and one of 85 patients had a ≤3 mm jet by TOE colour Doppler evaluation. There were no complications due to the device. There were three access-related complications, all conservatively managed without any patient requiring surgery. Adverse events included severe pericarditis post-operatively (n=2), late pericardial effusion (n=1), unexplained sudden death more than six months after the procedure (n=2) and late strokes thought to be non-embolic also occurring more than six months after the procedure (n=2). At one-month (81 of 85) and three-months (77 of 81) post-ligation, 95 % of the patients had complete LAA closure by TOE. Of the patients undergoing one-year TOE (n=65), there was 98 % complete LAA closure, including the patients with previous leaks.

The LARIAT is approved in Europe and was approved by the FDA in 2009. Data regarding its efficacy in cardioembolic reduction are accumulating.

Aegis System The Aegis system is an epicardial electrocardiogram-guided LAA capture and ligation system. It permits LAA closure in the closed pericardial space with a single sheath puncture. It has two components – an appendage grasper and a ligator. An atrial electrogram recorded between the two jaws identifies the tissue captured as atrial myocardium, thus distinguishing the LAA from epicardial fat and ventricular tissue. Additional recordings permit identification of the grasper’s position relative to electrically active cardiac tissue. Beyond TOE guidance, once the system is positioned near the LAA, injection of contrast outlines the LAA. The second component is a ligator/hollow suture to provide mechanical support and for fluoroscopic visualisation. Once the loop is in position it is cinched down, occluding the LAA, after which the wire is removed leaving only the suture behind. The loop can be repeatedly opened and closed until capture is achieved. An initial suture can also be used as a guide for more proximal sutures. Further studies have shown improving results on an intermediate basis.43 Human data are not available to date.

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Left Atrial Appendage Closure Devices for Stroke Prevention

Thorascopic Devices Beyond the aforementioned devices, other systems using a thorascopic approach are currently in development. These include the Epitek Anchorage Closure System™ and Medtronic Cardioblate®.44,45

Conclusions The LAA is a prominent source of cardioembolism. Systemic anticoagulation to treat what may be largely a localised phenomenon is associated with significant complications. These challenges have

1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2011 update: a report from the American Heart Association. Circulation 2011;123(4):e18–209.

2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study.

Arch Intern Med 1987;147(9):1561–4.

3. 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 2014;383(9921):955–62.

4. Su P, McCarthy KP, Ho SY. Occluding the left atrial appendage: anatomical considerations. Heart 2008;94(9):1166–70.

5. Heist EK, Refaat M, Danik SB, et al. Analysis of the left atrial appendage by magnetic resonance angiography in patients with atrial fibrillation. Heart Rhythm 2006;3(11):1313–8.

6. Al-Saady NM, Obel OA, Camm AJ. Left atrial appendage: structure, function, and role in thromboembolism. Heart 1999;82(5):547–54.

7. Agmon Y, Khandheria BK, Gentile F, Seward JB. Echocardiographic assessment of the left atrial appendage.

J Am Coll Cardiol 1999;34(7):1867–77.

8. Tabata T, Oki T, Yamada H, et al. Relationship between left atrial appendage function and plasma concentration of atrial natriuretic peptide. Eur J Echocardiogr 2000;1(2):130–7.

9. Madden JL. Resection of the left auricular appendix; a prophylaxis for recurrent arterial emboli. J Am Med Assoc 1949;140(9):769–72.

10. Manning WJ. Atrial fibrillation, transesophageal echo, electrical cardioversion, and anticoagulation. Clin Cardiol 1995;18(2):58,114.

11. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61(2):755–9.

12. Cox JL. Surgical treatment of atrial fibrillation: a review.

Europace 2004;5 Suppl 1:S20–9.

13. García-Fernández MA, Pérez-David E, Quiles J, et al. Role of left atrial appendage obliteration in stroke reduction in patients with mitral valve prosthesis: a transesophageal echocardiographic study. J Am Coll Cardiol 2003;42(7):1253–8.

14. Healey JS, Crystal E, Lamy A, et al. Left Atrial Appendage Occlusion Study (LAAOS): results of a randomized controlled pilot study of left atrial appendage occlusion during coronary bypass surgery in patients at risk for stroke. Am Heart J 2005;150(2):288–93.

15. Sievert H, Lesh MD, Trepels T, et al. Percutaneous left atrial appendage transcatheter occlusion to prevent stroke in highrisk patients with atrial fibrillation: early clinical experience.

Circulation 2002;105(16):1887–9.

16. Ostermayer SH, Reisman M, Kramer PH, et al. Percutaneous left atrial appendage transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with nonrheumatic atrial fibrillation: results from the international multi-center feasibility trials. J Am Coll Cardiol 2005;46(1):9–14.

17. Ussia GP, Mulè M, Cammalleri V, et al. Percutaneous closure of left atrial appendage to prevent embolic events in high-risk patients with chronic atrial fibrillation. Catheter Cardiovasc Interv 2009;74(2):217–22.

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led to interest in mechanical exclusion of the LAA. In this paper, we reviewed the current state of percutaneous left atrial exclusion for stroke prevention in AF, including transspetal endovascular and percutaneous epicardial devices. Early data from both categories is promising. There is accumulating data in both patients with contraindications to anticoagulation as well as those who have no contraindications. The availability of several approaches will allow physician selection of the optimal approach for a given patient based on clinical, physiological and anatomical considerations. n

18. Park JW, Leithäuser B, Gerk U, et al. Percutaneous left atrial appendage transcatheter occlusion (PLAATO) for stroke prevention in atrial fibrillation: 2-year outcomes. J Invasive Cardiol 2009;21(9):446–50.

19. Bayard YL, Omran H, Neuzil P, et al. PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) for prevention of cardioembolic stroke in non-anticoagulation eligible atrial fibrillation patients: results from the European PLAATO study.

EuroIntervention 2010;6(2):220–6.

20. Block PC, Burstein S, Casale PN, et al. Percutaneous left atrial appendage occlusion for patients in atrial fibrillation suboptimal for warfarin therapy: 5-year results of the PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) Study. JACC Cardiovasc Interv 2009;2(7):594–600.

21. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009; 374(9689):534–42.

22. Reddy VY, Holmes D, Doshi SK, et al. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation 2011;123(4):417–24.

23. Meier B, Palacios I, Windecker S, et al. Transcatheter left atrial appendage occlusion with Amplatzer devices to obviate anticoagulation in patients with atrial fibrillation. Catheter Cardiovasc Interv 2003;60(3):417–22.

24. Holmes DR, Doshi S, Kar S, et al. Presentation. Final results of randomised trial of left atrial appendage closure versus warfarin for stroke/thromboembolic prevention in patients with nonvalvular atrial fibrillation. American College of Cardiology Annual Scientific Session 2013, San Fransisco, US. 25. Reddy VY, Möbius-Winkler S, Miller MA, et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013;61(25):2551–6.

26. Viles-Gonzalez JF, Kar S, Douglas P, et al. The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial fibrillation: a PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) substudy. J Am Coll Cardiol 2012;59(10):923–9.

27. Bai R, Horton RP, DI Biase L, et al. Intraprocedural and longterm incomplete occlusion of the left atrial appendage following placement of the WATCHMAN device: a single center experience. J Cardiovasc Electrophysiol 2012;23(5):455–61.

28. Reddy VY, Doshi SK, Sievert H, et al. Long Term Results of PROTECT AF: The Mortality Effects of Left Atrial Appendage Closure versus Warfarin for Stroke Prophylaxis in AF. Presented at: Heart Rhythm Society 34th Annual Scientific Sessions, Denver, Colorado, US, 9 May 2013.

29. Meerkin D, Butnaru A, Dratva D, et al. Early safety of the

Amplatzer Cardiac Plug™ for left atrial appendage occlusion.

Int J Cardiol 2013;168(4):3920–5.

30. Park JW, Bethencourt A, Sievert H, et al. Left atrial appendage closure with Amplatzer cardiac plug in atrial fibrillation: initial European experience. Catheter Cardiovasc Interv 2011;77(5):700–6.

31. Lam YY, Yip GW, Yu CM, et al. Left atrial appendage closure with AMPLATZER cardiac plug for stroke prevention in atrial fibrillation: initial Asia-Pacific experience. Catheter Cardiovasc Interv 2012;79(5):794–800.

32. Cruz-Gonzalez I, Martín Moreiras J, García E. Thrombus formation after left atrial appendage exclusion using an Amplatzer cardiac plug device. Catheter Cardiovasc Interv 2011;78(6):970–3.

33. Urena M, Rodés-Cabau J, Freixa X, et al. Percutaneous left atrial appendage closure with the AMPLATZER cardiac plug device in patients with nonvalvular atrial fibrillation and contraindications to anticoagulation therapy. J Am Coll Cardiol 2013;62(2):96–102.

34. Park JW, Sievert H, Schillinger W, et al. TCT-86 Results of the Amplatzer Cardiac Plug European Multicenter Prospective Observational Study. J Am Coll Cardiol 2012;60(17):B27.

35. Freixa X, Chan JL, Tzikas A, et al. The Amplatzer™ Cardiac Plug 2 for left atrial appendage occlusion: novel features and first-in-man experience. EuroIntervention 2013;8(9):1094–8.

36. Coherex Medical. The WaveCrest Solution. Available at: www. coherex.com/finding-a-solution/the-wavecrest-solution/ (accessed 6 April 2014).

37. Cheng Y, Conditt G, Yi G, et al. TCT-765 First In-Vivo Evaluation of the Ultrasept Left Atrial Appendage Closure Device. J Am Coll Cardiol 2012;60(17):B223.

38. Lam YY. A new left atrial appendage occluder (Lifetech LAmbre Device) for stroke prevention in atrial fibrillation.

Cardiovasc Revasc Med 2013;14(3):134–6.

39. Kanthan A, Looi KL, Mottram P, et al. Percutaneous left atrial appendage closure using a PFO closure device. Heart Lung Circ 2013;22(9):784–5.

40. Lee RJ, Bartus K, Yakubov SJ, Catheter-based left atrial appendage (LAA) ligation for the prevention of embolic events arising from the LAA: initial experience in a canine model. Circ Cardiovasc Interv 2010;3(3):224–9.

41. Bartus K, Bednarek J, Myc J, et al. Feasibility of closed-chest ligation of the left atrial appendage in humans. Heart Rhythm 2011;8(2):188–93.

42. Bartus K, Han FT, Bednarek J, et al. Percutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation: initial clinical experience. J Am Coll Cardiol 2013;62(2):108–18.

43. Bruce CJ, Stanton CM, Asirvatham SJ, et al. Percutaneous epicardial left atrial appendage closure: intermediate-term results. J Cardiovasc Electrophysiol 2011;22(1):64–70.

44. Slater AD, Foley JL, Phillips L, Francischelli DE. Band occlusion of the atrial appendage. J Card Surg 2010;25(2):156–60.

45. McCarthy PM, Lee R, Foley JL, et al. Occlusion of canine atrial appendage using an expandable silicone band. J Thorac Cardiovasc Surg 2010;140(4):885–9.

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Device Therapy

Device-Based Approaches to Modulate the Autonomic Nervous System and Cardiac Electrophysiology W illia m J Huc k er, 1 Ja g me e t P S i n g h , 2 K i m b e r l y P a r k s 3 a n d A n t o n i s A A r m o u n d a s 4 1. Fellow in Cardiovascular Medicine, Division of Cardiology, Massachusetts General Hospital, US; 2. Associate Professor of Medicine, Harvard Medical School, Director, Resynchronization and Advanced Cardiac Therapeutics Program, Massachusetts General Hospital, US 3. Instructor in Medicine, Harvard Medical School, Advanced Heart Failure and Transplantation, Massachusetts General Hospital, US 4. Assistant Professor of Medicine, Harvard Medical School Cardiovascular Research Center, Massachusetts General Hospital, US

Abstract Alterations in resting autonomic tone can be pathogenic in many cardiovascular disease states, such as heart failure and hypertension.

Indeed, autonomic modulation by way of beta-blockade is a standard treatment of these conditions. There is a significant interest in developing non-pharmacological methods of autonomic modulation as well. For instance, clinical trials of vagal stimulation and spinal cord stimulation in the treatment of heart failure are currently underway, and renal denervation has been studied recently in the treatment of resistant hypertension. Notably, autonomic stimulation is also a potent modulator of cardiac electrophysiology. Manipulating the autonomic nervous system in studies designed to treat heart failure and hypertension have revealed that autonomic modulation may have a role in the treatment of common atrial and ventricular arrhythmias as well. Experimental data on vagal nerve and spinal cord stimulation suggest that each technique may reduce ventricular arrhythmias. Similarly, renal denervation may play a role in the treatment of atrial fibrillation, as well as in controlling refractory ventricular arrhythmias. In this review, we present the current experimental and clinical data on the effect of these therapeutic modalities on cardiac electrophysiology and their potential role in arrhythmia management.

Keywords Autonomic stimulation, spinal cord stimulation, renal denervation, vagal stimulation, arrhythmias Disclosure: William J Hucker and Antonis A Armoundas have no conflicts of interest to declare; Jagmeet P Singh recieves consulting and research grants from Boston Scientific, Biotronik, Medtronic, St. Jude Medical and Sorin, and is a consultant for CardioInsight, Respicardia Inc.; Kimberly Parks is a consultant for Biotronik and St Jude Medical, and has received honoraria from Biotronik, Medtronic and St Jude Medical Acknowledgment: The work was supported by NIA grant 1R21AG035128.

Received: 3 February 2014 Accepted: 4 April 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(1):30–5 Access at: www.AERjournal.com Correspondence: Antonis A Armoundas, Cardiovascular Research Center, Massachusetts General Hospitals 149, 13th Street, Charlestown, Boston, MA 02129, US. E: aarmoundas@partners.org

The interplay between the central nervous system and cardiac electrophysiology is fundamental, and becomes obvious each time one’s pulse quickens in response to stress. Normally, cardiac neurohormonal regulation is accomplished through the balanced effects of sympathetic and parasympathetic autonomic stimulation, along with the hormonal regulation of the renin-angiotensinaldosterone system (RAAS). Autonomic and hormonal input modulate multiple facets of cellular electrophysiology – action potential duration, ion channel kinetics and intracellular calcium dynamics (just to name a few) – which translate into macroscopic manifestations of autonomic modulation such as heart rate variability, atrioventricular (AV) conduction time and QT interval variability.1 Therefore, it is no surprise that neurohormonal regulation of cardiac electrophysiology is an area of active investigation for its potential antiarrhythmic effects.

Recent reviews have focused on the efficacy of neurohormonal modulation, via non-pharmacological methods, to enhance heart failure treatment.2,3 This review will attempt to provide a state-of-the-art on the potential antiarrhythmic efficacy of renal artery denervation, spinal cord stimulation and direct vagal stimulation.

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Neurohormonal Control in the Normal and Failing Heart Autonomic control of cardiac physiology is often conceptualised as parasympathetic (cholinergic) and sympathetic (adrenergic) innervation existing in a ‘yin and yang’ balance under normal circumstances; however, this concept may be over-simplified.4 In reality, the intrinsic cardiac nervous system, composed of several ganglia located primarily posterior to the atria, likely acts as a ‘little brain’ of the heart – it provides efferent input to the myocardium, collects afferent signals on a beat-to-beat basis and performs some integrative functions on its own, all under the tonic modulation of extrinsic sympathetic and parasympathetic input (see Figure 1).4–8 The ganglia are predominantly composed of cholinergic neurons; however, sympathetic efferent neurons are also present. Due to the complex interconnectivity between the ganglia, afferent mechanosensory, nociceptive and chemosensory signals from all four chambers of the heart may be processed within a single ganglion.4 Such interconnectivity implies that predicting the effect of stimulation or ablation of a particular ganglion may be difficult, because each ganglion performs multiple functions.7,9

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The intrinsic cardiac nervous system is constantly modulated by central autonomic tone via the extrinsic cardiac nervous system.10 Cardiac sympathetic innervation arises from the superior cervical ganglion, stellate ganglion and thoracic ganglia, which communicate with C1–3, C7–T2 and T1–T5, respectively. 4,11,12 Preganglionic parasympathetic innervation exits the medulla via the vagus nerve, which then provides several small branches to the intrinsic cardiac nervous system. Parasympathetic innervation is concentrated around the sinoatrial (SA) and AV nodes, with greater vagal innervation of the atria than the ventricles.

In heart failure, the balance of cardiac parasympathetic and sympathetic tone is significantly altered leading to sympathetic hyperactivity.13 Decreased cardiac output and myocardial ischaemia stimulate the arterial baroreflex, arterial chemoreflex and the cardiac sympathetic afferent reflex while attenuating afferent cardiac vagal reflexes leading to an overall increased sympathetic tone, peripheral vasoconstriction and sodium retention.14–18 Over time, chronic sympathetic hyperactivity is maladaptive in the heart, leading to decreased contractility through beta-receptor downregulation, increased cardiomyocyte apoptosis and myocardial fibrosis.14 Current cornerstones of pharmacological heart failure management are based on neurohormonal blockade, with a mortality benefit conveyed by beta-blockers,19–21 angiotensin-converting enzyme (ACE) inhibitors22 and aldosterone antagonists.23 Due to the growing need to improve heart failure therapies, there are now non-pharmacological approaches to re-establish autonomic balance that are currently under investigation, such as vagal stimulation and spinal cord stimulation.3 Similarly, renal denervation is an emerging technique to treat resistant hypertension, and may have a role in treating heart failure as well. Arrhythmias are common co-morbidities in patients with heart failure and resistant hypertension, therefore trials designed to investigate non-pharmacological autonomic modulation in these populations will likely provide significant insight into the possibility of employing autonomic modulation as an antiarrhythmic strategy.

Device-Based Approaches to Modulate the Autonomic Nervous System Renal Denervation Renal Denervation and Atrial Electrophysiology Recently, renal denervation (RDN) has become an increasingly studied method to control resistant hypertension.24 RDN is performed through endovascular ablation of several locations within the renal arteries, disrupting sympathetic renal efferent innervation. Reducing renal efferent input also decreases renal afferent output and is associated with reduced serum norepinephrine levels25–27 and decreased central sympathetic tone.28 Therefore, RDN is likely to influence cardiac electrophysiology through modulation of central adrenergic tone, and may have a role in antiarrhythmic therapy.29,30 Preclinical work in dogs and pigs have indicated that RDN affects heart rate variability,26 resting heart rate, heart rate during atrial fibrillation (AF), AV conduction time, and decreases AF incidence in a model of obstructive sleep apnoea.31,32 RDN does not appear to effect the atrial refractory period.33 RDN has also been shown to prevent structural and electrical remodeling in a canine model of chronic rapid atrial pacing.34 In humans, resting heart rate was decreased, and the PR interval was increased following RDN;35 indicating that RDN can affect autonomic

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Figure 1: Schematic of Cardiovascular Autonomic Control Cardioinhibitory Centre (Parasympathetic) Vagus Nucleus Cardioacceleratory Centre (Sympathetic)

Medulla Oblongata

Sympathetic Ganglia

Spinal Cord

Cardiac Nerve

Parasympathetic innervation exits the medullary centres via the vagus nerve, which then synapses with the intracardiac nervous system before providing post-ganglionic fibres to the myocardium. Sympathetic innervation exits the medulla and enters the spinal cord before exiting and traveling to the ganglia within the sympathetic chain. Post-ganglionic fibres travel along the major vessels prior to entering the myocardium. Sympathetic innervation also continues along the major vessels to the kidneys, supplying renal sympathetic innervation.

modulation of cardiac conduction in patients. The direct effect of RDN on atrial arrhythmias was recently investigated in a small trial of patients with a history of drug resistant hypertension and paroxysmal AF that were randomised to either pulmonary vein isolation (PVI) or PVI with RDN.36 In the RDN group, both the systolic and diastolic blood pressures were significantly decreased as compared with the PVI group. Echocardiographic data also revealed a decrease in left ventricular (LV) thickness – substantiated in other studies as well.37,38 In this setting, the freedom from AF was 69 % at one-year in the RDN group, versus 29 % in the PVI only group.36 However, because there was also a substantial decrease in blood pressure in the denervation group, these results beg the question: did blood pressure control alone account for the decrease in AF, or was it also influenced by decreased afferent renal sympathetic output?

Hypertension alone has been shown to cause atrial remodeling and is a significant reversible risk factor for AF.39 Therefore, removing the hypertensive stimulus for remodeling may be responsible for the decrease in AF, and not necessarily autonomic modulation. However, if it were solely the effect of hypertension, similar improvement in AF rates would have presumably been seen in prior large trials of hypertension treatment.40 While the blood pressure decrease seen in recent RDN trials has been larger than seen previously in trials of drug therapy for hypertension (which may potentiate its effect on AF), the true efficacy of RDN for hypertension management has been brought into question with the recent announcement that the Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-3) trial (clinicaltrials. gov; Identifier: NCT01418261) did not meet its primary efficacy endpoint.

Once published, the data from this trial will have to be examined

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Device Therapy carefully to determine if RDN affected the rates of atrial arrhythmias in the absence of a significant decrease in blood pressure.

Renal Denervation and Ventricular Electrophysiology Thus far, less is known about the impact of RDN on ventricular arrhythmias. Adrenergic stimulation is arrhythmogenic in the ventricles, with cardiac sympathetic denervation used as a possible treatment for refractory ventricular arrhythmias.41 RDN has been shown to decrease serum norepinephrine, aldosterone and central sympathetic tone.28 Therefore it is certainly possible that RDN may also reduce ventricular ectopy and arrhythmias through its ability to decrease central sympathetic tone. Recently a small study of RDN coupled with myocardial ischaemia demonstrated that RDN in pigs reduced premature ventricular contraction (PVC) burden and ventricular fibrillation (VF) induced by ischaemia.42 In humans, case reports of RDN used in patients with ventricular tachycardia (VT) storm, demonstrated a decrease in ventricular arrhythmias.43–45 Presumably, the mechanism is via decreased sympathetic tone; however, the true mechanisms will have to be elucidated in larger studies. Importantly, large clinical trials have demonstrated that aldosterone blockade is associated with decreased rates of sudden cardiac death after myocardial infarction (MI).23,46 Therefore, it may be that decreased renin and aldosterone secretion after RDN34,47 may influence its antiarrhythmic effect instead of (or in addition to) any change it causes in adrenergic activation.

Potential Adverse Effects of Renal Denervation The number of studies investigating RDN is increasing significantly.

Thus far, there have not been significant complications reported.

In a three-year follow-up of the Renal Denervation in Patients with Refractory Hypertension (Symplicity HTN-1) trial, one patient was noted to develop renal artery stenosis.48 At one-year, patients in the Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-2) trial had stable renal function and only one renal artery dissection was reported at the time of denervation.49 There has also been concern about the possibility of RDN causing orthostatic hypotension. This was investigated in a small study of 36 patients who had undergone RDN, where no increase in orthostasis or syncope was found with tilt table testing.50 Recently, announcements regarding the Symplicity HTN-3 trial indicated that the trial met its safety endpoint and did not raise any significant safety concerns.

Spinal Cord Stimulation Spinal Cord Stimulation and Atrial Electrophysiology Spinal cord stimulation (SCS) has been used for decades in the treatment of refractory angina, epilepsy and for chronic pain.51 The precise mechanism underlying its beneficial effect in angina is debated; however, experimental studies suggest that spinal cord stimulation likely modulates preganglionic sympathetic input to the intrinsic cardiac nervous system, decreases afferent sensory output from intrinsic cardiac nerves during ischaemia, and stabilises the activity of the intrinsic cardiac nervous system during an ischaemic challenge.3,4,52,53 SCS may have an antiarrhythmic role as well. SCS in dogs applied at the T1–T2 level prolonged sinus cycle length and increased AH interval conduction time, which was abolished by vagotomy, suggesting that SCS at T1–T2 has a predominantly vagal effect.54 However, a recent study by Bernstein et al.55 applied SCS to a canine model of

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AF induced by rapid atrial pacing, and showed that SCS prolonged the atrial effective refractory periods in both atria and reduced AF inducibility if SCS was applied at the time that rapid atrial pacing began. These changes would suggest a predominantly sympathetic effect of SCS in the atria. However, one important difference in this study as compared with the Olgin et al.54 study is that Bernstein et al.55 applied SCS from T1–T5 whereas Olgin et al. applied SCS to T1–T2. Therefore, it is possible that different populations of nerves were recruited with SCS in the two studies, which could have influenced the net effect of SCS stimulation. Nevertheless, their results suggest that spinal cord stimulation reduced the burden of AF and may be a useful strategy in the treatment of AF. Similarly, Cardinal et al.56 demonstrated that brady- and tachy-arrhythmias that were induced by excessive activation of the intrinsic cardiac nervous system were reduced by SCS.

Spinal Cord Stimulation and Ventricular Electrophysiology The beneficial effect of SCS on refractory angina and its predominantly sympatholytic effect54 suggests the possibility that SCS may decrease ventricular arrhythmias as well.57 Issa et al.58 observed a significant decrease in VT and VF in a canine heart failure model that was exposed to transient ischaemia. In this model, SCS reduced VT/VF incidence from 59 % to 23 % in the setting of acute ischaemia. Similarly, in a pig model of acute ischaemia, Odenstedt et al.59 observed a significant decrease in sustained and non-sustained VT in pigs receiving SCS. This study also demonstrated a reduction in spatial repolarization gradients with SCS. Similar effects were observed following chronic SCS by Lopshire et al.,60 in which case chronic SCS not only improved LV function in a canine model of ischaemic cardiomyopathy, but also decreased ventricular tachyarrhythmias, over and above the effect seen from standard medical therapy for heart failure.

The mechanism behind the antiarrhythmic effect of SCS is not completely understood and is likely multifactorial, involving modulation of the activity within the intrinsic cardiac nervous system, as well as altering the sympathetic and vagal efferents to the heart.53,60 In addition, inhibition of the cardiocardiac reflex may also contribute to the antiarrhythmic effect of SCS. In the setting of ischaemia, Foreman et al.53 demonstrated that SCS decreased afferent output from the intrinsic cardiac nervous system. In rats, disrupting the T1–T5 dorsal root ganglia to interrupt this reflex arc decreased the time to onset of ventricular arrhythmias.61 Clinically, disrupting cardiac sympathetic innervation either through epidural anaesthesia or through cardiac sympathetic denervation has been used to treat patients with refractory ventricular arrhythmias.62 Myocardial infarction interrupts autonomic innervation in the area of the infarct, with the subsequent development of sympathetic hypersensitivity, nerve sprouting and heterogeneous gradients of sympathetic innervation around the infarct.57,63 Interestingly, Zhou et al.64 demonstrated that in ambulatory dogs with ischaemic cardiomyopathy, ventricular tachyarrhythmias were predominantly preceded by bursts of sympathetic nerve activity in the stellate ganglia. Therefore, it is plausible that sympathetic input enhances the heterogeneity of conduction in the diseased myocardium due to gradients in sympathetic innervation creating a ventricular substrate that is more arrhythmogenic. SCS may mitigate this effect by decreasing sympathetic efferent signaling to the myocardium, thereby preventing the enhancement of heterogeneous conduction and decreasing the likelihood for a ventricular arrhythmia to arise. In support of this hypothesis, a report of three patients that

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received an implantable cardioverter defibrillator (ICD) and a spinal stimulator demonstrated a reduction in T-wave alternans when SCS was active, suggesting that SCS may reduce temporal repolarization gradients and stabilise the ventricular electrical substrate.65

well.4 Therefore, predicting the outcome of ganglion ablation may be difficult and unpredictable because it may tip the balance of parasympathetic and sympathetic innervation in one direction or another, producing contradictory results among patients.

Based largely on the data from dog models, there are clinical trials now enrolling patients to investigate the possible role of SCS in heart failure. The Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Heart Failure (DEFEAT HF) trial, sponsored

by Medtronic Inc., hopes to enrol 250 patients in a phase II study designed to measure changes in LV volume and exercise capacity in a population with systolic heart failure (ClinicalTrials.gov; Identifier: NCT01112579). Similarly, the Spinal Cord Stimulation For Heart Failure (SCS HEART) study is a small phase II study sponsored by St. Jude Medical that aims to enrol 20 patients in a trial designed to assess safety and develop efficacy parameters of spinal cord stimulation in patients with systolic heart failure (ClinicalTrials.gov; Identifier: NCT01362725). Neither of these trials have mentioned investigating arrhythmias in this population; however, it will be intriguing to see if there is any observed decrease in ventricular arrhythmias in this population, which is clearly at risk.

Extrinsic to the heart, vagal nerve stimulation (VNS) may also have a role in atrial arrhythmia management. Despite the fact that vagal stimulation has been used for years as a method to induce AF, recent experimental studies in dogs have demonstrated that low level VNS (below the threshold needed to reduce heart rate) may be antiarrhythmic in the atrium. Shen et al.80 demonstrated that left-sided low-level vagal stimulation decreased left-sided stellate ganglion activity, decreased the incidence of AF and atrial tachycardia, and decreased sympathetic innervation within the stellate ganglion.80 Similarly, Sha et al.,81 in a study of acute, right-sided, low-level vagal stimulation, found that the threshold to induce AF was higher in the VNS group, and the response of heart rate to direct sympathetic and parasympathetic stimulation was blunted in the setting of low level vagal stimulation. In addition, neural activity in a ganglion of the intrinsic cardiac nervous system was reduced with low level VNS, which may be the basis for its antiarrhythmic effect.80 Clearly more studies are needed to further explore the possibilities of low level VNS for arrhythmia management; however, these experimental results are intriguing.12

Potential Adverse Effects of Spinal Cord Stimulation The safety of SCS has been evaluated in trials using SCS for the treatment of angina. Large trials are lacking in this field; however, most studies indicate that the procedure is safe, with device-related infections and catheter dislodgements as the most common complications of the procedure.51 There was concern in the angina trials that SCS may mask a true MI; however, evaluation of patients with electrocardiogram (ECG) evidence of an MI occurring after implantation of the spinal cord stimulator demonstrated that they were aware when their MI occurred.66 Therefore, use of SCS for either heart failure treatment or possibly for arrhythmia control is unlikely to mask significant ischaemic pain. More safety information about the procedure will be obtained in the trials that are currently enrolling patients.

Vagal Stimulation and Ventricular Electrophysiology

Vagal Stimulation

Waxman et al. provided early clinical evidence, which demonstrated that VTs could respond to vagal activation, contrary to traditional belief,88,89 and that ventricular automaticity was decreased by vagal activity.90 Subsequently, experimental animal data in conscious dogs clearly demonstrated that increasing vagal tone by means of right vagus nerve stimulation can prevent ventricular tachyarrhythmias in a model with healed myocardial infarction, evaluated with exercise testing and intermittent ischaemia.91 Interestingly, the observed antifibrillatory effect was independent from heart rate reduction. In the setting of heart failure, the Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) study92 and the Cardiac Insufficiency Bisoprolol Study II (CIBIS II)93 demonstrated that diminished cardiac vagal activity and increased heart rate were powerful predictors of increased mortality in heart failure. Therefore, significant clinical evidence exists that vagal tone may be cardioprotective.

Vagal Stimulation and Atrial Electrophysiology In the atria, parasympathetic stimulation can be proarrhythmic. It shortens atrial myocyte action potential duration (APD) and reduces atrial effective refractory period (ERP),67 thereby shortening the atrial re-entrant wavelength (the product of ERP and conduction velocity) enhancing the possibility of re-entry.68,69 It also depresses intra-atrial conduction, and can induce re-entrant atrial arrhythmias.70 In addition, cholinergic stimulation produces atrial ERP heterogeneity, likely due to heterogeneous distribution of vagal innervation.71 There is a direct relationship between the intensity of parasympathetic stimulation, the spatial disparity of refractory periods and AF inducibility.72 As a result of its profound effect on atrial conduction, intracardiac vagal stimulation and ablation of intracardiac ganglia (predominantly cholinergic neurons) has been considered in the diagnosis and treatment of atrial arrhythmias. However, the results of this strategy have been mixed.73â&#x20AC;&#x201C;79 Choi et al. recently demonstrated that in ambulatory dogs, all episodes of atrial tachyarrhythmias were preceded by bursts of autonomic activity (both parasympathetic and sympathetic),6 suggesting that vagal activity alone may not explain arrhythmogenesis in the atria. Additionally, intracardiac ganglia not only provide some parasympathetic and sympathetic efferent innervation of the atria, they also process afferent information as

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In the ventricle, parasympathetic stimulation is thought to be cardioprotective as decreased vagal activity after myocardial infarction is associated with a higher risk of ventricular arrhythmias.1,6,82,83 It is generally accepted that VNS and cholinergic agonists prolong the ventricular effective refractory period in vivo, in animals.84â&#x20AC;&#x201C;86 In patients, reflex vagal stimulation causes a small but significant prolongation of right ventricular refractoriness. Finally, VNS can influence the vulnerability to VF. In contrast to sympathetic stimulation, VNS decreased the maximum slope of APD restitution, attenuated electrical alternans, and increased ventricular ERP and VF thresholds.87

More recent investigations have focused on the possibility that vagal stimulation may be a treatment modality for heart failure. De Ferrari et al.94 reported the first proof of concept trial using VNS in patients with class IIâ&#x20AC;&#x201C;IV heart failure (n=32 patients), which demonstrated significant improvement in functional ability and ejection fraction with VNS. From the arrhythmia perspective, three patients developed AF during the study, and two patients were reported to receive multiple ICD shocks, which resolved with medication changes and

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Device Therapy diuresis. The episodes of AF were thought to possibly be due to the intervention; however, the cases of ICD shocks were unlikely related to VNS. Importantly, no difference was found in VT rates observed on Holter monitors performed during the study.

The improvement in heart failure that was documented in this study has led to larger, randomised trials – the Increase of Vagal Tone in Chronic Heart Failure (INOVATE HF) and Neural Cardiac Therapy for Heart Failure (NECTAR-HF) study are currently ongoing. Both of these trials have endpoints centred around mortality and heart failure admissions, as well as measures of left ventricular function. However, analysing the data on arrhythmias from these studies (both atrial and ventricular) will provide significant insight into the potential use of VNS as an antiarrhythmic in the near future.

Potential Adverse Effects of Vagal Stimulation Parasympathetic nerve stimulation has been used historically to promote atrial arrhythmias and therefore it certainly has this potential. VNS also may influence the vulnerability to VF by increasing the VF threshold;87 however, others have reported that vagal effects are indirect and depend on concomitant sympathetic activity.95 Thus, VNS-induced elevation of the VF thresholds may require the presence of heightened adrenergic

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2. Lopshire JC, Zipes DP. Device therapy to modulate the autonomic nervous system to treat heart failure. Curr Cardiol Rep 2012;14(5):593–600.

3. Singh JP, Kandala J, John Camm A. Non-pharmacological modulation of the autonomic tone to treat heart failure. Eur Heart J 2014;35(2):77–85.

4. Armour JA. Potential clinical relevance of the ‘little brain’ on the mammalian heart. Exp Physiol 2008;93(2):165–76.

5. Armour JA, Murphy DA, Yuan BX, et al. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec 1997;247(2):289–98.

6. Choi EK, Shen MJ, Han S, et al. Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs. Circulation 2010;121(24):2615–23.

7. He B, Scherlag BJ, Nakagawa H, et al. The intrinsic autonomic nervous system in atrial fibrillation: a review. ISRN Cardiol 2012;2012:490674.

8. Randall DC, Brown DR, McGuirt AS, et al. Interactions within the intrinsic cardiac nervous system contribute to chronotropic regulation. Am J Physiol Regul Integr Comp Physiol 2003;285(5):R1066–75.

9. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial fibrillation inducibility: epicardial fat pad ablation does not have long-term effects. Heart Rhythm 2006;3(6):701–8.

10. Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res 2014;114(6):1004–21.

11. Kawashima T. The autonomic nervous system of the human heart with special reference to its origin, course, and peripheral distribution. Anat Embryol (Berl) 2005;209(6):425–38.

12. Shen MJ, Choi EK, Tan AY, et al. Neural mechanisms of atrial arrhythmias. Nat Rev Cardiol 2012;9(1):30–9.

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14. Sousa-Pinto B, Ferreira-Pinto MJ, Santos M, Leite-Moreira AF. Central nervous system circuits modified in heart failure: pathophysiology and therapeutic implications. Heart Fail Rev 2014 [Epub ahead of print].

15. Triposkiadis F, Karayannis G, Giamouzis G, et al. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol 2009;54(19):1747–62.

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tone. Also in some cases of idiopathic VT, enhanced vagal tone has been suggested to be profibrillatory.96,97 Less serious but important common side effects that have been reported from VNS include a cough, neck pain, swallowing difficulty or change in voice. In addition, procedural complications are certainly possible. However, as the technique improves and the clinical experience grows, VNS may emerge as a potential treatment strategy for atrial and ventricular arrhythmias.

Conclusions As our understanding of the autonomic nervous system and its role in pathophysiology of disease states grows, the potential applications of autonomic modulation will continue to expand significantly. The techniques of renal denervation, SCS and direct vagal stimulation are all emerging as possible treatments for hypertension and heart failure, respectively, and may in turn serve as non-pharmacological antiarrhythmic strategies for atrial and ventricular arrhythmias. As the results of larger clinical trials using these techniques become available, a careful analysis of the data will be crucial to determine if an antiarrhythmic effect truly emerges. The current state of preclinical and small clinical trials provides cautious optimism that RDN, SCS and direct vagal stimulation may all play a role in arrhythmia management in the near future. n

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41. Vaseghi M, Gima J, Kanaan C, et al. Cardiac sympathetic denervation in patients with refractory ventricular arrhythmias or electrical storm: Intermediate and long-term follow-up. Heart Rhythm 2014;11(3):360–6.

42. Linz D, Wirth K, Ukena C, et al. Renal denervation suppresses ventricular arrhythmias during acute ventricular ischemia in pigs. Heart Rhythm 2013;10(10):1525–30.

43. Hoffmann BA, Steven D, Willems S, Sydow K. Renal Sympathetic Denervation as an Adjunct to Catheter Ablation for the Treatment of Ventricular Electrical Storm in the Setting of Acute Myocardial Infarction. J Cardiovasc Electrophysiol 2013 [Epub ahead of print].

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45. Ukena C, Bauer A, Mahfoud F, et al. Renal sympathetic denervation for treatment of electrical storm: first-in-man experience. Clin Res Cardiol 2012;101(1):63–7.

46. Pitt B, White H, Nicolau J, et al. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol 2005;46(3):425–31.

47. Zhao Q, Yu S, Zou M, et al. Effect of renal sympathetic denervation on the inducibility of atrial fibrillation during rapid atrial pacing. J Interv Card Electrophysiol 2012;35(2):119–25.

48. Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 2014;383(9917):622–9.

49. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation 2012;126(25):2976–82.

50. Lenski M, Mahfoud F, Razouk A, et al. Orthostatic function after renal sympathetic denervation in patients with resistant hypertension. Int J Cardiol 2013;169(6):418–24.

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53. Foreman RD, Linderoth B, Ardell JL, et al. Modulation of intrinsic cardiac neurons by spinal cord stimulation: implications for its therapeutic use in angina pectoris.

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54. Olgin JE, Takahashi T, Wilson E, et al. Effects of thoracic spinal cord stimulation on cardiac autonomic regulation of the sinus and atrioventricular nodes. J Cardiovasc Electrophysiol 2002;13(5):475–81.

55. Bernstein SA, Wong B, Vasquez C, et al. Spinal cord stimulation protects against atrial fibrillation induced by tachypacing. Heart Rhythm 2012;9(9):1426–33.e3.

56. Cardinal R, Pagé P, Vermeulen M, et al. Spinal cord stimulation suppresses bradycardias and atrial tachyarrhythmias induced by mediastinal nerve stimulation in dogs. Am J Physiol Regul Integr Comp Physiol 2006;291(5):R1369–75.

57. Zipes DP. Heart-brain interactions in cardiac arrhythmias: role of the autonomic nervous system. Cleve Clin J Med 2008;75 Suppl 2:S94–6.

58. Issa ZF, Zhou X, Ujhelyi MR, et al. Thoracic spinal cord stimulation reduces the risk of ischemic ventricular arrhythmias in a postinfarction heart failure canine model.

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59. Odenstedt J, Linderoth B, Bergfeldt L, et al. Spinal cord stimulation effects on myocardial ischemia, infarct size, ventricular arrhythmia, and noninvasive electrophysiology in a porcine ischemia-reperfusion model. Heart Rhythm 2011;8(6):892–8.

60. Lopshire JC, Zhou X, Dusa C, et al. Spinal cord stimulation improves ventricular function and reduces ventricular arrhythmias in a canine postinfarction heart failure model.

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61. Lujan HL, Krishnan S, Dicarlo SE. Cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in conscious rats. Am J Physiol Regul Integr Comp Physiol 2011;301(3):R775–82.

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63. Cao JM, Fishbein MC, Han JB, et al. Relationship between regional cardiac hyperinnervation and ventricular arrhythmia. Circulation 2000;101(16):1960–9.

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66. Andersen C, Hole P, Oxhøj H. Does pain relief with spinal cord stimulation for angina conceal myocardial infarction?

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67. Prystowsky EN, Naccarelli GV, Jackman WM, et al. Enhanced parasympathetic tone shortens atrial refractoriness in man.

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68. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity.

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Diagnostic Electrophysiology & Ablation

Ablation of Arrhythmias in Patients with Adult Congenital Heart Disease R odrig o Ga lla rd o L o b o, 1 M i c h a e l G r i f f i t h 2 a n d J o s e p h D e B o n o 2 1. Senior Fellow in Electrophysiology , 2. Consultant Cardiologist, Queen Elizabeth Hospital, Birmingham, UK

Abstract Arrhythmias in adults with congenital heart disease, most commonly related to previous surgical procedures, are a frequent comorbidity in this growing population thanks to the improved outcome of surgical techniques. Re-entrant circuits around areas of scarring and natural barriers, combined with abnormal haemodynamics and the underlying anatomy, are the most common cause for these arrhythmias. They are often poorly tolerated and medical treatment is frequently inadequate. In recent years, catheter ablation has emerged as a successful therapeutic option. New advanced techniques such as the use of modern three-dimensional (3D) navigation systems have contributed to better understanding of the arrhythmia mechanisms and higher success rates of the ablation procedures.

In this article we briefly summarise the characteristics of the most common arrhythmias in this patient population and some key aspects in their treatment by catheter ablation.

Keywords Congenital heart disease, catheter ablation, Mustard, Senning, Fontan, Ebstein, Fallot Disclosure: The authors have no conflicts of interest to declare.

Received: 28 August 2013 Accepted: 28 October 2013 Citation: Arrhythmia & Electrophysiology Review 2014;3(1):36–9 Access at: www.AERjournal.com Correspondence: Joseph De Bono, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham B15 2TH, UK. E: Joseph.DeBono@uhb.nhs.uk

Around 0.8 % of live births are affected by some type of congenital heart disease; 30–50 % of whom will need one or more surgical interventions, generally during early childhood, involving in some cases complex corrections with patches, baffles or extracardiac circuits.1,2 As a result of advances in surgical interventions, the life expectancy of patients with congenital heart disease has significantly improved.

Consequently, a greater proportion of these patients reach adulthood where they face significant morbidities, among which cardiac arrhythmias have a considerable impact not only on their quality of life but also on their survival.3 The mechanisms responsible for the appearance of these cardiac arrhythmias vary depending on both the nature of the underlying defects and the type of surgical correction. These determine the electrophysiological substrate through a complex interplay between gross cardiac anatomy, chamber enlargement from increased pressure and volume loads, cellular injury from hypoxia and cardiopulmonary bypass, fibrosis at sites of suture lines and patches, and direct trauma to the specialised conduction tissues.2 Most surgical corrections involve manipulation of atrial chambers.

It is therefore not surprising that many of the arrhythmias seen in this patient population are atrial in origin, usually involving macro re-entrant circuits around areas of scarring and natural barriers.4 It is important to be aware that in patients with complex congenital heart disease and poor haemodynamic reserves these arrhythmias can be poorly tolerated and easily lead to haemodynamic collapse (e.g. in patients with previous Fontan correction) requiring urgent electrical cardioversion to restoration of haemodynamic stability.5

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Antiarrhythmic medication including type Ic and III drugs often fail to prevent arrhythmic events and are associated with the development of severe side-effects, including thyroid dysfunction and pulmonary fibrosis, which may limit their use.6 Catheter ablation has emerged as a highly successful alternative therapeutic option in most cases, either alone or in combination with ongoing drug treatment.7,8 New technological advances in catheters and energy sources, threedimensional (3D) navigation mapping systems and the development of magnetic navigation have improved the outcome of ablation procedures to a great extent.9 In recent years better knowledge of the circuits responsible for these arrhythmias has contributed to the modification of surgical techniques, which may also lead to a reduction in the incidence of cardiac arrhythmias.10,11

Macro Re-entrant Atrial Tachycardias and Atrial Flutter These are the most common arrhythmias in patients with CHD, usually secondary to a re-entrant circuit around scarred tissues due to patches, atriotomies or other natural or surgically created barriers to electrical conduction.4 Risk factors, in addition to the type of surgery, include concomitant sinus node dysfunction (tachy-brady syndrome), older age at operation and longer follow-up.12,13 In relatively simple CHD, such as lone atrial septal defect (ASD) or ventricular septal defect (VSD), the most common atrial substrate is a combination of typical atrial flutter around the cavotricuspid isthmus (CTI) and flutter around atriotomy scars.14 In these cases, typical atrial flutter may switch to flutter around the atriotomy during the ablation procedure as the cavotricuspid isthmus blocks with only

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a small change in cycle length.15 Following termination of the flutter by ablation it is essential to ensure not only that the cavotricuspid isthmus is blocked but also that the atriotomy scar is extended to the inferior vena cava. Block across this line can be confirmed by pacing the low right atrium posterior to the line and demonstrating high to low activation of the anterolateral right atrium. Other circuits may also be seen, particularly on the septum around the ASD repair itself.16 New atrial fibrillation is also frequently seen in patients with ASD even after a successful correction/closure. In these circumstances, left atrial access for pulmonary vein isolation may be difficult. It is usually straightforward to perform a transseptal puncture in postsurgical repairs particularly with echo guidance. It is more challenging in those patients with a previous percutaneous ASD closure. However, in the majority of cases transseptal puncture can be safely performed alongside or occasionally through the device under transoesophageal or intracardiac echo guidance (see Figure 1).17,18 Retrograde transaortic approach with the support of magnetic navigation is an alternative route when transseptal puncture is not possible.19

Figure 1: Transoesophageal Echocardiography-guided Transseptal Puncture Before Atrial Fibrillation Ablation in a Patient with a Previous Percutaneous Atrial Septal Defect Closure and a Dual Chamber Pacemaker Due to Sinus Dysfunction

The transseptal puncture could be performed safely away from the atrial septal defect closure device. Both ablation catheter and Lasso could be advanced into the left atrium and the ablation procedure was carried out normally. The image corresponds to a left anterior oblique projection.

Figure 2: Cavotricuspid Isthmus Ablation at Both Sides of the Baffle in a Patient with Previous Senning Intervention A

As the original disease and its surgical correction get more complex, the likelihood of a more complex intra-atrial re-entrant tachycardia (IART) increases.20 These circuits are often associated with slower cycle length than in typical atrial flutter (270–450 ms) allowing in some cases a 1:1 atrioventricular (AV) conduction, occasionally with poor haemodynamic tolerance needing urgent electrical cardioversion.4,5 In extreme cases the cycle length may be so long that they are mistaken for sinus rhythm and are only easily differentiated by a lack of heart rate variability.

B SVC

MA IVC TA TA

A group of patients that deserve special consideration are those who have had a Mustard or Senning correction for dextro-transposition of the great arteries (d-TGA). At least 30 % of them will also develop some type of IART.4 Most commonly these IART are CTI-dependent flutters.21 In our experience, even when no arrhythmia can be induced in the lab, performance of empiric CTI line ablation will often lead to a good outcome. This requires ablation at both sides of the baffle suture line, which can be achieved by either a retrograde approach or a trans-baffle puncture (see Figure 2).22,23 A careful analysis of the surgical procedure is necessary before attempting any type of electrophysiological study, as is confirmation of patency of venous access to the heart, as unilateral or even bilateral ileofemoral vein occlusion is not uncommon as a result of frequent history of balloon atrial septostomy as newborns and multiple catheterisations.24 Other types of supraventricular tachycardia, particularly atrioventricular nodal re-entry tachycardias (AVNRT), are seen in this group of patients, and they should be ruled out during the electrophysiological study. AVNRT can be treated by a standard AV nodal slow pathway modification, although this usually has to be approached retrogradely (see Figure 3).25 Focal atrial tachycardias usually arising from areas of abnormal atrial tissue are not uncommon either and can be equally targeted for ablation with good results.26 In patients with a single ventricle following a classic right atrial–right ventricular or atriopulmonary Fontan connection, complex IART can be observed in up to 50 % within a decade of the surgery.4 The electrophysiological procedures in these patients are particularly challenging due to the usually severely dilatation of the right atrium, thickness of atrial wall that may hinder or preclude transmural lesion

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Lobo_edited.indd 37

IVC

Images in left anterior oblique view (A) and clipped superior view (B). IVC = inferior vena cava; MA = mitral annulus; SVC = superior vena cava; TA = tricuspid annulus.

Figure 3: Atrioventricular Nodal Slow Pathway Modification for Atrioventricular Nodal Re-entrant Tachycardia in Patient with Previous Senning Surgical Procedure and Dual Chamber Pacemaker Due to Sinus Dysfunction

LAA

Abl cath

The ablation was targeted retrogradely through the aortic root. The image corresponds to a right anterior oblique projection. Abl cath = ablation catheter; LAA = left atrial appendage.

formation and the frequent existence of more than one re-entrant circuit.

The vast majority of the re-entrant circuits are located in the right atrium, mainly associated with the atriotomy scar (usually in low anterolateral area) and the CTI, and less frequently around caval orifices, crista terminalis or the atrial appendage.24 Prior to the electrophysiological procedure intra-atrial thrombus must be excluded.27 It is usual for multiple IARTs to be induced in a single patient, each requiring individual mapping and ablation. Empiric cavotricuspid and intercaval ablation may be useful particularly in patients with multiple tachycardias or more irregular tachycardias, or where the tachycardia is non-inducible or not haemodynamically tolerated. 3D mapping is essential but the

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Diagnostic Electrophysiology & Ablation use of arrays is limited by the large size of the Fontan chamber. Access to the atrial tissue can be difficult in patients with more modern surgical approaches such as the lateral tunnel and extracardiac total cavopulmonary connection, but can be achieved by collaboration with the congenital heart teams.28 Alternatively, remote magnetic navigation via a retrograde approach is particularly useful in these patient groups, allowing easy retrograde access to the atrial chambers without the need for more invasive interventional procedures.9

Accessory Atrioventricular Pathways The incidence of accessory atrioventricular pathways is similar to that of normal population with the clear exceptions of Ebstein’s anomaly and congenitally corrected levo-transposition of the great arteries (L-TGA). Indeed in Ebstein’s anomaly around 20 % of patients will show the presence of accessory atrioventricular connections (typically along the posterior and septal portion of the tricuspid ring), and 50 % of them will be affected by multiple accessory pathways.20,29 Accessory pathways are present in 2–5 % of patients with l-TGA with an Ebsteinoid malformation of their left-sided (systemic) tricuspid valve.24

of Fallot who have a prevalence of VT of 3–14 %, and an incidence of sudden cardiac death of 2 % per decade with increasing risk for older patients.34,35 Four main macro re-entrant routes have been described involving specific anatomical isthmuses: • between the right ventricular outflow tract/adjacent right ventricular scar and tricuspid annulus; • between the right ventricular scar and pulmonary valve; • between the pulmonary valve and septal scar; and • between the septal scar and the tricuspid annulus.

These can be targeted by ablation with a high degree of success.36 Secondly, progressive degrees of ventricular dysfunction or hypertrophy due to altered haemodynamic state as seen in aortic valve disease, right ventricular dysfunction after Senning or Mustard procedures for d-TGA, or in failing single ventricles can also increase the risk for ventricular arrhythmias independently of the presence or not of surgery-related scars.

Ablation of the accessory pathways in Ebstein’s anomaly or l-TGA can be challenging due to the displacement of the AV valves in relation to the real AV grooves, which is the optimal level for ablation of pathways.

Their location is generally parallel to the course of right coronary artery

Risk factors for VT include: older age at surgery, older age at follow-up, prior palliative shunts, high density of ventricular ectope on non-invasive monitoring, inducible VT at electrophysiological study, poor right ventricular haemodynamics, depressed left ventricular

or the coronary sinus. Therefore a selective angiography or placement of catheters inside these vessels can be useful to facilitate the ablation procedure.30 Ablation is acutely successful in 80 % of patients, with a recurrence rate of 25–40 %. This worse outcome after the ablation of accessory pathways is due to several factors, including the presence of frequent multiple accessory pathways, power limitation because of the proximity of coronary arteries or the AV node in a particularly thin right atrium as is usually the case in Ebstein’s anomaly.31,32 The use of 3D mapping, steerable sheaths and multipolar mapping catheters can be of particular use in this subgroup of patients.

function, markedly prolonged QRS duration (>180 ms) and previous symptoms of rapid palpitations, dizziness or syncope.2,4,34

A special situation is the case of patients with heterotaxy syndrome that can have the so-called ‘twin AV nodes’ consisting of two separate AV nodes and a diverse combination of possible re-entrant circuits.

The ablation of the AV node with poorer anterograde conduction properties, which generally constitutes the retrograde limb of the re-entrant tachycardia, has shown to be effective in this setting.33

Conclusions

Ventricular Tachycardias Two main mechanisms are involved in the development of ventricular tachycardias (VTs) in CHD patients. Firstly, the presence of surgical ventricular scars (ventriculotomy) or patching material may determine the appearance of macro re-entrant VT. This mechanism has been described particularly in patients following correction of tetralogy

1. Gatzoulis MA, Webb GD. Adults with congenital heart disease: a growing population. In: Gatzoulis MA, Webb GD, Daubeney PEF. Diagnosis and management of adult congenital heart disease 2nd ed. Philadelphia, US: Elsevier Saunders, 2011;2.

2. Walsh EP. Interventional electrophysiology in patients with congenital heart disease. Circulation 2007;115:3224–34.

3. Somerville J. Management of adults with congenital heart disease: an increasing problem. Annu Rev Med 1997;48:283–93.

4. Walsh EP. Arrhythmias in patients with congenital heart disease. Card Electrophysiol Rev 2002;6:422–30.

5. Garson Jr A, Bink-Boelkens M, Hesslein PS, et al. Atrial flutter in the young: a collaborative study of 380 cases. J Am Coll Cardiol 1985;6:871–8.

6. Thorne SA, Barnes I, Cullinan P, Somerville J. Amiodaroneassociated thyroid dysfunction: risk factors in adults with congenital heart disease. Circulation 1999;100:149–54.

7. van Hare GF. Radiofrequency ablation of accessory pathways

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Due to the high incidence of sudden cardiac death there is a low threshold for ICD implantation to treat VT in CHD, with ablation often reserved to reduce the number of shocks rather than as a first-line treatment, particularly in patients with impaired systemic ventricle.

New surgical procedures to improve the cardiac haemodynamics or antiarrhythmic medication may reduce the risk for VT and sudden cardiac death in the future.

Adult patients affected by congenital heart disease are a growing population thanks to the development of advanced techniques for surgical repair. These patients are at lifelong risk of complications, including a high incidence of arrhythmias that are generally sustained by complex macro re-entrant circuits. Although technically challenging, catheter ablation continues to be the best therapeutic option for these arrhythmias after a thorough analysis of the specific cardiac anomaly and its surgical correction. A better understanding of the electrophysiological substrates has led to improved outcome of ablation procedures, and has contributed to the modification of surgical techniques producing a significant reduction of the arrhythmic burden in younger generations. n

associated with congenital heart disease. Pacing Clin Electrophysiol 1997;20:2077–81.

8. Tanner H, Lukac P, Schwick N, et al. Irrigated-tip catheter ablation of intraatrial reentrant tachycardia in patients late after surgery of congenital heart disease. Heart Rhythm 2004;1:268–75.

9. Ueda A, Suman-Horduna I, Mantziari L, et al. Contemporary otuomes of supraventricular tachycardia ablation in congenital heart disease. A singe-centre experience in 116 patients. Circ Arrhythm Electrophysiol 2013;6:606–13.

10. Rhodes LA, Wernovsky G, Keane JF, et al. Arrhythmias and intracardiac conduction after the arterial switch operation.

J Thorac Cardiovasc Surg 1995;109:303–10.

11. Stamm C, Friehs I, Mayer JE Jr, et al. Long-term results of the lateral tunnel Fontan operation. J Thorac Cardiovasc Surg 2001;121:28–41.

12. Fishberger SB, Wernovsky G, Gentles TL, et al. Factors that

influence the development of atrial flutter after the Fontan operation.

J Thorac Cadiovas Surg 1997;113:80–6.

13. Durongpisitkul K, Porter CJ, Cetta F, et al. Predictors of early- and late-onset supraventricular tachyarrhythmias after Fontan operation. Circulation 1998;98:1099–107.

14. Wasmer K, Köbe J, Dechering DG, et al. Isthmus-dependent right atrial flutter as the leading cause of atrial tachycardias after surgical atrial septal defect repair. Int J Cardiol 2013;168:2447–52.

15. Uhm JS, Mun HS, Wi J, et al. Importance of tachycardia cycle length for differentiating typical atrial flutter from scar-related in adult congenital heart disease. Pacing Clin Electrophysiol 2012;35:1338–47.

16. Love BA, Collins KK, Walsh EP, Triedman JK. Electroanatomic characterization of conduction barriers in sinus/atrial paced rhythm and association with intra-atrial reentrant tachycardia circuits following congenital heart disease surgery.

J Cardiovasc Electrophysiol 2001;12:17–25.

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Ablation of Arrhythmias in Patients with Adult Congenital Heart Disease

17. Lakkireddy D, Rangisetty U, Prasad S, et al. Intracardiac echoguided radiofrequency catheter ablation of atrial fibrillation in patients with atrial septal defect or patent foramen ovale repair: a feasibility, safety, and efficacy study. J Cardiovasc Electrophysiol 2008;19:1137–42.

18. Santangeli P, Di Biase L, Burkhardt D, et al. Transseptal access and atrial fibrillation ablation guided by intracardiac echocardiography in patients with atrial septal closure devices. Heart Rhythm 2011;8:1669–75.

19. Miyazaki S, Nault I, Haïssaguerre M, Hocini M. Atrial fibrillation ablation by aortic retrograde approach usiing a magnetic navigation system. J Cardiovasc Electrophysiol 2010;21:455–7.

20. Triedman JK, Jenkins KJ, Colan SD, et al. Intra-atrial reentrant tachycardia after palliation of congenital heart disease: characterization of multiple macroreentrant circuits using fluoroscopically based three-dimensional endocardial mapping. J Cardiovasc Electrophysiol 1997;8(3):259–70.

21. Lukac P, Pedersen A, Mortensen PT, et al. Ablation of atrial tachycardia after surgery for congenital and acquired heart disease using an electroanatomic mapping system: Which circuits to expect in which substrate? Heart Rhythm 2005;2:64–72.

22. Kanter RJ, Papagiannis J, Carboni MP, et al. Radiofrequency catheter ablation of supraventricular tachycardia substrates after Mustard and Senning operations for d-transposition of the great arteries. J Am Coll Cardiol 2000;35:428–41.

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23. Jones DG, Jarman JW, Lyne JC, et al. The safety and efficacy of trans-baffle puncture to enable catheter ablation of atrial tachycardias following the Mustard procedure: a single centre experience and literature review. Int J Cardiol 2013;168(2):1115–20.

24. Kanter RJ. Pearls for ablation in congenital heart disease.

J Cardiovasc Electrophysiol 2010;21:223–30.

25. Wu J, Deisenhofer I, Ammar S, et al. Acute and long-term outcome after catheter ablation of supraventricular tachycardia in patients after the Mustard or Senning operation for D-transposition of the great arteries. Europace 2013;15:886–91.

26. de Groot NM, Zeppenfeld K, Wijffels MC, et al. Ablation of focal atrial arrhythmia in patients with congenital heart defects after surgery: role of circumscribed areas with heterogeneous conduction. Heart Rhythm 2006;3:526–35.

27. Grewal J, Al Hussein M, Feldstein J, et al. Evaluation of silent thrombus after the Fontan operation. Congenit Heart Dis 2013;8:40–7.

28. Dave AS, Aboulhosn J, Child JS, Shivkumar K. Transconduit puncture for catheter ablation of atrial tachycardia in a patient with extracardiac Fontan palliation. Heart Rhythm 2010;7:413–6.

29. Attenhofer Jost CH, Connolly HM, Edwards WD, et al.

Ebstein’s anomaly - review of a multifaceted congenital cardiac condition. Swiss Med Wkly 2005;135:269–81.

30. Shah MJ, Jones TK, Cecchin F. Improved localization of rightsided accessory pathways with microcatheter-assisted right coronary artery mapping in children. J Cardiovasc Electrophysiol 2004;15:1238–43.

31. Cappato R, Schlüter M, Weiss C, et al. Radiofrequency current catheter ablation of accessory atrioventricular pathways in Ebstein’s anomaly. Circulation 1996;94:376–83.

32. Roten L, Lukac P, DE Groot N, et al. Catheter ablation of arrhythmias in Ebstein’s anomaly: a multicenter study.

J Cardiovasc Electrophysiol 2011;22:1391–6.

33. Wu MH, Wang JK, Lin JL, et al. Long-term outcome of twin atrioventricular node and supraventricular tachycardia in patients with right isomerism of the atrial appendage.

Heart Rhythm 2008;5:224–9.

34. Gatzoulis MA, Balaji S, Webber SA, et al. Risk factors for arrhythmia and sudden cardiac death late after repair of tetralogy of Fallot: a multicentre study.

Lancet 2000;356:975–81.

35. Silka MJ, Hardy BG, Menashe VD, Morris CD. A populationbased prospective evaluation of risk of sudden cardiac death after operation for common congenital heart defects. J Am Coll Cardiol 1998;32:245–51.

36. Zeppenfeld K, Schalij MJ, Bartelings MM, et al. Catheter ablation of ventricular tachycardia after repair of congenital heart disease: electroanatomic identification of the critical right ventricular isthmus. Circulation 2007;116:2241–52.

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Supported Contribution

The Potential Role of Edoxaban in Stroke Prevention Guidelines 1

Oli v e r Pl u n k e t t a n d G r e g o r y Y H L i p

2

1. Research Fellow, 2. Professor of Cardiovascular Medicine, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK

Abstract With the emergence of edoxaban, the oral factor Xa inhibitors now appear consolidated as the dominant class of novel oral anticoagulants (NOACs) for stroke prevention in non-valvular atrial fibrillation (AF). The oral factor Xa inhibitors do not require an adequate time in therapeutic range to be effective, presenting a potential advantage over the vitamin K antagonists (VKAs). Guidelines are changing to reflect the increased choice of anticoagulants and as clinicians move away from the VKAs towards the relative safety and efficacy of NOACs, they must consider which one offers the best therapy for their patient. The ENGAGE-AF study was the latest phase III trial to report on the safety and efficacy of a new factor Xa inhibitor relative to warfarin. Both edoxaban 60mg once daily, and edoxaban 30mg once daily were found to be non-inferior compared to warfarin for the prevention of ischaemic stroke and systemic embolism, being associated with significantly lower rates of major bleeding, intracranial haemorrhage and cardiovascular death. A two-tiered dosing option may present clinicians with a further element of choice for the individual patient.

Keywords Atrial fibrillation, edoxaban, stroke prevention, CHA2DS2-VASc, novel oral anticoagulants, ENGAGE-AF, NOAC Disclosure: The authors have no conflicts of interest to declare.

Received: 11 January 2014 Accepted: 11 March 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(1):40–3 Access at: www.AERjournal.com Correspondence: Gregory Y H Lip, University of Birmingham, Centre for Cardiovascular Sciences, City Hospital, Dudley Road, Birmingham, B18 7QH, UK. E: g.y.h.lip@bham.ac.uk

Support: The publication of this article was supported by Daiichi Sankyo

The introduction of novel oral anticoagulants (NOACs) has widened the treatment options for oral anticoagulation in stroke prevention in non-valvular atrial fibrillation (AF). Guidelines for the management of non-valvular AF have changed to reflect the emerging evidence of their relative safety and efficacy compared with warfarin (see Table 1).1–6 NOACs are now licensed for stroke prevention in patients with nonvalvular AF in many countries around the world as an alternative to vitamin K antagonists (VKAs). Recent guidelines incorporating the NOACs often refer directly or indirectly to the augmented CHADS2 score or CHA2DS2-VASc score, advising that other non-CHADS2 stroke risk factors (including age 65–74 years, female gender and vascular disease) may also influence choice and combine to favour a decision to initiate anticoagulation.

What Do Recent Guidelines Say? The 2012 American College of Chest Physicians guidelines suggest the use of dabigatran 150 mg twice daily rather than warfarin where an oral anticoagulant (OAC) is recommended (i.e. for patients with a CHADS2 = 1 or CHADS2 ≥2). Back-up dual antiplatelet therapy may be considered for patients unsuitable for OAC therapy.1 Only dabigatran is mentioned, as at the time of publication only dabigatran was licensed in North America for stroke prevention in AF. The 2012 Canadian Cardiovascular Society focused guideline update suggests that when OAC therapy is indicated, most patients should

40

EDOXABAN.indd 40

receive dabigatran or rivaroxaban in preference to warfarin (i.e. for patients with a CHADS2 = 1 or CHADS2 ≥2).2 The 2012 American Heart Association/American Stroke Association Science Advisory recommend for patients with a CHADS 2 ≥1, dabigatran 150 mg twice daily as an alternative to warfarin in renally competent patients, or apixaban 5 mg twice daily in patients considered appropriate for warfarin but who have no more than one of the following characteristics: • weight <60 kg; • age >80 years; and • serum creatinine >1.5 mg/dl (i.e. who did not require the dose reduction to 2.5 mg twice daily).

For patients with a CHADS2 score ≥2, rivaroxaban 20 mg daily is considered a reasonable alternative to warfarin.3 The 2013 Scottish Intercollegiate Guidelines Network (SIGN) guidelines recommend that patients with non-valvular AF who have a CHADS2 or CHA2DS2-VASc score of ≥1 should consider taking warfarin or a NOAC, taking into account patient preference; while antiplatelet therapy should only be considered where warfarin or one of the novel anticoagulants has been declined. The SIGN guidelines are less specific in suggesting which NOAC is preferred, although they recognised that all the NOACs have been approved by the Scottish Medicines Consortium.4

© RADCLIFFE CARDIOLOGY 2014

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The Potential Role of Edoxaban in Stroke Prevention Guidelines

Table 1: Novel Oral Anticoagulants Compared with Warfarin in Recent Atrial Fibrillation Trials – RELY, ROCKET-AF, ARISTOTLE and ENGAGE-AF Effect on Outcome Event Versus Warfarin

D150

Non-inferiority stroke/SE

√ √ √ √ √ √

D110

Riva

Apix

Edo60

Edo30

Superiority for 1° endpoint of stroke/SE

√ √

Reduction haemorrhagic stroke/ICH √ √ √ √ √ √ Reduction ischaemic stroke

√ (↑)

Reduction all-cause mortality

(√) √ √

Reduction in CV mortality

√ √ √

Reduction major bleeding √ √ √ √ Reduction major and minor bleeds

√

Increased gastrointestinal bleeds

√

√ √

Increased myocardial infarction

? ? ?

√

√ √ √

RELY = Randomized Evaluation of Long-Term Anticoagulation Therapy; ROCKET-AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; ARISTOTLE = Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ENGAGE-AF = Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation; D150 = dabigatran at 150 mg twice daily dose; D110 = dabigatran at 110 mg twice daily dose; Riva = rivaroxaban; Apix = apixaban; Edo60 = edoxaban at 60 mg once daily dose; Edo30 = edoxaban at 30 mg once daily dose. CV = cardiovascular; ICH = intracranial haemorrhage; SE = systemic embolism

The 2012 European Society of Cardiology (ESC) focused guideline update recommends the use of the CHA2DS2-VASc score to assess the risk of stroke in AF patients. For patients with a CHA2DS2-VASc = 0, no therapy is advised, but if CHA2DS2-VASc = 1 or CHA2DS2-VASc ≥2 then OAC therapy is advised; preferably one of the NOACs (either

proteins, and thereby the synthesis of the vitamin K-dependent coagulation factors II, VII, IX and X.12–14

dabigatran or one of rivaroxaban/apixaban) should be considered instead of warfarin based on their net clinical benefit. However, female AF patients aged <65 years who score CHA2DS2-VASc = 1 for being female only, remain low risk and should not be actively considered for therapy. Again, these guidelines do not specifically recommend which NOAC as none of these drugs have been directly compared with each other in randomised trials.5

clinical monitoring schedules for AF patients is inherently problematic as VKA initiation regimens involve loading doses and periodic blood tests to maintain the INR and the patient’s overall time in therapeutic range (TTR), an index of INR control. For AF patients starting VKA therapy, poor TTR remains an independent risk factor for major bleeding,15 although even when within the therapeutic range VKAs can carry a bleeding risk.

The 2013 Asia Pacific Heart Rhythm Society (APHRS) guidelines recommend that the CHA2DS2-VASc score should be used to assess the risk of stroke, advising no therapy for patients with a CHA2DS2-VASc = 0 or 1, if scoring only for being female. For patients with a CHA2DS2-VASc = 1 OAC therapy is indicated, preferring dabigatran or apixaban over rivaroxaban, and warfarin if required. For patients with a CHA2DS2-VASc ≥2 then dabigatran, rivaroxaban, apixaban or warfarin are suggested. Where warfarin is to be used, an international normalised ratio (INR) of 1.6–2.6 for patients ≥70 years of age is preferred, at least in some countries such as Japan.6

INR control varies widely between clinical centres, affecting the treatment benefit of VKA therapy, although a target threshold TTR (approximately 58–65 %) helps to maintain the benefit of VKAs over antiplatelet therapy.16 While achieving good anticoagulation control in patients on VKAs is associated with a reduction in the risk of stroke, mortality is also reduced in those who have a TTR of 70 %.17 Indeed, a TTR of 70 % or greater would reflect high-quality VKA management; however, the TTR is often found to be lower in clinical practice.12

All Guidelines Have a Preference for Novel Oral Anticoagulants Over Vitamin K Antagonists

• a slow onset of action; • a variable dose requirement influenced by pharmacogenetics (e.g. of common polymorphisms, or variant alleles coding for VKORC1); and • a differential dietary vitamin K intake and drug–drug interactions that influence their pharmacokinetics or pharmacodynamics.

As antiplatelet therapy fades into the background, the NOACs are emerging as a favoured therapy. A number of reviews and analyses examining the effects of the NOACs have been published pointing to their clinical benefits in reducing stroke, systemic thromboembolism and mortality compared with VKAs.7–9 Indirect comparisons between NOACs have been made, but should be interpreted with caution until head-to-head trials are under way.10,11

Time in Therapeutic Range of the Vitamin K Antagonists To understand the advantages of NOACs, we need to take a closer look at the VKAs, such as warfarin. Warfarin acts diffusely at the initiation and amplification stages of the coagulation cascade, inhibiting the enzyme vitamin K epoxide reductase complex subunit 1 (VKORC1), disrupting the post-translational modification of vitamin K-dependent

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EDOXABAN.indd 41

VKAs are a widely used OAC for stroke risk reduction in patients with AF, but may be underused in this capacity.13 Establishing standard

The limitations of VKAs are due to:

Hepatic dysfunction, changes in gut flora and alcohol intake may also contribute. Patient compliance is no doubt linked to the medicalisation of the patient’s lifestyle that VKA therapy imposes.12 Prior to the emergence of NOACs, treatment practices for stroke prevention in patients with AF had focused on the identification of ‘high-risk’ patients to be targeted for warfarin. However, numerous studies have shown that clinicians consistently failed to achieve the full treatment potential that oral anticoagulation could bring to those AF patients who stood to benefit.18

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Supported Contribution Table 2: Definition of the SAMe-TT 2 R 2 Score Acronym Definitions

Points

S

Sex (female)

1

A

Age (<60 years)

1

Me

Medical history*

1

T

Treatment (interacting Rx e.g. amiodarone for

1

rhythm control)

T

Tobacco use (within two years)

2

R

Race (non-Caucasian)

2

Maximum points

8

* Two of the following: hypertension, diabetes mellitus, coronary artery disease/myocardial infarction, peripheral arterial disease, congestive heart failure, previous stroke, pulmonary disease, hepatic or renal disease

Furthermore, although the use of VKA therapy had increased since 1980, and the proportion of patients receiving no therapy has decreased, many patients with AF received either antiplatelet therapy (10–56 %, median 30 %) or no therapy (4–48 %, median 18 %). Thus, many patients at moderate or high risk for stroke were not treated according to guidelines.19 The benefits of oral anticoagulation over antiplatelet or no therapy are often highlighted within guidelines, but when we consider that patients on antiplatelet or no therapy may suffer bleeding rates comparable with those on VKAs,20 promoting their correct use becomes important.

European Society of Cardiology Guideline Supports Novel Oral Anticoagulants, Including Oral Factor Xa Inhibitors As the NOACs become more readily available, we may expect to see a reduction in the unacceptable numbers of these AF patients at increased risk for stroke who, once passed over for oral anticoagulation, remained unprotected. The ESC 2012 guidelines promote the NOACs in non-valvular AF because they show non-inferiority compared with VKAs and are inherently safer as their performance in phase III studies have shown.21–23 Currently, the oral factor Xa inhibitors are generating significant interest in stroke prevention as they dominate the NOAC field of choice.

The oral factor Xa inhibitors have predictable pharmacokinetics that allow for fixed dosing. Half-life, bioavailability, metabolism and excretion may differ somewhat, but universal advantages of the approved NOACs include: • • • • • •

rapid onset of action; lower likelihood of food–drug interactions; limited drug–drug interactions; predictable anticoagulant effect; no requirement for routine coagulation monitoring; and reduced risk of intracranial haemorrhage.24

When analysed together, the factor Xa inhibitors significantly reduce stroke, systemic thromboembolism and intracranial haemorrhage compared with warfarin in patients with AF.25 However, there are too few guidelines on how best to measure (and reverse) the in vivo activity in clinical settings.

Edoxaban is a New Oral Factor Xa Inhibitor Edoxaban is a new specific direct inhibitor of factor Xa. Rapidly absorbed orally, it has a half-life of approximately 10–14 hours26 and is approximately 40 % renally excreted with an element of active

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tubular secretion.27 Exposure increases with renal dysfunction and low body weight.28 It is not affected by food, and drug concentrations appear to have a linear correlation with anti-factor Xa activity and other coagulation indices. It appears safe and well tolerated with no adverse events in doses up to 150 mg and has predictable, consistent pharmacokinetic and pharmacodynamic profiles, and dose-proportional plasma concentrations.27 As with other oral Xa antagonists, it is a substrate for permeability (P)-glycoprotein; the P-glycoprotein inhibitors amiodarone and verapamil could increase plasma concentration, extending its half-life.29 A phase II comparison study with warfarin for patients with non-valvular AF found twice-daily doses of edoxaban 60 mg or edoxaban 30 mg were associated with higher bleeding rates, whereas a once-daily edoxaban dose of 60 mg or 30 mg had a similar safety profile to warfarin. 30 A randomised, double-blind study of edoxaban versus warfarin for treating symptomatic venous thromboembolism conducted on 8,292 adult patients with acute, symptomatic deep-vein thrombosis (n=4,921) of the lower limb or acute, symptomatic pulmonary embolism (n=3,319) trialled 60 mg edoxaban orally once-daily (30 mg if renal impairment, low body weight or potential drug interactions). The TTR (2.0–3.0) achieved for the warfarin group was 63.5 %. Edoxaban was confirmed to be non-inferior to warfarin (hazard ratio [HR] of 0.89; 95 % confidence incidence [CI], 0.70–1.13) in treating recurrent symptomatic venous thromboembolism and caused significantly less bleeding (HR 0.81; 95 % CI, 0.71–0.94).31 Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF–TIMI 48) was a large phase III randomised, double-blind and double-dummy trial comparing two exposure strategies of edoxaban to warfarin using a non-inferiority design. In total, 21,105 patients were randomised in a 1:1:1 ratio to edoxaban high exposure (60 mg daily), edoxaban low exposure (30 mg daily) or warfarin titrated to an INR of 2.0–3.0. Sham INRs in patients receiving edoxaban facilitated blinded treatment. The edoxaban exposure strategies of 60 mg and 30 mg allowed for dynamic dose reductions in subjects with anticipated increased drug exposure requiring dose adjustment according to drug clearance. Eligibility criteria included electrocardiographic verification of AF (paroxysmal, persistent or permanent) within 12 months of randomisation, in patients with a CHADS2 score ≥2. Randomisation was stratified by CHADS2 score (2–3 versus 4–6) and the clinical need for dose reduction of edoxaban. The primary objective was to determine whether edoxaban was non-inferior to warfarin for the prevention of stroke and systemic embolism and the primary safety endpoint was major bleeding. Rates of endpoints were represented for one year and the median follow-up was 2.8 years.28,32 The trial results, in essence, showed that edoxaban, when compared with warfarin, was non-inferior in the prevention of stroke or systemic embolism with significantly lower rates of bleeding and death from cardiovascular causes.32 Both dose regimens of edoxaban achieved significance in the non-inferiority analysis when compared with warfarin. The rate for the primary efficacy endpoint of stroke or systemic embolism in the on-treatment analysis was 1.50 % with warfarin (median TTR achieved, 68.40 %) compared with 1.18 % for edoxaban 60 mg (HR of 0.79; 97.5 % CI, 0.63–0.99) and 1.61 % for edoxaban 30 mg (HR of 1.07; 97.5 % CI, 0.87–1.31). High-dose edoxaban was significantly superior to warfarin

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The Potential Role of Edoxaban in Stroke Prevention Guidelines

in the on-treatment analysis. In the pre-specified intention-to-treat analysis, neither regimen of edoxaban was found to be superior to warfarin, although there was a trend favouring edoxaban 60 mg versus warfarin (HR of 0.87; 97.5 % CI, 0.73–1.04; P=0.08) over edoxaban 30 mg versus warfarin (HR of 1.13; 97.5 % CI, 0.96–1.34; P=0.10). For rates of ischaemic stroke only edoxaban 30 mg was associated with a significantly increased rate at 1.77 % (HR of 1.41; 95 % CI, 1.19–1.67), when compared with either edoxaban 60 mg or well-controlled warfarin, between which, ischaemic stroke rates were the same at 1.25 % (HR of 1.00; 95 % CI, 0.83–1.19; P=0.97).

with respect to bleeding risk and intra-cranial haemorrhage; while it may have the concomitant benefit of reducing cardiovascular mortality.

The rates for the primary endpoint of major bleeding were significantly lower for high- and low-dose edoxaban compared with warfarin: 3.43 % with warfarin versus 2.75 % for edoxaban 60 mg (HR of 0.80; 95 % CI, 0.71–0.91) and 1.61 % with edoxaban 30 mg (HR of 0.47; 95 % CI, 0.41–0.55). The rate of haemorrhagic stroke was significantly higher with warfarin, 0.47 % as compared with 0.26 % for high-dose edoxaban (HR of 0.54; 95 % CI, 0.38–0.77) and 0.16 % for low-dose edoxaban (HR of 0.33; 95 % CI, 0.22–0.50).

Conclusion

The rates of cardiovascular death were significantly lower for both regimens of edoxaban, 3.17 % among the warfarin group versus 2.74 % (HR of 0.86; 95 % CI, 0.77–0.97) for edoxaban 60 mg and 2.71 % (HR of 0.85; 95 % CI, 0.76–0.96) for edoxaban 30 mg. Corresponding rates of

A decision dilemma is how to predict upfront those newly diagnosed non-anticoagulated AF patients who would do well on warfarin with high TTR, given costs of the new drugs and that the benefits of NOACs over warfarin may be only marginal in those with high TTRs. The new SAMe-TT2R2 score33,34 (see Table 2) may help with the decision-making process, as this is a new user-friendly validated simple clinical score, which identifies those AF patients likely to do well on warfarin (SAMe-TT2R2 score 0–1) or those more likely to have poor anticoagulation control (SAMe-TT2R2 score ≥2). An ESC position document12 recommends that AF patients with a SAMe-TT2R2 score >2 should be considered to be better off being started on NOACs as initial therapy, or have more aggressive efforts to improve anticoagulation control. n

the composite of stroke, systemic embolism or all-cause cardiovascular death were 4.43 % versus 3.85 % (HR of 0.87; 95 % CI, 0.78–0.96; P=0.005) and 4.23 % (HR of 0.95; 95 % CI, 0.86–1.05; P=0.32).32

Edoxaban Would Fit in Nicely with Current Guidelines Edoxaban 60 mg would complement current guidelines on stroke prevention in non-valvular AF due to its consistency among the NOAC range in terms of its non-inferiority to warfarin, and its safety profile

1. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e531S–75S. 2. Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/ rhythm control. Can J Cardiol 2012;28:125–36.

3. Furie KL, Goldstein LB, Albers GW, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012;43:3442–53.

4. Scottish Intercollegiate Guidelines Network (SIGN). SIGN 129: Antithrombotics: indications and management, 2012.

Available at: www.sign.ac.uk/guidelines/fulltext/129/ (accessed 20 March 2014).

5. 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.

6. Ogawa S, Aonuma K, Tse H-F, et al. The APHRS’s 2013 statement on antithrombotic therapy of patients with nonvalvular atrial fibrillation. Journal of Arrhythmia 2013; 29:190–200.

7. Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012;126:2381–91.

8. Dogliotti A, Paolasso E, Giugliano RP. Novel oral anticoagulants in atrial fibrillation: a meta-analysis of large, randomized, controlled trials vs warfarin. Clin Cardiol 2013;36:61–7.

9. 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 2014;383:955–62.

10. Lip GY, Larsen TB, Skjoth F, Rasmussen LH. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation.

J Am Coll Cardiol 2012;60:738–46.

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It comes as a once-daily dose with a patient-friendly profile in terms of its tolerance and ease of use, and may indeed present a clinician-friendly profile too, allowing the drug to be fitted to the patient should concerns of safety over the risk of bleeding outweigh efficacy in stroke prevention. By reducing the dose to 30 mg where there is anticipated increased drug exposure, edoxaban would remain non-inferior to warfarin in such patients.

With the availability of so many NOACs as alternatives to warfarin, we are now rather spoilt for choice, and we have the opportunity to fit the drug to the patient (and vice versa). As discussed above, good quality anticoagulation control with warfarin is associated with high efficacy and safety (with low stroke and bleeding risks), and thus, effective stroke prevention in guidelines essentially means the use of well-controlled warfarin (TTR ≥70 %) or one of the NOACs.

11. Larsen TB, Lip GY. Warfarin or novel oral anticoagulants for atrial fibrillation? Lancet 2014;383:931–3.

12. De Caterina R, Husted S, Wallentin L, et al. Vitamin K antagonists in heart disease: Current status and perspectives (Section III). Position Paper of the ESC Working Group on Thrombosis -- Task Force on Anticoagulants in Heart Disease.

Thromb Haemost 2013;110:1087–107.

13. De Caterina R, Husted S, Wallentin L, et al. General mechanisms of coagulation and targets of anticoagulants (Section I). Position Paper of the ESC Working Group on Thrombosis – Task Force on Anticoagulants in Heart Disease.

Thromb Haemost 2013;109:569–79.

14. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):160S–98S. 15. Gallego P, Roldan V, Marín F, et al. Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation.

Thromb Haemost 2013;110:1189–98.

16. Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008; 118:2029–37.

17. Gallagher AM, Setakis E, Plumb JM, et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost 2011;106:968–77.

18. Ogilvie I, Newton N, Welner S, et al. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med 2010;123:638–45.e4.

19. Ogilvie IM, Welner SA, Cowell W, Lip GY. Characterization of the proportion of untreated and antiplatelet therapy treated patients with atrial fibrillation. Am J Cardiol 2011;108:151–61.

20. Ogilvie IM, Welner SA, Cowell W, Lip GY. Ischaemic stroke and bleeding rates in ‘real-world’ atrial fibrillation patients. Thromb Haemost 2011;106:34–44.

21. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.

22. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92.

23. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.

24. Tzeis S, Andrikopoulos G. Novel anticoagulants for atrial fibrillation: a critical appraisal. Angiology 2012;63:164–70.

25. Bruins Slot KM, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev 2013;8:CD008980.

26. Gonzalez-Quesada, CJ, Giuliano RP. Comparison of the phase III clinical trial designs of novel oral anticoagulants versus warfarin for the treatment of nonvalvular atrial fibrillation: implications for clinical practice. Am J Cardiovasc Drugs 2014;14:111-27.

27. Ogata K, Mendell-Harary J, Tachibana M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010;50:743–53.

28. Ruff CT, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J 2010;160:635–41.

29. Camm AJ, Bounameaux H. Edoxaban: a new oral direct factor xa inhibitor. Drugs 2011;71:1503–26.

30. Weitz JI, Connolly SJ, Patel I, et al. Randomised, parallelgroup, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 2010;104:633–41.

31. Hokusai-VTE Investigators, Büller HR, Décousus H, et al.

Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406–15.

32. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104.

33. Boriani G. Predicting the quality of anticoagulation during warfarin therapy: The basis for an individualized approach.

Chest 2013;144:1437–8.

34. Apostolakis S, Sullivan RM, Olshansky B, Lip GY. Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT2R2 score.

Chest 2013;144:1555–63.

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Supported Contribution

ThermoCool® SmartTouch® Catheter – The Evidence So Far for Contact Force Technology and the Role of VisiTag™ Module Tina Lin,1 Feifan Ouyang,2 Karl-Heinz Kuck3,4 and Roland Tilz4 1. Electrophysiology Fellow, 2. Electrophysiologist, 3. Director of Cardiology, 4. Electrophysiologist, Department of Cardiology, Asklepios Klinik St Georg, Hamburg, Germany

Abstract Catheter ablation has become an important modality in the treatment of most cardiac arrhythmias. In recent years there has been significant development of new ablation energies and technologies in an attempt to improve clinical outcomes and decrease disease burden. Ablation failure is often associated with inadequate lesion formation, and catheter-to-myocardial contact force (CF) and catheter stability are two of the parameters required to produce effective lesions during radiofrequency energy application. Recently, CF sensing catheters and tagging modules have been developed to give operators realtime data on catheter force and stability. This review describes the novel ThermoCool® SmartTouch® Catheter (Biosense Webster Inc., CA, US) and VisiTag™ Module (Biosense Webster Inc., CA, US) software, and discusses the results of several studies on CF and catheter stability during mapping and ablation of the left atrium and ventricle from our electrophysiology laboratory. We assess the short- and longer-term outcomes during mapping and ablation with and without CF data, as well as the use of the VisiTag Module™ software, which allows the evaluation of multiple parameters of lesion formation, then integrates and displays this as automatic tags in a relatively objective way.

Keywords Radiofrequency ablation, contact force, ThermoCool® SmartTouch® Catheter, VisiTag™, three-dimensional (3D) mapping Disclosure: Tina Lin received a clinical fellowship grant from St. Jude Medical, Inc. and EHRA. Feifan Ouyang has no conflicts of interest to declare. Karl-Heinz Kuck received research grants from Biosense Webster, St. Jude Medical, Medtronic, Inc. and Biotronik SE & Co. KG. He is a consultant to St. Jude Medical, Biotronik and Medtronic, and is a scientific advisor and shareholder of Endosense SA. Roland Tilz received travel grants, research grants and speaker honoraria from Biosense Webster and St. Jude Medical.

Received: 27 February 2014 Accepted: 31 March 2014 Citation: Arrhythmia & Electrophysiology Review 2013;3(1):44–7 Access at: www.AERjournal.com Correspondence: Roland Tilz, Department of Cardiology, Asklepios Klinik St Georg, Lohmuehlenstrasse 5, 20099 Hamburg, Germany. E: r.tilz@asklepios.com

Support: The publication of this article was supported by Biosense Webster Inc. Third party trademarks used herein are trademarks of their respective owners. If owned by Biosense Webster, ©Johnson & Johnson Medical NV/SA 2014 (if created in EMEA), ©Biosense Webster, Inc. 2014 (if created in US).

The role of percutaneous catheter ablation for the treatment of cardiac arrhythmias has become paramount over the last 30 years. Although there has been a dramatic increase in the number of different ablation energies and technologies (such as cryoablation,1,2 laser balloon3,4 and high-intensity focused ultrasound,5,6 multi-electrode ablation catheters,7,8 robotic navigation,9,10 and focal impulse and rotor modulation11,12), radiofrequency (RF) energy continues to be the cornerstone of catheter ablation.

Although the success rate for the ablation of most supraventricular tachycardias (SVTs) is acceptable,13,14 more complex arrhythmias such as atrial fibrillation (AF), atrial tachycardia (AT) and ventricular arrhythmias (VA) continue to have significant recurrence rates.15–18 This may be attributed to inadequate lesion formation or incomplete block during linear ablation.19 Therefore, effective lesion formation is important to decrease recurrence and the need for re-ablation.

Establishing contiguous, transmural RF ablation lesions involves several factors. These parameters include: impedance, power output, tissue temperature, catheter stability and catheter tip-to-myocardial contact force (CF).20–27 In addition, safety is also an important consideration during ablation. Excessive power, temperature and catheter-to-myocardial CF are associated with potential complications, such as thrombus formation, cardiac perforation or steam pop.23,28 CF has traditionally

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been assessed using surrogate markers, such as tactile feedback, local electrogram amplitude and impedance.20 In recent years, CF sensing technologies have been developed to assess realtime catheter tip-tomyocardial CF. TactiCath® (Endosense SA, Geneva, Switzerland) uses a fibre optic sensor, which detects realtime axial and lateral force changes at the catheter tip.26 Intellisense® (Hansen Medical Inc., Mountain View, CA, US) provides visual and vibration force feedback incorporated into a robotic catheter navigation system.9,10,29 Most recently, the novel ThermoCool® SmartTouch® Catheter (Biosense Webster Inc., CA, US) has been introduced into the market, providing realtime CF data in combination with the Carto® 3 (Biosense Webster Inc., CA, US) three-dimensional (3D) electroanatomical mapping system.

In combination with the new VisiTag™ Module (Biosense Webster Inc., CA, US) software, this provides operators with values to a number of parameters that assess catheter CF and stability, displayed in a relative objective fashion. This review discusses these two novel technologies and their potential application in clinical practice.

Contact Force Technology on the Market The TactiCath Quartz® (Endosense SA, Geneva, Switzerland) is a third generation standard open-irrigated 7 French (Fr), 3.5 mm ablation

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catheter that uses a fibre optic sensor, which detects realtime axial and lateral changes in CF without the need for pre-procedure calibration.26 This information is displayed both graphically and numerically during the procedure. In addition to the recognised force-time integral (FTI), a new algorithm, the lesions index parameter correlates lesion formation with RF power, ablation time and CF, and provides a realtime indication of lesion quality.

Figure 1: Diagram of the Novel T hermo C ool ® S mart Touch ® C atheter

The Intellisense System uses the 8 Fr Artisan® robotic ablation catheters to measure CF. It provides visual and vibration feedback of force via the Instinctive Motion® Controller when incorporated into the Sensei® X Robotic Catheter Navigation System.9,10,29

The T hermo C ool ® S mart Touch ® Ablation Catheter and Contact Force Technology The novel ThermoCool® SmartTouch® Catheter is a 7.5 Fr, 3.5 mm irrigated tip ablation catheter. The tip electrode is connected by a tiny precision spring to the catheter shaft, which allows a small amount of tip deflection and is also connected to a transmitter coil that emits a reference location signal (see Figure 1). The catheter tip-to-myocardial CF and direction of force are measured with a resolution of 1 g every 50 ms by three location sensors within the shaft, and the degree of spring bending via a magnetic transmitter at the catheter tip. This produces a CF reading averaged over one second. The catheter and information is then integrated into the Carto® 3 Mapping System and can be displayed to the operators.

This allows precise tracking of the catheter tip. The catheter needs to be equilibrated to body temperature, and this is achieved by placing it within the blood pool for a minimum of 15 minutes.

It is a 7.5 French, 3.5 mm contact force ablation catheter. There are four electrodes. The magnetic transmitter coil is located above the tip electrode and sends location reference signals about the spring position. The precision spring allows for small amounts of electrode deflection, enabling precise calculation of force in grams. Three location sensors monitor the magnetic transmitter coil location signals and records the movement of the spring. Image courtesy of Biosense Webster. CF = contact force; F = French.

The realtime CF that is displayed on the Carto® 3 Mapping System is updated every second. CF is also displayed on the system in other formats, such as a graphical representation seen as a force vector arrow at the catheter tip. User-defined value limits can be programmed, and operators can be graphically alerted to excessively high or low CF. All CF data, as well as data for impedance, power and temperature, in relation to the reconstructed electroanatomical map, are recorded and can be accessed offline. The CF information can also be integrated into the VisiTag™ Module software as one of the operator-defined parameters.

Figure 2: V isi Tag ™ Module Parameter Settings

The V isi Tag ™ M odule Software The VisiTag™ Module software is a novel algorithm that has been developed, which automatically tags the RF catheter ablation applications on the Carto® 3 Mapping System (see Figure 2). The VisiTag™ Module displays a tag when all pre-determined user-defined parameters are reached. These parameters include: • catheter stability, measured by the minimum time spent in an area and the maximum distance the ablation catheter has moved; • contact force, measured in combination with the ThermoCool® SmartTouch® Catheter; • impedance; and • temperature change.

The tags are displayed in two methods: VisiTag™; grid cells; or a combination of both (see Figure 3).

Each panel demonstrates the VisiTag™ and grid cell tags when different pre-defined parameters are used. The pre-defined values shown in the figure are considered standard during left atrium (LA) ablation in our institution.

VisiTag™ are large 4 mm2 tags representing each ablation application meeting all user-defined criteria. Grid cells are small tags representing each 2 x 2 mm area that has received RF energy and displays the cumulative amount of RF application time spent in this area. They

are coded using a colour gradient based on user-defined parameters, such as total time, average force and force-time interval. The tags are non-deletable and are therefore an objective recording of the RF applications. All data are recorded and can be accessed offline. The

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Supported Contribution Figure 3: Three-dimensional Electroanatomical Map (Bipolar Voltage Map) Demonstrating Pulmonary Vein Isolation Procedure

even when non-steerable sheaths were used. During ablation, median CFs were lower during ipsilateral circumferential PVI ablation around the left pulmonary veins, compared with the right (12.3 g and 22.8 g, respectively), and this was again predominantly due to the low CFs obtained at the LAA ridge. These results suggest a reason for pulmonary vein reconnection post circumferential PVI ablation, which has been shown in previous studies to occur most frequently at the LAA ridge and mitral isthmus.31 Although lesion formation is due to several parameters, one of which includes CF, force visualisation may help improve CF in these areas, potentially leading to more durable lesion formation. In contrast, excessively high CFs have been shown in animal models to be associated with steam pop and crater formation, and consciously avoiding such high forces with CF visualisation may reduce complication rates.32 Impedance values during mapping and impedance drop that occurs at the start of RF application was also shown to correlate with CF, which has since been confirmed in a recent publication by Reichlin et al.33 Secondly, comparison of CF guided with non-CF guided LA mapping and PVI ablation was performed, and the impact of CF on AF recurrence was analysed. A total of 70 patients underwent PVI, in which operators were blinded to CF data in 35 patients, and CF was displayed in the other 35. A total of 8,401 mapping and 2,064 ablation points were analysed. Our results demonstrated that during CF guided

The large pink tags indicate objective VisiTag™ indicating ablation within all pre-specified parameters. The small pink tags indicate grid cells. Grey points indicate VisiTag™ where all parameters except contact force cut-off levels are achieved. Green tags mark the ipsilateral pulmonary vein ostium. Imp = impedance; PA = posteroanterior.

parameters can also be adjusted offline to display ablation tags when different value limits are used (see Figure 2). The additional benefit of the VisiTag™ Module compared with conventional ablation tagging is the quantitative assessment of parameters that influence lesion formation, which may improve clinical outcomes.

The Impact of Contact Force Although CF data add another level of complexity to the information displayed on the Carto® 3 Mapping System, operators can quickly become familiar with this information. The addition of the VisiTag™ Module is also simply displayed to be operator-friendly. The fact that both new technologies have parameters that can be pre-defined and selectively displayed, assists to reduce the operator learning curve.

Our electrophysiology laboratory has performed a high volume of CF guided arrhythmia ablations to date. Our analysis of this technology includes several CF parameters.

Firstly, assessment of the relative CF obtained whilst mapping and ablating in the left atrium (LA) during pulmonary vein isolation (PVI) using a non-steerable SL1 sheath, and the correlation between CF and tissue impedance during LA mapping and ablation was performed.30 In this study, 30 patients underwent PVI with CF data recorded, but not displayed to the operators. A total of 3,475 mapping points and 878 ablation points were analysed. Overall median CF during mapping was 14.0 g, and interestingly we consistently showed that the median CF obtained at the left atrial appendage (LAA) ridge and mitral isthmus was very low (5.1 g and 6.9 g, respectively), and that extremely high and potentially dangerous levels of CF >100 g occurred

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ablation, more points were taken within the optimal CF range defined as between 10 g and 40 g, and in particular the median CF obtained at the mitral isthmus and LAA ridge was higher when CF was displayed (7.7 g versus 12.2 g and 5.3 g versus 11.7 g, respectively). In respect to complication risk, we noted that there were excessively high CFs seen at the roof areas when CF was not displayed, and this was not seen when operators were aware of forces applied and could avoid high and potentially dangerous CFs. Interestingly, there was no difference in the AF recurrence rates after a follow-up of six months, and these data will be further analysed with longer term follow-up.

Thirdly, catheter stability using CF data was assessed. Of the multiple factors influencing lesion formation, catheter stability has been shown to be important.34,35 During CF blinded PVI, performed in 32 patients, 932 points were analysed – 426 visually stable and 506 visually unstable points. Stability was calculated as standard deviation of CF, and relative standard deviation (RSD) was used, which significantly correlated with visual catheter stability. We demonstrated that catheter instability occurred predominantly at the LAA ridge and posteroinferior segments of the right PVs.

Finally, the clinical impact of CF during antegrade transseptal and retrograde transaortic mapping of the left ventricle (LV) was assessed.29 In total, 3,324 mapping points using non-steerable sheaths in 10 patients were analysed. Although we showed that the median CF obtained from either approach was similar (antegrade = 16.0 g, retrograde = 15.3 g), there were significant differences between the CFs obtained at different LV segments. This suggests that LV mapping with only one approach may lead to poorer catheter-to-myocardial tissue contact in various areas of the LV, and a combined approach may improve overall LV mapping.

T hermo C ool ® S mart Touch ® C atheter Ablation Using the V isi Tag ™ M odule There are currently no published data regarding the short- and long-term outcomes when the VisiTag™ Module is used in combination with CF

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data to guide catheter ablation. Our institutional standard for VisiTag™ Module settings during LA ablation are as follows:

successful ablation, and could potentially improve short- and longterm clinical outcomes.

• • • • •

Conclusion

a minimum time of 15 seconds; a maximum range of 4 mm; a force over time of 60 %; a minimum force of 6 g; and non-projected tags.

When the CF data are added as an additional parameter in the VisiTag™ Module criteria, regular tags as described above are taken, unless the CF is below the pre-specified cut-off. When all other parameters except the CF cut-off are met, a ‘grey point’ is tagged to mark this region (see Figure 1). Although several different parameters are required for effective lesion formation, the use of objective CF tagging may improve one of the major criteria for

1. Chun K-RJ, Schmidt B, Metzner A, et al. The ‘single big cryoballoon’ technique for acute pulmonary vein isolation in patients with paroxysmal atrial fibrillation: a prospective observational single centre study. Eur Heart J 2009;30(6):699–709.

2. Friedman PL, Dubuc M, Green MS, et al. Catheter cryoablation of supraventricular tachycardia: results of the multicenter prospective “frosty” trial. Heart Rhythm 2004;1(2):129–38.

3. Dukkipati SR, Kuck KH, Neuzil P, et al. Pulmonary vein isolation using a visually guided laser balloon catheter: the first 200-patient multicenter clinical experience. Circ Arrhythm Electrophysiol 2013;6(3):467–72.

4. Bordignon S, Chun KR, Gunawardene M, et al. Energy titration strategies with the endoscopic ablation system: lessons from the high-dose vs. low-dose laser ablation study. Europace 2013;15(5):685–9.

5. Davies EJ, Bazerbashi S, Asopa S, et al. Long-term outcomes following high intensity focused ultrasound ablation for atrial fibrillation. J Card Surg 2014;29(1):101–7.

6. Schmidt B, Chun KR, Metzner A, et al. Pulmonary vein isolation with high-intensity focused ultrasound: results from the HIFU 12F study. Europace 2009;11(10):1281–8.

7. Mulder AA, Balt JC, Wijffels MC, et al. Safety of pulmonary vein isolation and left atrial complex fractionated atrial electrograms ablation for atrial fibrillation with phased radiofrequency energy and multi-electrode catheters. Europace 2012;14(10):1433–40.

8. Jaïs P, Maury P, Khairy P, et al. Elimination of local abnormal ventricular activities: a new end point for substrate modification in patients with scar-related ventricular tachycardia. Circulation 2012;125(18):2184–96.

9. Rillig A, Schmidt B, Steven D, et al. Study design of the man and machine trial: a prospective international controlled noninferiority trial comparing manual with robotic catheter ablation for treatment of atrial fibrillation. J Cardiovasc Electrophysiol 2012;24(1):40–6.

10. Willems S, Steven D, Servatius H, et al. Persistence of pulmonary vein isolation after robotic remote-navigated ablation for atrial fibrillation and its relation to clinical outcome. J Cardiovasc Electrophysiol 2010;21(10):1079–84.

11. Shivkumar K, Ellenbogen KA, Hummel JD, et al. Acute termination of human atrial fibrillation by identification and catheter ablation of localized rotors and sources: first multicenter experience of focal impulse and rotor modulation (FIRM) ablation. J Cardiovasc Electrophysiol 2012;23(12):1277–85.

12. 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

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Contact force technology is a novel measurable parameter that can be measured and controlled during catheter ablation of various cardiac arrhythmias. Due to the importance of this parameter in achieving effective lesion formation and therefore potentially improving long-term clinical outcomes, several new ablation catheters that measure CF have been introduced into the market. This novel technology may also decrease the rate of complications associated with catheter ablation. Although further studies are required, the addition of the VisiTag™ Module, a relatively objective indicator for several different ablation parameters, may assist operators in forming long-lasting RF lesions, and may improve clinical outcomes from catheter ablation of various cardiac arrhythmias. n

Cardiol 2012;60(7):628–36.

13. Dagres N, Clague JR, Kottkamp H, et al. Radiofrequency catheter ablation of accessory pathways. Outcome and use of antiarrhythmic drugs during follow-up. Eur Heart J 1999;20(24):1826–32.

14. Deisenhofer I, Zrenner B, Yin Y-H, et al. Cryoablation versus radiofrequency energy for the ablation of atrioventricular nodal reentrant tachycardia (the CYRANO Study): results from a large multicenter prospective randomized trial. Circulation 2010;122(22):2239–45.

15. 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(19):1921–9.

16. Ouyang F, Tilz R, Chun J, et al. Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation 2010;122(23):2368–77.

17. Stevenson WG, Wilber DJ, Natale A, et al. Irrigated radiofrequency catheter ablation guided by electroanatomic mapping for recurrent ventricular tachycardia after myocardial infarction: the multicenter thermocool ventricular tachycardia ablation trial. Circulation 2008;118(25):2773–82.

18. Bella Della P, Riva S, Fassini G, et al. Incidence and significance of pleomorphism in patients with postmyocardial infarction ventricular tachycardia. Acute and long-term outcome of radiofrequency catheter ablation. Eur Heart J 2004;25(13):1127–38.

19. Ouyang F, Antz M, Ernst S, et al. Recovered pulmonary vein conduction as a dominant factor for recurrent atrial tachyarrhythmias after complete circular isolation of the pulmonary veins: lessons from double Lasso technique.

Circulation 2005;111(2):127–35.

20. Thiagalingam A, D’Avila A, McPherson C, et al. Impedance and temperature monitoring improve the safety of closedloop irrigated-tip radiofrequency ablation. J Cardiovasc Electrophysiol 2007;18(3):318–25.

21. Nakagawa H, Yamanashi WS, Pitha JV, et al. Comparison of in vivo tissue temperature profile and lesion geometry for radiofrequency ablation with a saline-irrigated electrode versus temperature control in a canine thigh muscle preparation. Circulation 1995;91(8):2264–73.

22. Wittkampf FH, Hauer RN, Robles de Medina EO. Control of radiofrequency lesion size by power regulation. Circulation 1989;80(4):962–8.

23. Yokoyama K, Nakagawa H, Shah DC, et al. Novel contact force sensor incorporated in irrigated radiofrequency ablation catheter predicts lesion size and incidence of steam pop and thrombus. Circ Arrhythm Electrophysiol

2008;1(5):354–62.

24. Okumura Y, Johnson SB, Bunch TJ, et al. A systematical analysis of in vivo contact forces on virtual catheter tip/tissue surface contact during cardiac mapping and intervention.

J Cardiovasc Electrophysiol 2008;19(6):632–40.

25. Kuck KH, Reddy VY, Schmidt B, et al. A novel radiofrequency ablation catheter using contact force sensing: Toccata study.

Heart Rhythm 2012;9(1):18–23.

26. Reddy VY, Shah D, Kautzner J, et al. The relationship between contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the TOCCATA study.

Heart Rhythm 2012;9(11):1789–95.

27. Tilz RR, Makimoto H, Lin T, et al. In vivo left-ventricular contact force analysis: comparison of antegrade transseptal with retrograde transaortic mapping strategies and correlation of impedance and electrical amplitude with contact force.

Europace 2014 [Epub ahead of print].

28. Perna F, Heist EK, Danik SB, et al. Assessment of catheter tip contact force resulting in cardiac perforation in swine atria using force sensing technology. Circ Arrhythm Electrophysiol 2011;4:218–24.

29. Di Biase L, Paoletti Perini A, Mohanty P, et al. Visual, tactile, and contact force feedback: Which one is more important for catheter ablation? Results from an in vitro experimental study. Heart Rhythm 2014;11(3):506–13.

30. Makimoto H, Lin T, Rillig A, et al. In vivo contact force analysis and correlation with tissue impedance during left atrial mapping and catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2014;7(1):46–54.

31. Fürnkranz A, Julian JKRC, Schmidt B, et al. Ipsilateral pulmonary vein isolation performed by a single continuous circular lesion: role of pulmonary vein mapping during ablation. Europace 2011;13(7):935–41.

32. Di Biase L, Natale A, Barrett C, et al. Relationship between catheter forces, lesion characteristics, “popping,” and char formation: experience with robotic navigation system.

J Cardiovasc Electrophysiol 2009;20(4):436–40.

33. Reichlin T, Knecht S, Lane C, et al. Initial impedance decrease as an indicator of good catheter contact: Insights from radiofrequency ablation with force sensing catheters. Heart Rhythm 2014;11(2):194–201.

34. Shah DC, Lambert H, Nakagawa H, et al. Area under the real-time contact force curve (force-time integral) predicts radiofrequency lesion size in an in vitro contractile model.

J Cardiovasc Electrophysiol 2010;21(9):1038–43.

35. Mizuno H, Vergara P, Maccabelli G, et al. Contact Force Monitoring for Cardiac Mapping in Patients with Ventricular Tachycardia. J Cardiovasc Electrophysiol 2013;24(5):519–24.

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Supported Contribution

The Role of Continuous Monitoring in Atrial Fibrillation Management A J o h n Ca m m Professor of Clinical Cardiology, Cardiac and Vascular Sciences, St. George’s University of London, London, UK

Abstract Atrial fibrillation (AF) is the most common cardiac arrhythmia and is strongly associated with stroke risk and a variety of cardiovascular conditions. AF early detection is of paramount importance, in order to define proper medical treatment. This can be challenging due to the often silent and intermittent nature of the rhythm disturbance. Long-term external ECG monitoring may be very helpful, but if less than fully continuous and of long duration it will be not reliable. For this reason continuous monitoring is of increased importance, and outcome measurements of AF treatment trials will be based on the AF burden detected by insertable cardiac monitors (ICM) or therapeutic devices such as pacemakers or ICDs, leading to the paradigm that the detection of AF in the presence of thromboembolic risk factors should be performed wherever possible in order to improve patients’ chances.

Keywords Atrial fibrillation, continuous monitoring, rhythm control, stroke, oral anticoagulation Disclosure: Professor A John Camm serves as advisor and speaker for Astra Zeneca, ChanRX, Gilead, Merck, Menarini, Otsuka, Sanofi, Servier, Xention, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Pfizer, Boston Scientific, Biotronik, Medtronic, St Jude Medical, Actelion, GlaxoSmithKline, InfoBionic, Incarda, Johnson and Johnson, Mitsubishi, Novartis, Takeda Received: 24 March 2014 Accepted: 23 April 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(1):48–50 Access at: www.AERjournal.com Correspondence: A John Camm, Professor of Clinical Cardiology, Cardiac and Vascular Sciences, St George’s University of London, Cranmer Terrace, London, SW17 0RE, UK E: jcamm@sgul.ac.uk

Support: The publication of this article is supported by an educational grant from Medtronic

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, occurring in 1–2 % of the general population and is increasingly prevalent in older people, occuring in about 10 % of over 80 year olds.1 AF is associated with a variety of cardiovascular conditions. The arrhythmia is associated with a five-fold rise in stroke risk and frequently coexists with heart failure, both leading to a further increase in mortality.2–5 About 15 % of strokes are attributed to underlying AF, and 50–60 % to documented cerebrovascular disease, but in about 25 % of patients who have ischaemic strokes, no aetiological factor is identified. Subclinical atrial fibrillation is often suspected to be the cause of stroke in these patients.3,6–8 A recent study with implantable cardiac monitors in survivors of ischaemic stroke has revealed that far more than expected instances of so-called “cryptogenic stroke” are associated with episodes of AF revealed by continuous ECG monitoring.9,10 Concomitant medical conditions have an additive effect on the perpetuation of AF by promoting a substrate that maintains AF. Conditions associated with AF are also markers for global cardiovascular risk and/or cardiac damage rather than simply causative factors.11 Altogether, AF causes a significant economic burden which has grown in recent decades and is expected to grow even further in the future with the increasing trend in AF prevalence and hospitalisations.12–14

Asymptomatic AF and the Low Yield of Intermittent Monitoring AF can show in several clinical scenarios. Some patients may suffer so much that they seek specialist help to be relieved from the arrhythmia.

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Others present with severe symptoms, often including fatigue and shortness of breath, and are found to be in AF on clinical or ECG examination. In yet others, AF is an incidental finding when an irregular heartbeat is detected on physical examination and/or an ECG is recorded for other reasons, such as during preoperative assessment.

The problem of early recognition of AF is greatly aggravated by the often silent and intermittent nature of the rhythm disturbance. In about one third of patients with this arrhythmia, patients are not aware of the so-called asymptomatic AF.15,16 The Suppression of Paroxysmal Atrial Tachyarrhythmias (SOPAT) trial17 showed that only 46 % of episodes recorded during the oneyear follow-up period were associated with specific symptoms. The remaining 54 % were asymptomatic AF episodes. Similarly in the Prevention of Atrial Fibrillation After Cardioversion (PAFAC) trial18 70 % of all AF recurrences were completely asymptomatic. Arya et al19 used seven-day Holter recordings before ablation and documented AF in 81 % of the population. All episodes were symptomatic in 38 %. In 52 patients (57 %), symptomatic and asymptomatic episodes were recorded, whereas in 5 patients (5 %), all documented AF episodes were asymptomatic.

Ziegler et al.20 compared continuous monitoring with different strategies of intermittent ECG monitoring in pacemaker patients. All intermittent and symptom-based monitoring resulted in significantly lower sensitivity (range 31–71 %) and negative predictive value (range 21–39 %) for the identification of patients with AF and underestimated AF burden. These results were confirmed by Botto et al.21

© RADCLIFFE CARDIOLOGY 2014

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The Role of Continuous Monitoring in Atrial Fibrillation Management

The Role of Monitoring in Rhythm Control Strategies In order to measure efficacy of rhythm control approaches and therapeutic techniques, it is widely accepted that continuous information is needed, because spotlight ECGs miss a major part of the AF activity which may lead to a wrong evaluation of therapy efficacy.

The relevance of increasing the Holter observation length from 24 hours to seven days has been demonstrated by Kottkamp et al.22 One hundred patients underwent 24-hour and seven-day Holter monitoring post-pulmonary vein ablation for paroxysmal AF. At 12 months, ablation success rate was 88 % when using the 24-hour Holter data, but only 74 % as indicated by the seven-day Holter. One might argue that this gap in capturing recurrences outside a Holter registration interval could be closed if an external event recorder were used. However, Klemm and co-workers demonstrated that, in 80 post-ablation patients using transtelephonic ECG recordings (minimum one ECG per day and in case of symptoms suggesting AF), during 54 % of transmitted ECGs demonstrating AF patients were asymptomatic.23 In 11 % of all tracings, the patients indicated symptoms but demonstrated stable sinus rhythm on the tracing. In line with this finding, it was demonstrated that, outside a blanking period of three months, the ablation success in patients with only symptomatic but ECG-documented recurrences was around 70 % whereas, counting all ECG-documented AF recurrences using a tele-ECG concept, the percentage of patients with no AF recurrences was reduced to almost 40 %.

Pokushalov and co-workers published for the first time the wide and routine use of an insertable cardiac monitor (ICM) to perform long-term continuous AF monitoring in their AF ablation patients. Furthermore, they tried to differentiate between sudden-onset and triggered-onset AF recurrence in order to tailor the treatment regimens for AF recurrences after the first catheter ablation.24,25 It was shown that an ICM-detected AF burden of >4.5 % during the blanking period was a powerful predictor of ablation failure. This information and correlation could trigger early re-intervention in those patients, shortening the period of time until stable sinus rhythm is reached.26 Similarly to catheter ablation, in surgical procedures there is a relevant proportion of patients with silent and intermittent AF recurrences, whereas a significant number of symptomatic AF episodes are not related to AF. Ip and co-workers report that in about 45 AF patients, who underwent video-assisted epicardial ablation and ICM implantation; as many as 46 % of the AF recurrences were asymptomatic, whereas only 66 % of the symptomatic episodes were AF-related.27 Bogachev-Prokophiev et al.28 reported ablation results for AF with mitral valve surgery after one year of continuous monitoring. Fortyseven patients with mitral valve disease and long-standing persistent AF underwent a left atrial maze procedure with bipolar radiofrequency ablation and valve surgery. At the 12-months follow-up examination, 65.2 % of patients had an AF burden <0.5 % and were classified as responders; 6.5 % of the non-responders had atrial flutter and 27.7 % had documented AF recurrences with an AF burden >0.5 %, and 4.3 % patients with AF recurrences were completely asymptomatic.

Among the symptomatic events manually stored by the patients, only 27.6 % were confirmed as genuine AF recurrences according to the concomitant ECG recorded by the ICM. The results in these surgical AF patients again show the usefulness of continuous rhythm monitoring to verify the true amount of successful ablation therapy and to identify

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asymptomatic recurrences in order to better discriminate between AFand non-AF-related symptoms.

If an ICM is implanted for a period before the procedure, this may help the assessment of AF behaviour and improve patient management.

In fact Verma et al.29 showed that the ratio of asymptomatic to symptomatic AF episodes increased from 1.1 before to 3.7 after ablation. In addition they demonstrated that the post-ablation state (rate of episodes) is the strongest predictor of asymptomatic AF, and symptoms alone underestimate post-ablation AF burden, with 12 % of patients having only asymptomatic recurrences. In addition Pedrote et al.30 showed that the prevalence of AF prior to an ablation can be highly variable and often lower than expected; therefore postablation assessment without knowledge of the pre-ablation burden can overvalue or undervalue the success of the procedure.

The Role of Monitoring in the Risk Stratification for Stroke Prevention If the risk of stroke is greater than approximately 1 % per annum, oral anticoagulation (OAC) is required for effective prevention of thromboembolic events, but in clinical practice with patients at moderate to high thromboembolic risk OAC is very often underutilised.31,32 Current guidelines for stroke prevention in AF do not differentiate between patients with symptomatic or asymptomatic AF, or between paroxysmal or persistent AF.33 The vast majority of AF episodes are asymptomatic, including many episodes of clinically significant duration.34 About 20–30 % of patients hospitalised for ischaemic stroke or transient ischaemic attack are discharged with the diagnosis of cryptogenic stroke, meaning that the cause of the clinical event is not diagnosed.7,8 Continuous monitoring with ICM is now widely used in patients with cryptogenic stroke to identify those with silent AF and drive the most appropriate antithrombotic therapy.35,36,37 In those studies AF was detected in 17–27.3 % of the patients in “real world” clinical practice underlining the limited yield of intermittent monitoring for secondary stroke prevention, where even the smallest amount of AF may play a role in stroke recurrence.38 Risk stratification for stroke prevention has been one of the most relevant issues debated by the medical community in recent years, and continuous monitoring now plays a pivotal role in this assessment. A series of studies performed in pacemaker or ICD patients indicate that longer times spent in AF are associated with a higher stroke risk, and that this increased risk is additional to known risk factors.21,39–41 Recently, the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) included 2,580 patients aged 65 years or older, with hypertension and no history of AF, implanted with a pacemaker or ICD.42 Episodes of subclinical atrial tachycardia occurred in 10 % of patients in the first three months and were associated with an increased risk of clinical AF (hazard ratio [HR] 5.56) and of ischaemic stroke or systemic embolism (HR 2.49). The conclusions of ASSERT were that subclinical atrial tachyarrhythmia occurs frequently and is associated with a significantly increased risk of ischaemic stroke or systemic embolism.

In addition a pooled analysis of individual patient data from three prospective studies, the Stroke Prevention Strategies based on Atrial

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Supported Contribution Fibrillation Information from Implanted Devices (SOS AF) project, where more than 10,000 patients were included, evaluated several thresholds for daily AF burden and found that one hour of atrial fibrillation identified the highest thromboembolic risk (HR 2.11).43

Future Perspectives Continuous AF monitoring has an increased importance, and outcome measurements of AF treatment trials, comparing rhythm versus rate control or different rhythms strategies, will now be based on the AF burden detected by ICM or therapeutic devices such as pacemakers or ICDs. Long-term external ECG monitoring may be very helpful but if less than fully continuous and of long duration will be less convincing than ICM data.

In the last few years it has become evident that it intermittent ECG documentation only captures a minority of the true AF burden.

In the current clinical arena, especially in the field of rhythm control, correlation of symptoms and underlying rhythm is still

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considered relevant. However, different levels of AF burden captured by continuous monitoring will provide a more solid base for proper assessment and for correct stroke risk stratification.

Implantable long-term ECG monitors offer many advantages but require a change of paradigm focusing on a minimally invasive approach when compared to the current standard of care. It is certainly possible to envision wider adoption of the new, miniaturised, generation of ICMs that are being released; the insertion procedure is minimally invasive reducing to a minimum the burden for the patient and the treating physician, and allowing the possibility of extending its use to new categories of patients.

In any event the detection of AF in patients with thromboembolic risk factors should be performed wherever possible. Even short lasting AF episodes with a low AF burden imply a significant risk increase of thromboembolic risk; therefore any verified AF detection should trigger OAC prophylaxis as recommended. n

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Botto GL, Padeletti L, Santini M et al. Presence and duration of atrial fibrillation detected by continuous monitoring: crucial implications for the risk of thromboembolic events. J Cardiovasc Electrophysiol 2009;20:241–8.

Kottkamp H, Tanner H, Kobza R, et al. Time courses and quantitative analysis of atrial fibrillation episode number and duration after circular plus linear left atrial lesions: trigger elimination or substrate modification: early or delayed cure?

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Ablation for atrial fibrillation during mitral valve surgery: 1-year results through continuous subcutaneous monitoring.

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Supported Contribution

The Promise of Leadless Pacing Based on Presentations at Nanostim Sponsored Symposium Held at the European Society of Cardiology Congress 2013, Amsterdam, The Netherlands, 2 September 2013 K a trina Mou n t f o r t , M e d i c a l Wr i t e r , R a d c l i f f e Ca r d i o l o g y R ev iewed for a c c ura c y b y : Re i n o u d Kn o p s , 1 J o h a n n e s S p e r z e l 2 a n d P e t r N e u z i l 3 1. Electrophysiologist, Academic Medical Centre, University of Amsterdam, The Netherlands; 2. Director, Department of Cardiology, Kerckhoff Heart Centre, Bad Nauheim, Germany; 3. Chairman, Department of Cardiology, Homolka Hospital, Prague, Czech Republic

Abstract Pacemaker technologies have advanced dramatically over the decades since they were first introduced, and every year many thousands of new implants are performed worldwide. However, there continues to be a high incidence of acute and chronic complications, most of which are linked to the lead or the surgical pocket created to hold the device. A leadless pacemaker offers the possibility of bypassing these complications, but requires a catheter-based delivery system and a means of retrieval at the end of the device’s life, as well as a way of repositioning to achieve satisfactory pacing thresholds and R waves, a communication system and low peak energy requirements.

A completely self-contained leadless pacemaker has recently been developed, and its key characteristics are discussed, along with the results of an efficacy and safety trial in an animal model. The results of the LEADLESS study, the first human trial to look at safety and feasibility of the leadless device, are discussed and the possible implications for future clinical practice examined.

Keywords Leadless pacemaker, cardiac arrhythmias, pacemaker-related complications, surgical pocket, venous thrombosis Disclosure: Reinoud Knops, Johannes Sperzel and Petr Neuzil have no conflicts of interest to declare Acknowledgement: The speaking panel acknowledge Radcliffe Cardiology for providing writing and editorial support.

Received: 7 October 2013 Accepted: 24 April 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(1):51–5. Access at: www.AERjournal.com

Support: The publication of this article was supported by St Jude Medical

Why Leadless Pacing?

Re i n o u d Kn o p s Academic Medical Centre, University of Amsterdam, The Netherlands

In 1958, the world’s first patient was implanted with a pacemaker.

It brought numerous benefits, the most important of which was increased survival. Since then, pacemaker technology has evolved with the development of improved device longevity, by including a high-energy density battery and utilising high impedance, low threshold leads. Implantable pulse generators (IPGs) for cardiac arrhythmias are now a proven and widely used treatment method. A worldwide cardiac pacing and implantable cardioverter-defibrillator (ICD) survey found that in 2009 there were over 700,000 new implants, with the majority of these implants being performed in the US and Europe, but the greatest growth occurring in Asia.1 Despite new developments in pacemaker technology, there is still a high incidence of pacemaker-related complications.2 A large prospective multicentre study found that after two months 12 % of patients present with acute complications (see Figure 1).3 Chronic

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complications subsequently occur in 10 % of patients. Most of these complications are related to the lead or the surgical pocket created to hold the pacemaker.

Local pocket-related complications include haematoma, wound pain, decreased mobility, pocket erosion and infection. Pocket infection can be a serious complication, which occurs in 0.5–1.5 % of implants, but has a mortality of 10 %. Staphylococcus aureus is the main source of infection and is becoming increasingly antibiotic resistant. Pocket haematoma is also a relatively common complication. It is usually benign and treated conservatively but sometimes requires repeated surgery, which can be a major issue in patients who use anticoagulant drugs.4,5 However, the greatest potential for a complication in a pacemaker procedure is related to the lead. The overall incidence of clinical problems related to the lead is around 8 %.6 Mechanical failure and lead dislodgement are relatively common complications.

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Supported Contribution

Survival free from any pacemaker complication

Figure 1: Kaplan–Meier Curve with Survival Free from Any Pacemaker Complication

Figure 3: Leadless Cardiac Pacemaker Delivery Catheter

1.00

0.95

12.4 % at 2 months 0.90

0.85

0.80

Figure 4: Positioning of the Leadless Cardiac Pacemaker in the Myocardium

0.75 0

2

4

6

8

Years after implantation Patients at risk

1,517

1068

815

271

Source: Udo, et al. 2012.3

Figure 2: Design of the Leadless Pacemaker Docking Button

Battery

Electronics

Fixation Sutures

Helix

Manufacturers’ databases report fracture or failure numbers of about 0.1–0.5 % per year,7–9 but in Danish pacemaker registry data, rates of 1.5 % per year were reported.10 Other potential complications include puncture of the lung with a pacemaker lead (incidence is around 2 %).11 The lead may also perforate the right ventricle, leading to pericardial infusion and necessitating surgery.12,13 Severe complications require lead extraction, which is performed percutaneously with a laser sheath or mechanical snare. This is a complex surgical procedure, with unavoidable risks, including possible tearing of the surrounding blood vessel or perforating the heart.14–16 The concept of a self-contained leadless pacemaker (LP) was first reported in 1970.17 However, the battery did not last more than a few weeks. Following advances in battery technology, endocardial fixation and delivery systems, the concept has been revisited. The requirements of a LP are a catheter-based delivery system and a dependable fixation design. It is also important to be able to reposition the device acutely to achieve satisfactory pacing thresholds and R waves, and then retrieve the device chronically after the device has reached end of service. The device should be small to enable percutaneous delivery, with low power electronics and a high-density energy source. This requires a novel communication scheme with low peak energy requirements. The device must be biocompatible and have features comparable to conventional pacemakers in terms of electrical output, battery longevity and other functions such as rate response.

Recently, a completely self-contained LP has been developed by St. Jude Medical (see Figure 2). The 1 cc and 2 g device is delivered percutaneously via the femoral vein through a Nanostim™ 18 F introducer with a steerable

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catheter. It has a docking feature, which allows attachment of the device to a catheter for delivery, repositioning and retrieval. The chemical cell is a lithium carbon monofluoride (Li-CFx) battery, with an equivalent longevity compared with conventional pacemakers. The single integrated circuit chip senses, paces and communicates to a programmer. The chip uses a quarter of the current of standard chips, providing the same longevity as a conventional pacemaker, while reducing battery volume.

The device is fixed into the right ventricle (RV) without leads or a surgical pocket. The primary fixation mechanism is provided via a helix and tines add secondary fixation. The distal tip features a steroid-eluting electrode that paces from the tip to the can.

The pacemaker functions are the same as standard single chamber rate responsive pacemakers (VVIR) with hysteresis. The standard means of communication via radiofrequency (RF) requires an antenna or a coil and a high active current (5 mA). The Nanostim™ leadless pacemaker therefore features conducted communication involving small electric pulses through the human body that are picked up with standard surface electrocardiogram (ECG) electrodes. This eliminates the need for an antenna or a coil; there is no added circuit module and the system communicates in the refractory period of the heart, and it has low active current of <100 μA. This results in a predicted battery life of 9–10 years with 100 % pacing. Pacing requirements <100 % result in an increase in battery life.

The delivery catheter is a single-operator design with three flush/ irrigation ports, an integrated LP introducer and a steerable delivery catheter (see Figure 3) with an expanded polytetrafluoroethylene (ePTFE) protective sleeve that protects the helix during the delivery and repositioning of the pacemaker.

The pacemaker is implanted as follows: the LP is placed into the 18 F sheath through the LP introducer, the device is advanced

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through the 18 F sheath up the inferior vena cava, where it is covered with the protective sleeve and then advanced into the right atrium.

Under fluoroscopic guidance, the delivery catheter with LP is deflected through the tricuspid valve, into the RV and positioned near the apex or lower septum. Contrast is injected through the protective sleeve to opacify the RV and establish the desired positioning of the LP. The protective sleeve is then pulled back to fully expose the pacemaker and the LP is slowly advanced until it reaches the endocardium. It is fixed in position by rotating the catheter handle and observing under fluoroscopy one and a quarter rotations

of the radiopaque marker inside the LP. There is also a tether mode that enables the implanter to perform a tug test confirming secure LP implant and facilitates more accurate electrical testing for pacing and sensing thresholds. If the values are unsatisfactory, it is possible to re-dock the pacemaker, unscrew it and place the sleeve over the pacemaker to allow repositioning. When satisfied with the threshold values, the operator can fully release the pacemaker. The delivery catheter is then removed and the pacemaker resides in the RV, fully functioning (see Figure 4). Follow-up data over six months indicate that the thresholds remain very low. n

Feasibility, Efficacy and Safety of Percutaneous Retrieval of a Leadless Cardiac Pacemaker in an In Vivo Ovine Model Johannes Sperzel Kerckhoff Heart Centre, Bad Nauheim, Germany

Simple and efficient percutaneous retrieval is a necessary capability for an LP in case of infection or at end of service. The Nanostim™ Leadless Pacemaker has unique design features that simplify this process. The docking button is flexible, easily snared and allows

immediately performed and in the other five sheep a re-implantation of the device was performed, followed by gross necropsy after six weeks.

The average time to snare the device was 1:48 minutes (min) (range: 13 seconds [sec] to 3:58 min) and the average total retrieval time was

for the unscrewing of the device. Retrieval is achieved via femoral access, and the retrieval procedure is a single-operator system. The catheter is deflectable and steerable and has a snare closure dock, which can be positioned independently from the retrieval catheter.

Two forms of retrieval catheter are available, the triple loop snare system and the single loop. The loop is positioned over the docking feature of the LP, the snare is closed and locked and then the retrieval catheter is docked with the LP. The protective sleeve is advanced over the device and the LP is then unscrewed and removed through the tricuspid valve and out the femoral vein.

2:35 min (1:00–4:04 min). For the five successful replacements of the devices, the average delivery time was 2:48 min (2–3 min). Upon examination of the gross pathology, no embolisations or perforations were observed. All animals were assessed by a veterinary pathologist.

Mild endocardial fibrosis was observed at the free wall (range 1.0–3.5 cm) and the septal wall (range 1–3 cm). All cardiac valves were normal in appearance. All LPs were implanted securely and were relatively free of connective tissue or thrombus at the distal tip. There was no evidence of pulmonary thromboembolism and, importantly, the original implant site in the heart could not be identified by the pathologist after the replacement of the device.

A pilot study of the retrieval procedure was performed in 10 sheep.18 After an implant duration of more than five months (159–161 days), the retrieval of the LP system was performed with an 18 F introducer sheath via the right femoral vein. The retrieval catheter was introduced into the RV and positioned at the proximal end of the LP behind the docking feature under fluoroscopic guidance. In five sheep, gross necropsy was

In summary, this study has demonstrated the feasibility, safety and efficacy of retrieval of the LP from the RV. It also demonstrates the ability for re-implantation of a new LP after successful retrieval.

Further studies will be necessary with longer term implantation and more subjects to assess the safety and efficacy of chronic retrieval. n

Percutaneous In Vivo Placement of a Novel, Intracardiac Leadless Pacemaker – Results from the First-in-Man LEADLESS Study Petr Neuzil Homolka Hospital, Prague, Czech Republic

The LEADLESS study was a feasibility study to evaluate the safety and performance of the LP.19 This was a prospective, non-randomised, single-arm, multicentre study, conducted at three European sites. The study population (n=33) comprised patients aged 18 years and over who were indicated for a VVIR pacemaker and were not pacemaker dependent. Inclusion criteria were: chronic atrial fibrillation (AF) with second or third degree of atrioventricular (AV) block, or normal sinus rhythm with second or third degree of AV block and a low level of physical activity, or sinus bradycardia with some infrequent pulses

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and unexplained syncope. Other criteria included life-expectancy of more than one year. Patients were required to comply with clinical investigation procedures and agree to return for all follow-up visits, tests and exams.

Exclusion criteria were: pacemaker dependency; known pacemaker syndrome, retrograde ventriculoarterial (VA) conduction or suffering a drop in arterial blood pressure with the onset of ventricular pacing; hypersensitivity to <1 mg dexamethasone sodium phosphate;

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Supported Contribution Table 1: Summary of the Key Findings of the LEADLESS study

of the study. By the end of the study, catheter in/out time was less than 20 min.

• Implantation success: 97 % • In–out time for introducer catheter: 28 min (range 11–74 min) • In–out time for delivery catheter: 16 min (range 3–57 min) • Mean number of times catheter needed repositioning: 0.5 • 70 % required no repositioning • All patients were discharged on average in 1 day (range 1–4) after the procedure • Procedure times decreased with experience Source: Reddy, 2013.19

mechanical tricuspid valve prosthesis; pre-existing pulmonary arterial hypertension or significant physiologically-impairing lung disease; pre-existing pacing or defibrillation leads; current implantation of an ICD or cardiac resynchronisation therapy (CRT); presence of an implanted vena cava filter; and presence of an implanted LP. The study procedure involved femoral vein assessment and access, LP delivery, positioning, assessment and programming. Postprocedure assessments included X-rays of the pacemaker, and LP assessment and programming. Parameter assessments were performed at implant, discharge, two weeks, six weeks and 90 days.

At two-week follow-up, a six-minute walking test was performed, as well as LP assessment and programming. At six weeks, the six-minute walking test was performed with the rate-response feature on, as well as LP assessment and programming, which was also performed at six months.

The mean age of patients was 75 (range 53–91), 64 % were male and 36 % female. The majority (60 %) had chronic AF and second or third degree heart block, 24 % had sinus rhythm with low activity or short lifespan and 28 % had infrequent pauses or unexplained syncope.

Implantation success was achieved in 32 of 33 patients (97 %). In terms of procedure times, the time from placing the introducer into the femoral vein to taking it out was 28 min (range 11–74 min) and for the delivery catheter 16 min (range 3–57 min). The mean number of times the catheter required repositioning was 0.5. No repositioning was required in 70 % of patients and only two patients needed repositioning of the LP three times. On average, patients were discharged one day (range 1–4) after the procedure. There was an experience effect with procedure times decreasing over the course

Safety endpoints for the study included one minor groin haematoma that did not require treatment. One serious complication occurred – cardiac perforation and tamponade in a 70-year-old man, with chronic AF. The patient was treated surgically, but the patient sustained a stroke five days after the operation. A computerised tomography (CT) scan showed occlusion of the right internal carotid artery causing oedema in the right cerebral hemisphere and the patient died. It is not believed that this complication was directly attributable to the use of the LP. Pacing threshold was 0.8 V at implant and dropped to around 0.5 V over 12 weeks, a similar change to that seen in traditional pacemaker implantation. R wave amplitudes and impedance changes over time were consistent with that expected in traditional pacemakers. The percentage of patients who were pacing was approximately 40 % at the end of the observation period.

Retrieval of the device was required in two patients. In the first, the device was implanted in the apex of the heart and achieved good sensing and pacing thresholds. After catheter release and removal, it was realised that the LP had transited into the left ventricle via a patent foramen ovale (PFO). Heparin was administered intravenously, a retrieval catheter introduced and the LP removed in around six minutes.

Another LP was then implanted into the RV apex. The second patient was an 86-year-old man, with syncope and AV conduction disease. The LP was successfully implanted at the RV apex, but after discharge from hospital, the patient sustained repeat syncope, came to hospital and had spontaneous ventricular tachycardia (VT) in the hospital. Eight days after implant, the LP was retrieved (procedure time around 13 min) and an ICD implanted.

In conclusion, this study has shown that leadless RV cardiac pacing is feasible (Table 1). Furthermore, acute and sub-acute LP retrieval is feasible. This was a relatively small feasibility study, but raises the possibility of eliminating the major causes of pacing complications – the lead and the surgical pocket required for traditional pacemakers.

There are plans to commercialise the technique in Europe this year.

There will be a large multicentre US study next year. Future needs include not only single-chamber but also dual-chamber or multichamber cardiac pacing. n

Discussion Re i n o u d Kn o p s Academic Medical Centre, University of Amsterdam, The Netherlands

Leadless RV cardiac pacing is a new therapy and requires further research.

The Nanostim leadless pacemaker is currently only capable of singlechamber pacing and does not enable dual-chamber (DDD) or CRT pacing.

The device size (almost 4 cm) renders it only suitable for placement in the RV apex or lower septum. Therefore AAI pacing is not yet possible. There are no data on retrieval after long-term treatment.

Pre-selection criteria for initial studies should be older patients whose first pacemaker will be their last pacemaker. Following data on retrieval

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of long-term implants, studies should include young patients who are very prone to lead complications.

There may be challenges in the initial use of this novel procedure.

There is a need for physician training in this new technique, which may result in learning curve complications. Another consideration is post-mortem removal of the device. In the past, this has been easily done by the funeral organisation or hospital morgue, but the LP will present problems in this respect. However, despite these issues, the

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device offers benefits in addition to those already mentioned. Testing still needs to be conducted to demonstrate magnetic resonance imaging (MRI) compatibility.

to a lead like conventional pacemakers. A patient who receives a traditional pacemaker is instructed not to overuse the arm adjacent to the placement of the pacemaker.

A problem associated with traditional pacemakers is that some serious cases of thrombosis have been reported with transvenous leads.20 In the case of the LP, since no lead passes the valve, these problems do not occur. With traditional pacemakers, up to 10 % of patients develop a venous thrombosis in the subclavian vein.

Experience of lead extractions shows that in the first two years leads are easy to remove but can become more difficult in the longer term after fibrosis occurs. Another important benefit of this pacemaker is the lack of mobility restrictions for patients; the LP is not tethered

The results of the LEADLESS study have now been published,21 and the LP received the CE mark during the third quarter of 2013. The European post-CE mark trial with target enrolment of 1,000 patients and the US Investigational Device Exemption trial were initiated in 2014.

1. Mond HG, Proclemer A. The 11th world survey of cardiac pacing and implantable cardioverter-defibrillators: calendar year 2009--a World Society of Arrhythmia’s project. Pacing Clin Electrophysiol 2011;34:1013–27.

2. van Eck JW, van Hemel NM, Zuithof P, et al. Incidence and predictors of in-hospital events after first implantation of pacemakers. Europace 2007;9:884–9.

3. Udo EO, Zuithoff N, van Hemel NM, et al. Incidence and predictors of short- and long-term complications in pacemaker therapy: the FOLLOWPACE study. Heart Rhythm 2012;9:728–35.

4. Wiegand UK, LeJeune D, Boguschewski F, et al. Pocket hematoma after pacemaker or implantable cardioverter defibrillator surgery: influence of patient morbidity, operation strategy, and perioperative antiplatelet/anticoagulation therapy. Chest 2004;126:1177–86.

5. Przybylski A, Derejko P, Kwasniewski W, et al. Bleeding complications after pacemaker or cardioverter-defibrillator implantation in patients receiving dual antiplatelet therapy: Results of a prospective, two-centre registry. Neth Heart J 2010;18:230–5.

6. Klug D, Balde M, Pavin D, et al. Risk factors related to infections of implanted pacemakers and cardioverter-defibrillators: results of a large prospective study, Circulation 2007;116:1349–55.

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For now, the LP is only suitable for those with VVIR indications.

Interestingly, while VVIR pacemakers have restricted use in North America and Europe, in the rest of the world VVIR pacemakers are sometimes the first choice.1 n

7. Medtronic. Cardiac Rhythm Disease Management, Product Performance Report, 2013 First Edition – Issue 68. Available at: wwwp.medtronic.com/productperformance-files/ Issue%2068%20MDT%20CRDM%20PPR%202013%201st%20 Edition.pdf (accessed 1 April 2014).

8. St Jude Medical, Implantable Electronic Systems Division.

Product Performance Report. First Edition, 2013.

9. Boston Scientific. CRM Product Performance Report 2013 Q3 Edition. Available at: www.bostonscientific-international. com/templatedata/imports/HTML/PPR/ppr/references/ report_download_2013_q3.shtml (accessed 1 April 2014).

10. Kirkfeldt RE, Johansen JB, Nohr EA, et al. Risk factors for lead complications in cardiac pacing: a population-based cohort study of 28,860 Danish patients. Heart Rhythm 2011;8:1622–8.

11. van Rees JB, de Bie MK, Thijssen J, et al. Implantation-related complications of implantable cardioverter-defibrillators and cardiac resynchronization therapy devices: a systematic review of randomized clinical trials. J Am Coll Cardiol 2011;58:995–1000.

12. Banaszewski M, Stepinska J. Right heart perforation by pacemaker leads. Arch Med Sci 2012;8:11–3.

13. Howell C, Bergin JD. A case report of pacemaker lead perforation causing late pericardial effusion and subacute cardiac tamponade. J Cardiovasc Nurs 2005;20:271–5.

14. Bracke F, Meijer A, van Gelder LM. Pacemaker lead complications: when is extraction appropriate and what can we learn from published data? Heart 2001;85:254–9.

15. Buch E, Boyle NG, Belott PH. Pacemaker and defibrillator lead extraction. Circulation 2011;123:e378–80.

16. Maytin M, Epstein LM, Henrikson CA. Lead extraction is preferred for lead revisions and system upgrades: when less is more. Circ Arrhythm Electrophysiol 2010;3:413–24.

17. Spickler JW, Rasor NS, Kezdi P, et al. Totally self-contained intracardiac pacemaker. J Electrocardiol 1970;3:325–31.

18. Sperzel J, Khairkhahan A, Ligon D, Zaltsberg S. Feasibility, efficacy and safety of percutaneous retrieval of a leadless cardiac pacemaker in an in vivo ovine model. Abstract 859.

Europace 2013;15(suppl 2):ii112–3.

19. Reddy V. Percutaneous In Vivo Placement Of A Novel Intracardiac Leadless Pacemaker: Results From The First-in-man Leadless Study (SP22, Presentation LB02-01). Presented at: Heart Rhythm Society Meeting, Denver, CO, US, 8–11 May 2013.

20. Barakat K, Robinson NM, Spurrell RA. Transvenous pacing lead-induced thrombosis: a series of cases with a review of the literature. Cardiology 2000;93:142–8.

21. Reddy VY, Knops RE, Sperzel J et al. Permanent leadless cardiac pacing: results of the LEADLESS trial. Circulation 2014; ePub ahead of print.

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Supporting life-long learning for arrhythmologists Arrhythmia & Electrophysiology Review, led by Editor-in-Chief Demosthenes Katritsis and underpinned by an editorial board of world-renowned physicians, comprises peer-reviewed articles that aim to provide timely update on the most pertinent issues in the field. Available in print and online, Arrhythmia & Electrophysiology Reviewâ&#x20AC;&#x2122;s articles are free-to-access, and aim to support continuous learning for physicians within the field.

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