Improving the Early Diagnosis and Treatment of Cardiac Arrhythmias - Biosense Webster by Global Business Media

SPECIAL REPORT

Improving the Early Diagnosis and Treatment of Cardiac Arrhythmia The Principles NICE Follows When Developing Its Guidance and Recommendations The Prevalence of Under-Diagnosis and Late Referral and the Importance of Early Detection The Socio-Economic Burden of Atrial Fibrillation and Cardiac Arrhythmias Risks and Issues Associated with Treating Patients with Anti-Arrhythmic Drugs How Cardiac Ablation Can Offer a Safe and Efficacious Alternative to Antiarrhythmic Drug Therapies New Approaches to Managing Atrial Fibrillation and Other Complex Arrhythmias Technological Innovations to Improve the Safety, Efficacy and Efficiency of Radiofrequency Catheter Ablation in Atrial Fibrillation Increased Risk of Stroke and Mortality Associated with Atrial Fibrillation Future Outlook

Published by Global Business Media

IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

SPECIAL REPORT

Contents

The Socio-Economic Burden of Atrial Fibrillation and Cardiac Arrhythmias Risks and Issues Associated with Treating Patients with Anti-Arrhythmic Drugs How Cardiac Ablation Can Offer a Safe and Efficacious Alternative to Antiarrhythmic Drug Therapies New Approaches to Managing Atrial Fibrillation and Other Complex Arrhythmias Technological Innovations to Improve the Safety, Efficacy and Efficiency of Radiofrequency Catheter Ablation in Atrial Fibrillation Increased Risk of Stroke and Mortality Associated with Atrial Fibrillation Future Outlook

Foreword

Sophie Laurenson, Ph.D., Editor

The Principles NICE Follows When Developing Its Guidance and Recommendations

Prof Gillian Leng, Co-CEO of NICE

The Prevalence of Under-Diagnosis and Late 5 Referral and the Importance of Early Detection Published by Global Business Media

Published by Global Business Media

The early detection and subsequent diagnosis of Atrial Fibrillation (AF) is essential in saving the lives of patients who may experience an AF-related stroke, heart failure or possible death. Trudie Lobban, MBE FRCP Edin

Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom

The Socio-Economic Burden of Atrial Fibrillation (AF)

Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org

Sophie Laurenson, Ph.D., Editor

Publisher Kevin Bell

The Danger of AADs.

Business Development Director Marie-Anne Brooks Editor Sophie Laurenson Senior Project Manager Steve Banks

AF is a significant challenge for health systems, placing increased economic and social burdens on patients, carers and healthcare providers.

Risks and Issues Associated with Treating 11 Patients with Anti-Arrhythmic Drugs (AADs) Lisa WM Leung MRCP, Banu Evranos MD, Mark M Gallagher MD Cardiology Clinical Academic Group, St. George’s University Hospitals NHS Foundation Trust, St. George’s, University of London, United Kingdom

How Cardiac Ablation Can Offer a Safe and 14 Efficacious Alternative to Anti-Arrhythmic Drug Therapies Evidence to support the implementation of AF ablation therapy.

Advertising Executives Michael McCarthy Abigail Coombes

Dr. Adam S. C. Dennis, Ross J. Hunter MRCP PhD FESC St. Bartholomew’s Hospital, Barts Health NHS Trust, West Smithfield, London, United Kingdom

Production Manager Paul Davies

New Approaches to Managing Atrial Fibrillation 18 and Other Complex Arrhythmias

For further information visit: www.globalbusinessmedia.org The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated. Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor. While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles. © 2019. The entire contents of this publication are protected by copyright. Full details are available from the Publishers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical photocopying, recording or otherwise, without the prior permission of the copyright owner.

Sabine Ernst MD PhD FESC Department of Cardiology, Royal Brompton & Harefield NHS Foundation Trust, London, UK and National Heart and Lung Institute, Imperial College of London, United Kingdom

Technological Innovations to Improve the Safety, 22 Efficacy and Efficiency of Radiofrequency Catheter Ablation in Atrial Fibrillation (AF) Advances in catheter ablation have enabled this procedure to become an established strategy in the management of AF. Graca Costa; Laura Goldstein; Maria Velleca; Tom Wei Biosense Webster, Inc. Leonardo Da Vincilaan 15 Diagem 1831, Belgium

Increased Risk of Stroke and Mortality 29 Associated with AF AF is associated with increased risk of stroke and mortality, requiring effective prevention and management strategies. Sophie Laurenson, Ph.D., Editor

Future Outlook

Future advances in AF prevention and management. Sophie Laurenson, Ph.D., Editor

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IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

Foreword

trial fibrillation (AF) is a chronic, progressive

and patients often suffer from comorbidities including

disorder characterized by a fast and irregular

stroke and thromboembolisms, heart failure, cognitive

heart rhythm. It is the most common cardiac rhythm

impairment and diminished quality of life (QOL).

disorder, with an increasing global prevalence and

Combined, the impact of AF and its associated

incidence. Currently more than 33 million people

comorbidities places a considerable social and

are affected by AF, with the highest prevalence

economic burden on health systems.

in high-income countries. This trend is the result

This report focuses on the key issues in AF diagnosis

of increasing life expectancies and improved

and management today. The importance of patient

management of other chronic conditions. Adults

and caregiver awareness, early detection and

over 40 years of age have a one in four lifetime

intervention is critical in preventing AF and minimizing

risk of developing AF, with individuals of European

the risk associated with other conditions. Current

ancestry experiencing the highest incidence.

state-of-the-art practice in AF detection as well as in

AF is a highly heterogeneous disease, with

interventions are described, including advances in

significant variation in symptoms both between

ablation procedures and the use of pharmacologic

and within individual patients. The precise

therapy. The socio-economic impact of AF and

pathophysiological processes underpinning the

its related conditions is described, with particular

development and progression of AF remain under

emphasis on the importance of stroke and mortality

investigation. It is believed to arise from anomalies

risk conferred by AF. The report concludes with a

in the cardiac tissue, altering the propagation of

review of the future prospects for AF management and

electrical impulses through the heart. This results

opportunities for prevention and improved outcomes.

in dysfunctional stimulation of the myocardium and arrhythmic contractions. The progressive nature of AF contributes to increased mortality and morbidity,

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Sophie Laurenson, Ph.D. Editor

IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

The Principles NICE Follows When Developing Its Guidance and Recommendations Prof Gillian Leng, Co-CEO of NICE

HE NATIONAL Institute for Health and Care Excellence (NICE) provides national guidance and advice to improve health and social care. NICE was established in 1999, primarily to offer professionals in the National Health Service (NHS) advice on providing care that is both effective and cost effective, and to reduce variation in the availability and quality of NHS treatments and care. NICE’s role has been expanded several times. Firstly in 2005 to include the provision of advice to the broader public health community on preventing ill health and maintaining good health, and then in 2013 to take on responsibility for developing guidance and quality standards in social care. NICE owes its success to a number of factors, but chief among them is the great care NICE has taken to develop a methodologically rigorous approach to guidance development. This has been set out in a series of documents which together guide the work of our independent advisory groups, and help those involved and interested in NICE understand how we work. All these documents have helped inform a set of principles on which we base our approach to our work. This includes concepts such as transparency, engagement and contestability. Until now we used the statement of our approach to making social value judgments to do this. As our programmes have developed and new responsibilities have been added, we have had to keep these principles up to date and be able to set out, clearly and simply, why and how we work in the way that we do. At the end of 2018 we opened a public consultation on the latest iteration of these principles. Briefly, they are as follows: Principle 1. Prepare guidance and standards and topics that reflect national priorities and the population’s health and care. This describes how we prioritise topics to ensure we cover the breadth of health, public health and social care topics set out in NICE’s remit. Suggestions for topics come from a range of

sources, including NHS England, people using services, health and care professionals, and manufacturers. Topics are selected and prioritised in collaboration with our partners using criteria that include disease prevalence, variation in care, and the available evidence. Principle 2. Use evidence that is relevant, reliable and robust. NICE guidance and standards are underpinned by evidence, so we need to ensure that the evidence we use is relevant, reliable and robust. We have a range of processes for identifying research evidence, for assessing its quality, and for determining whether it is relevant to the question under consideration. We take a comprehensive approach to assessing evidence, and don’t focus on traditional ‘hierarchies of evidence’ alone. Our process and methods manuals set out the types of evidence that are generally appropriate for different types of question. This can include evidence derived from qualitative and quantitative methodology from the literature or submitted by stakeholders, as well as real world data and evidence from expert and public testimonies.

NICE owes its success to a number of factors, but chief among them is the great care NICE has taken to develop a methodologically rigorous approach to guidance development

Principle 3. Set out frameworks for interpreting the evidence in our process and methods manuals, and review them regularly. All our guidance and standards programmes have detailed process and methods manuals that go through rigorous review, assessment and consultation before being published, and are updated regularly. We are required to follow our documented processes and methods and are accountable for the decisions that we make. If it is appropriate for us to depart from the documented processes and methods we clearly explain our rationale in the documentation. Principle 4. Use independent advisory committees to develop recommendations. To ensure that our recommendations are unbiased, objective and truly evidence-based, WWW.HOSPITALREPORTS.EU| 3

IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

we use independent advisory committees to consider the evidence. Committees include people from the NHS and social care services, academia, relevant industries, patient–carer organisations and the general public. All committee members declare any relevant interests both annually and for each committee meeting they attend.

NICE’s longevity owes much to the way it has defined itself from the outset in terms of its core principles

Principle 5. Take into account the advice and experience of people using services, health and social care professionals, commissioners and providers. NICE needs to ensure that we involve people who will be affected by our recommendations, and to reflect their needs and priorities. We build in these perspectives through the membership of our guidance development committees or, when this isn’t possible, by inviting people to provide expert testimony to the committee. Committee members are selected for their knowledge and experience. They are each there in their own right and do not represent organisations they work in. Lay members reflect the experiences of a wide range of people affected by the guidance. Organisations that represent patients, service users, carers and the wider public, alongside health professionals and others, are also involved in defining the scope of our products, and invited to submit evidence for the committee to consider. Principle 6. Base our recommendations on an assessment of population benefits and value for money. NICE has to take into account both the costs and benefits of interventions, and encourage the effective use of resources. We also have a commitment under the NHS Constitution to provide “the best value for taxpayers’ money and the most effective, fair and sustainable use of finite resources”. The way we assess value for money takes into account the ‘opportunity cost’ of recommending something new, highlighting that there would have been other potential uses of the resource. It considers the needs of other people using services (both now and in the future) who are not known and not represented in the decision. Therefore the primary consideration underpinning our guidance and standards is the overall population need. For treatments that extend life for people at the end of life, and for highly specialised technologies where specific criteria are satisfied, we may recommend an intervention with a cost-effectiveness estimate above our normally acceptable range.

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Principle 7. Give people interested in the topic area the opportunity to comment on and influence our recommendations. NICE recommendations are based on complex considerations of the evidence by our committees, and it is important that a wider group of stakeholders also have the opportunity to comment. This wider consultation helps ensure the validity of the final recommendations. The principles of the NHS Constitution also require us to make decisions in a clear and transparent way. Our advisory committees consider and respond objectively to comments and, where appropriate, amend the recommendations. Principle 8. Lead work with partners in the health and care system to encourage and support the adoption of our recommendations. Our implementation strategy supports adoption of our recommendations by ensuring relevant audiences know about our recommendations, motivating and encouraging improvement, highlighting practical support to improve local capability and opportunity, and evaluating impact and uptake. Principle 9. Assess the need to update our publications in line with new evidence. We regularly assess the need to update our guidance and standards. If we find evidence that might result in a change to our recommendations, we may initiate a review of the guidance. We normally consult with relevant organisations on a proposal about whether or not guidance needs updating and, if so, how to conduct the update. Principle 10. Propose new research questions and data collection to resolve uncertainties in the evidence. NICE examines the available evidence when developing guidance, and this often highlights a number of unanswered questions. If these uncertainties could affect future recommendations, we set these out as research recommendations, and liaise with the research community to ensure they are addressed. Committees may also recommend the provisional use of an intervention to allow collection of more data. NICE’s longevity owes much to the way it has defined itself from the outset in terms of its core principles - principles which I am confident will ensure NICE remains an integral component of the UK health care environment for the foreseeable future. Note from Editor: In 2020, NICE will be undertaking a guideline review on the clinical management of atrial fibrillation

IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

The Prevalence of Patients Being Under-Diagnosed and Referred Too Late and the Vital Importance of Early Detection The early detection and subsequent diagnosis of Atrial Fibrillation (AF) is essential in saving the lives of patients who may experience an AF-related stroke, heart failure or possible death. Trudie Lobban MBE FRCP Edin

Introduction It is critical that early detection and diagnosis of Atrial Fibrillation (AF) become a global priority. With the rising number of AF-related strokes, heart failure and death, AF has become the most common cardiac arrhythmia disorder. According to the Centers for Disease Control and Prevention (CDC), AF is the reason for more than 750,000 hospital admissions. AF affects an estimated 33.5 million people worldwide. It is further associated with 130,000 deaths each year.6 Left untreated or poorly monitored, AF can lead to serious medical complications and possibly death. Risk factors include high blood pressure, heart disease, heart failure, stroke, obesity, diabetes, lung disease, sleep apnoea and a family history of AF. AF can occur in adults of any age but is more common in those between the ages 65-85 and is more prevalent in men. During an episode of AF, the heart beat is often rapid, with an irregular rhythm and of varying intensity. This can cause unpleasant symptoms such as palpitations, light headedness, breathlessness, chest pain and may even lead to syncope (fainting). If these episodes are intermittent, then it is termed paroxysmal AF (PAF). Paroxysmal AF is due to other areas of the atrium producing rapid, uncontrolled electrical impulses. In permanent or persistent AF, the electrical activity of the atria is continuously chaotic, because the cells of the atria do not conduct electrical activity smoothly. Because of this rapid activity, the sinus node has no opportunity to control the heart rhythm. While

the mechanisms of paroxysmal and persistent AF are slightly different, the end result in both situations is rapid and chaotic quivering of the atria.1 Paroxysmal AF involves multiple episodes that cease within seven days without treatment. Persistent AF episodes last longer than seven days or less than seven days when treated. Permanent AF occurs when a patient accepts the presence of AF, and the physician/strategies to restore sinus rhythm are not being pursued.4

It is critical that early detection and diagnosis of Atrial Fibrillation (AF) become a global priority

Methods of Detection Identifying the undiagnosed person can be successfully accomplished in a variety of ways including the following methods: Pulse Checks One of the easiest ways to detect AF is through a simple 30-second pulse check to feel your heart rhythm. These checks are important because they may indicate an abnormal heart rate or rhythm. Routine pulse checks could save thousands of lives every year. A normal pulse is between 60 and 100 beats per minute. However, there are normal factors that may cause a pulse to be slower or faster including age, medication, caffeine, fitness levels, stress, anxiety, and other illness or heart conditions. More importantly a pulse check can detect an irregular rhythm, all too often this is AF. Arrhythmia Alliance and AF Association â&#x20AC;&#x153;Know Your Pulseâ&#x20AC;? (KYP) campaign and Global AF Aware Week (GAFAW) - www.gafaw.org - promote the need for everyone to be aware of their pulses as well as the need to maintain routine manual

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IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

The “Detect, Protect, Correct & Perfect” campaign aims to identify AF using a simple 30-second pulse check, preventing AF-related stroke or heart failure

pulse rhythm checks. KYP events have been held globally in hospitals, primary care clinics, pharmacists, shopping malls, sports activities, even schools where the children are trained to take the pulse of their parents, grandparents and elderly neighbours. Many have reported being diagnosed after a child has taught them the importance of knowing their pulse. Over half a million pulse rhythm checks have been conducted in efforts to detect AF through the ‘Know Your Pulse’ campaign. AF Association Global AF Aware Week (GAFAW) is an annual awareness week that brings attention to AF. The “Detect, Protect, Correct & Perfect” campaign aims to detect AF with a simple 30-second pulse check preventing AF-related stroke or heart failure. Physician-Led Electrocardiogram (ECG) AF can be confirmed with an electrocardiogram (ECG). With advances in technology, there are a number of new mobile devices that are available to measure ECG and detect AF. Everyone should become pulse-rhythm aware. Using both manual pulse rhythm checks and new mobile ECG technology makes it even easier to confirm an irregular heart rhythm and possible AF. Using manual pulse rhythm checks and mobile ECG technology will help save thousands of lives from undiagnosed AF-related strokes and heart failure, reduce the levels of misdiagnosis, and by ruling out benign ectopic heart beats, reduce individuals’ worry and concern and unnecessary hospital admissions. Typically, mobile heart-monitor devices are purchased by patients who are experiencing symptoms, such as palpitations, breathlessness, or an irregular heart rhythm. Patients are able to share this information with healthcare professionals and take charge of their heart health.3 Automated Blood Pressure (BP) Monitors There are automated BP monitors that have a built-in AF algorithm to analyze any irregularity of the pulse rate and apply a threshold for detecting AF. These monitors are referred to as ‘AF detectors.’

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Reducing the Risk of AF-Related Stroke Once AF is detected and diagnosed a patient should be given anticoagulation therapy to help reduce the risk of a clot forming and travelling to the brain causing an AF-related stroke. AFrelated strokes are known to be more disabling, debilitating and all too often fatal more than any other type of stroke. Where once there was only one anticoagulation drug there are now five, with the latest four not requiring regular blood tests. In discussion with the patient, the physician and patient should decide what is the most appropriate way to manage the risk of AF-related stroke, including anticoagulation, ablation, drug therapy or left atrial appendage occlusion (LAAO). It is a minimally invasive surgical procedure (carried out under general anaesthetic but without having to make large incisions in the skin). The device, in trials and in practice, has proven to be an effective option in reducing the risk of AFrelated stroke in AF patients for whom an oral anticoagulant is unsafe or contraindicated.

Treatment Options There are a variety of treatment options for AF that include lifestyle changes, medications, procedures and possible surgery. The goal of treatment in AF is to restore the heart’s normal rhythm. If this is not possible, then the goal is to slow the irregular heart rate in order to alleviate symptoms and prevent medical complications.4 The main distinctions in treatment are nonsurgical interventions (medication, cardioversion or catheter ablation) or surgical procedures (pacemakers and surgical ablation). All management types aim to achieve one or more of the following goals for treating AF: • Managing and controlling symptoms • Restoring a normal heart rhythm • Reducing the risk of a stroke No single treatment has been shown to be effective for all AF patients. The best treatment option for each patient depends upon the severity of symptoms, the likelihood that the patient will respond to a particular treatment and consideration of the risk versus benefits of each treatment option.1

IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

Medication: Drugs such as flecainide, amiodarone, sotalol or propafenone may be prescribed for AF patients to restore and maintain a normal heart rhythm and are referred to as antiarrhythmic drugs. They work by altering the electrical properties of the heart cells in order to reduce the likelihood of the arrhythmia occurring. Drugs such as beta blockers, calcium channel blockers or digoxin are used in atrial flutter in order to slow the heart rate by reducing the number of atrial beats. As the majority of symptoms experienced by people with atrial flutter are due to the fast heart rate, these drugs can be very effective at controlling symptoms.4 Interventional Procedures: Interventional procedures in which catheters (wires) are placed into the heart via blood vessels) can help. Using these wires, doctors are able to measure the electrical activity of heart and heat small areas creating scar tissue that does not conduct electricity. The distribution of electricity throughout the heart is altered in order to reduce the likelihood of AF. The successful management of atrial fibrillation can be difficult. At some point, the term ablation may arise. In this context, ablation means the destruction of abnormal conducting

tissue. Using the various types of ablation, the abnormal electrical signals within the heart can be blocked. The success of each approach varies on the type of AF. Surgical procedures also carry small but significant risks. Ablation is not suitable for everybody and is currently indicated for those who have failed to respond to various drug strategies.1

Importance of Early Detection and Prevention Expanding awareness of this global epidemic is critical for increasing early detection of AF. Though AF cannot be prevented entirely, there are ways to maintain a heart-healthy lifestyle through exercise and diet. Through new technologies, anticoagulation therapy and various treatment methods, countless lives could be saved globally and decrease the number of AF-related strokes, heart failure, and death. A simple 30-second pulse check is often all that is needed to detect AF and should be part of routine procedure when visiting the physician, nurse, flu clinic or even at home. If we were all pulse rhythm aware, more AF would be detected and diagnosed and costs to health providers would be reduced and importantly lives saved.

Expanding awareness of this global epidemic is critical for increasing early detection of AF

References Treatment Options for Atrial Fibrillation, Professor John Camm, Jayne Mudd, Professor Richard Schilling

& Dr Matthew Fay, AF Association, www.heartrhythmalliance.org/afa/uk/booklets, 2018. Atrial Fibrillation Factsheet, Dr Matthew Fay & Peter Spector, MD, AF Association,

www.heartrhythmalliance.org/afa/uk/factsheets, 2016. 3.

Identifying the Undiagnosed Person – How mobile devices can make a difference,

Dr Charlotte D’Souza, AF Association, www.heartrhythmalliance.org/afa/uk/booklets, 2018. Living with AF and Atrial Flutter Booklet, Dr Charlotte D’Souza, AF Association,

www.heartrhythmalliance.org/afa/uk/booklets, 2018.

Mobile ECG Technology, Volume 10, W.G. Newham, M.H. Tayejebee, University of Leeds, www.jafib.com, 2017.

Centers for Disease Control and Prevention (CDC) Worldwide Epidemiology of Atrial Fibrillation,

A Global Burden of Disease 2010 Study,

https://www.healthline.com/health/living-with-atrial-fibrillation/facts-statistics-infographic#5, 2013.

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The Socio-Economic Burden of Atrial Fibrillation (AF) AF is a significant challenge for health systems, placing increased economic and social burdens on patients, carers and healthcare providers. Sophie Laurenson, Ph.D.

Introduction

It is the most common form of cardiac arrythmia affecting an estimated worldwide population of over 33 million

Atrial fibrillation (AF) is rapidly becoming one of the most important issues in global health. It is the most common form of cardiac arrythmia1 affecting an estimated worldwide population of over 33 million2. Improved cardiovascular outcomes and an aging population are the primary drivers behind this trend and the number of affected individuals is predicted to rise exponentially in the future3,4. The prevalence of AF and development of associated comorbidities is a significant challenge for many health systems. The progressive nature of AF is associated with increasing disease and symptom severity, requiring frequent outpatient visits and hospitalisations. This puts a financial and social burden on patients, healthcare providers and carers.

Epidemiology One in four 40-year-old people of European descent are anticipated to develop AF during their lifetimes5. In the countries of France, Germany, Italy and the United Kingdom, there are more than 1 million AF patients6. By 2050, Europe is expected to have the highest prevalence of AF when compared to other regions7. The current understanding of the epidemiology of AF is based primarily on data from North America and Western Europe. Data from other geographic regions are limited and the burden of AF in low and middle-income countries is not well characterized2. This may be the underlying reason for the observed regional variability, with a higher prevalence and incidence of AF reported in patients of European heritage compared to non-Europeans8. Regional variation may also be a consequence of improved surveillance, longer life expectancy and management of risk factors in high- income countries. Despite the increasing levels of reported AF, it is widely believed that AF is under-diagnosed as a result of asymptomatic cases. It is estimated that between 15% to 30% of AF patients are affected by undiagnosed ‘silent’ AF9. As unrecognised AF is associated with increased risk of stroke and 8 |WWW.HOSPITALREPORTS.EU

other comorbidities, many health systems are recommending proactive screening strategies to identify these patients for early interventions.

Health Services Utilisation AF results in poor quality of life (QOL), functional impairment and increased healthcare resource utilization10. The burden of AF in 2010 was 64.5 per 100,000 men and 45.9 per 100,000 women, as measured by age-adjusted disability- adjusted life years (DALYs). These figures indicate an increase of 19% in AF-related burden since 1990. It has been linked with numerous complications and as the prevalence of AF increases, the socioeconomic burden on health systems is also expected to rise in a rapidly aging population11. This may be the result of increased health services utilization, additional hospitalisations and interventions resulting from AF or its sequalae. The financial burden on the healthcare system across European countries is estimated to be between e660-e3,286 million annually8. Currently, AF accounts for between 0.28% and 2.6% of total healthcare expenditure in Europe12. Independent country assessments in France, Germany, Italy and the United Kingdom, estimate the annual cost at between e0.6 and e3.3 billion13. AFrelated costs are largely influenced by treatment costs and related morbidity1, with increased hospitalisations as the largest contributing factor. AF-related hospitalisations have increased from ~35 to over 100 admissions per 10,000 persons between 1996 and 2006. Recent studies suggest that the number of AF-related hospitalisations could reach 3.5 – 4 million over the next 12 years. Further, the number of outpatient visits is predicted to be between 100 – 120 million. AF is a life-long, chronic disease with heterogeneous presentation. The variation in AF episode severity and frequency can make clinical management difficult. Symptoms are the main reason for AF patients to seek medical care. As symptoms often persist, even in patients receiving treatment, this can be a major contributing factor to costs.

IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

Quality of Life (QOL)

Mortality

Patients with AF experience symptoms that impair function and affect daily activities, impacting quality of life (QOL) in addition to other AF-related morbidities. QOL may be affected by a variety of factors that are related to symptoms or disease management. AF patients commonly suffer from symptoms such as chest pain, palpitations, fatigue and dyspnoea (propensity to fainting). Concerns over disease management such as adherence to pharmacological regimens, potential side effects and adverse drug-drug interactions contribute to poor QOL. Further, the unpredictability of AF is a source of concern for many patients. The frequency and duration of AF episodes may vary widely between and within patients, leading to variation in symptoms over time. Lastly, AF is frequently accompanied by comorbid conditions such as cardiovascular disease and diabetes. Patients with AF often have a poorer QOL than the general population and is more pronounced among patients over 65 years of age14. The Health-related QOL (HRQOL) is used to investigate patient-reported outcomes and changes to HRQOL are an important metrics for measuring the social impact of interventions. The assessment of HRQOL is particularly useful in assessing chronic diseases and is recommended in AF management15. QOL impact is not limited to AF patients. Caregivers may also be impacted adversely by the effects of AF and underlying comorbidities.

AF confers a significant, independent increased risk of mortality16,17. The burden of AF and AFassociated mortality contribute to the overall public health burden of AF. AF is more common in elderly individuals with concomitant conditions including hypertension, cardiovascular disease, diabetes, chronic kidney disease and obesity8. The common coexistence of multiple chronic, progressive diseases contributes to the increased mortality and morbidity faced by AF patients.

AF results in poor quality of life (QOL), functional impairment and increased healthcare resource utilization

Conclusion The chronic and progressive nature of AF make this disease particularly challenging for heath systems to address. AF patients often suffer from multiple chronic conditions, conferring increased risk of developing cardiac disease, stroke and cognitive impairment. Although AF patients frequently seek medical attention for symptom alleviation, comorbidities also contribute to the costs associated with AF health care. AF patients frequently access health services for outpatient visits and often require hospitalisation for issues related to both AF and associated conditions. This places a high burden on health systems, patients and carers. As global life-expectancies increase and the management of other chronic diseases improves, this burden is likely to increase. In the future, strategies to prevent the development and progression of AF would be valuable tools in reducing the social and economic impact of AF.

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IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

References Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg. 2016;50(5):e1-e88.

Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837-847.

Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. The American journal of cardiology. 2013;112(8):1142-1147.

Krijthe BP, Kunst A, Benjamin EJ, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. European heart journal. 2013;34(35):2746-2751.

Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110(9):1042-1046.

Network GBoDC. Global Burden of Disease Study 2016 (GBD 2016) Results. In: Institute for Health Metrics and Evaluation (IHME) Seattle, United States; 2017.

Rahman F, Kwan GF, Benjamin EJ. Global epidemiology of atrial fibrillation. Nature Reviews Cardiology. 2014;11(11):639.

Ball J, Carrington MJ, McMurray JJ, Stewart S. Atrial fibrillation: profile and burden of an evolving epidemic in the 21st century. International journal of cardiology. 2013;167(5):1807-1824.

Rienstra M, Lubitz SA, Mahida S, et al. Symptoms and functional status of patients with atrial fibrillation: state of the art and future research opportunities. Circulation. 2012;125(23):2933-2943.

Goren A, Liu X, Gupta S, Simon TA, Phatak H. Quality of life, activity impairment, and healthcare resource utilization associated with atrial fibrillation in the US National Health and Wellness Survey. PLoS One. 2013;8(8):e71264.

10.

Di Carlo A, Bellino L, Consoli D, et al. Prevalence of atrial fibrillation in the Italian elderly population and projections from 2020 to 2060 for Italy and the European Union: the FAI Project. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2019.

11.

European Society of Cardiology. Atrial fibrillation set to affect more than 14 million over-65s in the EU by 2060. 2019; http://bit.ly/341EXTq. Accessed September, 2019.

12.

Cotte F-E, Chaize G, Gaudin A-F, Samson A, Vainchtock A, Fauchier L. Burden of stroke and other cardiovascular complications in patients with atrial fibrillation hospitalized in France. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2015;18(4):501-507.

13.

Pepine CJ. Effects of pharmacologic therapy on health-related quality of life in elderly patients with atrial fibrillation: a systematic review of randomized and nonrandomized trials. Clinical Medicine Insights Cardiology. 2013;7:1-20.

14.

Anker SD, Agewall S, Borggrefe M, et al. The importance of patient-reported outcomes: a call for their comprehensive integration in cardiovascular clinical trials. European heart journal. 2014;35(30):2001-2009.

15.

Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107(23):2920-2925.

16.

Benjamin EJ, Wolf PA, Dâ&#x20AC;&#x2122;Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98(10):946-952.

17.

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Risks and Issues Associated with Treating Patients with Anti-Arrhythmic Drugs (AADs) The Danger of AADs Lisa WM Leung MRCP, Banu Evranos MD, Mark M Gallagher MD, Cardiology Clinical Academic Group, St. George’s University Hospitals NHS Foundation Trust, St. George’s, University of London, United Kingdom

Introduction Sustained arrhythmias are common conditions in the general population, with atrial fibrillation (AF) accounting for a significant majority of cases. AF is found in 0.5% of persons in their 50s, rising to 8.8% of those in their 80s.1 Many of these patients are highly symptomatic, affected by fatigue and exertional dyspnoea to a disruptive and disabling degree. Pharmacological agents are fundamental in treating chronic conditions that promote arrhythmias, particularly hypertension and heart failure. Pharmaceuticals also have a vital role in preventing stroke and controlling the heart rate in AF, and a minority of cases of supraventricular tachycardia can be controlled safely by agents that slow atrioventricular conduction. These applications are uncontested and will not be addressed in this article. Arrhythmia can be suppressed directly in some cases by medications that block ion channels. These pharmaceuticals are optimistically labelled as “anti-arrhythmic drugs” (AADs) implying an ability to achieve blanket suppression of any arrhythmia. We prefer the more descriptive term “ion channel blocking medication” (ICBM) which contains no such implicit judgement. ICBMs built a significant market in the late 20th century at a time when there was little alternative treatment for arrhythmias apart from major surgery, for example, for Wolff Parkinson White Syndrome. Modern curative treatment of arrhythmias relies on understanding their anatomical circuits and largely consists of the delivery of thermal therapy through catheter electrodes to interrupt these circuits. There may still be a role for ICBMs as the primary long-term treatment option in some cases, but considerable risks are involved.

History and Classification The use of ion-channel blocking drugs to control arrhythmias derived from the chance

observation in the 19th century that quinine and related alkaloids suppressed palpitations in some individuals. Agents related to quinine were developed, and later unrelated agents that had similar effects on the electrical activity of isolated myocardium. These drugs were later shown to act by blocking sodium channels and are widely known as class I agents, referring to a classification proposed by Singh and Vaughan Williams.2 The other important group of ICBM, the Class III agents were also chanced upon; the antihypertensive agent bretylium and the anti-anginal drugs amiodarone and sotalol all turned out to have effects on the heart rhythm later shown to derive from blockade of potassium channels. The class I and class III agents can be used acutely to terminate an arrhythmia or chronically to reduce the frequency of recurrences. In the long term, they can achieve palliation of symptoms, reducing the frequency of episodes in a way that is statistically significant across study cohorts but falls short of achieving reliable control.

The use of ion-channel blocking drugs to control arrhythmias derived from the chance observation in the 19th century that quinine and related alkaloids suppressed palpitations in some individuals

The CAST Trial The pivotal event in the evolution of arrhythmia therapy was the CAST trial3, designed to measure the effect of ICBMs on the risk of sudden death. The investigators expected that the suppression of ventricular ectopic beats by flecainide or similar ICBMs would reduce the incidence of sudden death. They chose a population expected to best demonstrate this expected protection: Patients known to be at risk of sudden death because of impaired ventricular function and the presence of coronary artery disease. Death was 2.5-times more frequent in the ICBM group than in the placebo group in CAST, attributable to a 3.5-fold excess of sudden death or cardiac arrest, events that occurred in 33 out of 730 active therapy patients but only 9 of 725 in the placebo group. The result stunned the cardiology community; it had already been understood that quinidine could WWW.HOSPITALREPORTS.EU| 11

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ILLUSTRATIVE CASE 1

These pharmaceuticals are optimistically labelled as “antiarrhythmic drugs” (AADs) implying an ability to achieve blanket suppression of any arrhythmia. We prefer the more descriptive term “ion channel blocking medication” (ICBM)

provoke life-threatening arrhythmia, but it was expected that the newer, more selective ICBMs would reduce mortality. CAST showed that the risk of promoting lethal arrhythmia was present across a raft of the most promising class I drugs. In the wake of CAST, post-hoc analyses attempted to dismiss the result as a product of exceptional characteristics of the trial population. Class I ICBMs have rightly been considered unacceptably hazardous in patients with coronary artery disease or ventricular dysfunction, but their safety in other patient groups is unclear. In patients with structurally normal hearts, the risk of death is certainly not comparable to that in CAST. Meta-analysis shows that patients treated with flecainide for supraventricular arrhythmias have no demonstrable excess of mortality risk,4 but with only 2015 patient-years of follow-up data, this cannot exclude the possibility that the same 3.5-fold increase in the rate of sudden death applies across all populations.

Illustrative Case 1 A 32-year-old woman who was completely healthy in other respects was prescribed oral flecainide for highly symptomatic episodes of AF. Two months later she presented in a state of collapse in a broad complex tachycardia

which contains no such implicit judgement

ILLUSTRATIVE CASE 2

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(Figure 1). The arrhythmia was atrial flutter with aberrant atrioventricular conduction which was treated acutely by electrical cardioversion. She subsequently underwent catheter ablation which eliminated both fibrillation and flutter.

Illustrative Case 2 A 60-year-old lady with a structurally normal heart underwent a successful ablation with cryotherapy for paroxysmal AF. As the procedure was concluding, AF occurred. Flecainide was given by slow intravenous injection with the intention of terminating the arrhythmia to permit additional mapping. As the infusion finished, the arterial pressure collapsed from more than 100mm to less than 50mm systolic (Figure 2A-C). After 10 minutes, the AF terminated, and the arterial pressure returned to normal. These cases exemplify some of the range of adverse effects that may have contributed to the excess mortality in CAST. Blockade of sodium channels can produce haemodynamic effects due to suppression of myocardial contractility and can provoke a variety of life-threatening arrhythmias. The patients described both survived because of prompt intervention and because both had normal baseline cardiac function. Similar events occurring in the absence of medical

IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

assistance on a background of prior cardiac dysfunction would probably have proved fatal.

Other ICBMs A comprehensive meta-analysis of the efficacy and safety of ICBMs in AF patients shows a clear excess of mortality in association with sotalol.5 For most other agents, there is insufficient evidence to draw a conclusion, but there is a trend toward increased mortality. The notable exception is amiodarone. Despite its propensity to cause lifethreatening and life-changing adverse effects on the lungs, thyroid and peripheral nerves in the long term, it appears from the trial evidence to be mortality-neutral at least for the first year of therapy.6 Unfortunately, the risk of pulmonary and other adverse effects make amiodarone unacceptable as the mainstay of treatment for a chronic condition such as AF, other than in patients with a limited life expectancy through advanced age or comorbidity.

Alternatives Attempts to reduce the risk of sudden death by use of ICBMs were abandoned in the 1990s in favour of implanted defibrillator therapy. The treatment of the supraventricular arrhythmias by catheter ablation has proved so effective that ICBMs have been largely eliminated from this role in developed health care systems. AF is

treatable by ablation with a mortality risk of less than 1 per 1,000 patients treated7 and with an effectiveness in terms of maintenance of sinus rhythm and symptom control that far exceeds that which is achievable by ICBMs.8 The mortality risk is mostly due to peri-procedural risks that may be minimised as operators and institutions gain experience and to injury to extra-cardiac structures which may be protected by emerging methods.9 Even at the current state of the fastimproving science of AF-ablation, it is clearly more effective and probably much safer than ICBM therapy for a significantly large proportion of AF sufferers. Continued improvements in the safety and effectiveness of ablation look assured and innovation in ICBM therapy has ceased.

Conclusion Over recent years, evidence has mounted indicating that anti-arrhythmic agents tend to increase the risk of sudden death. The only apparent exception to this trend is amiodarone which has many other risks that make it unsuitable for long-term use. Although these drugs may provide short term relief of symptoms in patients who are well screened for risk factors for sudden death and are maintained under careful surveillance for the emergence of new risk factors, they are no longer suitable for widespread first-line use as a long-term therapeutic strategy.

Over recent years, evidence has mounted indicating that antiarrhythmic agents tend to increase the risk of sudden death

References Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham

Study. Stroke. 1991;22:983–988. Vaughan Williams, EM (1970) Classification of antiarrhythmic drugs. In Symposium on Cardiac Arrhythmias

(Eds. Sandoe E, Flensted- Jensen E, Olsen KH). Astra, Elsinore. Denmark (1970) The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and

flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321:406-412. Wehling M. Meta-analysis of flecainide safety in patients with supraventricular arrhythmias.

Arzneimittelforschung 2002;52:507–14 Lafuente-Lafuente C, Valembois L, Bergmann JF, Belmin J. Antiarrhythmics for maintaining sinus rhythm after

cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2015; 3:CD005049. Julian DG, Camm AJ, Frangin G, et al. Randomized trial of effect of amiodarone on mortality in patients with

left-ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet 1997; 349:667–73. Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, Kim YH, Klein G, Packer D, Skanes A.

Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation. 2005; 111:1100-5. Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, Noseworthy PA, Rosenberg YD, Jeffries

N, Mitchell LB, Flaker GC, Pokushalov E, Romanov A, Bunch TJ, Noelker G, Ardashev A, Revishvili A, Wilber DJ, Cappato R, Kuck KH, Hindricks G, Davies DW, Kowey PR, Naccarelli GV, Reiffel JA, Piccini JP, Silverstein AP, Al-Khalidi HR, Lee KL; CABANA Investigators. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321:1261-1274. Leung LMW, Bajpai A, Li A, Zuberi Z, Norman M, Sohal M, Louis-Auguste J, Hayat J, Gallagher MM. IMPACT

trial. Improving Oesophageal Protection for Catheter Ablation of AF. The IMPACT Randomized Controlled Trial. In: Heart Rhythm Congress (HRC) Oral Abstract Presentation; 07.10.2019; Birmingham, UK.

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How Cardiac Ablation Can Offer a Safe and Efficacious Alternative to Anti-Arrhythmic Drug Therapies Evidence to support the implementation of AF ablation therapy Dr. Adam S. C. Dennis, Ross J. Hunter MRCP PhD FESC St. Bartholomewâ&#x20AC;&#x2122;s Hospital, Barts Health NHS Trust, West Smithfield, London, United Kingdom

Introduction

Today, AFA has an established role in AF management within international clinical guidance

This article reviews the role that atrial fibrillation ablation (AFA) fills within the current management of atrial fibrillation (AF), as an alternative to antiarrhythmic drugs (AADs) and its developing role for specific patient sub-groups. The optimal management of AF remains a major challenge in 21st century cardiology. It requires integrated management between healthcare providers, patient education and shared decision making1,2. AF is the most common sustained cardiac arrhythmia. An estimated 33 million individuals with AF based on data from 20103.This is predicted to increase over coming decades4. From middle age onwards, the lifetime risk of developing AF in individuals of European heritage is approximately 25%5. AF is associated with increased all-cause mortality, an increase in cardiovascular mortality and rises in cardiovascular co-morbidities such as heart failure and stroke6,7. The management of AF represents a significant economic burden, with historic data from the UK estimating the direct costs as approximately 1% of National Health Service (NHS) spending between 1995 and 2000. Over recent decades our understanding of8 the mechanisms of AF has progressed9,10. Nevertheless, ablation strategies are focused on pulmonary vein isolation (PVI) at present. Technological advances in PVI methods include radiofrequency (RF) ablation with contact force sensing catheters using weighted formulae such as ablation index to determine ablation output and cryoballoon catheters10 - 13.

The Current Guidelines Historically the cornerstones of AF management were anti-arrhythmic medication, and the assessment and consideration of treatment with anti-coagulation therapies for reduction in stroke risk1,2,14,15. Today, AFA has an established role in AF management within international clinical guidance. 14 |WWW.HOSPITALREPORTS.EU

The current National Institute of Clinical Excellence (NICE) guidance in the United Kingdom, recommends AFA in paroxysmal AF where drug therapy has failed to control the symptoms of AF or is inappropriate, or in cases of heart failure presumed secondary to nonpermanent AF15. The European Society of Cardiology (ESC) and American College of Cardiology (ACC) reflect a similar approach, with a Class IA recommendation for AFA in paroxysmal AF patients with ongoing symptoms despite anti-arrhythmic therapy. In addition to this, as a Class IIa recommendation, AFA should be considered as a first line option on the basis of patient choice and the balance of benefit and risk1,2. A 2019 update from the American Heart Association (AHA) has now included the recommendation that AFA may be considered in symptomatic patients with AF and heart failure with reduced left ventricular systolic function as a Class IIb recommendation16.

AF Ablation Versus Pharmacologic Interventions After Drug Failure The greatest strength of evidence supports the use of AFA following the failure of anti-arrhythmic medications, typically Class I or Class III anti-arrhythmic drugs1,2. Randomised controlled trials (RCTs) have demonstrated the superiority of AFA in paroxysmal AF resistant to at least one AAD, including the A4 study17 and the STOP AF trial18. Data from a meta-analysis by Calkins et al., of RF AFA versus AADs, supported improved outcomes in AFA with a multiple procedure success rate off AADS of 71%, compared to 52% in the AAD group. Lower complication rates following AFA were also reported, 5% compared to 30% with AADs, although the complications were of greater severity with ablation19. The ESC AF guidance describes a potentially

IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

life-threatening complication rate of 2 - 3%1. Additionally, although the recent CABANA trial yielded disappointing results for the primary outcome, it did reconfirm the relative safety of AFA with a 0.8% incidence of cardiac tamponade in over 1000 patients20. Trials looking specifically at persistent AF, have demonstrated that AFA can have better outcomes compared to AADs. Oral et al., randomised 146 patients to PVI versus amiodarone and cardioversion, with higher rates of sinus rhythm in the ablation group, although this trial was limited by a high cross-over rate (77%)21. The SARA study compared AFA versus AADs in 146 patients and demonstrated that ablation was superior to medical therapy in maintaining sinus rhythm at 12 months follow up22. Although not blinded, the CAPTAF trial suggests that ablation may also offer an advantage in quality of life over AADs at 12 months23. In addition to patient outcomes, there is an economic consideration to all medical interventions. BrĂźggenjĂźrgen et al. reviewed 19 cost-effectiveness studies and six cost studies, and suggested ablation as a more cost-effective treatment over the medium to long term (3.2 63.9 years). Both ablation and rate control methods were more cost-effective than rhythm control with medication and cardioversion24. Retrospective data in a relatively small number of paroxysmal AF patients undergoing AFA (n=118), suggests that although ablation has a higher initial cost, this drops below the ongoing costs of AADs after 5 years, suggesting it is a cost-effective long term strategy25. Data from 1,556 Canadian patients shows that patients significantly reduce health care resource usage in the 24 months following ablation, compared to the 12 months pre-ablation, although there was no AAD control arm in this study26.

AF Ablation Versus Drugs as a First Line Treatment There is growing evidence to consider AFA as a first line therapy. The MANTRA-PAF trial randomised 294 patients into a RF AFA strategy, versus standard AAD therapy, with primary end points including burden of AF at 24 months, freedom from AF and symptoms from AF. The primary endpoints favoured AFA, however this was balanced against the procedural complications from AFA27. Further RCT data from the RAAFT-2 trial, which randomised 127 treatment-naive paroxysmal AF patients into RF AFA versus AAD arms, also favoured ablation in the primary outcome of recurrence of atrial arrhythmia, although recurrence was frequent in both groups. There were no deaths or strokes reported in either arm over a follow up of 24 months. However, there were 4 cases of cardiac

tamponade observed within the 66 patients in the ablation arm28. The recently presented ATTEST trial reported that early AFA treatment in paroxysmal AF cases may decrease progression to persistent AF by up to 10-times when compared with AAD treatment with a concomitant reduction in the rate of recurrent arrhythmic episodes29. In addition to these studies, there are select subgroups of patients, where the use of early AFA may be considered.

Athletes The management of AF in elite athletes presents an interesting challenge, as AADs may have a negative impact on high-level performance and many are prohibited substances in competitive sport30. The ESC and AHA guidance both recommend consideration of AFA to prevent recurrence of AF (IIa)1,2, and outcomes from AFA in athletes have been found to be comparable to non-athletes31.

Tachycardia-Bradycardia Syndrome The tachycardia-bradycardia syndrome has smaller studies that support the use of AFA versus AAD and pacemaker (PM) implantation. Retrospective data from Chen et al. showed that patients with paroxysmal AF and symptomatic sinus pauses on termination of AF, had higher rates of sinus rhythm, lower rates of tachycardia admissions and fewer AADs versus PM implant following AFA32. Consideration of AFA as an alternative to PM implantation is a Class IIa recommendation in European and US guidance 1,2, 33, 34.

There is growing evidence to consider AFA as a first line therapy

Heart Failure Ablation in patients with AF and left ventricular (LV) systolic failure has mounting evidence to support improvements in quality of life (QOL), symptoms, LV function and mortality, as well as reducing hospitalisations10,35-40. The 2016 European guidance advises a Class IIa recommendation to improve symptoms and cardiac function when tachycardiomyopathy is suspected1. The US guidance has recently added a IIb recommendation in 2019, to consider offering AFA in this patient cohort due to the potential for impact on mortality and hospital admissions16. The AATAC Trial studied ablation versus amiodarone in persistent AF and reduced LV function in more than 200 patients, and demonstrated superiority of ablation in freedom from AF, hospitalisations and mortality36. In ablation (n=179) versus rate control (n=184), the CASTLE-AF trial demonstrated a significant reduction in the composite primary endpoint of all-cause mortality and HF admissions, over a median WWW.HOSPITALREPORTS.EU| 15

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follow up of over 3 years37. Although in ssmaller numbers, the CAMTAF trial (n=26 versus n=24) and CAMERA-MRI (n=33 versus n=33) demonstrated an improvement in LV function38,39.

Conclusion Over recent decades there has been a growing body of evidence to support AF ablation as a safe and effective treatment in the management of AF. There is also now evidence to support offering ablation as a first line therapy, particularly in select patient sub-groups. Future research in these areas will allow cardiologists to provide a more tailored management strategy, with better informed shared decision making between patients and healthcare professionals.

References Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS, Eur Heart J 2016; 37 (38): 2893–2962 2. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland Jr JC, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64(21):e1–76. 3. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014;129:837–847. 4. Krijthe BP, Kunst A, Benjamin EJ, Lip GY, Franco OH, Hofman A, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J 2013;34: 2746 – 2751. 5. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110:1042–6. 6. Odutayo A, Wong C, Hsiao A, Hopewell S, Altman DG, Emdin CA A et al. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis BMJ 2016; 354:i4482 7. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946 – 952. 8. Stewart S, Murphy N, Walker A, McGuire A, McMurray JJV. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90: 286 – 292. 9. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339: 659 – 666. 10. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/ EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Heart Rhythm 2012;9:632–96. 11. Kuck KH, Brugada J, Fürnkranz A, Metzner A, Ouyang F, Chun KR, et al. FIRE AND ICE Investigators. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med. 2016 Jun 9;374(23):2235-45. 12. Jourda F, Providencia R, Marijon E, Bouzeman A, Hireche H, Khoueiry Z, Cardin C, et al. Contact-force guided radiofrequency vs. second-generation balloon cryotherapy for pulmonary vein isolation in patients with paroxysmal atrial fibrillation—a prospective evaluation, EP Europace 2015, 17(2): 225–231. 13. Dhillon G, Ahsan S, Honarbakhsh S, Lim W, Baca M, Graham A, Srinivasan N, Sawhney V, Sporton S, Schilling RJ, Chow A, Ginks M, Sohal M, Gallagher MM, Hunter RJ. New A multicentered evaluation of ablation at higher power guided by ablation index: Establishing ablation targets for pulmonary vein isolation. J Cardiovasc Electrophysiol. 2019 Mar;30(3):357-365. 14. National Institute for Health and Care Excellence, Quality Standard 93. Atrial fibrillation. Published: 9 July 2015. https://www.nice.org.uk/guidance/qs93 [accessed 5/10/19]. 15. National Institute for Health and Care Excellence, Clinical Guideline 180. Atrial fibrillation: management. Published: 18 June 2014. https://www.nice.org.uk/guidance/cg180 [accessed 5/10/19]. 16. January CT, L. Wann S, Calkins H, Chen LY, Cigarroa JE, Cleveland Jr JC, Patrick T. Ellinor PT, et al. 2019 AHA/ ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation. 2019;140:e125–e151. 17. Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation 2008;118:2498–505. 1.

Future research in these areas will allow cardiologists to provide a more tailored management strategy, with better informed shared decision making between patients and healthcare professionals

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Packer DL, Kowal RC, Wheelan KR, Irwin JM, Champagne J, Guerra PG et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol 2013;61(16):1713–23..

18.

Calkins H, Reynolds MR, Spector P, Sondhi M, Xu Y, Martin A et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and meta-analyses. Circ Arrhythm Electrophysiol 2009;2(4):349–61.

19.

Packer DL, Mark DB, Robb RA, et al. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients with Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA. 2019. 321(13):1261–1274.

20.

Oral H, Pappone C, Chugh A, Good E, Bogun F, Pelosi F Jr, et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med. 2006 Mar 2;354(9):934-41.

21.

Mont L, Bisbal F, Hernandez-Madrid A, Perez-Castellano N, Vinolas X, Arenal A, et al. SARA investigators. Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study). Eur Heart J 2014;35: 501 – 507.

22.

Blomström-Lundqvist C, Gizurarson S, Schwieler J, et al. Effect of Catheter Ablation vs Antiarrhythmic Medication on Quality of Life in Patients With Atrial Fibrillation: The CAPTAF Randomized Clinical Trial. JAMA. 2019;321(11):1059–1068

23.

Brüggenjürgen B., Kohler S., Ezzat N. et al. Cost effectiveness of anti-arrhythmic medications in patients suffering from atrial fibrillation. PharmacoEconomics 2013. 31: 195.

24.

Weerasooriya R, Jais P, Heuzy JL, Scavee C, Choi K, Macle L, et al. Cost Analysis of Catheter Ablation for Paroxysmal Atrial Fibrillation. Pacing and Clinical Electrophysiology 2003, 26: 292-294.

25.

Samuel, M, Avgil Tsadok, M, Joza, J, et al. Catheter ablation for the treatment of atrial fibrillation is associated with a reduction in health care resource utilization. J Cardiovasc Electrophysiol. 2017; 28: 733– 741.

26.

Cosedis Nielsen J, Johannessen A, Raatikainen P, Hindricks G, Walfridsson W, Kongstad O, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med 2012;367(17):1587–95.

27.

Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency Ablation vs Antiarrhythmic Drugs as First-Line Treatment of Paroxysmal Atrial Fibrillation (RAAFT-2): A Randomized Trial. JAMA. 2014;311(7):692–700.

28.

Kuck KH, Dimitry Lebedev D, Mikhaylov E, Romanov A, Gellér L, Kalejs O, et al. Catheter Ablation Can Delay Progression From Paroxysmal to Persistent Atrial Fibrillation. ESC Late-breaking Science, August 2019. Paris, France.

29.

World Anti-Doping Agency Website “https://www.wada-ama.org/en/content/what-is-prohibited” [Accessed 5th October 2019]

30.

Calvo N, Mont L, Tamborero D, Berruezo A, Viola G, Guasch E, Nadal M, et al. Efficacy of circumferential pulmonary vein ablation of atrial fibrillation in endurance athletes. Europace 2010;12:30–36.

31.

Chen Y, Bai R, Lin T, Salim M, Sang C, Long D, Yu R, et al. Pacing or Ablation: Which Is Better for Paroxysmal Atrial Fibrillation-Related Tachycardia-Bradycardia Syndrome? Pacing and Clinical Electrophysiology 2014, 37: 403-411.

32.

Inada K, Yamane T, Tokutake K, Yokoyama K, Mishima T, Hioki M, et al. The role of successful catheter ablation in patients with paroxysmal atrial fibrillation and prolonged sinus pauses: outcome during a 5- year follow-up. Europace 2014;16(2):208–13.

33.

Khaykin Y, Marrouche NF, Martin DO, Saliba W, Schweikert R, Wexman M, et al. Pulmonary vein isolation for atrial fibrillation in patients with symptomatic sinus bradycardia or pauses. J Cardiovasc Electrophysiol 2004;15:784–789.

34.

Al Halabi S, Qintar M, Hussein A, Alraies MC, Jones DG, Wong T, et al. Catheter Ablation for Atrial Fibrillation in Heart Failure Patients: A Meta-Analysis of Randomized Controlled Trials. JACC Clin Electrophysiol. 2015 Jun 1;1(3):200-209.

35.

Di Biase L, Mohanty P, Mohanty S, et al. Ablation versus amiodarone for treatment of persistent atrial brillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter randomized trial. Circulation. 2016;133: 1637–44.

36.

Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L et al. Catheter ablation for atrial brillation with heart failure. N Engl J Med. 2018;378: 417–27.

37.

Hunter RJ, Berriman TJ, Diab I, Kamdar R, Richmond L, Baker V. et al. A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial). Circ Arrhythm Electrophysiol 2014;7(1):31–8.

38.

Prabhu S, Taylor AJ, Costello BT, Kaye DM, McLellan AJA, Voskoboinik A et al. Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction: the CAMERA-MRI Study. J Am Coll Cardiol. 2017;70:1949–61.

39.

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New Approaches to Managing Atrial Fibrillation and Other Complex Arrhythmias Sabine Ernst MD PhD FESC Royal Brompton & Harefield NHS Foundation Trust, London, UK and National Heart and Lung Institute, Imperial College of London, United Kingdom

Introduction

With the introduction of contact force (CF) measurements combined with “smart” tags, the operator can obtain feedback on the deployed ablation energy over time

Catheter ablation of atrial fibrillation (AF) has developed into a routine clinical procedure and is a valuable alternative to antiarrhythmic medication to many patients1-4. The most current guidelines recommend considering ablation following antiarrhythmic medication failure in a given patient as a class 1 recommendation5. In selected patients, catheter ablation can be considered as a first line therapy6,7.

Importance of Pulmonary Vein Isolation Over the last 15 years the basic ablation strategy has essentially remained the same: isolation of the “ipsilateral” right and left pulmonary veins (PV) by a long linear lesion is the recommended procedure for all patients with paroxysmal AF8. The endpoint of complete electrical isolation with evidence of entry (and if possible, exit block) is important. Only a complete electrical isolation line can prevent re-initiation of AF upon the PVs trigger. Previously, the simple deployment of radiofrequency (RF) applications around the PVs to perform a “wide area circumferential ablation” (WACA) was widespread. This approach did not include an endpoint of PV

FIGURE 1

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potentials elimination and it was easy to “collect” enough ablation tags along any intended ablation line9,10. To demonstrate the electrical endpoint of PV isolation, two catheters need to enter the left atrium in a transseptal fashion. Initially, a normal “straight” multipolar catheter was positioned in the ipsilateral PV, whilst the ablation catheter was moved along the indented ablation line8. Subsequently, the double lasso technique was introduced (which required triple transseptal access), with two circumferential mapping (or “Lasso”) catheters in the ipsilateral PVs11. The simultaneous information from both PVs validated the effect of the isolating ablation line. When the last gap was closed, the PV potentials on all Lasso electrodes disappeared simultaneously. On occasion, this would result in AF continuing within the isolated PV segment whilst the rest of the atria converted into sinus rhythm (SR) (Figure 1). Using two Lasso catheters also identified conduction gaps along the ablation line indicated by the earliest activated Lasso electrodes12. Today, many operators use a double transseptal approach with a single Lasso catheter which is moved between PVs to demonstrate complete electrical isolation.

IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

FIGURE 2

Alternate Ablation Energies for PV Isolation Over nearly two decades, various ablation energies have been evaluated for PV isolation13-15. Whilst irrigated tip RF ablation remains the standard of care, balloon-based ablation using cryothermia, laser or ultrasound energy have been introduced into clinical practice16-18. The risk of collateral damage to adjacent structures, such as phrenic nerve paralysis or extraoesophageal fistula formation, has been more evident. This may be due to deeper penetration of the ablation energy19,20.

Need for Direct Lesion Assessment The initial 3D mapping systems enabled identification of the RF ablation delivery sites by “tagging” with coloured 3D spheres ranging from 1- 4 mm. However, these ablation tags only documented the 3D location of the ablation catheter whilst RF energy was deployed. Feedback on the energy entering the tissue relative to the blood pool was not provided. With the introduction of contact force (CF) measurements combined with “smart” tags, the operator can obtain feedback on the deployed ablation energy over time21. Recently, the ablation index (AI) resulting from CF, stability and time has been evaluated in the CLOSE trial22. The recommendation is to minimise AI, to achieve a transmural lesion, and to maximise AI to avoid collateral damage. However, direct assessment of the ablation lesion has been only achieved in experimental settings. Ultrasound or optic coherence imaging detectors embedded in the tip of an ablation catheter have been recently proposed for this purpose23-25.

Remote Navigation Automation of the ablation procedure has been attempted by several robotic systems. While mechanical robotic systems are no longer in

clinical use, the remote magnetic navigation platform has demonstrated delivery of an ablation procedure to a standard equal to that of manually performed operations26-28. Most recently, a novel mechanical robotic system using ultrasound for both 3D image acquisition and as the ablation energy source has been introduced. The system acts autonomously, with the operator designing the ablation line, but not interfering with the energy deployment29. Theoretically, autonomous ablation can also be performed with the magnetic ablation system, although no formal investigation has been conducted to date.

Ablation of Atrial Tachycardia Due to Failed AF Ablation Beyond the established PV isolation, further ablation strategies have been proposed. These consist of an additional linear lesion (for example, to form a “box lesion” around the posterior wall of the left atrium), ablation of complex fractionated atrial electrograms (CFAE), encircling of low voltage areas (the “substrate approach”) or guided by simultaneous mapping information of rotors or maintainers of sustained AF29-34. These approaches may result in incomplete lesions that do not anchor to non-conduction areas. In turn, this can lead to persistent atrial tachycardia, decompensation and heart failure due the partially fixed and rapid ventricular activation35,36. Multipolar imaging using small electrodes mounted on steerable mapping catheters allow for rapid and detailed 3D mapping of these iatrogenic arrhythmias. Improvements to auto-annotation and 3D visualisation of functional and de facto conduction blocks have increased the resolution of local activation, facilitatating the detection of conduction gaps (Figure 2). Bidirectional block criteria should be applied for all linear lesions and non-inducibility of further arrhythmia should be the endpoint of these repeat procedures8,37,38.

The inability to visualize and assess lesions as they are generated and the uncertainty surrounding the longevity of applied ablation designs, remain the greatest challenges in AF ablation strategies

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AF Ablation in Patients with Complex Congenital Heart Disease A growing number of patients with congenital heart disease are presenting with sustained atrial fibrillation episodes39. This can be a consequence of the underlying congenital defect or the result of additional factors such as hypertension, obesity or sleep apnoea. However, catheter ablation of AF in this patient subset has not been reported in larger cohorts. Recently, two groups have presented results demonstrating that outcomes are dependent on the complexity of the underlying congenital defect, the type of AF and the size the atria40,41. A patient with a simple congenital defect, such as an atrial septal defect and paroxysmal AF, can expect a similar result from AF ablation compared with a non-congenital patient. In contrast, patients with complex congenital lesions, atrial dilatation and persistent AF, require multiple ablation attempts and overall success is low.

Summary and Outlook for Future AF Ablation Strategies The inability to visualize and assess lesions as they are generated and the uncertainty surrounding the longevity of applied ablation designs, remain the greatest challenges in AF ablation strategies. As the operator cannot be certain that an acutely achieved lesion set is permanent, the source of AF recurrence is unclear. Recurrence could be the result of an incompletely achieved but, in principle, correct ablation strategy, or a failure of a complete ablation strategy. Additional individual a priori data from imaging modalities such as magnetic resonance imaging (MRI), CT or nuclear imaging may help to identify patients who will benefit most from an ablation procedure.

References Asad ZUA, Yousif A, Khan MS, Al-Khatib SM, Stavrakis S. Catheter Ablation Versus Medical Therapy for Atrial Fibrillation. Circ Arrhythm Electrophysiol 2019;12:e007414.

Clarnette JA, Brooks AG, Mahajan R, et al. Outcomes of persistent and long-standing persistent atrial fibrillation ablation: a systematic review and meta-analysis. Europace 2018;20:f366-f76.

Khan SU, Rahman H, Talluri S, Kaluski E. The Clinical Benefits and Mortality Reduction Associated With Catheter Ablation in Subjects With Atrial Fibrillation: A Systematic Review and Meta-Analysis. JACC Clin Electrophysiol 2018;4:626-35.

iu W, Wu Q, Yang XJ, Huang J. The trend of change in catheter ablation versus antiarrhythmic drugs for the L management of atrial fibrillation over time: a meta-analysis and meta-regression. J Geriatr Cardiol 2018;15:441-50.

Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016;18:1609-78.

Andrade JG, Champagne J, Deyell MW, et al. A randomized clinical trial of early invasive intervention for atrial fibrillation (EARLY-AF) - methods and rationale. Am Heart J 2018;206:94-104.

Giehm-Reese M, Kronborg MB, Lukac P, et al. Recurrent atrial flutter ablation and incidence of atrial fibrillation ablation after first-time ablation for typical atrial flutter: A nation-wide Danish cohort study. Int J Cardiol 2019.

Ernst S, Ouyang F, Lober F, Antz M, Kuck KH. Catheter-induced linear lesions in the left atrium in patients with atrial fibrillation: an electroanatomic study. J Am Coll Cardiol 2003;42:1271-82.

Pappone C, Rosanio S, Oreto G, et al. Circumferential radiofrequency ablation of pulmonary vein ostia: A new anatomic approach for curing atrial fibrillation. Circulation 2000;102:2619-28.

Pappone C, Oreto G, Lamberti F, et al. Catheter ablation of paroxysmal atrial fibrillation using a 3D mapping system. Circulation 1999;100:1203-8.

10.

Ouyang F, Bansch D, Ernst S, et al. Complete isolation of left atrium surrounding the pulmonary veins: new insights from the double-Lasso technique in paroxysmal atrial fibrillation. Circulation 2004;110:2090-6.

11.

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;111:127-35.

12.

Reddy VY, Neuzil P, Themistoclakis S, et al. Visually-guided balloon catheter ablation of atrial fibrillation: experimental feasibility and first-in-human multicenter clinical outcome. Circulation 2009;120:12-20.

13.

Lesh MD, Diederich C, Guerra PG, Goseki Y, Sparks PB. An anatomic approach to prevention of atrial fibrillation: pulmonary vein isolation with through-the-balloon ultrasound ablation (TTB-USA). Thorac Cardiovasc Surg 1999;47 Suppl 3:347-51.

14.

Chun KR, Schmidt B, Metzner A, et al. The â&#x20AC;&#x2DC;single big cryoballoonâ&#x20AC;&#x2122; technique for acute pulmonary vein isolation in patients with paroxysmal atrial fibrillation: a prospective observational single centre study. Eur Heart J 2009;30:699-709.

15.

Nagase T, Bordignon S, Perrotta L, et al. Analysis of procedural data of pulmonary vein isolation for atrial fibrillation with the second-generation laser balloon. Pacing Clin Electrophysiol 2019;42:837-45.

16.

Kottkamp H, Hindricks G, Ponisch C, et al. Global multielectrode contact-mapping plus ablation with a single catheter in patients with atrial fibrillation: Global AF study. J Cardiovasc Electrophysiol 2019.

17.

Van Belle Y, Janse P, Rivero-Ayerza MJ, et al. Pulmonary vein isolation using an occluding cryoballoon for circumferential ablation: feasibility, complications, and short-term outcome. Eur Heart J 2007;28:2231-7.

18.

Sacher F, Jais P, Stephenson K, et al. Phrenic nerve injury after catheter ablation of atrial fibrillation. Indian Pacing Electrophysiol J 2007;7:1-6.

19.

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IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

Kuck KH, Brugada J, Furnkranz A, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med 2016;374:2235-45.

20.

Pranata R, Vania R, Huang I. Ablation-index guided versus conventional contact-force guided ablation in pulmonary vein isolation - Systematic review and meta-analysis. Indian Pacing Electrophysiol J 2019;19:155-60.

21.

Taghji P, El Haddad M, Phlips T, et al. Evaluation of a Strategy Aiming to Enclose the Pulmonary Veins With Contiguous and Optimized Radiofrequency Lesions in Paroxysmal Atrial Fibrillation: A Pilot Study. JACC Clin Electrophysiol 2018;4:99-108.

22.

Haines DE, Wright M, Harks E, et al. Near-Field Ultrasound Imaging During Radiofrequency Catheter Ablation: Tissue Thickness and Epicardial Wall Visualization and Assessment of Radiofrequency Ablation Lesion Formation and Depth. Circ Arrhythm Electrophysiol 2017;10.

23.

Yu X, Singh-Moon RP, Hendon CP. Real-time assessment of catheter contact and orientation using an integrated optical coherence tomography cardiac ablation catheter. Appl Opt 2019;58:3823-9.

24.

Liang D, Taeschler D, Goepfert C, et al. Radiofrequency ablation lesion assessment using optical coherence tomography - a proof-of-concept study. J Cardiovasc Electrophysiol 2019;30:934-40.

25.

Virk SA, Kumar S. Remote Magnetic Versus Manual Catheter Navigation for Atrial Fibrillation Ablation: A MetaAnalysis. Circ Arrhythm Electrophysiol 2019;12:e007517.

26.

Rillig A, Schmidt B, Di Biase L, et al. Manual Versus Robotic Catheter Ablation for the Treatment of Atrial Fibrillation: The Man and Machine Trial. JACC Clin Electrophysiol 2017;3:875-83.

27.

Steven D, Servatius H, Rostock T, et al. Reduced fluoroscopy during atrial fibrillation ablation: benefits of robotic guided navigation. J Cardiovasc Electrophysiol 2010;21:6-12.

28.

Chen YH, Lin H, Wang Q, Hou JW, Li YG. Efficacy and Safety of Adjunctive Substrate Modification During Pulmonary Vein Isolation for Atrial Fibrillation: A Meta-Analysis. Heart Lung Circ 2019.

29.

Fink T, Schluter M, Heeger CH, et al. Stand-Alone Pulmonary Vein Isolation Versus Pulmonary Vein Isolation With Additional Substrate Modification as Index Ablation Procedures in Patients With Persistent and LongStanding Persistent Atrial Fibrillation: The Randomized Alster-Lost-AF Trial (Ablation at St. Georg Hospital for Long-Standing Persistent Atrial Fibrillation). Circ Arrhythm Electrophysiol 2017;10.

30.

Kottkamp H, Berg J, Bender R, Rieger A, Schreiber D. Box Isolation of Fibrotic Areas (BIFA): A Patient-Tailored Substrate Modification Approach for Ablation of Atrial Fibrillation. J Cardiovasc Electrophysiol 2016;27:22-30.

31.

Lee KN, Choi JI, Kim YG, et al. Comparison between linear and focal ablation of complex fractionated atrial electrograms in patients with non-paroxysmal atrial fibrillation: a prospective randomized trial. Europace 2019;21:598-606.

32.

Knecht S, Sohal M, Deisenhofer I, et al. Multicentre evaluation of non-invasive biatrial mapping for persistent atrial fibrillation ablation: the AFACART study. Europace 2017;19:1302-9.

33.

Grace A, Willems S, Meyer C, et al. High-resolution noncontact charge-density mapping of endocardial activation. JCI Insight 2019;4.

34.

Heck PM, Rosso R, Kistler PM. The challenging face of focal atrial tachycardia in the post AF ablation era. J Cardiovasc Electrophysiol 2011;22:832-8.

35.

Takigawa M, Derval N, Maury P, et al. Comprehensive Multicenter Study of the Common Isthmus in Post-Atrial Fibrillation Ablation Multiple-Loop Atrial Tachycardia. Circ Arrhythm Electrophysiol 2018;11:e006019.

36.

Ernst S, Ouyang F, Clausen C, et al. A model for in vivo validation of linear lesions in the right atrium. J Interv Card Electrophysiol 2003;9:259-68.

37.

Maurer T, Metzner A, Ho SY, et al. Catheter Ablation of the Superolateral Mitral Isthmus Line: A Novel Approach to Reduce the Need for Epicardial Ablation. Circ Arrhythm Electrophysiol 2017;10.

38.

Labombarda F, Hamilton R, Shohoudi A, et al. Increasing Prevalence of Atrial Fibrillation and Permanent Atrial Arrhythmias in Congenital Heart Disease. J Am Coll Cardiol 2017;70:857-65.

39.

Guarguagli S, Kempny A, Cazzoli I, et al. Efficacy of catheter ablation for atrial fibrillation in patients with congenital heart disease. Europace 2019;21:1334-44.

40.

Sohns C, Nurnberg JH, Hebe J, et al. Catheter Ablation for Atrial Fibrillation in Adults With Congenital Heart Disease: Lessons Learned From More Than 10 Years Following a Sequential Ablation Approach. JACC Clin Electrophysiol 2018;4:733-43.

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Technological Innovations to Improve the Safety, Efficacy and Efficiency of Radiofrequency Catheter Ablation in Atrial Fibrillation (AF) Advances in catheter ablation have enabled this procedure to become an established strategy in the management of AF Graca Costa; Laura Goldstein; Maria Velleca; Tom Wei Biosense Webster, Inc., Brussels, Belgium

Background

20%-30% OF ALL STROKES OCCUR IN AF PATIENTS3; 31

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Atrial fibrillation (AF) is the most common cardiac arrhythmia1 and is associated with a 2.4-times increase in the risk of stroke. This elevated risk of stroke is illuminated by the fact that up to 30% of all strokes can be attributed to a diagnosis of AF2. AF is also an independent risk factor for mortality3 and is associated with increased renal morbidity and cognitive impairment in elderly patients1,4. Currently, over 1 million people suffer from AF in each of France, Germany, Italy and the United Kingdom5. By 2050, Europe is expected to have the highest prevalence of AF when compared to other regions6. AF is also associated with poor quality of life (QOL), functional impairment and high healthcare resource utilization7. AF accounts for 0.28% to 2.6% of total healthcare expenditure in Europe8, and its annual cost is between e0.6 to e3.3 billion in each of France, Germany, Italy and the United Kingdom 9. These healthcare costs are primarily driven by AF- related morbidity and AF-related treatment costs1. It is projected that the burden of AF on healthcare systems and society will increase dramatically in response to Europeâ&#x20AC;&#x2122;s rapidly aging population10. Anti-arrhythmic drug (AAD) therapy is used for the management of paroxysmal and persistent AF and is currently considered to be the standard of care11. However, evidence has shown that AAD therapy is not effective in many patients and it is associated with high rates of adverse events and arrhythmia recurrence12-17. Only 33%-56% of patients achieve normal sinus rhythm with AAD use after one year18 and 12%-19% withdraw from AAD therapy due to adverse events19. Non-pharmacological approaches such as surgery, direct current cardioversion and implantable cardioverter defibrillators (ICD) have

historically been used to manage AF. However, since its advent in the 1990s20, radiofrequency (RF) catheter ablation has become one of the most commonly used non-pharmacological treatment options21. RF catheter ablation was initially used for the management of supraventricular tachycardias20. An important study by HaĂŻssaguerre et al. in 1998 paved the way for pulmonary vein isolation (PVI) through catheter ablation as an efficacious treatment option for AF22. The technology used for RF ablation procedures is continuously evolving and its application in AF has broadened to include ablation of non-pulmonary vein triggers and modification of the left atrial (LA) substrate22.

Advantages of Catheter Ablation Compared with Alternative Treatment Options Efficacy of Catheter Ablation Several randomised controlled trials (RCTs) have demonstrated the superiority of catheter ablation (CA) as compared to AADs in achieving freedom from AF23-32. A meta-analysis by Chen et al. reported that ablation was associated with significantly greater odds of freedom from AF recurrence (OR: 9.41, 95% CI: 5.0017.71) compared to AADs. Another metaanalysis found a 60% reduction in the risk of atrial tachyarrhythmia recurrence with CA, as compared to pharmacotherapy (RR: 0.40, 95% CI: 0.31-0.52)33. The Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial, a large multicenter, prospective randomised study of 2,204 AF patients, showed that compared to drug therapy, CA reduced the risk of arrhythmia recurrence by 48% over a 4-year follow-up period and

IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

reduced the risk of death or CV hospitalization by 17% over 5 years34. In a database analysis with over 7-year follow-up data, Noseworthy et al. found that ablation was associated with a 25% reduction in the risk of a composite endpoint of death, stroke, serious bleeding, and cardiac arrest when compared to AAD treatment. When examining individual outcomes, catheter ablation was associated with a 33% reduction in death, 41% reduction in stroke and 46% reduction in cardiac arrest compared to AADs35. Other metaanalyses and systematic reviews have also corroborated these findings36-39. Bunch et al. reported that at 3 year follow-up, patients with AF who had been treated with CA had similar health-related events as those who did not have AF (mortality (6% vs. 9%), stroke (2% vs. 2%) and dementia (0.2% vs. 0.5%)40. Additional evidence has documented the efficacy of CA in restoring sinus rhythm in AF patients with low left ventricular ejection fraction (LVEF), diabetes mellitus41, hypertrophic cardiomyopathy42, heart failure (HF)43-47 and left ventricular systolic dysfunction48. While CA has been shown to restore sinus rhythm and reduce recurrence, it has also been shown to slow the risk of disease progression. The recently presented ATTEST study showed that patients treated with catheter ablation (aged 67.8 ± 4.8 years) were almost 10-times less likely to develop persistent AF than patients on AADs at three years after study initiation23. Catheter Ablation as a First-line Treatment for AF Generally, CA is only recommended as a treatment option after failure or intolerance to initial AAD therapy. This is reflected in clinical practice guidelines and is often a requirement for inclusion in clinical trials33. Three randomized trials24,31,32 have shown that CA may be beneficial as a first-line treatment in select populations. A pooled estimate of these trials showed that CA was associated with a 24% lower risk of AF recurrence compared to AAD therapy (RR: 0.63, 95% CI: 0.44-0.92) in young patients with AF and no major comorbidities49. Another meta-analysis reported a 48% risk reduction of AF recurrence with CA compared with AAD as a first-line therapy (RR: 0.37, 95% CI: 0.29-0.48)33. First-line treatment of AF with CA was also estimated to be cost-effective for AF, with an incremental cost effectiveness ratio of e50,570 for each quality adjusted life year (QALY)50. Safety of Catheter Ablation The incidence of adverse events associated with ablation, including transient ischemic attack23, pericardial complications26, hemorrhage23,29 and death27,31, are lesser or comparable to that of AAD therapy. Meta-analyses that compared the safety of CA with AADs in AF patients

with HF reported a comparable rate of major complications 43. A few studies, however, have reported a higher incidence of major complications with CA. This may be attributed to procedure volume and clinician experience, as indicated by a national survey (2000-2010) that reported a higher incidence of complications with procedures performed at low-volume centers and performed by less experienced clinicians51. In addition, complication rates have decreased in recent studies. This is the combined result of the development of innovative, safer technologies, as well as improved operator skill and experience33. Improvement in Quality of Life (QOL) with Catheter Ablation The CABANA trial also demonstrated the effect of CA and AADs on QOL as measured by the Atrial Fibrillation Effect on Quality of Life (AFEQT) summary score (adjusted difference vs. AADs, 5.3 points, p < .001), the Mayo AF-Specific Symptom Inventory (MAFSI) frequency score (adjusted difference vs AAD, -1.7 points, p < .001) and the MAFSI severity score (adjusted difference, -1.5 points, p < .001), all favoring CA52. Four other studies have also found an improvement on both the physical and mental domains of the SF-36 in patients who had CA28-31. AF patients with heart failure have also shown improved QOL with CA47,53. Cost-effectiveness of Catheter Ablation Several studies conducted from the perspective of different healthcare systems have found that RF ablation is a cost-effective treatment COSTS for AF PROJECTING 53-55 10 YEARS AFTER . A French when compared to AADTO therapy cost-effectiveness study ABLATION* reported that although CA is associated with high up-front costs, it may be a cost saving alternative to long-term drug therapy in patients with symptomatic, drug refractory AF56. In a real-world, single-center study that compared the cost of treatment between RF ablation with drugs in patients with drug-refractory AF, RF ablation was associated with 35% lower costs over a time horizon of 10 years57.

PAROXYSMAL AF

PERSISTENT AF

Patients with paroxysmal AF are 10 TIMES LESS LIKELY TO PROGRESS TO PERSISTENT AF than those on AADs*59

€

PROJECTING COSTS TO 10 YEARS AFTER ABLATION*

€

catheter ablation was associated with a

35% SAVINGS

IN COSTS COMPARED TO DRUG THERAPY 66

Innovative Technologies That Have Improved Outcomes for AF Ablation Efficacy of Innovative Technologies The advent of technologies such as contactforce (CF) sensing catheters, advanced threedimensional (3D) mapping, and software modules, such as ablation index (AI) have helped to improve outcomes for AF ablation procedures. Prior to the invention of CF, physicians used indirect means to assess the force used at the catheter-myocardium interface, which were not

up to CATHETER ABLATION was also associated with

Death

46% Stroke

reductions in the probability of AF-RELATED complications**

Cardiac arrest

Cardiovascular hospitalization

compared to drug therapy over 7-years follow-up.

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always reliable. CF has been a very influential innovation, allowing direct measurement of realtime, intraprocedural contact data, which in turn has facilitated improved lesion transmurality58. Numerous prospective studies with the use of CF catheters59-68 have reported efficacy rates of more than 80%, for single-procedure, 12-month freedom from AF. In a recent meta-analysis, Macle et al.69 reported increased odds of freedom from atrial tachyarrhythmia (OR: 1.56; 95% CI: 1.09, 2.24) and reduced odds of PV reconnection (OR: 0.49, 95% CI: 0.29, 0.82) with CF catheters, when compared to non-CF RF catheters in IMPROVEMENT patients IN with AF. Taghji et al.68 demonstrated that the use of AI, 12-MONTH FREEDOM UP TO a novel ablation lesion quality marker module improves 12-month freedom from atrial arrhythmia WITH ABLATION INDEX by up to 32% compared to ablation without the 70,71 use of AI . Several recent studies have also reported very high rates (84% to 94%) of freedom from atrial arrhythmias at one year after a single IMPROVEMENT IN procedure with advanced catheter ablation 12-MONTH FREEDOM technology, such as CF and AI, in eligible patients with AF72-77.

32%

from atrial arrhythmias

from atrial arrhythmias WITH ABLATION INDEX

Safety of Innovative Technologies Retrospective observational studies78, prospective non-randomized studies79, prospective randomized studies80,81 and meta-analyses69,82,83 have reported lower or comparable complication rates with CF catheters, compared to non-CF catheters. Use of procedural innovations such as AI have also helped to lower complication rates 70,71 . Since ablation-related complications are associated with a cost burden, a potential reduction in the incidence of complications may also translate into reduced healthcare resource utilization84. CA may require high volumes of fluid to cool the area at electrode-tissue interface. However, UP TO 65% REDUCTION high fluid volumes may also increase the risk of fluidDOSE overload, heart failure, acute respiratory IN FLUOROSCOPY distress, hypoxia, pleural effusion and pulmonary edema85-88 leading to costly hospitalizations89. Catheters with innovative porous tips may help UP TO 65% REDUCTION to reduce fluid delivery. Chinitz et al. studied the IN FLUOROSCOPY DOSE impact of porous tip, CF catheters and found that they provide uniform cooling at half the flow rate of standard 6-hole irrigated catheters, lowering fluid delivery by 52.2% 110,111. This lowered fluid delivery may help to reduce fluid-related complications79,90. A retrospective analysis using the U.S. Premier Hospital Database found that porous-tip catheters significantly reduced allcause readmissions, cardiovascular-related readmissions and direct-current cardioversions by 55%, 55%, and 39%, respectively, when compared to conventional, irrigated catheters. These benefits were greater in AF patients with a high comorbidity burden, who were more susceptible to fluid overload91. 24 |WWW.HOSPITALREPORTS.EU

Efficiency of Innovative Technologies New technologies have enabled faster workflows and reduced total ablation and total procedure time. A series of prospective trials80,92,93 showed that CF catheters may reduce the time needed for PVI by up to 35% compared to non-CF catheters. Moreover, porous-tip catheters with CF sensing may further reduce procedure and ablation time by up to 19% and 14%, respectively79. Innovative ablation modules, such as AI, have also been reported to minimize procedure time60,70,94 by up to 36% with observational studies documenting a total procedure time of <2 hours95-98. Incorporating AI optimizes lesion creation during ablation, standardizes workflow, increases reproducibility and facilitates first-pass isolation, helping to improve procedure efficiency.68,70,71,95,96,99,100. Minimisation of Radiation Exposure with Innovative Technologies Advances in imaging technology have progressively helped to reduce fluoroscopy time and dose101105 by up to 82% and 65%, respectively102. Two retrospective and one prospective, nonrandomized studies comparing CF and nonCF catheters, reported up to 77% reduction in fluoroscopy time60,78,106 and up to 71% reduction in radiation dose60,78. The benefits of CF catheters were also reported in two meta-analyses69,82 and a real-world study107 where PVI was accomplished with <1 min of fluoroscopy exposure. Economic impact of innovative technologies Reduced likelihood of complications and procedural efficiency with innovative technology may potentially lead to cost savings as compared to procedures that use conventional ablation technology. In a cost minimization analysis108, due to reduced readmission rates, average per-patient savings on expected 1-year post ablation costs were significantly higher with CF catheters than with non-CF technology. In a metaanalysis, Zhou et. al82 demonstrated that use of CF catheters resulted in a 42% relative reduction in major complications per 100 events compared to non-CF catheters. Ablation technology has evolved rapidly over the decades and has allowed for superior efficacy, safety, efficiency, radiation reduction and economic benefit. Continuous advancements in technology will allow for more efficacious treatment of patients with advanced forms of AF, such as long-standing persistent patients and patients with multiple comorbid conditions.

Awareness and Education Public awareness of AF, its risk factors, symptoms and treatment options are critical for prompt diagnosis and treatment and reduction in the risk of AF related conditions, such as stroke.

IMPROVING THE EARLY DIAGNOSIS AND TREATMENT OF CARDIAC ARRHYTHMIAS

However, a large study across six continents documented that only 48% of the participants had heard of AF, 8-52% were aware of AF-related risk factors and 36-49% were familiar with the fact that AF can cause stroke109. In another study, about 45% patients and 57% physicians did not believe that AF was a life-threatening condition110. AF is known to be under-diagnosed and according to the European Society of Cardiology (ESC) guidelines for AF management, it is also undertreated1. Improved adherence to guidelines and awareness of treatment options may help to reduce AF-related disease burden. Campaigns that educate patients, such as the â&#x20AC;&#x2DC;Get Smart About AFIBTMâ&#x20AC;&#x2122; initiative are critical to increase awareness and knowledge of AF across the general public and with patients. These initiatives encourage earlier detection and diagnosis of AF and support earlier treatment and referral of AF by general practitioners and cardiologists.

Conclusion AF is a life-threatening disease that contributes to an increased risk of heart failure, stroke, and mortality and places a substantial burden on patients as well as society. AF ablation has been shown to provide superior outcomes in some patient populations, when compared to AADs. Technological advancements in AF ablation have effectively decreased the AF recurrence rate, procedure time, fluoroscopy time and helped to improve procedural safety. These improvements translate into a reduction in the patient and economic burden associated with AF. It is crucial to increase public awareness and standardize clinical practice to take advantage of these innovations and further reduce the burden of AF.

AF is a life-threatening disease that contributes to an increased risk of heart failure, stroke, References Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg. 2016;50(5):e1-e88. 2. Odutayo A, Wong CX, Hsiao AJ, Hopewell S, Altman DG, Emdin CA. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis. Bmj. 2016;354:i4482. 3. 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):2368-2377. 4. Lamassa M, Di Carlo A, Pracucci G, et al. Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project). Stroke. 2001;32(2):392-398. 5. Network GBoDC. Global Burden of Disease Study 2016 (GBD 2016) Results. In: Institute for Health Metrics and Evaluation (IHME) Seattle, United States; 2017. 6. Rahman F, Kwan GF, Benjamin EJ. Global epidemiology of atrial fibrillation. Nature Reviews Cardiology. 2014;11(11):639. 7. Goren A, Liu X, Gupta S, Simon TA, Phatak H. Quality of life, activity impairment, and healthcare resource utilization associated with atrial fibrillation in the US National Health and Wellness Survey. PLoS One. 2013;8(8):e71264. 8. European Society of Cardiology. Atrial fibrillation set to affect more than 14 million over-65s in the EU by 2060. 2019; https://www.escardio.org/The-ESC/Press-Office/Press-releases/Atrial-fibrillation-set-to-affect-more-than14-million-over-65s-in-the-EU-by-2060. Accessed September, 2019. 9. Cotte F-E, Chaize G, Gaudin A-F, Samson A, Vainchtock A, Fauchier L. Burden of stroke and other cardiovascular complications in patients with atrial fibrillation hospitalized in France. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2015;18(4):501-507. 10. Di Carlo A, Bellino L, Consoli D, et al. Prevalence of atrial fibrillation in the Italian elderly population and projections from 2020 to 2060 for Italy and the European Union: the FAI Project. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2019. 11. Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/ AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011;123(10):e269-367. 12. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. Journal of the American College of Cardiology. 2003;41(10):1690-1696. 13. Cheng X, Li X, He Y, et al. Catheter ablation versus anti-arrhythmic drug therapy for the management of a trial fibrillation: a meta-analysis. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing. 2014;41(3):267-272. 14. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation--Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356(9244):1789-1794. 15. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. The New England journal of medicine. 2008;358(25):2667-2677. 1.

and mortality and places a substantial burden on patients as well as society

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Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. The New England journal of medicine. 2002;347(23):1834-1840. 17. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. The New England journal of medicine. 2002;347(23):1825-1833. 18. Kuck K, Lebedev D, Mikaylov E, et al. Catheter ablation delays progression of atrial fibrillation from paroxysmal to persistent atrial fibrillation. ESC Late-breaking Science. 2019. 19. Blomström-Lundqvist C, Gizurarson S, Schwieler J, et al. Effect of catheter ablation vs antiarrhythmic medication on quality of life in patients with atrial fibrillation: the CAPTAF randomized clinical trial. Jama. 2019;321(11):1059-1068. 20. Shivkumar K. Catheter Ablation of Ventricular Arrhythmias. New England Journal of Medicine. 2019;380(16):1555-1564. 21. Joseph J, Rajappan K. Radiofrequency ablation of cardiac arrhythmias: past, present and future. QJM: An International Journal of Medicine. 2011;105(4):303-314. 22. Mahida S, Berte B, Yamashita S, et al. New Ablation Technologies and Techniques. Arrhythmia & electrophysiology review. 2014;3(2):107. 23. Krittayaphong R, Raungrattanaamporn O, Bhuripanyo K, et al. A randomized clinical trial of the efficacy of radiofrequency catheter ablation and amiodarone in the treatment of symptomatic atrial fibrillation. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2003;86 Suppl 1:S8-16. 24. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. Jama. 2005;293(21):2634-2640. 25. Oral H, Pappone C, Chugh A, et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. The New England journal of medicine. 2006;354(9):934-941. 26. Pappone C, Augello G, Sala S, et al. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study. Journal of the American College of Cardiology. 2006;48(11):2340-2347. 27. Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study). European heart journal. 2006;27(2):216-221. 28. Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation. 2008;118(24):2498-2505. 29. Forleo GB, Mantica M, De Luca L, et al. Catheter ablation of atrial fibrillation in patients with diabetes mellitus type 2: results from a randomized study comparing pulmonary vein isolation versus antiarrhythmic drug therapy. Journal of cardiovascular electrophysiology. 2009;20(1):22-28. 30. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. Jama. 2010;303(4):333-340. 31. Cosedis Nielsen J, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. The New England journal of medicine. 2012;367(17):1587-1595. 32. Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial. Jama. 2014;311(7):692-700. 33. Khan AR, Khan S, Sheikh MA, Khuder S, Grubb B, Moukarbel GV. Catheter ablation and antiarrhythmic drug therapy as first- or second-line therapy in the management of atrial fibrillation: systematic review and metaanalysis. Circulation Arrhythmia and electrophysiology. 2014;7(5):853-860. 34. Packer DL, Mark DB, Robb RA, et al. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. Jama. 2019;321(13):1261-1274. 35. Noseworthy PA, Gersh BJ, Kent DM, et al. Atrial fibrillation ablation in practice: assessing CABANA generalizability. European heart journal. 2019;40(16):1257-1264. 36. Gjesdal K, Vist GE, Bugge E, et al. Curative ablation for atrial fibrillation: a systematic review. Scandinavian cardiovascular journal : SCJ. 2008;42(1):3-8. 37. Noheria A, Kumar A, Wylie JV, Jr., Josephson ME. Catheter ablation vs antiarrhythmic drug therapy for atrial fibrillation: a systematic review. Archives of internal medicine. 2008;168(6):581-586. 38. Calkins H, Reynolds MR, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and meta-analyses. Circulation Arrhythmia and electrophysiology. 2009;2(4):349-361. 39. Bonanno C, Paccanaro M, La Vecchia L, Ometto R, Fontanelli A. Efficacy and safety of catheter ablation versus antiarrhythmic drugs for atrial fibrillation: a meta-analysis of randomized trials. Journal of cardiovascular medicine (Hagerstown, Md). 2010;11(6):408-418. 40. Bunch TJ, Crandall BG, Weiss JP, et al. Patients treated with catheter ablation for atrial fibrillation have longterm rates of death, stroke, and dementia similar to patients without atrial fibrillation. Journal of cardiovascular electrophysiology. 2011;22(8):839-845. 41. Anselmino M, Matta M, D’Ascenzo F, et al. Catheter ablation of atrial fibrillation in patients with diabetes mellitus: a systematic review and meta-analysis. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2015;17(10):1518-1525. 42. Ha HS, Wang N, Wong S, et al. Catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy patients: a systematic review. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing. 2015;44(2):161-170. 43. Briceno DF, Markman TM, Lupercio F, et al. Catheter ablation versus conventional treatment of atrial fibrillation in patients with heart failure with reduced ejection fraction: a systematic review and meta-analysis of randomized controlled trials. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing. 2018;53(1):19-29. 44. Elgendy AY, Mahmoud AN, Khan MS, et al. Meta-Analysis Comparing Catheter-Guided Ablation Versus Conventional Medical Therapy for Patients With Atrial Fibrillation and Heart Failure With Reduced Ejection Fraction. Am J Cardiol. 2018;122(5):806-813. 45. Kheiri B, Osman M, Abdalla A, et al. Catheter ablation of atrial fibrillation with heart failure: An updated metaanalysis of randomized trials. International journal of cardiology. 2018;269:170-173. 46. Smer A, Salih M, Darrat YH, et al. Meta-analysis of randomized controlled trials on atrial fibrillation ablation in patients with heart failure with reduced ejection fraction. Clinical cardiology. 2018;41(11):1430-1438. 47. Virk SA, Bennett RG, Chow C, et al. Catheter Ablation Versus Medical Therapy for Atrial Fibrillation in Patients With Heart Failure: A Meta-Analysis of Randomised Controlled Trials. Heart Lung Circ. 2019;28(5):707-718. 48. Anselmino M, Matta M, D’Ascenzo F, et al. Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: a systematic review and meta-analysis. Circulation Arrhythmia and electrophysiology. 2014;7(6):1011-1018. 16.

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Hakalahti A, Biancari F, Nielsen JC, Raatikainen MJ. Radiofrequency ablation vs. antiarrhythmic drug therapy as first line treatment of symptomatic atrial fibrillation: systematic review and meta-analysis. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2015;17(3):370-378. 50. Aronsson M, Walfridsson H, Janzon M, et al. The cost-effectiveness of radiofrequency catheter ablation as first-line treatment for paroxysmal atrial fibrillation: results from a MANTRA-PAF substudy. Ep Europace. 2014;17(1):48-55. 51. Deshmukh A, Patel NJ, Pant S, et al. In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: analysis of 93 801 procedures. Circulation. 2013;128(19):2104-2112. 52. Mark DB, Anstrom KJ, Sheng S, et al. Effect of Catheter Ablation vs Medical Therapy on Quality of Life Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. Jama. 2019;321(13):1275-1285. 53. Ruzieh M, Foy AJ, Aboujamous NM, et al. Meta-Analysis of Atrial Fibrillation Ablation in Patients with Systolic Heart Failure. Cardiovascular Therapeutics. 2019;2019. 54. McKenna C, Palmer S, Rodgers M, et al. Cost-effectiveness of radiofrequency catheter ablation for the treatment of atrial fibrillation in the United Kingdom. Heart. 2009;95(7):542-549. 55. Reynolds MR, Zimetbaum P, Josephson ME, Ellis E, Danilov T, Cohen DJ. Cost-effectiveness of radiofrequency catheter ablation compared with antiarrhythmic drug therapy for paroxysmal atrial fibrillation. Circulation: Arrhythmia and Electrophysiology. 2009;2(4):362-369. 56. Weerasooriya R, Jaïs P, HEUZEY JYL, et al. Cost analysis of catheter ablation for paroxysmal atrial fibrillation. Pacing and clinical electrophysiology. 2003;26(1p2):292-294. 57. Khaykin Y, Wang X, Natale A, et al. Cost comparison of ablation versus antiarrhythmic drugs as first-line therapy for atrial fibrillation: An economic evaluation of the RAAFT pilot study. Journal of cardiovascular electrophysiology. 2009;20(1):7-12. 58. Ullah W, Schilling RJ, Wong T. Contact Force and Atrial Fibrillation Ablation. J Atr Fibrillation. 2016;8(5):1282. 59. Andrade JG, Monir G, Pollak SJ, et al. Pulmonary vein isolation using “contact force” ablation: the effect on dormant conduction and long-term freedom from recurrent atrial fibrillation--a prospective study. Heart Rhythm. 2014;11(11):1919-1924. 60. Marijon E, Fazaa S, Narayanan K, et al. Real-time contact force sensing for pulmonary vein isolation in the setting of paroxysmal atrial fibrillation: procedural and 1-year results. J Cardiovasc Electrophysiol. 2014;25(2):130-137. 61. Jourda F, Providencia R, Marijon E, et al. Contact-force guided radiofrequency vs. second-generation balloon cryotherapy for pulmonary vein isolation in patients with paroxysmal atrial fibrillation-a prospective evaluation. Europace. 2015;17(2):225-231. 62. Providencia R, Marijon E, Combes S, et al. Higher contact-force values associated with better mid-term outcome of paroxysmal atrial fibrillation ablation using the SmartTouch catheter. Europace. 2015;17(1):56-63. 63. Stabile G, Solimene F, Calo L, et al. Catheter-tissue contact force values do not impact mid-term clinical outcome following pulmonary vein isolation in patients with paroxysmal atrial fibrillation. J Interv Card Electrophysiol. 2015;42(1):21-26. 64. Sigmund E, Puererfellner H, Derndorfer M, et al. Optimizing radiofrequency ablation of paroxysmal and persistent atrial fibrillation by direct catheter force measurement-a case-matched comparison in 198 patients. Pacing Clin Electrophysiol. 2015;38(2):201-208. 65. Pedrote A, Arana-Rueda E, Arce-Leon A, et al. Impact of Contact Force Monitoring in Acute Pulmonary Vein Isolation Using an Anatomic Approach. A Randomized Study. Pacing Clin Electrophysiol. 2016;39(4):361-369. 66. Pambrun T, Combes S, Sousa P, et al. Contact-force guided single-catheter approach for pulmonary vein isolation: Feasibility, outcomes, and cost-effectiveness. Heart Rhythm. 2017;14(3):331-338. 67. Stabile G, Di Donna P, Schillaci V, et al. Safety and efficacy of pulmonary vein isolation using a surround flow catheter with contact force measurement capabilities: A multicenter registry. J Cardiovasc Electrophysiol. 2017;28(7):762-767. 68. Taghji P, El Haddad M, Phlips T, et al. Evaluation of a Strategy Aiming to Enclose the Pulmonary Veins With Contiguous and Optimized Radiofrequency Lesions in Paroxysmal Atrial Fibrillation: A Pilot Study. JACC Clin Electrophysiol. 2018;4(1):99-108. 69. Macle L, Frame D, Gache LM, Monir G, Pollak SJ, Boo LM. Atrial fibrillation ablation with a spring sensorirrigated contact force-sensing catheter compared with other ablation catheters: systematic literature review and meta-analysis. BMJ Open. 2019;9(6):e023775. 70. Phlips T, Taghji P, El Haddad M, et al. Improving procedural and one-year outcome after contact force-guided pulmonary vein isolation: the role of interlesion distance, ablation index, and contact force variability in the ‘CLOSE’-protocol. Europace. 2018;20(FI_3):f419-f427. 71. Hussein A, Das M, Chaturvedi V, et al. Prospective use of Ablation Index targets improves clinical outcomes following ablation for atrial fibrillation. J Cardiovasc Electrophysiol. 2017;28(9):1037-1047. 72. Giovanni GD, Wauters K, CHIERCHIA GB, et al. One-year follow-up after single procedure cryoballoon ablation: A comparison between the first and second generation balloon. Journal of cardiovascular electrophysiology. 2014;25(8):834-839. 73. Hussein AA, Saliba WI, Martin DO, et al. Natural history and long-term outcomes of ablated atrial fibrillation. Circulation: Arrhythmia and Electrophysiology. 2011;4(3):271-278. 74. Jourda F, Providencia R, Marijon E, et al. Contact-force guided radiofrequency vs. second-generation balloon cryotherapy for pulmonary vein isolation in patients with paroxysmal atrial fibrillation – a prospective evaluation. Ep Europace. 2014;17(2):225-231. 75. Phlips T, Taghji P, El Haddad M, et al. Improving procedural and one-year outcome after contact force-guided pulmonary vein isolation: the role of interlesion distance, ablation index, and contact force variability in the ‘CLOSE’-protocol. EP Europace. 2018;20(FI_3):f419-f427. 76. Solimene F, Schillaci V, Shopova G, et al. Safety and efficacy of atrial fibrillation ablation guided by Ablation Index module. Journal of Interventional Cardiac Electrophysiology. 2019;54(1):9-15. 77. Taghji P, El Haddad M, Phlips T, et al. Evaluation of a strategy aiming to enclose the pulmonary veins with contiguous and optimized radiofrequency lesions in paroxysmal atrial fibrillation: a pilot study. JACC: Clinical Electrophysiology. 2018;4(1):99-108. 78. Lee G, Hunter RJ, Lovell MJ, et al. Use of a contact force-sensing ablation catheter with advanced catheter location significantly reduces fluoroscopy time and radiation dose in catheter ablation of atrial fibrillation. Europace. 2016;18(2):211-218. 79. Chinitz LA, Melby DP, Marchlinski FE, et al. Safety and efficiency of porous-tip contact-force catheter for drug-refractory symptomatic paroxysmal atrial fibrillation ablation: results from the SMART SF trial. Europace. 2018;20(FI_3):f392-f400. 49.

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Itoh T, Kimura M, Tomita H, et al. Reduced residual conduction gaps and favourable outcome in contact forceguided circumferential pulmonary vein isolation. Europace. 2016;18(4):531-537. 81. Kimura M, Sasaki S, Owada S, et al. Comparison of lesion formation between contact force-guided and non-guided circumferential pulmonary vein isolation: a prospective, randomized study. Heart Rhythm. 2014;11(6):984-991. 82. Zhou X, Lv W, Zhang W, et al. Impact of contact force technology on reducing the recurrence and major complications of atrial fibrillation ablation: A systematic review and meta-analysis. Anatol J Cardiol. 2017;17(2):82-91. 83. Shurrab M, Di Biase L, Briceno DF, et al. Impact of Contact Force Technology on Atrial Fibrillation Ablation: A Meta-Analysis. J Am Heart Assoc. 2015;4(9):e002476. 84. Neyt M, Van Brabandt H, Devos C. The cost-utility of catheter ablation of atrial fibrillation: a systematic review and critical appraisal of economic evaluations. BMC Cardiovasc Disord. 2013;13:78. 85. Hwang ES, Pak HN, Park SW, et al. Risks and benefits of an open irrigation tip catheter in intensive radiofrequency catheter ablation in patients with non-paroxysmal atrial fibrillation. Circ J. 2010;74(4):644-649. 86. Waldo AL, Wilber DJ, Marchlinski FE, et al. Safety of the open-irrigated ablation catheter for radiofrequency ablation: safety analysis from six clinical studies. Pacing Clin Electrophysiol. 2012;35(9):1081-1089. 87. Oza SR, Hunter TD, Biviano AB, et al. Acute safety of an open-irrigated ablation catheter with 56-hole porous tip for radiofrequency ablation of paroxysmal atrial fibrillation: analysis from 2 observational registry studies. J Cardiovasc Electrophysiol. 2014;25(8):852-858. 88. Huang HD, Waks JW, Contreras-Valdes FM, Haffajee C, Buxton AE, Josephson ME. Incidence and risk factors for symptomatic heart failure after catheter ablation of atrial fibrillation and atrial flutter. Europace. 2016;18(4):521-530. 89. Cotte FE, Chaize G, Gaudin AF, Samson A, Vainchtock A, Fauchier L. Burden of stroke and other cardiovascular complications in patients with atrial fibrillation hospitalized in France. Europace. 2016;18(4): 501-507. 90. Natale A, Reddy VY, Monir G, et al. Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the prospective, multicenter SMART-AF trial. J Am Coll Cardiol. 2014;64(7):647-656. 91. Chinitz L, Goldstein LJ, Barnow A, et al. Comparison of real-world clinical and economic outcomes between the ThermoCool((R)) SF and ThermoCool((R)) catheters in patients undergoing radiofrequency catheter ablation for atrial fibrillation. Clinicoecon Outcomes Res. 2018;10:587-599. 92. Martinek M, Lemes C, Sigmund E, et al. Clinical impact of an open-irrigated radiofrequency catheter with direct force measurement on atrial fibrillation ablation. Pacing Clin Electrophysiol. 2012;35(11):1312-1318. 93. Sciarra L, Golia P, Natalizia A, et al. Which is the best catheter to perform atrial fibrillation ablation? A comparison between standard ThermoCool, SmartTouch, and Surround Flow catheters. J Interv Card Electrophysiol. 2014;39(3):193-200. 94. Tanaka N, Inoue K, Tanaka K, et al. Automated Ablation Annotation Algorithm Reduces Re-conduction of Isolated Pulmonary Vein and Improves Outcome After Catheter Ablation for Atrial Fibrillation. Circ J. 2017;81(11):1596-1602. 95. Pontoppidan J, Sandgaard N, Riemann M, Djurhuus S, Dalhoej J, Johansen J. Introducing a rigorous atrial fibrillation ablation strategy with ablation index and point-by-point ablation is feasible and safe (#P909). EP Europace. 2017;19(Supplement 3):iii179. 96. De Potter T, Hunter T, Boo L, Chatzikyriakou S, Strisciuglio T, Garcia E. Ablation Efficiency with Contact Force Stability and Ablation Index in Paroxysmal Atrial Fibrillation. Heart Rhythm. 2017;14(5):S179. 97. Riemann M, Sandgaard N, Dalhoej J, Djurhuus S, Johansen J, Pontoppidan J. Ablation index in atrial fibrillation ablation, initial experience with a novel endpoint in point-by-point ablation in pulmonary vein isolation (#P914). EP Europace. 2017;19(Supplement 3):iii181. 98. Weberndoerfer V, Toggweiler S, Schefer T, Russi I, Brinkert M, Kobza R. Early experience with ablation indexguided pulmonary vein isolation compared with force-time integral-guided ablation using surround flow catheter tip irrigation or ablation of atrial fibrillation (#P1160). EP Europace. 2017;19(3 Supplement 3):iii246. 99. De Ruvo E, Solimene F, Zucchelli G, et al. Contact-force with quality lesion assessment may reduce procedural burden in AF ablation (#P358). EP Europace. 2017;19(Supplement 3):iii65. 100. El Haddad M, Taghji P, Phlips T, et al. Determinants of Acute and Late Pulmonary Vein Reconnection in Contact Force-Guided Pulmonary Vein Isolation: Identifying the Weakest Link in the Ablation Chain. Circ Arrhythm Electrophysiol. 2017;10(4). 101. Brooks AG, Wilson L, Chia NH, et al. Accuracy and clinical outcomes of CT image integration with Carto-Sound compared to electro-anatomical mapping for atrial fibrillation ablation: a randomized controlled study. Int J Cardiol. 2013;168(3):2774-2782. 102. Cano O, Alonso P, Osca J, et al. Initial Experience with a New Image Integration Module Designed for Reducing Radiation Exposure During Electrophysiological Ablation Procedures. J Cardiovasc Electrophysiol. 2015;26(6):662-670. 103. Christoph M, Wunderlich C, Moebius S, et al. Fluoroscopy integrated 3D mapping significantly reduces radiation exposure during ablation for a wide spectrum of cardiac arrhythmias. Europace. 2015;17(6):928-937. 104. Akbulak RO, Schaffer B, Jularic M, et al. Reduction of Radiation Exposure in Atrial Fibrillation Ablation Using a New Image Integration Module: A Prospective Randomized Trial in Patients Undergoing Pulmonary Vein Isolation. J Cardiovasc Electrophysiol. 2015;26(7):747-753. 105. De Ponti R. Reduction of radiation exposure in catheter ablation of atrial fibrillation: Lesson learned. World J Cardiol. 2015;7(8):442-448. 106. Naniwadekar A, Joshi K, Greenspan A, Mainigi S. Use of the new contact force sensing ablation catheter dramatically reduces fluoroscopy time during atrial fibrillation ablation procedures. Indian Pacing Electrophysiol J. 2016;16(3):83-87. 107. Osorio J, Hunter T, Bubien R, Thorington S, Rajendra A, Arciniegas J. Efficiency and predictability in paroxysmal atrial fibrillation ablation with contact force catheter and stability module integration (#P1719). EP Europace. 2017;19(3 Supplement 3):iii371-iii372. 108. Osorio J, Imhoff RJ, Mallow PJ, et al. Cost minimization analysis of catheter ablation for paroxysmal atrial fibrillation by catheter technology. J Comp Eff Res. 2019;8(4):241-249. 109. Wendelboe AM, Raskob GE, Angchaisuksiri P, et al. Global public awareness about atrial fibrillation. Res Pract Thromb Haemost. 2018;2(1):49-57. 110. Aliot E, Breithardt G, Brugada J, et al. An international survey of physician and patient understanding, perception, and attitudes to atrial fibrillation and its contribution to cardiovascular disease morbidity and mortality. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2010;12(5):626-633. 80.

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Increased Risk of Stroke and Mortality Associated with AF AF is associated with increased risk of stroke and mortality, requiring effective prevention and management strategies. Sophie Laurenson, Ph.D.

Introduction Atrial fibrillation (AF) is a progressive disease, with one in five patients with paroxysmal AF progressing to persistent disease with one year1. AF patients experience higher risks of stroke (2.4-times increase)2 and heart failure (HF) (2 to 3-times increase)3, increased morbidity and more hospital admissions compared to individuals without arrhythmia. AF is also an independent risk factor for mortality4 and is associated with increased renal morbidity and cognitive impairment in elderly patients5,6. Increasing evidence also suggests an association between AF and an increased risk of ‘premature’ dementia7.

Pathogenesis of Thrombosis in AF The electromechanical abnormalities that are characteristic of AF have important clinical implications. Although the exact pathogenic mechanisms underpinning AF remain elusive, it is thought that cardiac remodeling contributes to AF progression. The absence of effective atrial contraction increases the risk of blood coagulation and thrombosis, particularly in the left atrial appendage (LAA). This may occur as a consequence of several aberrant processes described by Virchow’s triad for thrombogenesis including atypical blood flow, blood components and vessel walls changes. In AF, this manifests as blood stasis within the atria, endothelial dysfunction and hypercoagulability8. The evidence supporting the role of these phenomena in thrombosis development includes both in vitro and in vivo models as well as clinical studies. Studies in animal models of AF established that decreased myofibrillar sensitivity to Ca2+ resulted in dysfunctional atrial contractions9. Observational clinical studies have uncovered coagulation irregularities in patients

suffering with AF-related strokes, including increased prothrombin fragment and thrombin– antithrombin complexes10. Further studies have indicated other molecular abnormalities in AF patients which may contribute to aberrant coagulation including factor VIII, d-dimer, fibrinogen and von Willebrand factor11,12. However, these abnormalities are not easily attributable to AF alone and may result from other comorbidities such as cardiovascular disease. In addition to the specific mechanisms mentioned, inflammation may contribute to both endothelia cell dysfunction and hypercoagulation leading to thrombosis development. In AF-related stroke, the region of the left atrial appendage (LAA) has received substantial attention in clinical studies. Decreases in the emptying velocity of the LAA observed in transesophageal echocardiography is associated with spontaneous echo contrast, thrombus formation and stroke13. Fitting LAA closure devices in patients with AF-associated stroke has also proved efficacious, further supporting the role of thrombus formation within the LAA in stroke14.

The electromechanical abnormalities that are characteristic of AF have important clinical implications

AF-Associated Stroke Risk and Outcomes AF patients have significant increase in the risk of stroke15. Studies have estimated that up to 30% of all strokes can be attributed to underlying AF16 and approximately 10% of initial AF diagnoses are made in patients presenting with a stroke. The data contributing to our understanding of the risk factors and outcomes in AF-associated stroke are mostly derived from large clinical cohorts. The Framingham Heart Study (FHS) observed that age was a significant risk factor in stroke development. They found that the attributable risk of AF for stroke was 1.5% among 50 to 59 years old individuals, compared to 23.5% in 80 to 89 years old patients2. This study also

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Studies have estimated that up to 30% of all strokes can be attributed to underlying AF [16] and approximately 10% of initial AF diagnoses are made in patients presenting with a stroke

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demonstrated that AF-related stroke conferred increased mortality. The 30-day mortality in AFrelated strokes was increased relative to non-AF strokes. Further, AF patients showed decreased 1-year survival rates following stroke and increased risk of recurrences17. In the Copenhagen Stroke Study, the size and location of stroke infarcts was investigated. AF patients had larger stroke infarcts, which were more often located within the cerebral cortex, compared with non-AF stroke patients. They were also observed to have longer hospitalization durations and higher rates of inhospital death18. The risk of AF-related stroke is heterogeneous and is dependent on other risk factors including age over 65, hypertension, cardiovascular disease (including HF), diabetes mellitus, previous history of thromboembolism and gender19. These risk factors have been identified in clinical trial and observational cohorts of patients who were not receiving anticoagulation therapy20. Stroke risk stratification schemes have been developed based on these risk factors21. The most common clinical risk stratification schemes are the CHADS2 and CHA2DS2-VASc scores. These systems are intentionally reductionist and designed to be implemented in a variety of clinical settings22. The presence of comorbidities is particularly relevant for calculating stroke risk in AF patients. Up to 80% of AF patients have a co-existing condition or cardiac disease23. This is most prominent for patients with permanent AF, 63% of whom have four conditions in addition to AF. Finally, the natural history of AF itself is a contributing factor in stroke risk for AF patients. Individuals that progress from paroxysmal AF to persistent AF have a greater risk of thromboembolism as well as heart failure1.

AF-Associated Stroke Management Strokes in AF patients are associated with increased morbidity and mortality and stroke management is a cornerstone of AF treatment regimens17. Thromboprophylaxis with oral anticoagulation (OAC) therapies are commonly prescribed to AF patients as a stroke prevention strategy. This is reflected in key clinical guidelines on stroke management for AF patients. Treatment with vitamin K antagonists (VKA), such as warfarin has been shown to reduce the risk of stroke by 64% 24. VKA therapies have also been shown to reduce all-cause mortality by 26%. Treatment is based on risk scores and clinicians are advised to offer OAC to AF patients with at least one risk factor. When determining the optimal treatment regimen, healthcare professionals should assess the risk of bleeding resulting from OAC therapy. Monitoring of coagulation parameters, such as the international normalized ratio (INR), should be performed for patients receiving OACs. In addition to OAC therapies, non-VKA oral anticoagulant (NOAC) therapies have been included in stroke prevention strategies and have shown early promise. Antiplatelet therapy has been used in patients with AF, although results have shown a reduction of only 22% in the incidence of stroke, with no significant reduction in mortality.

AF-Associated Mortality The risk of death in AF patients is estimated to be 46%16. The mortality rate in newly diagnosed patients is estimated at 40% and increases to 60% from 5 to 10 years following diagnosis25. Asymptomatic AF confers a greater risk of mortality, of up to 2-times increase26. Risk factors

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associated with increased mortality include age, existing cardiovascular or thrombotic disease, renal disease and diabetes.

Future Outlook for AFAssociated Stroke and Mortality Thromboprophylaxis with anti-coagulation therapies is an effective strategy for stroke prevention in AF patients. However, patients with asymptomatic AF are at increased risk of stroke but may not be receiving thromboprophylaxis therapy. Implementation of routine screening for AF would identify individuals with silent AF who may be candidates for thromboprophylaxis.

Improved screening and risk stratification approaches could also assist in determining the optimum treatment strategies to manage the symptoms and sequalae of AF. There is increasing recognition that stroke risk is a continuum and that compartmentalizing patients into rigid risk stratification schemes is often ambiguous. The introduction of novel biomarkers and imaging (echocardiography and cerebral) techniques could help to refine stroke risk stratification. Combined, these advances could aid in identifying and assessing the risk of developing AF-associated strokes earlier, leading to more effective management and prevention.

References Nieuwlaat, R., et al., Prognosis, disease progression, and treatment of atrial fibrillation patients during 1 year: follow-up of the Euro Heart Survey on atrial fibrillation. Eur Heart J, 2008. 29(9): p. 1181-9.

Wolf, P.A., R.D. Abbott, and W.B. Kannel, Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke, 1991. 22(8): p. 983-8.

Wang, T.J., et al., Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation, 2003. 107(23): p. 2920-5.

Ouyang, F., et al., Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation, 2010. 122(23): p. 2368-2377.

Kirchhof, P., et al., 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg, 2016. 50(5): p. e1-e88.

Lamassa, M., et al., Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project). Stroke, 2001. 32(2): p. 392-8.

Kalantarian, S., et al., Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med, 2013. 158(5 Pt 1): p. 338-46.

Watson, T., E. Shantsila, and G.Y. Lip, Mechanisms of thrombogenesis in atrial fibrillation: Virchowâ&#x20AC;&#x2122;s triad revisited. Lancet, 2009. 373(9658): p. 155-66.

Thromboprophylaxis with anti-coagulation therapies is an effective strategy for stroke prevention in AF patients

Yeh, Y.H., et al., Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure. Circ Arrhythm Electrophysiol, 2008. 1(2): p. 93-102.

Turgut, N., et al., Hypercoagulopathy in stroke patients with nonvalvular atrial fibrillation: hematologic and cardiologic investigations. Clin Appl Thromb Hemost, 2006. 12(1): p. 15-20.

10.

Kahn, S.R., S. Solymoss, and K.M. Flegel, Nonvalvular atrial fibrillation: evidence for a prothrombotic state. Cmaj, 1997. 157(6): p. 673-81.

11.

Lip, G.Y., et al., Fibrinogen and fibrin D-dimer levels in paroxysmal atrial fibrillation: evidence for intermediate elevated levels of intravascular thrombogenesis. Am Heart J, 1996. 131(4): p. 724-30.

12.

Goldman, M.E., et al., Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study). J Am Soc Echocardiogr, 1999. 12(12): p. 1080-7.

13.

Holmes, D.R., 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): p. 534-42.

14.

Krijthe, B.P., et al., Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J, 2013. 34(35): p. 2746-51.

15.

Odutayo, A., et al., Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis. BMJ, 2016. 354: p. i4482.

16.

17.

Lin, H.J., et al., Stroke severity in atrial fibrillation. The Framingham Study. Stroke, 1996. 27(10): p. 1760-4.

Bekwelem, W., et al., Extracranial Systemic Embolic Events in Patients With Nonvalvular Atrial Fibrillation: Incidence, Risk Factors, and Outcomes. Circulation, 2015. 132(9): p. 796-803.

18.

Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med, 1994. 154(13): p. 1449-57.

19.

20.

Pisters, R., et al., Stroke and thromboembolism in atrial fibrillation. Circ J, 2012. 76(10): p. 2289-304.

Olesen, J.B., et al., Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. Bmj, 2011. 342: p. d124.

21.

Diemberger, I., et al., Atrial fibrillation and prediction of mortality by conventional clinical score systems according to the setting of care. Int J Cardiol, 2018. 261: p. 73-77.

22.

23.

Zoni-Berisso, M., et al., Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol, 2014. 6: p. 213-20.

Hart, R.G., L.A. Pearce, and M.I. Aguilar, Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med, 2007. 146(12): p. 857-67.

24.

Boriani, G. and M. Proietti, Atrial fibrillation prevention: an appraisal of current evidence. Heart, 2018. 104(11): p. 882-887.

25.

Boriani, G., et al., Asymptomatic atrial fibrillation: clinical correlates, management, and outcomes in the EORPAF Pilot General Registry. Am J Med, 2015. 128(5): p. 509-18.e2.

26.

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Future Outlook Future advances in AF prevention and management Sophie Laurenson, Ph.D.

Introduction

Recent work has revealed that AF can be prevented by targeting fundamental risk factors, offering opportunities for earlier interventions to reduce the progression of AF and development of comorbidities

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Significant advances have been made in the diagnosis and management of atrial fibrillation (AF) in recent years. However, the molecular mechanisms underpinning AF development and progression remain unclear and are a subject of intense investigation. As AF is a progressive disease, management and prevention of AF and its common comorbidities is tightly linked to our current understanding of its characteristic electromechanical perturbations. This has highlighted the need for preventive therapy to proactively inhibit development of the AF substrate. Recent work has revealed that AF can be prevented by targeting fundamental risk factors, offering opportunities for earlier interventions to reduce the progression of AF and development of comorbidities1,2.

Early Detection and Management The management of AF-associated stroke has improved markedly in recent years, with multiple prevention strategies now available. However, the effect of asymptomatic AF on thromboembolism remains substantial. As stroke is the first manifestation of ‘silent’ AF in up to 10% of cases3, opportunistic screening of high risk populations for undetected AF has been recommended in several guidelines4,5. Previous work has shown that systematic screening with 12-lead ECG instruments is not cost effective5. However, recent advances in electronics have led to the development of smaller, mobile instruments that can be used to assess cardiac rhythm by optical instruments6, oscillometry7 or portable ECG rhythm detectors8. These advances could enable screening in target populations, such as individuals ≥65 years of age, with increased risk of AF-associated morbidity and mortality. This approach has been estimated to identify 1.4% of those with undetected AF9 and is likely to be a cost-effective strategy for stroke prevention10. Earlier management of ‘silent’ AF episodes may be beneficial for managing the development of sequalae, although more clinical evidence on the value of ECG screening and monitoring tools in high risk populations is required. It is unclear

whether the type of device and length of recording in mobile and implanted devices have the same clinical implications and prognostic value. Current data implies that longer recording times increase the likelihood of identifying AF and predicting risk. This may restrict the use of single measurement and mobile technologies in some clinical settings. Several risk score schemes to determine AF susceptibility have been developed. These have been based on risk factors that are commonly associated with the occurrence of AF in specific patient populations11,12. However, additional epidemiological studies are required to accurately identify target populations that would benefit from AF screening and early intervention.

Advances in Rhythm Control Current approaches to early rhythm control include prevention of AF substrate development, earlier ablation procedures and novel AADs candidates13. However, there are a variety of novel therapeutic options in development. These include pharmacologic interventions for altering microRNA function, inducing heat shock proteins, vagal stimulation and calcium transport modulation. Several new classes of AADs are under development. These include derivatives of the AAD amiodarone (celivarone and budiodarone)14, atrial-selective agents (vernakalant, AVE0118 and XEN-D0101)15 and multichannel blockers including ranolazine and vanoxerine16. Ablation has emerged as an important tool in AF management. However, long-term success of certain ablation procedures remains low for specific patient populations. Techniques using more aggressive ablation strategies have been investigated17. The most common AF ablation procedure involves pulmonary vein isolation (PVI) from the left atrium of the heart, although it is not suitable for all patients. Techniques are being developed to improve outcomes for patients with persistent arrhythmia using this procedure. Recently, strategies to improve sinus rhythm maintenance in patients with complex patterns of arrhythmia have been investigated. These include atrial substrate analysis using advanced imaging techniques and the identification of driver

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domains18,19. However, these newly identified targets have not been studied in large-scale trials and their applicability in routine clinical care is uncertain. Many novel ablation techniques have been developed to improve both efficacy and safety of ablation procedures. These include balloon cryoablation, circular catheter ablation, laser ablation and robotic navigation 20. Robotic navigation systems that allow remote ablation will aid in the automation of ablation procedures21. Minimising the difficulty associated with performing ablation procedures is valuable in expanding access to ablation and facilitating uptake as a first line treatment option. Advances in imaging technologies has also led to performance improvements. The information obtained from 3D electroanatomic mapping systems has improved safety and efficacy as well as minimizing difficulty. Other imaging techniques are in development and it is likely that ablation procedures will become increasingly tailored to individual patients22.

Risk Assessment and Management of Comorbidities The CHA2DS2VASc score is valuable tool to identify patients at risk of stroke as candidates for oral anticoagulation therapies (OAC). However, it is becoming increasingly clear that not all AF patients can be easily assigned to a risk-related group for management. AF is a complex and heterogeneous disease with extensive variation in aetiology, symptoms and comorbidities. Subsequently, some parties have recently advocated thromboprophylaxis for individuals at risk of developing comorbidities, even in the absence of detected AF. Despite advances in the prevention and management of comorbidities in AF patients, significant challenges remain for certain patient populations. The optimum thromboprophylaxis

strategy for AF patients with high risk of cardiovascular events and haemorrhage is not yet established. There is currently a lack of evidence supported by high quality trial data to inform treatment strategies for these patients and management is usually based on expert opinion. The use of non-VKA oral anticoagulation (NOAC) therapies for AF patients is a relatively recent advance and is currently indicated in patients with non-valvular AF. The eligibility criteria for receiving NOACs is dependent on the definition of nonvalvular AF, which remains under debate23. Further trials comparing NOACs with alternative OAC treatments in patients with AF and bioprosthetic valves are required.

Conclusion

Minimising the difficulty associated with performing ablation procedures is valuable in expanding access to ablation and facilitating uptake as a first line treatment option

The recent focus on precision medicine and outcomes-driven healthcare is likely to change the AF management landscape. Current strategies for prevention and management of AF and its comorbidities are largely disconnected from the pathophysiological processes underlying disease development and progression. Future advances will likely arise from the development and validation of mechanism-based interventions. This will enable disease-specific, tailored approaches to managing AF and improve outcomes for specific patient subgroups. Further epidemiological research is also required to understand the global burden of AF and design screening and therapeutic interventions for appropriate target populations. The key to reducing the social and economic impact of AF will be in promoting prevention and patient engagement. Further research is required to assess the effect of self-care behaviours and symptom management. Further studies are also needed to inform patients and healthcare professionals about the risks and benefits of AF management options. WWW.HOSPITALREPORTS.EU| 33

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References Pathak RK, Middeldorp ME, Meredith M, et al. Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY). Journal of the American College of Cardiology. 2015;65(20):2159-2169.

Fein AS, Shvilkin A, Shah D, et al. Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. Journal of the American College of Cardiology. 2013;62(4):300-305.

Friberg L, Rosenqvist M, Lindgren A, Terent A, Norrving B, Asplund K. High prevalence of atrial fibrillation among patients with ischemic stroke. Stroke. 2014;45(9):2599-2605.

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. European heart journal. 2012;33(21): 2719-2747.

Hobbs FD, Fitzmaurice DA, Mant J, et al. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study. Health technology assessment (Winchester, England). 2005;9(40):iii-iv, ix-x, 1-74.

McManus DD, Lee J, Maitas O, et al. A novel application for the detection of an irregular pulse using an iPhone 4S in patients with atrial fibrillation. Heart rhythm. 2013;10(3):315-319.

Wiesel J, Arbesfeld B, Schechter D. Comparison of the Microlife blood pressure monitor with the Omron blood pressure monitor for detecting atrial fibrillation. The American journal of cardiology. 2014;114(7):1046-1048.

Tieleman RG, Plantinga Y, Rinkes D, et al. Validation and clinical use of a novel diagnostic device for screening of atrial fibrillation. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2014;16(9):1291-1295.

Lowres N, Neubeck L, Redfern J, Freedman SB. Screening to identify unknown atrial fibrillation. A systematic review. Thrombosis and haemostasis. 2013;110(2):213-222.

Lowres N, Neubeck L, Salkeld G, et al. Feasibility and cost-effectiveness of stroke prevention through community screening for atrial fibrillation using iPhone ECG in pharmacies. The SEARCH-AF study. Thrombosis and haemostasis. 2014;111(6):1167-1176.

10.

Schnabel RB, Sullivan LM, Levy D, et al. Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study. Lancet (London, England). 2009;373(9665):739-745.

11.

Alonso A, Krijthe BP, Aspelund T, et al. Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. Journal of the American Heart Association. 2013;2(2):e000102.

12.

Kirchhof P, Breithardt G, Aliot E, et al. Personalized management of atrial fibrillation: Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2013;15(11):1540-1556.

13.

Khitri AR, Aliot EM, Capucci A, et al. Celivarone for Maintenance of Sinus Rhythm and Conversion of Atrial Fibrillation/Flutter. Journal of Cardiovascular Electrophysiology. 2012;23(5):462-472.

14.

Ford J, Milnes J, Wettwer E, et al. Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor. Journal of cardiovascular pharmacology. 2013;61(5):408-415.

15.

Dittrich HC, Feld GK, Bahnson TD, et al. COR-ART: A multicenter, randomized, double-blind, placebocontrolled dose-ranging study to evaluate single oral doses of vanoxerine for conversion of recent-onset atrial fibrillation or flutter to normal sinus rhythm. Heart rhythm. 2015;12(6):1105-1112.

16.

Nattel S, Guasch E, Savelieva I, et al. Early management of atrial fibrillation to prevent cardiovascular complications. European heart journal. 2014;35(22):1448-1456.

17.

Kottkamp H, Bender R, Berg J. Catheter ablation of atrial fibrillation: how to modify the substrate? Journal of the American College of Cardiology. 2015;65(2):196-206.

18.

Haissaguerre M, Hocini M, Denis A, et al. Driver domains in persistent atrial fibrillation. Circulation. 2014;130(7):530-538.

19.

20.

Lip GYH, Fauchier L, Freedman SB, et al. Atrial fibrillation. Nature Reviews Disease Primers. 2016;2(1):16016.

Saliba W, Reddy VY, Wazni O, et al. Atrial fibrillation ablation using a robotic catheter remote control system: initial human experience and long-term follow-up results. Journal of the American College of Cardiology. 2008;51(25):2407-2411.

21.

Bax JJ, Marsan NA, Delgado V. Non-invasive imaging in atrial fibrillation: focus on prognosis and catheter ablation. Heart (British Cardiac Society). 2015;101(2):94-100.

22.

Boriani G, Cimaglia P, Fantecchi E, et al. Non-valvular atrial fibrillation: potential clinical implications of the heterogeneous definitions used in trials on new oral anticoagulants. Journal of cardiovascular medicine (Hagerstown, Md). 2015;16(7):491-496.

23.

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