Original Article

Catheter Ablation for Atrial Fibrillation

Stuart P. Thomas, PhD, FCSANZ a, and Prashanthan Sanders, PhD, FCSANZ b
b a Department of Cardiology, Westmead Hospital, University of Sydney and Macquarie University, Australia Centre for Heart Rhythm Disorders (CHRD), Royal Adelaide Hospital and University of Adelaide, Adelaide, Australia

Atrial brillation (AF) is the most common clinically important cardiac arrhythmia. It is an important cause of stroke, contributes to the burden of heart failure and is a major contributor to health expenditure. Percutaneous catheter ablation is superior to medical therapy in reducing AF recurrences. It has an important role in treatment of patients with failed drug therapy. Successful catheter ablation improves left ventricular function in patients with heart failure. In addition, it may be appropriate for selected highly symptomatic patients as rst line therapy. Catheter ablation for AF has been shown in randomised trials to reduce hospital admissions and improve quality of life. There is evidence from registry data to suggest it reduces the risk of stroke and improves mortality. Cost effectiveness has been demonstrated by modelling studies in both Europe and the United States. (Heart, Lung and Circulation 2012;21:395401) Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Keywords. Atrial brillation; Catheter ablation; Pulmonary veins; Pulmonary vein isolation; Cost effectiveness; Stroke

Introduction

Costs of Atrial Fibrillation

AF is a chronic disease requiring long-term management when medically managed. Indeed, it is the fastest growing heart disorder and the second fastest growing of all conditions managed in primary care; representing a 117% increase in the last 10 years [8]. Management may involve regular outpatient care to monitor arrhythmia rate or rhythm control, prevention of thromboembolism, and monitoring for adverse drug events. The costs are substantially further increased by hospital admissions for the treatment of highly symptomatic episodes and the care of complications including stroke, syncope and heart failure. The cost of AF has been estimated in several studies. The major cost in these studies is hospital admissions. In the Fractal Registry [9], the annual cost of treatment varied from US$3385 in patients with no documented recurrences to US$10312 in patients with three or more recurrences. A French study also showed the main cost was hospital admission (D1296) from a total cost of D3308/year [10]. Other major costs were treatment of complications including heart failure (D334) and stroke (D334). None of these studies take into account the cost of new antithrombotic drugs. The penetration of these drugs which are relatively expensive in the place of warfarin will vastly increase the cost of AF and its relative contribution to health expenditure.

trial brillation (AF) is the most common clinically important cardiac arrhythmia; [1] with 25% of adults >40 years developing the condition during their lifetime [2]. It is associated with signicant morbidity from palpitations, fatigue, reduced exercise capacity, syncope, and heart failure and is a leading cause of stroke. Total mortality and cardiovascular mortality are signicantly and independently increased in patients with AF [35]. The prevalence of AF increases with age from 1.7% in those aged 6064 years to 11.6% in those over the age of 75 years [6]. The burden of atrial brillation is increasing. Australian hospitalisation data suggests an exponential rise in AF admission rates; with 47,000 separations in the last nancial year [7]. Indeed, the increase in hospitalisation due to AF now exceeds that of patients with heart failure. Pharmacological therapy to restore and maintain sinus rhythm in patients AF is often unsuccessful. The most effective agent, amiodarone, has a diverse adverse effect prole that limits its use. There is a large group of patients with disabling symptoms despite optimal pharmacological management and for this group catheter ablation is an important treatment option. Recently, clinical trials have claried the role of catheter ablation in the treatment of AF. In this review we will examine the evidence supporting catheter ablation for AF and discuss the implications for patient selection.
Available online 9 May 2012 Corresponding author at: Department of Cardiology, Westmead Hospital, Westmead 2145, Australia. Tel.: +61 2 9845 6795; fax: +61 2 9845 8323. E-mail address: stuart.thomas@sydney.edu.au (S.P. Thomas).

Catheter Ablation
Catheter ablation of AF is performed percutaneously through the femoral vein. A variety of energy sources can be used to create lines of scar within the atria at critical sites. The most frequently used energy source 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2012.03.122

Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).

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Figure 1. Electrical isolation of the pulmonary veins using two rings around the left and right pulmonary vein pairs. The yellow structure is the computerised tomography rendered image of the left atrial cavity used to guide catheter ablation. It shows the atrial cavity and pulmonary veins in a posterior view (left) and superior view (right). The red dots indicate the sites of radiofrequency energy application. At the conclusion of the procedure the pulmonary veins are electrically disconnected from the remainder of the myocardium. Ablation may be guided by radiography or three dimentional position sensing systems employing either impedance mapping or magnetic localisation. Catheters may be moved manually or using robotic systems.

is radiofrequency. The best established alternative is cryoablation using a cold balloon to isolate the veins. The cornerstone of AF ablation is ablation of the region around the pulmonary veins with the endpoint of electrically isolating these structures from the atria (Fig. 1). This part of the procedure relates to the seminal observation that intermittent atrial brillation was almost always initiated by ectopic beats arising from the pulmonary veins [11]. The segmental pulmonary vein isolation technique subsequently developed by Hassaguerre was able to control AF in most patients with intermittent episodes [12]. There is variation in the approach to this common endpoint ranging from isolation very close to the veins to broader isolation of the veins and part of the posterior left atrium. The success of this approach in patients with paroxysmal AF remains high and reported in a variety of series as greater than 80% (Fig. 2). The extent of ablation required for patients with persistent (episodes lasting longer than 7 days) or longstanding persistent AF (episodes lasting longer than 12 months) is still under evaluation. Most centres undertake further adjunctive ablation in addition to pulmonary vein isolation [13,14]. These strategies comprise of linear lesions connecting anatomic structures (veins or the mitral annulus) or using electrogram targeted techniques. The latter consists of ablation of complex fractionated electrograms, however, other individualised approaches are

under evaluation. Procedures using a combination of these techniques are associated with superior outcomes in case series reports (Fig. 2) [15].

Patient Selection and the Role of Catheter Ablation in the Treatment of Atrial Fibrillation
The role of ablation in the treatment of AF is dened by clinical trials and summarised in current guidelines. A consensus statement from the leading international subspecialty bodies (Heart Rhythm Society, European Heart Rhythm Association and European Cardiac Arrhythmia Society) recommends catheter ablation for the following groups: (1) Symptomatic AF refractory or intolerant to at least one Class 1 or 3 antiarrhythmic medication (paroxysmal AF Class I, Level A, persistent Class IIa, Level B, longstanding persistent Class IIb, Level B); (2) Symptomatic AF prior to intiation of antiarrhythmic therapy with a class 1 or 3 antiarrhythmic agent (paroxysmal, Class IIa, Level B, persistent Class IIb, Level C, longstanding persistent Class IIb, Level C) [16].

Catheter Ablation in Patients Failing Medical Therapy

There is excellent evidence to demonstrate that catheter ablation for AF is more effective than medical therapy in reducing the burden of disease and reducing hospital admissions. There are eight randomised trials comparing

Figure 2. Summary of results from studies of catheter ablation for paroxysmal AF (A) and persistent and permanent AF (B).

catheter ablation of AF to antiarrhythmic therapy [1724]. All but one underpowered trial [24] showed catheter ablation is markedly more effective than medical therapy for controlling AF in short to medium term follow-up. These studies included patients with both paroxysmal and persistent AF. One study included only patients with type 2 diabetes mellitus. Grouped together the relative risks for paroxysmal (RR 2.26; 95% CI 1.742.94) and persistent AF (RR 3.20; 95% CI 1.298.41) strongly favour catheter ablation over antiarrhythmic drug therapy for the maintenance of sinus rhythm [25]. Catheter ablation was also associated with improvement in symptoms, exercise capacity and quality of life [23]. Catheter ablation for symptomatic patients who have failed medical therapy is recommended in American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society [26] and European Society of Cardiology Guidelines [27]. Clinical trials have concentrated on symptomatic patients and therefore the role in asymptomatic patients remains uncertain.

Catheter Ablation as First Line Therapy

Antiarrhythmic therapy for atrial brillation is effective in reducing the frequency and duration of episodes in many patients. However pharmacological therapy almost universally fails to prevent recurrences of atrial brillation. Catheter ablation outcomes are best for patients with

structurally normal hearts in paroxysmal atrial brillation suggesting that pulmonary veins isolation may be most effective early in the course of the disease. This is supported by studies demonstrating that the burden of atrial brillation causes pathological changes in the atrial tissue resulting in an increased propensity to persistence of atrial brillation episodes [28]. The poor outcomes for patients treated with antiarrhythmic therapy and the risk of further disease progression have led to the recommendation that catheter ablation is appropriate for selected patients without trial of antiarrhythmic therapy. There is a single small randomised trial comparing catheter ablation and antiarrhythmic therapy as rst line therapy for patients with atrial brillation. The arrhythmia recurrence rate was dramatically lower in the catheter ablation group (13% vs. 63%, p < 0.001). Hospital admissions were also decreased and quality of life improved with catheter ablation [22]. As a result of these observations, the current European Society of Cardiology Guidelines for treatment of atrial brillation suggest catheter ablation may be considered as rst line therapy in selected patients with paroxysmal atrial brillation [27].

Catheter Ablation in Patients with Heart Failure

Atrial brillation may precipitate heart failure and poorly controlled ventricular rate may result in a rate related

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cardiomyopathy. Studies of catheter ablation in patients with heart failure and atrial brillation have demonstrated marked improvement in left ventricular function related to restoration of sinus rhythm. Hsu et al. reported a 21% increase in ejection fraction, decreased ventricular diameters and improvements in exercise capacity, quality of life and symptoms [29]. Importantly, these observations are restricted to patients with poor rate control and an absence of structural heart disease. Several reports from single centre series have demonstrated comparable results. A recent meta-analysis including nine studies demonstrated an absolute improvement in ejection fraction of 11.1% after catheter ablation [30]. This improvement is in a similar range to that observed with biventricular pacing and drug trials examining the role of beta adrenergic blockade and block of the rennin angiotensin axis. Khan et al. compared catheter ablation and a strategy of His bundle ablation and biventricular pacing in a population with drug resistant atrial brillation, an ejection fraction of 40% or less, and New York Heart Association class II or III heart failure [31]. After six months subjects undergoing the pulmonary vein isolation strategy had a higher ejection fraction (35% vs. 28%, p < 0.001) a longer 6-min-walk test result (340 m vs. 297 m, p < 0.01) and improved symptoms compared to those undergoing His ablation and biventricular pacing. Catheter ablation in patients with heart failure is technically more demanding because they usually require more than pulmonary vein isolation alone. The procedures are also likely to be associated with a higher risk because of the co-morbidities of the patients. However outcomes similar to those observed in cohorts without structural heart disease can be achieved and these additional risks are likely to be outweighed by the substantial benets in this group of patients [29,32,33]. Catheter ablation of AF in patients with heart failure is recommended in the European Society of Cardiology Guidelines for patients in whom antiarrhythmic drug therapy does not control symptoms [27].

Catheter Ablation and the Risk of Stroke or Death

A quarter of all strokes are attributed to atrial brillation [3436]. Patients with atrial brillation have more debilitating strokes with worse outcomes [3639]. These strokes result in higher costs than those of other patients [3942]. Data from the AFFIRM trial demonstrated that stroke was reduced in patients for whom sinus rhythm was maintained [43]. There is non-randomised data to suggest catheter ablation for atrial brillation reduces stroke. Results from a multicentre registry including 1273 catheter ablation patients showed a low risk of stroke after catheter ablation (0.5%/patient year) compared with a matched medically treated cohort (2.8%, p = 0.0001) [44]. In registry trials the risk of stroke after catheter ablation for atrial brillation was in the range of 0.42.4%/year compared with 2.89.4% in medically treated patients [4450]. The low stroke risk after catheter ablation extends to those with a CHADS2 score greater than 1 and patients who have stopped oral antithrombotic agents. Thermistoclakis

studied 3355 patients after catheter ablation for atrial brillation of whom 2692 stopped antiarrhythmic therapy [50]. None of the 347 patients in that study with a CHADS2 score greater than 1 experienced stroke after a mean follow-up period of two years. In the whole group only two patients off anticoagulation and three taking oral antithrombotic agents experienced stroke. There was one major haemorrhage in the group off anticoagulation and 13 (2%) in the group taking oral antithrombotic agents. Another large registry trial compared 4212 patients who underwent catheter ablation for atrial brillation with 16848 age and gender matched patients with atrial brillation and a similar group without atrial brillation [48]. Patients were followed for at least three years. The risk of stroke and death in the post-ablation group was similar to the no-atrial-brillation group and lower than that of the group with medically treated atrial brillation. Atrial brillation has also been associated with dementia and this is thought to be due to subclinical thromboembolic events. Bunch et al. [48] also noted a lower incidence of dementia in the post-ablation group compared to the medically treated atrial brillation population (0.2% vs. 0.9%, p < 0.0001). The risk of death for patients with atrial brillation is approximately twice the expected rate after adjustment for relevant co-morbidities [35]. This nding is supported by the meta-analysis observation that all cause mortality was reduced by warfarin in patients with non-valvular atrial brillation [51] Mortality was reduced by 26% (95% CI 343) with an absolute reduction of 1.6%. Therefore, it can be assumed that at least some of the excess mortality is due to thromboembolic events. An analysis from the AFFIRM trial demonstrated that achievement of sinus rhythm was associated with a reduction in mortality, but treatment with anti-arrhythmic drugs signicantly increased the risk for death [43]. There has been no randomised trial sufciently large to address the question of whether catheter ablation reduces mortality. A non-randomised comparison of patients undergoing catheter ablation or medical therapy for atrial brillation demonstrated a reduction in mortality [46]. This study of 1171 patients in a single centre demonstrated a hazard ratio of 0.46 (95% CI 0.310.68, p < 0.001) for death in the ablation arm. Hunter et al. also demonstrated a lower rate of death in patients undergoing catheter ablation compared with a matched medically treated cohort (0.5%/year vs. 5.3%/year, p < 0.01) [44].

Anticoagulation After Catheter Ablation

As described above the risk of stroke after catheter ablation is relatively low. Therefore the risk of anticoagulation outweighs the benets. The decision about the duration of anticoagulation after catheter ablation is complex and must take into account the individual patient risks of stroke and bleeding, the likelihood of arrhythmia recurrence and, in some cases, the results of ambulatory monitoring studies and echocardiographic estimation of atrial function.

at least 12 months), recurrence of arrhythmia was low at <10% at 5 years [55,56].

The Future of Endocardial Ablation

The future directions of catheter ablation for atrial brillation include, (1) renement of the technique to improve outcomes and (2) improvement of our understanding of the underlying pathophysiology to improve patient selection, optimise the procedure for each patient and ultimately prevention of atrial brillation by early intervention in high risk patients. A major limitation of catheter ablation is the recurrence rate. Arrhythmia recurrence is usually associated with recurrence of conduction between the pulmonary veins and left atrial myocardium. Research is being devoted to improving durability of isolation using improved techniques for delivering radiofrequency energy or alternative energy sources. Atrial brillation is the common observed outcome for a wide range of pathological processes. More work is required to understand the variations in atrial brillation mechanisms and how these relate to treatment. Patients undergoing catheter ablation for intermittent or paroxysmal atrial brillation are treated by pulmonary vein isolation alone except in the context of clinical trials. However a subgroup of these patients will have recurrence of atrial brillation despite persistent pulmonary vein isolation. There is also a group of patients with persistent atrial brillation who may be successfully treated by pulmonary vein isolation alone. Long term studies of procedural outcomes and a better understanding of the underlying pathology will help operators perform procedures better tailored to the needs of the patient.

Figure 3. Cost comparison of ablation versus antiarrhythmic drugs. An economic evaluation of the RAAFT Pilot Study.

Reproduced from Kahykin Y et al. J Cardiovasc Electrophysiol 2009;20:712, with permission.

Cost Effectiveness of Catheter Ablation

It is important to consider the cost effectiveness of catheter ablation because this intervention is relatively underfunded in the Australian health system. There is mandatory reimbursement of stents, pacemakers and debrillators by private insurers but equipment required for catheter ablation of AF is re-imbursed only on an ad hoc basis. This limits patient access to ablation procedures in the private hospital system. Similarly in the public hospital system the funding formula discourages catheter ablation for AF. Several studies have presented data on the cost effectiveness of AF ablation. A European study estimated it took three years [52] while in the US it took ve years (Reynolds Circ AE 2009) for AF ablation to be less expensive than drug therapy [53]. Recently a comprehensive study of the cost effectiveness of catheter ablation was presented by Rodgers et al. for the British National Institute for Health Research, Health Technology Assessment Programme [54]. In that review it was noted that cost effectiveness was very dependent on the durability of outcomes after catheter ablation. The randomised trials comparing catheter ablation and alternative therapies for atrial brillation provide robust outcomes only to 12 months. They concluded that if the benets were sustained for the life of the patient the cost per additional QALY was 77637910. If the benet was sustained for only ve years the cost per additional QALY was 2300038000. Thus, while the short term benet is likely to be greatest in patients with highest risk of complications and frequent hospital presentations, a sustained successful outcome in a younger patient that has not yet entered the period of highest risk may also be cost effective (Fig. 3).

Summary
Catheter ablation for atrial brillation is the most effective treatment modality for prevention of recurrence and improvement of symptoms. It may also reduce the risk of stroke and improve survival. The indications for catheter ablation include symptomatic atrial brillation in patients who have failed medical therapy, selected highly symptomatic patients as rst line therapy and patients with impaired left ventricular function. Catheter ablation is a cost effective technique for addressing the growing burden of atrial brillation.

Acknowledgements
This work is not associated with any nancial support. The Authors thank Dr Barbara Davis for her careful reading of the manuscript.

Long Term Outcomes of AF Ablation

Several studies have recently reported their long term outcomes of AF ablation. These have demonstrated quite variable results and represent that initial experience in pioneering centres with variable types of patients (AF type and substrate) and technique of AF ablation. Two studies have evaluated the long term outcomes of pulmonary vein isolation alone in patients with paroxysmal AF and have demonstrated that after achieving initial success (for

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ORIGINAL ARTICLE

Heart, Lung and Circulation 2012;21:395401

Thomas and Sanders Catheter ablation for AF

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