Best Practices for Atrial Fibrillation Ablation CME

Transcription

1 Best Practices for Atrial Fibrillation Ablation CME Author: A. John Camm Complete author affiliations and disclosures are at the end of this activity. Release Date: November 29, 2006; Valid for credit through November 29, 2007 Target Audience This activity is intended for cardiologists, clinical cardiac electrophysiologists, and attendant healthcare personnel who must maintain a current understanding of the status of catheter ablation for atrial fibrillation. Goal The goal of this activity is to assist physicians and other healthcare professionals to understand the current practice of ablation for atrial fibrillation. Learning Objectives Upon completion of this activity, participants will be able to: 1. Differentiate between anatomic and physiologic ablation techniques 2. Discuss the results of studies comparing catheter ablation with antiarrhythmic drug therapies 3. Review the study design of the CABANA trial Credits Available Physicians - maximum of 1.25 AMA PRA Category 1 Credit(s) for physicians All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Physicians should only claim credit commensurate with the extent of their participation in the activity. Accreditation Statements For Physicians Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Medscape, LLC designates this educational activity for a maximum of 1.25 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity: CME@medscape.net. For technical assistance, contact CME@webmd.net. Instructions for Participation and Credit There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. Follow these steps to earn CME/CE credit*: 1. Read the target audience, learning objectives, and author disclosures.

2 2. Study the educational content online or printed out. 3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. Medscape encourages you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates by accessing "Edit Your Profile" at the top of your Medscape homepage. *The credit that you receive is based on your user profile. This activity is supported by funding from St. Jude. Legal Disclaimer The material presented here does not necessarily reflect the views of Medscape or companies that support educational programming on These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Copyright 2006 Medscape. Contents of This CME Activity 1. Best Practices for Atrial Fibrillation Ablation Introduction -- Epidemiology and Pathophysiology of Atrial Fibrillation Rate vs Rhythm Control Rhythm Control and the Role of AF Catheter Ablation Approaches to AF Ablation International Ablation Registry on AF Catheter Ablation AF Ablation: Observations From Outcomes From Multicenter Randomized Trials Single-Center Randomized Studies AF Ablation and Survival Benefits Limitations to Existing Data Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) Trial Complications Conclusion References Best Practices for Atrial Fibrillation Ablation Introduction -- Epidemiology and Pathophysiology of Atrial Fibrillation Atrial fibrillation (AF) is a supraventricular tachyarrhythmia in which multiple reentrant electrical wavelets rapidly spread across the atria, causing uncoordinated atrial systole. [1] It is the most common arrhythmia seen in clinical practice, and its prevalence continues to rise throughout the Western world as a result of aging populations, an increase in the incidence of chronic heart disease, and more frequent AF diagnoses. [2] It is expected that these trends will continue, and recent estimates suggest that as many as 15.9 million Americans may have the disease by [3] This troubling estimate emphasizes the importance of developing effective approaches for the primary prevention of AF. [3] Currently, the arrhythmia is known to occur in 1% of the general population, amounting to approximately 2.2 million people in the United States [4] and 4.5 million in Europe. [5] The disorder is most prevalent in those aged 65 years (median age, 75 years), and its prevalence increases with advancing age, affecting approximately 9% of the population over 80 years old. [6] Data from the Framingham Heart Study suggest that 1 in 4 older individuals will experience AF during their lifetime. [7] Formerly considered a relatively benign disease, AF is now known to be an independent predictor of both death and stroke and is associated with significant morbidity. [1] Compared with people in normal sinus rhythm, the presence of AF confers twice the risk of mortality. [8] This risk increases with the severity of underlying heart disease and is particularly acute in AF patients with chronic heart failure, [9] as the coexistence of the 2 conditions creates a vicious cycle. Stroke is an especially serious concern, since nonvalvular AF confers a 5-fold increase in the risk of ischemic stroke, which increases as patients age. [8] It is estimated that 15% to 20% of all strokes (or 1 in every 6) that occur annually in the United States are secondary to AF [10] -- a statistic that highlights the necessity for some type of anticoagulation in these patients, including the use of warfarin in patients at the highest risk for stroke. [1]

3 There are also some significant pathoanatomic and pathophysiologic changes in the heart that are associated with long-term AF, particularly in patients with concomitant heart disease. These include severe atrial fibrosis and loss of muscle mass, which may disrupt normal conduction and can make normal sinus rhythm difficult to reestablish. Such changes contribute to atrial remodeling, which perpetuates the arrhythmia. Rate vs Rhythm Control In recent years, physicians have debated whether certain AF patients (eg, those with persistent AF who are older and less symptomatic) are best treated with rate-controlling drugs, such as calcium channel blockers, beta-blockers, and digoxin, or with an approach that aims to restore and maintain sinus rhythm using antiarrhythmic drugs (AADs) and cardioversion. Initially, therapy for AF was guided towards a rhythm-control approach, but the results of the landmark Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) [11] trial found no significant difference in patient outcomes between the 2 treatment strategies results that are consistent with the findings of the Pharmacological Intervention in Atrial Fibrillation (PIAF), [12] Strategies of Treatment of Atrial Fibrillation (STAF), [13] and Rate Control vs Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) [14] trials (Table 1). Table 1. Rate- vs Rhythm-Control Trials Trial (Year) Patients Studied Results PIAF [12] (2000) AFFIRM [11] (2002) RACE [14] (2002) STAF [13] (2003) N = 225; persistent AF of 7 to 360 days in duration N = 4060; > 65 years of age or who had other risk factors for stroke or death and had AF that was likely to recur The study included patients with intermittent self-terminating episodes of AF and those who required cardioversion. N = 522; persistent AF after previous electrical cardioversion; mean age 68 years N = 200; persistent AF; 44.5% were years of age and 79% had at least 1 risk factor. No difference in symptom improvement Rhythm patients had higher exercise tolerance but significantly higher rate of hospitalizations. Only 23% of patients taking amiodarone were in NSR at follow-up, although 56% of patients who were successfully cardioverted could be maintained in NSR. Amiodarone was discontinued in 25% of the rhythm patients due to drug side effects. At 5-year follow-up, 63% of rhythm patients were in NSR vs 34.6% of rate patients. No significant difference in the rate of death between the 2 groups (23.8% vs 21.3%; P =.08) The number of hospitalizations during follow-up was greater in the rhythm group (P <.001). The stroke rate was low (about 1% per year in both groups); majority of strokes occurred in patients who had stopped taking warfarin or whose INR was subtherapeutic at the time of the stroke. After mean follow-up of 2.3 years, there was no significant difference in the composite of cardiac death, heart failure, thromboembolic complications, bleeding, implantation of a pacemaker, and severe adverse drug effects. Overall results showed a trend for better outcomes in rate patients (17.2% vs 22.6%). Only 39% of rhythm patients were in NSR, and thromboembolic events were more likely in rhythm patients. No difference in the combination of death, CPR, cerebrovascular event, and systemic embolism after 19.6 mos Rhythm group had significantly more hospitalizations. Rate group showed trend toward higher rate of mortality. Most primary endpoints occurred in AF; only 1 occurred in NSR, shortly after cardioversion. The percentage of patients who were in NSR in the rhythm group after up to 4 cardioversions was 23% at 36 mos. AF = atrial fibrillation; AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; CPR = cardiopulmonary resuscitation; INR = international normalized ratio; NSR = normal sinus rhythm; PIAF = Pharmacological Intervention in Atrial Fibrillation; RACE = Rate Control vs Electrical Cardioversion for Persistent Atrial Fibrillation; STAF = Strategies of Treatment of Atrial Fibrillation AFFIRM [11] randomized 4060 patients with intermittent (mildly symptomatic) AF and at least 1 risk factor for stroke to a rate-control or rhythm-control strategy. Baseline characteristics were well balanced between the 2 groups; mean age was 69.7 years; and 39.3% and 38.2% of patients had hypertension and coronary artery disease, respectively. In 69.2% of patients, the qualifying episode of AF lasted > 2 minutes and approximately 35% of patients were enrolled following their first episode of AF. At 5-year follow-up, there was no mortality benefit associated with rhythm control (23.8% vs 21.3%; P =.08). However, rhythm-control patients were more likely to be hospitalized than those in the rate-control arm (80.1% vs 73.0%; P <.001), and only 63% of patients in this group were actually able to maintain normal sinus rhythm over the 5-year follow-up. Stroke rates were similar in both rhythm- and rate-control arms (8.9% vs 7.4%; P.93), and strokes occurred most frequently in patients who had stopped their anticoagulation medication altogether or who were on medication but were not adequately anticoagulated (ie, had international normalized ratios [INR] < 2.0). Such findings suggest that continued anticoagulation therapy is warranted in all patients, regardless of treatment strategy. Similar findings were demonstrated in the STAF [13] and RACE [14] randomized studies. However, the results of all of these trials can

4 only be applied to the fairly limited group of patients enrolled -- primarily older AF patients (> 65 years of age) who are mildly symptomatic. Thus, a rate-control strategy may not be the best option for all AF patients, particularly younger patients, those with first-onset AF or poor left ventricular function, or those who are highly symptomatic. 1. Which approach would you use for first-line treatment of your patients with persistent AF? nmlkj nmlkj nmlkj Rate control Rhythm control Ablation Rhythm Control and the Role of AF Catheter Ablation The use of rhythm control in these patient populations is further bolstered by the advent of catheter-based ablation, which has the potential to permanently restore sinus rhythm and, in some cases, obviate the need for AADs, thus addressing concerns about serious drug side effects. AF ablation has evolved considerably over the past several years and now is emerging as a recognized standard treatment option for selected patients. In fact, the recent AF clinical guidelines released jointly this year by the American College of Cardiology, American Heart Association, and European Society of Cardiology [1] for the first time characterize catheterbased AF ablation as a viable treatment option in patients with paroxysmal or persistent AF who have failed at least 1 AAD. This change came about as a result of significant clinical developments that have emerged over the past 5 years, including single-center trials demonstrating that catheter ablation is a relatively safe and effective treatment, with a substantial percentage of patients achieving eradication of their AF. The new guidelines are certain to help drive further interest in AF ablation and will likely expand the number of patients referred for this treatment. Although catheter-based ablation is rapidly becoming a part of the mainstream AF treatment armamentarium, it is important to remember that the procedure continues to evolve, with outcomes influenced by physician experience. Currently, catheter-based AF ablation carries a major complication rate of 3% to 6%, [15] even in the best of hands, although complications that are lethal or that affect long-term quality of life are rare. Success rates at experienced centers currently hover around 70% for the first procedure, with many patients requiring a repeat ablation to achieve the desired result. Moreover, ablative methods and techniques continue to vary widely, and there is a lack of large, randomized trials and long-term follow-up data that would provide the platform needed to evaluate these different approaches. Approaches to AF Ablation The underlying mechanisms of AF are an ongoing matter of debate. In general, current ablation techniques can be characterized by anatomic or physiologic approaches. The anatomic approach follows the premise that AF is characterized by reentrant loops in the atrial myocardium initiated by the rapid discharge of ectopic foci that arises from particular anatomic areas, such as the pulmonary veins (PVs). [16] Following this line of thought, the anatomic approach to ablation would involve isolating the PVs around the immediate orifice of the vein, or applying a wide-area circumferential approach. Alternatively, the physiologic approach to AF ablation centers on analyzing the functional involvement of certain areas of the heart that may initiate or perpetuate the arrhythmia and ablating those areas in an attempt to address specific arrhythmogenic foci. This can be accomplished by interrupting the continuity of the substrate with lines of block linking the PVs and/or mitral annulus or by mapping regions of slowed conduction using complex fractionated electrograms. These areas are found throughout the atria, but are primarily confined to the interatrial septum, PVs, the roof of the left atrium, and left posteroseptal mitral annulus and coronary sinus ostium (Figure 1). [17]

5 Figure 1. Sites of complex fractionated electrograms in atrial fibrillation: (1) septum including the Bachmann bundle; (2) left posteroseptal mitral annulus and coronary sinus ostium; (3) pulmonary veins; (4) roof of the left atrium; (5) mitral annulus; (6) cavotricuspid isthmus; (7) crista terminalis; (8) right and left atrial appendages; and (9) superior vena cava-right atrial junction. LAO = left anterior oblique; PA = posterior anterior. Source: J Am Coll Cardiol. 2004;43: Permission pending. Another physiologic approach uses electroanatomic mapping and high-frequency stimulation to identify areas of nerve bundle formations (ganglion plexus) in the heart that are believed to be involved in autonomic AF activation. Researchers have identified areas of atrial ganglion plexuses on the superior surfaces of the right and left atrium, the posterior surface of the right atrium, the posterior medial surface of the left atrium, and the inferior and lateral aspect of the posterior left atrium. [18] All 4 major left atrial ganglionated plexuses can be identified in vivo using electroanatomic mapping followed by endocardial or epicardial high-frequency stimulation to induce positive autonomic vagal response (as defined by an increased R-R interval induced by sinus bradycardia and/or AV block). Sites of autonomic ganglia are usually located at least 1-2 cm outside the PV ostia and represent a potential electrophysiologic substrate for AF ablation. Anatomic vs Physiologic Approach Unfortunately, there is a lack of solid, evidence-based outcomes from large, multicenter, randomized trials, which makes it difficult to discern which ablative technique may be the most optimal, and it is unlikely that a single approach to ablation will be effective for all patients. Researchers are currently modifying their approach to best fit the needs of individual patients. It is important to remember that there may be more similarities than differences between the various approaches. For instance, there is likely a significant degree of overlap in both how these procedures are performed and in the outcomes achieved. An isolation ablation, for example, may be wide enough to extend into and include some of the same ablation foci targeted during a physiologic approach. However, one technique may be more beneficial than another when treating specific forms of AF. For example, there is evidence to suggest that paroxysmal AF and permanent AF are actually distinct diseases and should be treated as such, with different ablation approaches. In the early stages of AF, the disease is more likely to be trigger-dependent, even though a vulnerable substrate is also an essential element. This suggests that patients with paroxysmal AF may be well suited to circumferential PV ablation (CPVA), regardless of the width of the ablation area. However, as the disease progresses and becomes more persistent, the substrate becomes much more important to the process. Therefore, in patients with permanent AF, initiation triggers may not play a significant role in the process. Such patients may benefit more from a wider approach to ablation or one that combines anatomic and physiologic components. Regardless of the method used, it is important to remember that while AF elimination previously referred to the absence of symptomatic AF, ideally both symptomatic and asymptomatic AF should be eliminated. International Ablation Registry on AF Catheter Ablation The results of the International Ablation Registry, [15] published last year, have provided us with a wealth of data identifying trends in catheter ablation among a heterogeneous (paroxysmal, persistent, and permanent AF) population from a large number of centers worldwide. Survey results on the methods, efficacy, and safety of catheter ablation were collected from 181 centers, including 100 centers with ongoing catheter ablation programs between 1995 and 2002 (median number of procedures per center was 37.5). During this period, the number of patients undergoing catheter ablation for AF increased dramatically at these centers, from 18 patients in 1995 to 5050 in a near doubling each successive year. The most common indication for catheter ablation was paroxysmal AF. In the early years of the study, between 1995 and 1997, the most common ablation technique was right atrial compartmentalization. Of interest, as techniques evolved (and were reported in the literature), ablation of the triggering focus became the most common technique in 1998 and 1999, and PV isolation became the most common technique between 2000 and 2002 (Figure 2). However,

6 only 26.0% of centers reported that they adhered to the same technique during the surveyed period. Figure 2. Distribution of ablation technique by year (percentage of total procedures) reported in the International Ablation Registry. LA = left atrial; PV = pulmonary vein; RA = right atrial Of the 8745 patients who completed the ablation protocol, 27.3% required > 1 procedure (24% required 2 and 3.1% required 3 procedures). Major complications occurred in 5.9% (n = 524) of all patients, which predominately included cardiac tamponade (n = 107), pseudoaneurysm (n = 47), arteriovenous fistula (n = 37), stroke (n = 20), and transient ischemic attack (n = 47). Over the course of 12 months, only 52.0% of patients were asymptomatic without the need for AADs and another 23.9% of patients were asymptomatic with the use of formerly ineffective AADs. Of note, there was wide variability between the success rates of centers, ranging from 14.5% to 76.5%, and as expected, the higher-volume centers had higher overall success rates. Overall, success rates were higher in centers with mid-range follow-up (7 to 18 months) than in centers with shorter or longer follow-up periods. This suggests that AF relapses may occur more than 18 months after ablation, possibly due to PV reconnection. These outcome rates differ somewhat from those reported previously -- a reflection of the learning curve for each technique, the inconsistency of how operators perform these procedures, and the heterogeneity of the patients. This survey also canvassed results from ordinary rather than only pioneering centers. But despite the variance in results, this survey clearly demonstrates that catheter ablation for AF is evolving into a mainstay of treatment and, as techniques improve, so too will outcomes. AF Ablation: Observations From The results from the International Ablation Registry provide us with an understanding of the current trends in clinical practice, namely that there is a learning curve associated with the procedure (reflected in the high success rates of more experienced centers) and that techniques continue to evolve and improve outcomes. Similarly, if we track the results from AF ablation studies conducted between 1999 and 2005, we can see specific trends suggesting that greater experience and improved techniques result in better outcomes. Such data will also enable us, in part, to see how far we have come and also to determine exactly what is missing in terms of solid outcomes data. The early studies of AF ablation (performed between 1999 and 2002) mostly involved patients with paroxysmal AF, although some included a few patients with persistent AF, and most used circumferential ablation techniques. [19-31] In addition, the follow-up in these early studies was short and there was a fair number of redo procedures in some series. Despite these inconsistencies, most studies achieved drug-free success rates of around 70%. In more recent studies ( ), success rates are closer to 80%. [15,32-40] Unfortunately, we are still missing significant data, thus leaving many of our questions unanswered (Table 2). Table 2. Outcomes of AF Ablation: Later Studies ( ) Lead Author (Year) Patients (N) Follow-up (mos) % Redo AF Elimination (%)* Chen [32] (2003) n/a 73

7 Marchilnski [33] (2003) Marrouche [34] (2003) n/a 86 Oral [35] (2003) Pappone [36] (2003) n/a 80 Haissaguerre [37] (2004) Mansour [38] (2004) Nademanee [39] (2004) Pappone [40] (2004) n/a 90 Cappato [15] (2005) *Without drugs Outcomes From Multicenter Randomized Trials As evidenced by the aforementioned studies, the use of catheter ablation for the treatment of AF has been under investigation for several years. However, it was not until recently that data from randomized, prospective trials have emerged. Catheter Ablation for the Cure of Atrial Fibrillation (CACAF) Trial The Catheter Ablation for the Cure of Atrial Fibrillation (CACAF) [41] trial was the first open, prospective, multicenter, randomized study to examine the adjunctive role of catheter ablation to AAD therapy in patients in whom prior AAD therapy failed. The study enrolled 137 patients (mean age, 62 years) with paroxysmal or persistent AF who had failed at least 2 previous courses of AADs. All patients had their first diagnosis of AF at least 6 months prior to enrolling in the study, and most had a long history of AF (mean history, 6 years). Patients were randomized to CPVA and AAD treatment (n = 68) or AADs alone (n = 69). Patients in the ablation group had a significantly longer history of AF and were more likely to be on oral anticoagulant therapy than patients in the control group (Table 3). Table 3. CACAF: Baseline Characteristics Characteristic Ablation (n = 68) Control (n = 69) Clinical Age (yrs) Female (%) Paroxysmal AF (%) AF history (yrs) * Left atrial diameter (mm) Ejection fraction (%) Concomitant Drug Therapy Amiodarone (%) Flecainide (%) Propafenone (%) 7 10 ACE inhibitors (%) Statins (%) Oral anticoagulant (%) Previous ablation (n) *P =.02; P =.003 ACE = angiotensin-converting enzyme; AF = atrial fibrillation At 12-month follow-up, the use of catheter ablation with AAD therapy was associated with a significantly lower rate of atrial arrhythmia recurrence compared with patients who received AADs alone (44.1% vs 91.3%; P <.001). Of the 30 patients in the ablation group with recurrence, 26 had AF and 4 patients had atrial flutter. In addition, arrhythmia-free survival at 12 months was significantly higher in the ablation arm (~64% vs 10%; P <.001). There was no significant difference in the number of hospitalizations over the study period between the 2 groups (P =.34). Atrial Fibrillation Ablation vs Antiarrhythmic Drugs (A4) Trial

8 The Atrial Fibrillation Ablation vs Antiarrhythmic Drugs (A4) [42] trial was a randomized multicenter study comparing catheter ablation with AADs in patients with symptomatic paroxysmal AF who failed prior AAD therapy. The primary endpoint was AF for 3 minutes (beyond Month 3) that was either symptomatic or documented. At baseline, 112 patients (mean age, 51 years) with a mean of 20 AF episodes per month lasting 9 ± 9 hours who had failed at least 1 course of AAD therapy were randomized to ostial PV isolation ablation (n = 53) or AAD therapy (n = 59). Crossovers were permitted at 3 months in case of failure and by study end, 37 patients in the AAD arm crossed over to the ablation group. At 1-year follow-up, freedom from AF was significantly higher in patients treated with ablation than in those in the AAD group (75% vs 7%; P <.0001). In addition, 60% of patients in the ablation group were able to discontinue oral anticoagulation therapy compared with 25% of AAD patients who did not cross over. Patients in the ablation group reported a significantly higher quality of life than patients treated with AAD alone. The results of A4 suggest that in patients with symptomatic paroxysmal AF who have failed prior AAD therapy, catheter ablation may be a better treatment option than switching to another AAD. Radiofrequency Ablation for Atrial Fibrillation Trial (RAAFT) Whereas the CACAF and A4 trials evaluated the role of catheter ablation as a second-line therapy in patients who failed prior AAD treatment, the Radiofrequency Ablation for Atrial Fibrillation Trial (RAAFT) [43] was designed to test the feasibility of PV isolation as a front-line therapy for treating patients with symptomatic AF. The pilot phase of the trial, completed in Europe, randomized 70 patients with monthly symptomatic AF episodes for at least 3 months who had not received prior AAD treatment to PV isolation radiofrequency ablation (n = 33) or AAD (n = 37). The majority of patients (~95%) in both arms had paroxysmal AF; mean duration of AF symptoms and ejection fraction were similar for the 2 groups. At 12-month follow-up, the rate of AF recurrence was significantly lower in the ablation group than in the AAD group (13% vs 63%; P <.001). Hospitalizations were also significantly lower in the ablation group (9% vs 54%; P <.001). In addition, improved quality of life was significantly better in the ablation group. All 4 patients in the ablation group with AF recurrence underwent a second ablation procedure; at the time of publication, the authors reported that 3 of these patients were free of AF and not on AAD therapy and 1 patient was in sinus rhythm on active AAD treatment. The pivotal phase of the RAAFT trial is scheduled to begin in the first quarter of Single-Center Randomized Studies In addition to the aforementioned multicenter trials, 2 recent studies from the group at San Raffaele University Hospital (Milan, Italy) [44,45] demonstrated that in patients treated at their center, CPVA was more effective than AADs for the treatment of paroxysmal and chronic AF. Ablation for Paroxysmal Atrial Fibrillation (APAF) The Ablation for Paroxysmal Atrial Fibrillation (APAF) [44] study was a controlled, randomized trial that enrolled 198 patients (age 56 ± 10 years) with paroxysmal AF (duration 6 ± 5 years, mean AF episodes 3.4 per month) who had failed an average of 2 prior AAD therapies. Patients were randomized to CPVA (n = 99) or to AAD therapy (n = 99) with flecainide, sotalol, or amiodarone (either as single drugs or in combination at the maximum tolerable dose). The follow-up period began after a 6-week blanking period; crossover was permitted after 3 months. The trial's primary endpoint was freedom from documented recurrent atrial arrhythmias (AF, atrial tachycardia, and atrial flutter lasting > 30 seconds) at 1 year; secondary endpoints included monthly rhythm analysis, adverse events, and left atrial remodeling. Repeat ablation was performed in 9% of ablation patients for recurrent AF (6%) or atypical atrial flutter (3%). There were 42 crossovers in the AAD group after a mean of 5.8 months of follow-up. Of these patients, 36 were free of recurrent AF in the absence of AAD at 6.2 months of follow-up. By Kaplan-Meier analysis at 1 year, of the patients randomized to CPVA, 86% were arrhythmia free compared with only 22% of patients randomized to the AAD group (P <.001). Multivariate analysis identified CPVA as an independent predictor of freedom from paroxysmal AF. Of patients in the AAD group, a lower ejection fraction, hypertensive cardiomyopathy, and age were all independent predictors of AF recurrence; there were no independent predictors of recurrence in ablation-treated patients. Patients in the ablation group had a significantly lower rate of cardiovascular hospitalization than the AAD group (P <.001). In addition, at 12 months, left atrial diameter significantly decreased from baseline in the CPVA group (P <.001). Adverse events in the ablation group included 1 transient ischemic attack and 1 pericardial effusion; 23 patients in the AAD group reported side effects. Of note, the low rate of adverse events in the ablation group is likely a reflection of the extensive experience the Italian researchers have with catheter ablation for AF. Ablation vs AAD in Chronic AF Similar success rates were noted by Oral and colleagues, [45] who reported the outcomes of CPVA vs AAD therapy patients with chronic AF. With the exception of enrolling patients with chronic (vs paroxysmal) AF, baseline characteristics of patients in this study were relatively similar to those enrolled in APAF: mean age 57 ± 9 years, 8% had clinically significant structural heart disease, duration of AF 4-5 years, and had failed an average of 2 prior AAD therapies. A total of 145 patients were randomized to receive amiodarone and undergo 2 cardioversions within the first 3 months alone (n = 69) or in combination with CPVA (n = 77). The study's primary endpoint was freedom from AF and atrial flutter in the absence of AAD therapy at 12-month follow-up. Secondary endpoints included the incidence of complications, changes in left atrial diameter, as well as changes in the severity of symptoms at 12 months. Of the patients in the CPVA group, repeat ablation was performed in 26% of patients for recurrent AF and in 6% of patients who developed atypical atrial flutter. By intention-to-treat analysis, investigators reported that freedom from recurrent AF or atrial flutter at 1 year was significantly higher in patients treated with ablation vs AAD therapy (74% vs 58%; P <.05). During the follow-up period, 77% of patients In the AAD group crossed over and underwent CPVA for recurrent AF; only 4% of all AAD patients were in sinus rhythm without the need for AAD therapy or ablation. Of patients in the CPVA group who maintained sinus rhythm after the

9 procedure, left atrial diameter significantly decreased from baseline, as did symptom severity score (P <.001 for both comparisons from baseline to follow-up). With the exception of atypical flutters in the CPVA group, there were no reported complications in either group. AF Ablation and Survival Benefits At the recent 2006 Scientific Sessions of the American Heart Association, investigators at the Mayo Clinic (Rochester, Minnesota) reported their findings indicating that patients with AF who undergo catheter ablation have a lower long-term mortality rate than that of a disease-matched control population who do not undergo the procedure. [46] The study included 731 patients who underwent radiofrequency ablation for AF between 1999 and The rate of survival at 5 years was assessed in the ablation patients and compared with a control group consisting of 4429 residents of Olmsted County, Minnesota who had AF but did not undergo ablation. Patients in the ablation group were younger than the control population (54 years vs 73 years), were more likely to be male, and were more likely to have persistent or permanent AF (43% vs 26%). Mean duration of AF in the ablation group was 6.3 ± 5.9 years. Ablation technique consisted of PV isolation using a lasso-guided approach (46%), a wide area circumferential ablation (41%), or a more focal or segmental approach (13%). Investigators reported that survival at 5 years was significantly higher in the ablation vs control groups (94% vs 52%, P <.001). Subgroup analyses showed that the survival rates in the ablation group were higher in patients with paroxysmal AF vs those with persistent/permanent AF (98% vs 85%); the survival rate in the control group was ~50% regardless of the type of AF (Table 4). After adjusting for age and gender, ablation remained an independent predictor of survival (hazard ratio 0.16 [CI ]; P <.001). Table 4. Five-Year Survival by AF Type AF Type Ablation Control All (%) Paroxysmal AF (%) Persistent/Permanent (%) P <.001 for all comparisons The results from this study suggesting a survival benefit, coupled with the results of the aforementioned studies (Table 5), are extremely promising and emphasize the need to conduct large, randomized, prospective clinical trials to fully assess the comprehensive role of catheter ablation in a heterogeneous AF population. Table 5. Randomized Trials Comparing Ablation Therapy With AADs Trial (Study Design) Patients Studied Results Multicenter CACAF [41] (2006)(Adjunctive CPVA + AAD vs AAD alone) A4 [42] (2006) [42] (Ostial PV isolation ablation vs AAD alone) RAAFT [pilot] [43] (2005) (Primary PVI ablation vs AAD alone) Single center APAF [44] (2006)(CPVA vs treatment with 1 of 3 AADs [flecainide, sotalol, or N = 137; paroxysmal or persistent AF; first diagnosis > 6 mos prior to enrollment; failed 2 AADs N = 112; symptomatic paroxysmal AF > 6 mos' duration; > 2 AF episodes per month; resistance to 1 Class I or III AAD N = 70; monthly symptomatic (primarily paroxysmal) AF episodes 3 mos; no prior AAD therapy N = 198; paroxysmal AF > 6 mos (mean duration 6 ± 5 yrs); AF burden > 2 episodes/mo; failed > 1 prior AAD At 12 mos, compared with AAD only, ablation + AAD was associated with: Lower atrial arrhythmia recurrence (91.3% vs 44.1%; P <.001) Higher arrhythmia-free survival (10% vs ~64%; P <.001). No significant difference in hospitalizations At 12 mos, compared with AAD only, ablation was associated with: Higher rate of freedom from AF recurrence (7% vs 75%; P <.0001) Higher rate of ability to discontinue anticoagulation therapy (25% vs 60%) Compared with AAD only, primary ablation was associated with: Lower rate of AF recurrence at 12 mos (63% vs 13%; P <.001) Lower rate of hospitalizations at 12 mos (54% vs 9%; P <.001) Significant improvements in quality of life at 6 mos At 12-mo follow-up, compared with AAD therapy, ablation was associated with a significant(ly):

10 amiodarone]) therapy; age yrs Higher freedom from recurrent atrial arrhythmias (AF, atrial tachycardia, and atrial flutter) (93% vs 35%, P <.001) Decrease in left atrial diameter (15 ± 10%, P <.01) Lower rate of cardiovascular hospitalization (P <.01) Oral [45] (2006)(Amiodarone + 2 cardioversions alone or in combination with CPVA) N = 146; chronic AF (defined as AF > 6 mos without spontaneous episodes of sinus rhythm that recurred 1 week after cardioversion) At 12 mos, freedom from recurrent AF or flutter without AAD therapy was significantly higher in the ablation group (74% vs 58%; P =.05) Significant decrease in left atrial diameter (P <.001) and symptom severity score (P <.001) in patients who remained in sinus rhythm after ablation Limitations to Existing Data The studies discussed above add to the growing body of evidence suggesting that catheter ablation for AF is becoming a mainstay of clinical practice. Although promising, the studies comparing catheter ablation with AADs have some significant limitations. For instance, these trials were small in size, included selected populations with longer histories of AF (> 3 months) and a control group that consisted of rhythm-control patients only. In addition, long-term outcomes and outcomes of patients treated with a single procedure have not been reported. [47] Furthermore, it is important to remember that the patients in these studies had mostly been referred after multiple drug failure to an experienced ablation center for an ablation. The crossover rate was very high (predominantly crossing over to ablation), and there was usually a blanking period with ablation but none with the drug arm. Finally, the monitoring for recurrence was often simplistic. For example, in the A4 trial, the primary endpoint was symptomatic AF recurrence, suggesting that recurrence of AF was reported with the mere mention of palpitations from patients without confirmation on electrocardiogram. Although we remain optimistic regarding the general success rates after catheter ablation, we must remember that these limitations leave many unanswered questions. In addition, as we are all well aware, the degree of benefit noted from clinical trials generated in a controlled setting is often less favorable in real-world practice. The results of a recent study from researchers at the Johns Hopkins University School of Medicine (Baltimore, Maryland) [47] help instill some realism about the general success rates post ablation in current clinical practice. The investigators reported the long-term success rates (defined as freedom from symptomatic AF on and off of AAD therapy) after a single procedure in 200 consecutive patients (67% male; mean age, 56 years; 46% had paroxysmal AF) treated at their center. At 2-year follow-up, researchers reported a success rate of 28% in patients who underwent a single procedure. The rate was increased to 41% when incorporating the outcomes of those patients who underwent a repeat procedure. Of note, by subgroup analysis, patients with paroxysmal AF achieved a 69% success rate, suggesting that these patients may be considered optimal candidates for the procedure. The rate of major complications was 7.9%. These results show some room for improvement and demonstrate that the real-world rate of success (defined as off drug) following catheter ablation may be considerably lower than the 80% success rates reported in other studies. Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) Trial The limitations described above identify the significant need for large, randomized, multicenter, prospective trials that: Include a broad range of AF patients with recent onset AF; Allow physicians to determine drug therapy and ablation technique; Have a hard primary endpoint such as all-cause mortality; and Plan prespecified subgroup analyses Acknowledging this need, the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial was designed to test the hypothesis that in patients with new-onset AF, a treatment strategy of left atrial catheter ablation will be superior to current state-of-the-art therapy (either rate control or AAD therapy) to reduce the primary endpoint of total mortality. [48] This trial will include patients with recent-onset AF who are eligible for ablation and drug therapy. Patients 65 years of age or 65 years with at least 1 risk factor for coronary artery disease or stroke -- a population similar to AFFIRM -- will be randomized to drug therapy or to primary ablation. Patients randomized to ablation will undergo a subsequent randomization to continue or discontinue anticoagulation therapy (Figure 3). Up to 3000 patients will be enrolled in this trial and will be followed for an estimated duration of 5 years.

11 Figure 3. CABANA trial design. Adapted from Packer DL. Ablation of atrial fibrillation: outcomes. Program and abstracts from the 2005 Scientific Sessions of the American Heart Association; November 13-16, 2005; Dallas, Texas. To mimic real-world practice and avoid confounders such as a physician's unfamiliarity with a specific ablative approach, the trial design leaves the actual course of drug (rate- or rhythm-control) treatment strategy as well as the technique for performing ablation (PV isolation, wide-area circumferential ablation, complex fractionated electrogram, or ganglion plexus ablation) to the discretion of the physician. Prespecified secondary analyses will examine the influence of sinus rhythm, underlying heart disease, age, AF type, and the effects of anticoagulation on outcomes. As one of the first randomized trials to offer these types of comparisons, the CABANA trial should provide a great deal of the data and outcomes necessary to fill in some of the gaps we currently have in clinical experience with AF ablation. Complications Cather ablation procedures are not without risks and complications. The most common complications include vascular complications secondary to venous access, PV stenosis, transient ischemic attack, cardiac tamponade, phrenic nerve dissection, and proarrhythmia resulting from reentrant tachycardia. Less frequent complications include valvular injury, thromboembolic stroke, cerebrovascular aneurysm, PV dissection, bradycardia, and death. Injuries to the laryngeal nerve, vagal nerve, and esophagus (with the fatal development of atrio-esophageal fistula) have also been reported following AF ablation procedures. Although it is important to remember that lethal or significantly morbid complications are relatively rare, patients must be apprised of these risks. The rates of major complications vary, ranging from 3% at experienced centers (Table 6) to as high as 6% to 8% in centers with less experience. [15,34-36,38,39,49] This reflects the fact that complications tend to decline in frequency as we gain more experience with this procedure. Thus, reported complication rates can be affected by a wide range of variables; however, we may not know what these variables are when we look at the outcomes data. Table 6. Adverse Events of AF Ablation From Experienced Centers Lead Author N Follow-up (mos) Death (%) Stroke (%) Tamponade (%) PV Stenosis (%) Marrouche [34] (2003) Oral [35] (2003) Pappone [36] (2003) Mansour [38] (2004) Nademanee [39] (2004)

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