Catheter ablation for atrial fibrillation: Should it be first-line therapy?

Catheter ablation for atrial fibrillation: Should it be first-line therapy? J. Marcus Wharton, MD Charleston, SC Although much has changed in the management of atrial fibrillation (AF) over the past 20 years, pharmacologic therapy still remains the principal means of treatment. h-adrenergic blockers, calcium-channel blockers, and digoxin are used to slow the ventricular rate during AF. Warfarin and aspirin are used to decrease the stroke risk associated with AF. Class I (eg, propafenone, flecainide, disopyramide) and class III (eg, sotalol, dofetilide, amiodarone) antiarrhythmic drugs are used to decrease the frequency of recurrences of AF. Although these pharmacologic approaches are all relatively effective, there are significant limitations and risks of side effects. Rate control drugs frequently have associated nuisance side effects, such as fatigue, decreased exercise capacity, and sexual dysfunction, and may exacerbate bradyarrhythmias, heart failure, and obstructive lung disease. Pharmacologic approaches for rate control may also be ineffective for controlling rate during AF in up to 25% of patients. 1 Warfarin is substantially more effective than either aspirin alone or the combination of aspirin and clopidogrel for prevention of strokes in patients with AF. 2,3 Nonetheless, pooled data from prospective trials with warfarin demonstrate only a 65% reduction in stroke risk by intention-to-treat analysis. 2 This lower than expected risk reduction is primarily related to the frequent discontinuation of warfarin because of concerns about bleeding risks and the difficulties maintaining patients in the relatively narrow therapeutic international normalized ratio range of 2 to 3. Based on pooled data from clinical trials, warfarin is associated with a 1% per patient-year risk of major bleeding and a 0.3% per patientyear risk of intracerebral hemorrhage. 2 Accumulated over time; this represents a substantial risk to patients. The risks of anticoagulation therapy are even worse under more typical clinical circumstances (ie, outside of controlled clinical studies), where the risk of major bleeding may be as high as 12%. 4 Perhaps most controversial is the use of class I or III antiarrhythmic drugs for suppression of AF recurrences. From the Division of Cardiology, Medical University of South Carolina, Charleston. Reprint requests: J. Marcus Wharton, MD, Division of Cardiology, Medical University of South Carolina, 135 Rutledge Ave., Charleston, SC 29425. E-mail: whartonj@musc.edu Am Heart J 2007;153:S74- S80 0002-8703/$ - see front matter n 2007, Published by Mosby, Inc. doi:10.1016/j.ahj.2007.01.017 These drugs only decrease the frequency of recurrences, but they do not prevent all recurrences. Thus, they are not curative, but only palliative. Although they may suppress episodes of AF for some period of months or years, they tend to lose efficacy over time. Amiodarone has been shown to be more effective in the short term than other antiarrhythmic drugs. However, it too becomes less efficacious during long-term follow-up. 5 There is also a price to pay for antiarrhythmic drugs, not only in what patients pay at the pharmacy (typically about $100-$250 per month for a class I or III antiarrhythmic drug), but also in terms of both nuisance and more serious side effects. Although amiodarone is the most effective available antiarrhythmic drug, the rates of discontinuation because of toxicity after several years of low-dose amiodarone may be as high as 40%. 6 Antiarrhythmic drugs may even worsen survival. 1 Subanalysis of the data from the AFFIRM trial demonstrates that maintaining sinus rhythm in patients with AF reduce mortality by 50%. 7 However, this benefit is counterbalanced by the observation that the use of class I and III antiarrhythmic drugs used to maintain sinus rhythm increases mortality, so that the overall net therapeutic effect on mortality of the rhythm control approach is neutral at best when compared with rate control approaches. 1,7 Clearly, what is needed is a better strategy for maintaining sinus rhythm that does not require the use of antiarrhythmic drugs with their multiple associated adverse effects. Catheter ablation of AF One approach that has evolved as our understanding of AF has increased is the use of catheter ablation to eliminate the pulmonary vein (PV) initiators that start most episodes of AF. 8 One ablation technique, called ostial isolation, creates either segmental or circumferential lesions at the ostia of the PVs. 9 The goal of this procedure is to electrically isolate the PV myocardial sleeve, along with their AF initiation sites from the left atrium. Another related approach, called wide-area circumferential ablation, extends the circle of ablation much further out beyond the ostium and into the atrial antrum of the PVs. 10 Each of these approaches has been relatively effective for treating most patients with either paroxysmal or persistent AF. Figure 1 is from a retrospective analysis from this institution that evaluated the success of these AF ablation techniques. 11 Although

American Heart Journal Volume 153, Number 4 Wharton S75 Figure 1 Figure 2 Retrospective comparison of three AF ablation methods. wide-area circumferential isolation appears to be somewhat more effective than either segmental or circumferential PV ostial isolation, the difference among the procedures was not statistically significant ( P =.1). Other studies have shown that wide-area circumferential ablation is both significantly better and worse than segmental isolation. 12,13 Regardless of the conflicting results of these studies, they demonstrate significant efficacy for cure of AF with some form of PV isolation procedure. There are several emerging catheter technologies that are designed to make ostial ablations easier to perform. One is the cryoablation balloon catheter. The cryoablation balloon catheter is a deflectable, balloon-tipped catheter that is inserted into the PV. After inflation, a freezing agent is introduced into the balloon. Tissue in contact with the balloon is frozen and destroyed, isolating the PV. The freezing process occurs relatively quickly, taking about 5 minutes per PV per application, although several applications may be necessary for complete isolation. Preliminary studies using the cryoballoon have shown cure rates approaching 80% in patients with paroxysmal AF; however, to date, it has been considerably less effective in treating patients with persistent or chronic AF. 14 Another emerging technology is the high-intensity focused ultrasound balloon catheter (Figure 2). This catheter has a unique balloon design. It consists of a balloon with an inner, smaller diameter, distal portion designed to insert into the PV, whereas the larger diameter, outer balloon rests outside the PV ostium. A piezoelectric crystal incorporated into the catheter emits ultrasound, which is reflected and focused by a second balloon interface within the larger portion of the primary balloon. This reflecting surface is designed to focus the ultrasound to achieve ablation up to 6 mm High-intensity focused ultrasound PV isolation catheter. Image courtesy of ProRhythm, Inc, Ronkonkoma, NY. from the surface of the larger portion of the balloon adjacent to the PV ostia. It is not necessary for the balloon to be in contact with the myocardium to achieve adequate ablation. Preliminary studies have shown that high-intensity focused ultrasound approach is also very effective in treating patients with paroxysmal AF. 15 Despite the potential ease of use of these higher powered balloon ablation catheters, the question remains as to whether their higher energy use will be associated with a high risk of collateral damage to such organs as the phrenic nerve and esophagus. Several studies have shown that the overall cure rate in patients with persistent AF using PV isolation techniques can be improved by adding linear ablation lesions across the left atrium to connect the left and right PV isolation rings, and across the mitral isthmus from the left-sided PVs to the mitral valve. 16-18 The purpose of these additional ablation lines is to prevent left atrial macroreentrant tachycardias, which are a fairly common problem after AF ablation. When these lines are added to the procedure, long-term maintenance of sinus rhythm improves significantly, from about 70% to 85% in patients with persistent AF. 16-18 Beyond PV isolation and wide-area circumferential ablation, 2 other techniques have shown promise in improving the long-term success of AF ablation. One technique focuses on ablating autonomic targets, specifically the 4 parasympathetic ganglionic plexuses located in the epicardium of the left atrium. Interest in ablating these areas derives from the well-known

S76 Wharton American Heart Journal April 2007 relationship between increased vagal tone and the onset of AF. 19 Studies have also shown that vagal denervation in the canine model decreases the incidence of inducible AF. 19 Small studies to date of this ablation procedure have shown that when used in conjunction with widearea circumferential ablation, the addition of ganglionic plexus ablation results in a higher AF-free success rate than if wide-area circumferential ablation is used alone (91% vs 70%). 19 However, some studies have shown that over time the effect of parasympathetic ganglia ablation resolves, raising questions about the long-term effect of this approach on efficacy. 20 Another evolving ablation technique, called substrate ablation, identifies areas during AF where the electrogram on the ablation catheter is very fractionated and continuous compared with other sites. Ablation of these areas has proved to be effective in curing both paroxysmal and chronic AF. In a study by Nademanee et al 21 of 121 patients with refractory AF (57 paroxysmal, 64 chronic) undergoing substrate ablation, 91% of patients remained free of arrhythmia and symptoms at 1 year. Addition of substrate ablation to PV isolation may be particularly important for treatment of patients with chronic AF. As old techniques continue to evolve and new techniques are developed, prospective studies will be needed to determine the best approach for different patient populations with AF. Figure 3 Candidates for AF ablation Because of the significant advances in ablation techniques and technology that have occurred over the past decade, AF ablation can now be safely and effectively performed in just about any patient with paroxysmal, persistent, or even chronic AF. Catheter ablation of AF has been shown to be highly successful regardless of patient age, history of prior cardiac surgery, or presence of concomitant valvular disease. 22-24 Even patients with a prosthetic mitral valve, a group previously considered to be particularly difficult to ablate, have single-procedure AF-free rates that are similar to those of patients without a mitral valve prosthesis. 24 Catheter ablation has also been shown to be highly effective in treating AF in patients with heart failure. 25 In the heart failure population, sinus rhythm may improve overall left ventricular (LV) function. This is illustrated well in Figure 3, A and B, which is from a study by Hsu et al 25 of the effects of AF ablation in patients with heart failure. Figure 3, A clearly shows significant improvement in LV ejection fraction (LVEF) after the restoration of sinus rhythm after ablation. This is perhaps not too surprising because AF-related, tachycardia-induced cardiomyopathy is eliminated after ablation. The more surprising finding from the study is shown in Figure 3, B, which shows the effect of rate control before ablation on LV function after ablation. Remarkably, even patients A, Effect of AF ablation on LVEF in patients with heart failure. Plotted values are means FSD. P values, which are for the comparison with baseline data, were determined with the use of Fisher least significant difference test. B, Effect of rate control before ablation on LVEF after ablation in patients with heart failure. Plotted values are means FSD. P values are for the comparison with baseline data. Reprinted with permission from New England Journal of Medicine. 25 Copyright n 2004, Massachusetts Medical Society. All rights reserved. who had well-controlled heart rates during AF before ablation had a significant improvement in their LVEF after ablation. This suggests that it is not just the tachycardia that makes heart failure worse, but also the rate irregularity of AF that poses a hemodynamic burden. AF ablation versus medical therapy Clearly, our understanding of what type of ablation should be performed for various AF patient subsets is

American Heart Journal Volume 153, Number 4 Wharton S77 Figure 4 Figure 5 Quality of life after AF ablation versus medical therapy. Adapted from Pappone et al. 26 Retrospective comparison of survival between medical and PV isolation ablation therapies. Adapted from Pappone et al. 26 still evolving; nonetheless, we are now able to cure most AF patients with ablation, even those with chronic AF. But how does ablation compare overall to antiarrhythmic drug therapy for AF? Recurrence of AF Retrospective studies certainly show much less AF with ablation than with antiarrhythmic drug therapy. 26 If we look at the patients who have a recurrence of their AF after undergoing ablation, it is usually due to recurrence of conduction between the left atrium and the PV. 27 In these patients, a touch-up procedure to reisolate the PVs is usually all that is needed to eliminate the AF. At present, single-procedure cure rates run about 70% to 85% for paroxysmal and persistent AF, whereas cumulative procedure cure rates after one or more ablation procedure now run about 95% or better. 23,26,27 There is also an emerging body of evidence from prospective, randomized trials that shows long-term, AFfree rates after catheter ablation are significantly better than those achieved with antiarrhythmic drug therapy. In the recently published results from the CACAF study, where patients were randomized to antiarrhythmic drug therapy or antiarrhythmic drug therapy plus AF ablation, combined therapy proved vastly superior in maintaining sinus rhythm after 1 year of follow-up (56% vs 9%). 28 The APAF trial has also shown favorable results, with 86% remaining AF-free at 9 months in the ablation group compared with only 22% in the antiarrhythmic drug group. 29 Recently, Oral et al 30 published results from a prospective comparison of amiodarone versus wide-area circumferential ablation for chronic AF. Overall, 74% of the patients in the ablation group were AF-free at 1 year versus 58% of the patients in the antiarrhythmic drug group. Although the 74% cure rate for chronic AF is certainly less than that for paroxysmal or persistent AF, it is still very good, especially when compared with antiarrhythmic drug therapy. Quality of life and survival There is also emerging evidence to suggest that AF ablation may significantly improve patient quality of life. Figure 4 is from a large retrospective study by Pappone et al 26 that compared the long-term outcomes of patients who underwent ablation for AF to patients who received long-term antiarrhythmic drug therapy. For patients in the ablation group, both mental and physical functioning scores on the SF-36 rather quickly normalized to that of age- and sex-matched control patients who did not have AF. For patients in the antiarrhythmic drug group, however, both scores remained significantly depressed during follow-up. Data from the same study also suggest that AF ablation may improve survival. 26 As Figure 5 shows, ablation lengthened survival to almost that expected for the general population, whereas survival of medically treated patients was significantly worse. It is important to be careful when interpreting these data, however, as they are based on a single retrospective analysis with the inherent biases that may affect retrospective studies. Nonetheless, there are many theoretical reasons why sinus rhythm may improve survival and these are the first available data hinting at a significant survival benefit with ablation compared with medical therapy. Clearly, a large-scale, prospective study is needed to evaluate the impact of catheter ablation on survival. If a survival benefit can be confirmed from such trial, this would have important implications for the use of AF ablation as first-line therapy for AF.

S78 Wharton American Heart Journal April 2007 Table I. Impact of AF ablation on health care use and costs Figure 6 Before ablation After ablation P Clinic visits 7.4 F 2.5 1.1 F 0.6 b.05 Emergency 1.7 F 0.9 0.03 F 0.17 b.05 room visits Hospitalizations 1.6 F 0.81 0 b.05 Health care costs $1920 F 889 $87 F 68 b.01 Procedure cost $17,173 F 2466 All values in US dollars. Table II. Complications after AF ablation Complication Incidence (%) Vascular injury 0-8 Cardiac perforation 0.1 Stroke Pulmonary vein stenosis Myocardial infarction Phrenic nerve injury Esophageal fistula 0.03 Total 0-6 Cost-effectiveness Catheter ablation has proved to be highly costeffective compared with medical therapy for AF. Table I is from an analysis performed by Goldberg et al 31 of the impact of AF ablation on health care use and costs. 31 Although the initial cost of ablation is high (about $20,000), subsequent health care resource use is much lower than it is for antiarrhythmic drug therapy, decreasing from about $2000 per year to $87 per year. A preliminary analysis from the Canadian Registry of Atrial Fibrillation suggests that the increased cost of AF ablation is equaled after about 4 to 6 years of medical therapy across patient subgroups. 32 Clearly, this represents a large net savings over a patient s lifetime and hopefully will result in a reduction in national health care expenditures for AF. Potential risks Like all invasive procedures, AF ablation carries some risk. Fortunately, complication rates are relatively low, ranging from about 0% to 6% at experienced centers. 33 As Table II shows, the majority of complications are vascular related, with most involving the femoral vessels. This is not surprising because several femoral cannulations are performed during the procedure and patients are discharged home on aggressive anticoagulant therapy, typically enoxaparin with or without aspirin to maintain anticoagulation as warfarin is restarted. Fortunately, most vascular complications are not life-threatening. A more serious potential complication is cardiac perforation and tamponade requiring pericardial drainage. Although the risk of cardiac perforation decreases Radio frequency ablation versus antiarrhythmic drugs as first line therapy for atrial fibrillation. Adapted from Wazni et al. 40 as operator experience increases, it never goes away completely. The risk of cardiac perforation is about 1% and increases as patients get older and cardiac tissue becomes more frail. 33 This is an important risk to consider when advising elderly patients about AF ablation. There is a small risk of stroke with AF ablation, which occurs in about 0.1% to 1%. 33,34 Myocardial infarction is another potential complication in at-risk patients, but this can be avoided by adequate screening of patients before their procedure. Phrenic nerve injury may also occur in up to 0.5% of patients, 35 and may be higher with some of the newer high-energy technologies. There is also a risk of atrioesophageal fistula formation after AF ablation. 36,37 This potentially lethal complication was originally described after intraoperative RF ablation. 37 The estimated incidence in a recent retrospective analysis of catheter ablation of AF was 0.03%. 38 However, various means of limiting RF injury to the esophagus are now being used or evaluated, so hopefully even fewer cases will be seen in the future. AF ablation: ready for prime time? For the first time, the recently updated American College of Cardiology/American Heart Association/European Society of Cardiology guidelines for the treatment of AF include catheter ablation as a treatment option. 39 Medical therapy remains first-line therapy, but now catheter ablation is listed as second-line therapy for symptomatic patients with AF who have not responded to at least one trial of a class I or III antiarrhythmic drug. However, given the remarkable success rates that are now achieved with AF ablation, should AF ablation be considered for first-line therapy?

American Heart Journal Volume 153, Number 4 Wharton S79 Definitive data are unfortunately lacking at present, although there is one small, randomized clinical trial by Wazni et al 40 to suggest that AF ablation is a reasonable choice for first-line therapy for AF. In the study, 70 patients, most of whom had paroxysmal AF, were randomized for their first therapy to either catheter ablation or antiarrhythmic drugs. Inclusion criteria required patients to have AF for at least 3 months and to have no prior cardiac surgery, no prior catheter ablation or antiarrhythmic drugs, and no contraindications to anticoagulation. Patients in the trial were relatively young, had a normal left atrial size, and had a preserved ejection fraction. As Figure 6 shows, those randomized to the catheter ablation group did much better than those in the antiarrhythmic drug group, with 90% in the ablation group being cured of AF with a single procedure. Patients in the ablation group also experienced a significantly greater improvement in quality of life and fewer hospitalizations than the antiarrhythmic drug therapy group. Complication rates were similar between the 2 groups. Of course, additional prospective, randomized trials of AF ablation are needed before we can definitively say it should be first-line therapy, but at least we have some early evidence suggesting that AF ablation is a reasonable alternative to antiarrhythmic drug therapy. Summary Although catheter ablation is not a totally benign procedure, it clearly has a number of important benefits over antiarrhythmic drug therapy: it is curative over a broad range of patients; it eliminates the need for antiarrhythmic drugs and potentially chronic anticoagulation; it is associated with a lower long-term risk of adverse events; it improves quality of life; it decreases hospitalizations and office visits; it is more cost-effective; and it may improve survival. However, nearly 200,000 new cases of AF are diagnosed each year in the United States, but only about 100 centers are currently performing AF ablation. Thus, the medical system is not at the point where it can provide this care for all AF patients. Hopefully, as new techniques and technologies make the procedure easier, safer, and quicker to perform, catheter ablation of AF will emerge as a first-line therapy for AF. References 1. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825-33. 2. Albers GW. Atrial fibrillation and stroke. Three new studies, three remaining questions. Arch Intern Med 1994;154:1443-8. 3. Active Waiting Group, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomized controlled trial. 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