doi: 10.1161/CIRCULATIONAHA.104.478263
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(Circulation. 2005;112:1214-1230.)
© 2005 American Heart Association, Inc.
Controversies in Cardiovascular Medicine |
Should atrial fibrillation ablation be considered first-line therapy for some patients?
Why Atrial Fibrillation Ablation Should Be Considered First-Line Therapy for Some Patients
From the Section of Cardiac Pacing and Electrophysiology, Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio (A.V., A.N.), and The Care Group, LLC, Indianapolis, Ind (B.J.P., E.N.P.).
Correspondence to Andrea Natale, MD, Co-Section Head of Pacing and Electrophysiology, Co-Chairman Center for Atrial Fibrillation, Cleveland Clinic Foundation, Desk F 15, 9500 Euclid Ave, Cleveland, OH 44195. (e-mail natalea{at}ccf.org); or Eric N. Prystowsky, MD, FACC, The Care Group, LLC, 8333 Naab Rd, No. 400, Indianapolis, IN 46260 (e-mail eprystow@thecaregroup.com).
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Introduction |
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 Top Introduction The Importance of Sinus...The Inadequacy of Nonablative...AF Ablation: A Cure...Ablation: For Whom and...ConclusionsReferences |
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Atrial fibrillation (AF) is an increasingly common disease that affects patient morbidity and mortality. To date, treatments of AF have been frustrating, serving at best to palliate this arrhythmia. AF ablation, on the other hand, has emerged as a promising new treatment strategy. In contrast to rate control or antiarrhythmic drugs, ablation offers the possibility of a lasting cure. When ablation was first described, it was prudently reserved as a "last-line" treatment for highly symptomatic patients who were refractory to all other options. However, over the past 5 years, many centers worldwide have been reporting high success rates and few complications with ablation. There is also an increasing consistency in the way in which the procedure is performed, although some of the tools may still differ. AF ablation has reached "prime time," and it appears appropriate that we expand its indications.
We believe that it is now appropriate to offer AF ablation as first-line therapy for selected patients in experienced centers. Here, we stress the importance of maintaining sinus rhythm, the poor efficacy of nonablative treatments, and the emergence of an effective and safe approach to AF ablation.
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The Importance of Sinus Rhythm |
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TopIntroductionThe Importance of Sinus...The Inadequacy of Nonablative...AF Ablation: A Cure...Ablation: For Whom and...ConclusionsReferences |
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Recently, the importance of maintaining sinus rhythm has been called into question. A few large clinical trials have been published comparing treatment strategies for AF. In particular, the AF Follow-up Investigation of Rhythm Management (AFFIRM),1 Rate Control Versus Electrical Cardioversion for AF (RACE),2 and Strategies for Treatment of AF (STAF)3 trials compared a strategy of rate control and a rhythm control approach using antiarrhythmic drugs. Using an intention-to-treat analysis, these trials concluded that there was no mortality difference between the 2 approaches and that, for the patients enrolled, a rate control approach may be adequate treatment for AF. However, it would be incorrect to extrapolate that sinus rhythm offers no benefit over AF and that effective treatments to maintain sinus rhythm need not be pursued. First, these trials were not comparisons of sinus rhythm and AF. They compared a rate control strategy to a rhythm control strategy that attempted to maintain sinus rhythm but fell very short. The success rates of the rhythm control strategy were very poor (Figure 1). Additionally, many patients in the rate control arm were spontaneously in sinus rhythm by the end of the study periods, from 10% in STAF and RACE to 35% in AFFIRM. When the data from these trials are analyzed according to the patient’s actual rhythm (as opposed to their treatment strategy), the benefit of sinus rhythm over AF becomes apparent. In a recently published "on-treatment" analysis from the AFFIRM investigators,4 the presence of sinus rhythm was 1 of the most powerful independent predictors of survival, along with use of warfarin, even after adjustment for all other relevant clinical variables. Patients in sinus rhythm were almost half as likely to die compared with those with AF (adjusted hazard ratio, 0.53; 99% CI, 0.39 to 0.72; P<0.0001). This benefit, however, was offset by the use of antiarrhythmic drug therapy, which increased the risk of death. The reduction in mortality with sinus rhythm has also been demonstrated in the DIAMOND and CHF-STAT trials.5,6 These findings are also consistent with large population-based studies that have long shown the negative prognostic impact of AF on survival.7 Even in an analysis of 46 984 post–coronary bypass patients from 1972 to 2000 at the Cleveland Clinic, we found that survival was significantly reduced in patients with postoperative AF after matching patients for age, comorbidities, left ventricular dysfunction, and left main disease (Figure 2A and 2B).
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Finally, it is also important to acknowledge that the patients enrolled in these studies do not represent the full spectrum of AF patients. In particular, patients with "frequent or severe symptoms might have been considered unsuitable...and therefore may not have been enrolled," according to the AFFIRM investigators themselves.1 The trial largely excludes the highly symptomatic subgroup that would most benefit from sinus rhythm, a subgroup that represents at least one third of all AF patients.8
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The Inadequacy of Nonablative Rhythm Control |
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TopIntroductionThe Importance of Sinus...The Inadequacy of Nonablative...AF Ablation: A Cure...Ablation: For Whom and...ConclusionsReferences |
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Unfortunately, apart from AF ablation, the treatments available for maintaining sinus rhythm have poor efficacy and significant drawbacks. Indeed, the failure of AFFIRM, RACE, or STAF in showing any difference between rate and rhythm control is not so much a positive statement for rate control but rather a testimony on the ineffectiveness of the rhythm control methods used. The authors of the STAF trial themselves state that their findings "may suggest that rhythm control failed to demonstrate superiority over rate control because maintenance of sinus rhythm could not be achieved in the long-term [in the rhythm control group]."3 The main modalities for nonablative rhythm control are antiarrhythmic medication (AAM) and device-based therapy. Device-based therapy has demonstrated poor efficacy in treating AF. Burst atrial pacing may effectively convert atrial tachycardias but fails to terminate or minimize AF.9 Atrial defibrillators can terminate AF with high acute success rates, but the need for repeated shocks and the resulting patient discomfort often render this option intolerable.10 Similarly, dual-site atrial pacing has failed to demonstrate any consistent reduction in AF burden or improvement in AF symptoms.11 Therefore, the mainstay of nonablative rhythm control is AAM.
Indeed, data from several trials have demonstrated that the success of AAM in maintaining sinus is borderline, at best, with increasing failure rates over time. Even amiodarone, considered the most effective AAM, has limited ability to maintain sinus. The largest prospective randomized trial to evaluate the efficacy of amiodarone against other AAMs was the Canadian Trial of Atrial Fibrillation. This trial compared amiodarone and both sotalol and propafenone in maintaining sinus rhythm in patients with at least 1 episode of AF in the past 6 months. After a mean of 16 months’ follow-up, AF recurred in 35% of patients taking amiodarone and 63% of patients taking sotalol or propafenone.12 However, the true success of amiodarone is definitely <65%. The absence of a placebo arm in CTAF does not allow discernment of the absolute effect of amiodarone, because we cannot know how many patients would have remained in sinus spontaneously. To answer this question, a recent meta-analysis of randomized trials on the efficacy of AAM showed that about one third (32%) of patients were in sinus rhythm in the placebo arms of these trials, whereas 55% of patients in the AAM arms were in sinus.13 The incremental treatment effects were only 21.5%, 33.1%, and 17.4% for class IA, IC, and III agents, respectively. This somewhat disappointing experience is mirrored in the AFFIRM, RACE, and STAF trials (shown in Figure 1). A substudy of the AFFIRM trial confirmed that the success rate of amiodarone was 
60% compared with a meager 23% for patients taking class I agents and 38% for patients taking sotalol, whereas 34.6% of patients in the rate control group were spontaneously in sinus without AAM.14 Even more disappointing was the RACE trial, which used a very aggressive, stepwise approach to maintaining sinus rhythm: 3 cardioversions and progressive therapy from sotalol to a class Ic agent to amiodarone. Despite this approach, AF had to be accepted in 116 patients (44%), with an additional 18% of patients in AF waiting for their next cardioversion or drug.2
AAMs clearly do not cure AF; at best, they are a palliative treatment used to reduce the burden of AF as opposed to eliminating it altogether. It is true that a significant reduction in AF burden may be considered a "success" for some patients in clinical practice. However, it is not well known if a "small" AF burden presents any lesser risk of morbidity and mortality compared with a "large" burden, and the quantitative cutoff point for defining a "low-risk" AF burden has never been defined. Furthermore, in severely symptomatic patients, even 1 brief recurrence a year may be too much. Clearly, there is a need for therapy that can offer a true cure of AF.
For the "lucky" few who are able to maintain sinus rhythm on AAM, these drugs frequently cause debilitating side effects. Discontinuation rates for AAM are consistently high in most trials. In CTAF, 18% of the patients receiving amiodarone and 11% of patients receiving sotalol or propafenone had to discontinue therapy because of adverse effects.12 In the AFFIRM substudy, 12.3%, 11.1%, and 28.1% of patients taking amiodarone, sotalol, and class I agents, respectively, had to stop taking the drug within 1 year of initiating therapy.14 Although amiodarone may be the most effective AAM, it is also associated with the most dangerous side effect profile. After 5 years, 
30% of patients on amiodarone will discontinue therapy because of side effects.15 Specifically, 4.5% experience intolerable skin discoloration, 3.6% pulmonary fibrosis, 2.7% an intolerable thyroid state, and 1.8% neurological or ophthalmic problems.15 Certainly, we can do better than offer therapy with such poor efficacy and significant morbidities.
Even more alarming is the observation that AAMs not only produce side effects but also may increase patient mortality. This is a well-established paradigm given the results of the CAST and SWORD trials. In these trials, class I agents and d-sotalol were directly associated with increased mortality when given prophylactically after myocardial infarction.16,17 The Stroke Prevention in AF Investigators also demonstrated that in patients given AAM for AF, both cardiac mortality and arrhythmic death were significantly increased, particularly in patients with heart failure.18 Analysis of the AFFIRM population reveals a similar disturbing trend. Use of AAM was associated with an increased risk of mortality after adjustment for other variables, including presence of sinus rhythm (hazard ratio, 1.49; P=0.0005).4 If AAM use and sinus rhythm were not treated as separate variables in the multivariate analysis, AAM use could be made to appear unassociated with any increased mortality. This suggests that whatever benefit is obtained by sinus rhythm is offset by the deleterious effects of AAM. Interestingly, it was noncardiac deaths that were increased in the AAM group, which revealed higher rates of pulmonary and cancer-related mortality.19 Although the direct relationship is not clear, the AFFIRM investigators point out that amiodarone, in particular, has previously been reported to be associated with higher noncardiac mortality in both the EMIAT and AVID trials.20,21 Because of the inefficacy and dangers with nonablative therapies currently available for maintaining sinus rhythm, alternative treatments are certainly desirable.
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AF Ablation: A Cure Is Available |
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TopIntroductionThe Importance of Sinus...The Inadequacy of Nonablative...AF Ablation: A Cure...Ablation: For Whom and...ConclusionsReferences |
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In contrast to AAM, catheter ablation directly eliminates the inciting factors for AF and offers the possibility of a lasting cure. The goal of present-day AF ablation is to electrically "disconnect" the pulmonary veins (PVs) from the rest of the atrium by ablating around the origin of the veins. When this idea was first proposed several years ago, it was understandably met with some skepticism. However, there is little controversy now that the PVs indeed play a major role in both triggering and maintaining AF, as established by both animal and human models. First, fibrillatory conduction is likely initiated by rapid discharges from 1 or several focal sources within the atria. In their seminal article, Haissaguerre et al22 nicely demonstrated that in most AF patients (94%), the focus was in
1 of the PVs. Extra-PV sites may trigger AF, but this occurs in the minority, likely no more than 6% to 10% of patients.23 AF is also perpetuated by microreentrant circuits, or "rotors," that exhibit high-frequency, periodic activity from which spiral wave fronts of activation radiate into surrounding atrial tissue.24,25 Conduction becomes slower and less organized with increasing distance from the rotors, likely because of atrial structural remodeling, resulting in fibrillatory conduction. Interestingly, the dominant rotors in AF are localized primarily in the junction between the left atrium (LA) and PVs, as demonstrated by several investigators.25–27 A recent study has also demonstrated that the PV-LA region has heterogeneous electrophysiological properties capable of sustaining reentry (micro or macro).28 Finally, vagal inputs may be very important in both triggering and maintaining AF, and many of these inputs are clustered close to the PV-LA junction.29 Thus, the PVs play a critical role in both triggering and maintaining AF. This was elegantly confirmed with both electrophysiological and histological data in an open-heart, human model involving patients undergoing AF surgery.30 The mechanism also applies to a wide spectrum of AF patients, including adolescents31 and adults with structural heart disease.32,33 Therefore, it does not seem reasonable to continue recommending pharmacological and device-based therapies that, unlike AF ablation, fail to address the "root cause."
It seems especially unreasonable to avoid AF ablation now that there is much greater consistency in the methodology of the technique. Initially, a multitude of methods for ablating AF existed.23 Some were performing "focal" ablative procedures, in which only specific sites exhibiting earliest triggered activity in "culprit" PVs were ablated. Some chose to circumferentially ablate around 1 PV. Others were attempting to mimic the surgical Maze procedure by performing linear lesions in the right atrium and LA. However, after recognizing the limited success and risks associated with some of these approaches, we learned important lessons that have shaped the present-day technique. First, the vast majority of centers performing AF ablation are empirically isolating all 4 PVs. It was quickly recognized that any of the PVs can serve as a trigger and that ablating only a single "culprit" could unmask triggers in another PV.34 Ablating all 4 PVs was also found to be more effective than ablating only 3.35 Furthermore, most groups are ablating "outside" the tubular portion of the PV to avoid the risk of PV stenosis and to improve the efficacy of the procedure. This makes sense given that the PV is funnel shaped with a large proximal end, which we call the antrum. The antrum blends into the posterior wall of the LA, and on the posterior wall, there is little space between adjacent antra (Figure 3). Therefore, to encompass as much of the PV structure as possible, ablation needs to be performed around the entire antrum, along the posterior LA wall.36 Although different groups may refer to ablation in this region by different names such as LA catheter ablation, circumferential PV antrum ablation, or extraostial isolation, the lesion sets produced by the procedures are all very similar (Figure 4).
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With time, operator experience, and greater consistency in the technique, AF ablation has proved itself to be a very effective treatment for AF, with similar success rates being reported by several different groups. In a recent review23 including 19 studies, the success rates ranged from 6% to 93%. However, some of these studies were published very early on in the ablation experience, and there was a great deal of variation in the technique. Furthermore, the definition of "success" was highly variable, with some groups using off-drug cure as the definition of success and others including patients who could maintain sinus rhythm on AAMs. Looking at the most recent publications from several groups using ablation of all 4 PVs outside the tubular portion, the cure rate off chronic drug therapy is much more consistent, at 80.5% overall (Table 1).37–42 A further 10% to 20% of patients may become responsive to previously ineffective AAM.43 Some variation remains, partly because of variations in the precise end point used (see Table 1) and operator experience. However, although the cure rates are not 100%, they are 2- to 3-fold better than anything achievable by AAM. Furthermore, the cures seem to be durable, given the long follow-up (almost three years) reported by some groups37 and the observation that most recurrences tend to occur early in the follow-up period, and rarely occur very late after ablation.44 At our own institution, our most recent statistics from multiple operators show a 1-procedure, off-drug success rate approaching 80% and a 2-procedure success rate of >90%. As future larger-scale trials evaluating AF ablation are designed, it will be important to ensure a consistent definition of cure (eg, off AAM) and decide on a universal end point (eg, PV isolation) to best interpret the results.
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Although the success of AF ablation appears high, it is especially encouraging that it can be achieved with a very low incidence of complications. Complications from AF ablation include vascular complications secondary to venous access, cardiac perforation/tamponade, valvular injury, embolic stroke or systemic embolism, esophageal injury, PV stenosis, and proarrhythmia resulting from reentrant tachycardias arising from incomplete ablative lesions. Finta and Haines23 pooled data from 63 clinical studies on AF ablation encompassing 3339 patients between 1994 and 2003. Cerebrovascular events occurred in an average of 1.0% of patients, manifest PV stenosis in 0.9%, and atrial macroreentry tachycardia in 29%. When only the more recent reports using a more consistent technique are reviewed, the complication rates are similar if not lower (Table 2). The complication rates are continuing to fall with more recent modifications to the technique and presently available technologies. For example, aiming for higher activated clotting times of 300 to 400 seconds can reduce the chance of thromboembolism without increasing bleeding risk,45 and ablation outside the tubular portion of the veins greatly minimizes the risk of PV stenosis. Char formation, tissue disruption, and esophageal injury can also be avoided with strict limitations on radiofrequency energy output46 and avoidance of ablating directly on top of the esophagus. Intracardiac echocardiography (ICE) has been demonstrated to be a particularly effective (and readily available) tool to minimize procedural complications. By providing real-time imaging, ICE allows one to perform safe transseptal access and avoid ablating within the PVs to prevent stenosis.42 Furthermore, by titrating radiofrequency energy output to prevent microbubble formation on ICE, tissue disruption and coagulum formation causing stenosis and embolic events can be minimized.42 Procedure-related atrial flutters can also be avoided if care is taken to document total electrical isolation of the PVs at the level of the antra, thereby eliminating the triggers for flutter. With an ICE-guided PV antrum isolation technique, our rate of flutter recurrence after ablation is very low at <3%.47 We have also shown that in patients with both typical atrial flutter and AF, both arrhythmias can be treated with PV antrum isolation alone by eliminating the common trigger48 in most cases. Other groups have successfully used additional linear ablation lesions to avoid postablation flutters such as a line across the mitral valve isthmus.39 Newer technologies to reduce complications and improve the ease of performing ablation are also imminent, including real-time 3D CT and electroanatomic mapping integration, robotic/magnetic-controlled catheter systems, and balloon-guided systems.
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With such a high success rate and a low attendant complication rate, it is not surprising that current evidence shows that AF ablation not only is more effective than nonablative therapy but also may reduce both the morbidity and mortality associated with medical therapy. In a controlled, long-term study (median follow-up, 900 days), Pappone et al37 reported that 589 patients who underwent AF ablation had significantly improved survival compared with 582 matched patients who received antiarrhythmic medications. Survival among the ablated patients did not differ significantly from the expected survival of healthy, age- and gender-matched persons of the Italian population (Figure 5). The total number of adverse events, including stroke, were much less in the ablated group, and freedom from AF was significantly higher (78% versus 37% in the ablated and medical groups, respectively; P<0.001). The Cleveland Clinic is leading a prospective, randomized, multicenter trial comparing AF ablation as first-line therapy to AAM known as the Radiofrequency Ablation for Atrial Fibrillation Trial (RAAFT). A randomized pilot study has already been completed in Europe involving a total of 70 patients, 33 randomized to ablation and 37 to AAM. Results are shown in Figure 6, with symptomatic AF recurring in 63% of AAM patients compared with only 13% of ablation patients (P<0.05). Ablated patients also experienced greater improvements in quality of life and had fewer adverse events. Others have also reported similar results in head-to-head comparison,49 and other trials are underway. Ablation may even be more cost-effective than medical therapy. Weerasooriya et al50 demonstrated that assuming a conservative ablation cure rate of 72% after 1.5 procedures, the initially high cost of ablation would offset the ongoing costs of AAM by 3 years; after 4 years, ablation becomes more cost-effective, and the benefit continues to increase thereafter. AF ablation is clearly superior than our current standard of care, and with data showing greater efficacy, less morbidity and mortality, and even less cost, it seems reasonable that ablation be moved up to first-line therapy for some patients.
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Ablation: For Whom and By Whom? |
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TopIntroductionThe Importance of Sinus...The Inadequacy of Nonablative...AF Ablation: A Cure...Ablation: For Whom and...ConclusionsReferences |
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Although we advocate for AF ablation as a first-line therapy, we do not yet believe that it should be offered first to all patients with AF. We acknowledge that large-scale, comparative clinical trials have yet to be performed and that these data are required before recommending ablation as first-line therapy for a very broad AF population. The studies to date have included only highly symptomatic, paroxysmal or persistent AF patients who have already failed medical therapy, with minimal or moderate structural heart disease. This group experiences considerable morbidity and mortality from AF, with exacerbation of heart failure, poor exercise tolerance, and a major reduction in quality of life. These patients were also, for the most part, excluded from the large rate and rhythm control trials. In our experience and in many others’, rhythm control with AAM is not only ineffective and poorly tolerated but only delays an inevitable ablation. Therefore, if first-line ablation is offered, it should at least be considered for those patients with symptomatic AF, mild to moderate structural heart disease, and paroxysmal or persistent AF. AF should be recurrent and should not be secondary to a transient, treatable cause. Ablation may particularly benefit younger patients with lone AF who are frequently symptomatic and for whom very-long-term antiarrhythmic and anticoagulation poses higher risks and lifestyle costs. Asymptomatic or minimally symptomatic AF patients may also benefit from ablation and sinus rhythm in the long term, but until further clinical data are available, it is difficult to justify an invasive procedure to a patient who may not be aware that they have a problem.
There will be a time in the near future when AF ablation can be offered as first-line therapy to a broader AF population. Data already exist showing that good ablative success can be achieved in patients with impaired left ventricular function,32 previous cardiac surgery or valvular heart disease,33 and advanced age.51 We have also found that the cure rate after 2 ablations is similar in both paroxysmal and nonparoxysmal AF patients.52 The only group that seems destined to fail ablation is that with extensive, preexistent LA scarring.53 Although at the present time this can be identified only invasively, noninvasive methods may soon become available to detect advanced atrial myopathy. In the future, novel therapies to slow or even reverse the scarring process may help make AF more amenable to ablation.
Another important limitation of AF ablation is that it is being performed only at a few select centers in most countries and is not yet widely available. Therefore, it is prudent that only centers with considerable experience in performing AF ablation should consider offering ablation as first-line therapy. As with any new invasive or surgical procedure, the benefit is highly operator dependent. The present reality will gradually evolve, and advances such as robotically controlled catheters and real-time MRI or CT imaging will eliminate operator experience as a component affecting the outcome of ablative procedures.
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Conclusions |
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TopIntroductionThe Importance of Sinus...The Inadequacy of Nonablative...AF Ablation: A Cure...Ablation: For Whom and...ConclusionsReferences |
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AF is an arrhythmia associated with increased morbidity and mortality, and it is in the patient’s best interest to pursue effective and safe treatments to eliminate this disease. Current therapies, especially AAM, not only are ineffective but also pose a threat to patient quality of life and even longevity. In the hands of experienced operators, AF ablation is an effective, safe, and established treatment for AF that offers an excellent chance for a lasting cure. Unlike other therapies, ablation tackles AF at its electrophysiological origin. Therefore, it is about time that AF ablation be used as a first-line option for selected patients with this disease. There is no reason to be afraid of marching toward a future when growing experience plus evolving technology will allow us to apply ablation to most AF patients, and the question of using ablation as first-line therapy will no longer be such a "burning issue." To paraphrase the Wright brothers, "If you don’t go further than your front yard fence, you will discover nothing."
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Acknowledgments |
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Dr Verma is supported by a Heart and Stroke Foundation of Canada Fellowship Award. We gratefully acknowledge the assistance of Dr Samy Claude Elayi for his editorial help in critically reviewing this manuscript.
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References |
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TopIntroductionThe Importance of Sinus...The Inadequacy of Nonablative...AF Ablation: A Cure...Ablation: For Whom and...ConclusionsReferences |
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The opinions opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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