Editor's Note: Nielsen JC, et al. This article is based on Radiofrequency Ablation as Initial Therapy in Paroxysmal Atrial Fibrillation. N Engl J Med 2012; 367:1587-95.

Introduction

Numerous studies have documented the marginal efficacy of antiarrhythmic drugs (AAD) for maintaining sinus rhythm in patients with paroxysmal atrial fibrillation (AF). The ongoing episodes of AF subsequently lead to adverse electrical remodeling and perpetuate AF, thus "AF begets AF."^1-3 Radiofrequency ablation (RFA) has been demonstrated to significantly reduce and eliminate AF episodes, reduce symptoms and reduce the need for medical therapy.^4-7 However, the low single-procedure success rate and the complication rate associated with RFA have led to the recommendation that RFA be implemented as secondary therapy after failing one AAD.⁸ This study by Nielsen et. al completed a prospective, multicenter, randomized trial of RFA vs. AAD as primary therapy for patients with symptomatic, paroxysmal AF.

Methods

Patient Population:

To be included, patients had ≥2 episodes of symptomatic paroxysmal AF within the preceding six months but no episode of AF that was longer than seven days requiring cardioversion. The exclusion criteria were age > 70 years, prior AAD trial, prior RFA for AF, left atrium > 50mm, ejection fraction <40%, heart failure (NYHA Class III or IV), significant structural/valvular heart disease and secondary causes of AF. From June 2005 through March 2009, a total of 294 patients were randomized to either AAD or RFA as a rhythm-control strategy for AF. The mean age of the patient population was 55 and 70% were male. The mean CHADS2 score was 0.6 and the mean left atrial size was 40mm.

Rhythm-Control Strategies:

First-line AAD therapy was Class IC, and if contraindicated, then either amiodarone or sotalol. Electrical cardioversion and multiple AAD trials were utilized to maintain sinus rhythm. If AAD therapy was considered unsuccessful then patients could cross over to RFA.

Encircling ablation lesions around the pulmonary vein os and a connecting roof line was completed with either an 8mm tip or irrigated RFA catheter. Mitral and tricuspid isthmus lines were optional. AAD could be used during the first 3 months post ablation. Thereafter, if AF recurred, a second RFA procedure was offered.

Assessment of AF:

Seven-day Holter monitors and clinical evaluations were completed at enrollment and then at three, six, 12, 18 and 24 months post-initiation of treatment.

Study Endpoints:

The primary study end points were burden of AF (percentage of time in AF on each Holter) lasting > one minute, and the cumulative burden of AF (defined as the percentage of time in AF on all Holter recordings).

Secondary endpoints included freedom from any AF and freedom from symptomatic AF at 24 months, cumulative and per visit burden of symptomatic AF, time to first recurrence of AF after the blanking period, and atrial flutter longer than 1 minute. Quality of life (SF-36) was measured at baseline, 12 and 24 months after enrollment.

Statistical Analysis:

Outcomes were based on intention-to-treat analysis. Cross over to alternative therapy was permitted and was not considered a treatment failure.

Results

RFA:
140 patients underwent a mean of 1.6 RFA procedures, and 13 patients (9%) were prescribed AAD.

AAD:
146 patients were treated with AAD (Class IC, 90%; Class III, 10%). After a mean of nine months, 54 patients (36%) crossed over to RFA.

Primary Endpoints:
Compared to baseline measurements, the burden of AF was significantly reduced for both AAD and RFA.

There was no difference in the cumulative burden of AF between the two treatment arms (90th percentile of arrhythmia burden, 13% RFA and 19% AAD, p = 0.10) or in the burden of AF at three, six, 12, or 18 months. However, RFA had a significant reduction in AF burden compared to AAD at the 24 month follow up (90th percentile, 9% vs. 18%; p = 0.007).

Secondary Endpoints:
Significantly more patients in the RFA group compared to AAD group were free from any AF (85% vs. 71%, p = 0.004) and from symptomatic AF (93% vs. 84%, p = 0.01) at 24 months.

There was no significant difference in time to first recurrence of AF (median time, 25 days RFA and 27 days with AAD, p = 0.16).

There was no difference in the cumulative burden of symptomatic AF between RFA and AAD, p = 0.12). At 24 months, the burden of symptomatic AF was lower in the RFA group (90th percentile, 0% vs. 3%; P = 0.01).

Atrial flutter was detected in 31 patients in RFA group and in 40 patients in AAD group (p = 0.25).

For quality of life measures, the physical-component summary score improved more over time with RFA vs. AAD (p = 0.01); otherwise there was no significant differences between the groups.

Adverse Events
Adverse events occurred in 20 patients in RFA and 16 patients with AAD (p = 0.45). One patient undergoing RFA died due to a procedure-related stroke and two patients died suddenly (one in the AAD group and one in the RFA group).

Conclusions

Considering the primary endpoint, there was no significant difference between the two treatment strategies in the cumulative burden of AF over a period of two years. The authors conclude that considering the risks of an RFA procedure, their data supports current recommendations of implementing AAD as an initial treatment strategy and then proceeding to RFA as secondary therapy.

The authors highlight the advantages of RFA. After 24 months, the burden of AF was lower and more patients were free from AF reflecting the common clinical experience that initially effective AAD therapy becomes progressively ineffective over time. Also, physical measurements of quality of life improved with RFA; and, 36% of patients assigned to AAD crossed over to RFA.

Perspective

Nielsen et al. should be complemented for completing an important study with long follow-up and providing novel data regarding the best strategy as initial therapy for paroxysmal AF. There are, however, several points that need to be recognized so that the conclusions of this study are kept in proper perspective.

Since over one-third of patients assigned to AAD crossed over to RFA, without being considered a treatment failure, it is difficult to appreciate the independent effect of AAD on managing AF. Considering the significant increase in freedom from AF with RFA, it seems probable that a large minority of patients assigned to AAD achieved sinus rhythm by crossing over to RFA. To clarify this point, an on-treatment analysis or categorizing patients that cross over as treatment failure would provide further important data. Thus, although the outcome of each initial strategy may be equivalent, the intention-to-treat analysis may obscure the fact that RFA is superior to AAD.

For most clinicians and patients, reduction of AF burden is an important goal, but this type of philosophy represents a key bias to the study design. It implies that recurrences of AF are expected and will be tolerated. However, for some, a reduction of AF burden is an inadequate goal and rather freedom from AF is the targeted endpoint. The current study provides data that suggests that both options are reasonable as primary therapy and that a patient-specific treatment plan can be developed.

When discussing treatment options, the patient and physician need to identify the goal(s) of therapy. If the goal is reduction of AF burden, then AAD is the appropriate primary therapy. For some patients, however, taking chronic medical therapy for mere reduction of AF burden may not be desired, but rather, freedom from AF is the objective. This objective likely explains why 36% of patients assigned to AAD crossed over to RFA. For these and other patients, RFA can be offered as first-line therapy. Indeed, compared to AAD, RFA resulted in a significantly greater freedom from AF and significant reduction in AF burden at 24 months, albeit no difference in cumulative AF burden during the study. A significant increase in freedom from AF, as well as reduction in hospitalization and AF frequency without any significant complications, was also reported in an earlier study comparing AAD vs. RFA as primary therapy.⁶

In part, the authors seem to reach the conclusion that AAD should be offered as primary therapy for all patients with paroxysmal AF due to the adverse event rate, in particular the procedure-related mortality. They state, "Given the risk of complications with ablation, our data support the current guidelines recommending antiarrhythmic drugs as first-line treatment in most patients with paroxysmal atrial fibrillation." This statement, though, is contrary to the data presented. There was no difference in adverse events, including mortality, between AAD and RFA. Furthermore, the authors report, but do not highlight, that in the AAD group, one patient experienced sudden death, which may represent a proarrhythmic event. Finally, although AF RFA procedures may result in death, in experienced centers this may be less likely than a death from proarrhythmia. Procedure-related mortality in this trial may be indicative of an important limitation noted by the authors, that some enrolling sites may not be high volume ablation centers.

Review of the data may lead one to a conclusion that differs from that put forth by the authors. Considering no significant differences in mortality and adverse events, this study supports a patient-specific approach to managing paroxysmal AF among young patients with minimal structural heart disease and a low CHADS2 score. For patients that prefer to reduce AF burden and to avoid invasive procedures, AAD should be the initial therapy. However, if the objective of therapy is freedom from AF with the hope of avoiding chronic medical therapy, then, supported by the findings of the current study, RFA may be appropriate initial therapy.

References

1. Schotten U, Duytschaever M, Ausma J, et al: Electrical and contractile remodeling during the first days of atrial fibrillation go hand in hand. Circulation 2003; 107:1433-9.
2. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002;54:230-46.
3. Wijffels MC, Kirchhof CJ, Dorland R, et al: Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995; 92:1954-68.
4. Wilber DJ, Pappone C, Neuzil P, et al: Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010; 303:333-40.
5. Pappone C, Augello G, Sala S, et al: A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study. J Am Coll Cardiol 2006; 48:2340-7.
6. Wazni OM, Marrouche NF, Martin DO, et al: Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA 2005; 293:2634-40.
7. Jaïs P, Cauchemez B, Macle L, et al: Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation 2008; 118:2498-505.
8. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines. Circulation 2011; 123:e269-e367.

Keywords: Amiodarone, Atrial Fibrillation, Atrial Flutter, Heart Failure, Sotalol, Stroke

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