Catheter Ablation vs Antiarrhythmic Drugs for Atrial Fibrillation

Abstract & commentary

By John P. DiMarco, MD, PhD

Source: Jais P, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation. 2008;118:2498-2505.

The catheter ablation versus antiarrhythmic Drugs for Atrial Fibrillation (A4) study compared radio-frequency catheter ablation to antiarrhythmic therapy in selected patients with paroxysmal atrial fibrillation (PAF). Patients were eligible for the study if they had frequent episodes of symptomatic PAF that had been present for at least six months. All patients had experienced recurrence during at least one prior antiarrhythmic drug trial prior to enrollment. Patients were randomized to either a treatment strategy based on catheter ablation or on serial antiarrhythmic drug trials for a 90-day period.

During this stabilization period, patients could undergo up to three catheter ablation procedures (pulmonary vein isolation ± additional left or right atrial linear of focal ablations) or enroll in up to three antiarrhythmic drug trials using single- or combination-drug therapy. Follow-up started at 91 days and continued through day 365. Data routinely collected during the evaluation period included 12-lead ECGs, quality-of-life questionnaires, AF symptom frequency and severity check lists, and 24-hour Holter recordings at baseline and at 3, 6, and 12-month follow-ups. Treadmill exercise testing and 2-D echocardiograms were performed at baseline and one year. The primary endpoint was the proportion of patients free of recurrent AF between days 91 and 365. Any episode of AF of > 3 minutes duration, either reported by the patient or documented by an ECG, was considered a valid endpoint. Cross-over was permitted after a single episode of recurrent AF during the days 91-365.

The study group included 112 patients with the following characteristics: 84% male; mean age of 51.1 years; AF episode median frequency of 12/month; hypertension 26%; structural heart disease 24%; mean left ventricular ejection fraction 64%; 2.1 prior antiarrhythmic drug trials. Four randomized patients were excluded due to either withdrawal of consent or poor compliance with drug therapy.

Fifty-three patients underwent catheter ablation, with a median of two procedures per patient. Repeat procedures were required due to either pulmonary vein reconnection, gaps in prior ablation lines, or emergence of non-pulmonary vein foci. Forty-six catheter ablation patients (89%) remained free of recurrent AF without antiarrhythmic drugs from days 91 to 365; five patients randomized to catheter ablation required antiarrhythmic drugs for AF suppression. Fifty-five patients were initially treated with an antiarrhythmic drug therapy strategy. Of these, 13 (27%; p < 0.0001 vs ablation strategy) remained free of recurrent AF during the nine-month study evaluation period. Thirty-seven patients (63%) crossed over to an ablation approach after 192 ± 80 days.

There were no differences between the ablation and the drug therapy groups in left atrial or left ventricular size, or left ventricular ejection fraction. Catheter ablation patients experienced a significant decrease in AF burden, calculated as the mean numbers of hours of AF per 24-hour Holter recording. Quality-of-life, symptom frequency, and symptom severity scores improved in both groups, but the improvement was significantly better in the ablation-strategy patients. Exercise duration and the maximum work load achieved were higher in the ablation-strategy group.

Procedural complications were noted in five patients. There were two pericardial tamponades requiring paracentesis, two groin hematomas, and one pulmonary vein stenosis that was treated with a stent. Antiarrhythmic therapy resulted in one case of hyperthyroidism. There were two deaths in the drug-strategy group that were considered to be due to causes unrelated to the trial. Jais et al concluded that a catheter ablation strategy is superior to repeat drug trials in patients with PAF who have had recurrent episodes during one or more previous trials.


The A4 trial confirms the clinical observation that pulmonary vein isolation is an effective treatment for selected patients with highly symptomatic PAF. The study results, however, should definitely not be interpreted as proof that catheter ablation should be preferred over drug therapy in all, or even most, patients with PAF.

The patients in this trial were nearly ideal candidates for a catheter ablation approach. They were relatively young, and most had normal ventricular function and left atrial dimensions. They were highly symptomatic, with very frequent episodes of PAF, and had already had recurrent symptoms despite a mean of two prior antiarrhythmic drug trials. Most electrophysiologists would currently refer such a patient for catheter ablation if there were no contraindications. However, these patients are not really representative of most patients with PAF who may be considerably older and have fewer or better tolerated episodes in association with some form of structural heart disease.

Time-to-first event is an endpoint that has frequently been used in trials of drugs for atrial fibrillation. For the purpose of a clinical trial, a time-to-first event analysis has the advantage that it is easy to measure and has been shown to correlate, in general, with other measures of antiarrhythmic effect. However, the real goal of drug therapy in atrial fibrillation is not total suppression of recurrent AF, but a decrease in overall frequency and severity. A single recurrence during drug therapy is rarely a "clinical failure." Since catheter ablation is designed to eliminate AF completely, a comparison of the two strategies, using a single recurrence as the primary endpoint, may not be the most clinically relevant approach. Even in this trial, if events such as repeat procedures or hospital admissions during the first 90 days were counted as endpoints, the results may not have seemed so much in favor of an ablation strategy.

Catheter ablation is now a well-established procedure for patients with PAF, but it remains a first choice option only for highly selected patients. Even in these patients, future efforts to reduce the need for repeat procedures are needed for the full promise of catheter ablation to be realized.