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Abstract & Commentary
The Prevention of Atrial Fibrillation After Cardioversion (PAFAC) Trial was a placebo-controlled study comparing sotalol and a quinidine/verapamil combination in patients with persistent atrial fibrillation after cardioversion. Patients between 18 and 80 years of age with documented persistent atrial fibrillation and a clinical indication for direct current cardioversion were eligible for inclusion. Patients were anticoagulated for at least 3 weeks prior to attempted cardioversion. Patients with implanted pacemakers or defibrillators, recent myocardial infarctions or cardiac surgery, uncontrolled valvular disease, QTc prolongation at baseline, or recurrent hypokalemia were excluded. Eligible patients were brought in to the hospital and cardioverted electrically.
Patients who maintained sinus rhythm after cardioversion for at least 2 hours were then eligible for randomization. Patients were randomized to either sotalol (80 mg 3 × daily for 1 day, then 160 mg 2 × daily), a fixed combination of quinidine plus verapamil (160 mg quinidine plus 80 mg verapamil 2 × daily for 1 day, then 3 × daily thereafter), or placebo. The approximate desired randomization ratio was 4:4:1.
Patients were kept in-hospital for at least the first 3-4 days after drug initiation. After discharge, each patient was given a credit card sized ECG recorder and instructed to record and transmit at least 1 ECG every day independent of symptoms. This type of recorder stores 1 minute of a single lead electrocardiogram which can subsequently be transmitted to a monitoring center over any regular telephone. At the time of the transmission, the patient was asked if they were experiencing any symptoms. The transmitted ECGs were analyzed by trained staff at the monitoring center. When atrial fibrillation was detected on the 1 minute recording, the study site was notified to contact the patient for further ECG documentation and clinical correlation.
The primary outcome parameter was the time to first recurrence of any type of atrial fibrillation or death. Secondary outcome measures included the occurrence of, and time to, persistent atrial fibrillation, the number of occurrences, and time to symptoms.
The study was conducted in Germany and the Czech Republic. In 68 trial centers, 1182 patients were enrolled. Of these, 848 patients were successfully cardioverted and randomized. There were 88 patients assigned to placebo, 383 patients to sotalol, and 377 patients to quinidine/verapamil. There were no significant differences in baseline demographic data between the 3 groups. For the entire group, the mean age was 63 ± 9 years, and 66% were male. Atrial fibrillation had been present for a median time of 365 days. Only 11% of the patients had previously undergone a direct current cardioversion. Coronary artery disease was seen in only 21%, and 61% of the patients were New York Heart Association functional class I. The prevalence of hypertension was not specified.
During follow-up, 572 of the 848 patients developed an ECG documented recurrence of atrial fibrillation. The 1 year actuarial recurrence rate was 83% in the placebo group, 67% in the sotalol group, and 65% in the quinidine plus verapamil group. The probability of remaining free of persistent AF was, however, considerably better. After 1 year, persistent AF had recurred in 38% in the quinidine/verapamil group, 51% in the sotalol group, and 77% in the placebo group. Fetsch and colleagues noted that in 70% of all documented recurrences, the patients did not report associated symptoms. The proportion of symptomatic vs asymptomatic episodes of AF were similar between the 3 groups.
There were 11 deaths in the study; 6 on sotalol, 5 on quinidine/verapamil, and none on placebo. Torsades de pointes ventricular tachycardia was seen only in patients on sotalol (9/383, 2.3%). Bradycardia was more common in patients treated with sotalol, whereas QT interval prolongation, diarrhea, and peripheral edema were more common in patients treated with quinidine and verapamil. All 3 documented lethal episodes of ventricular fibrillation, as well as 6 of 9 episodes of torsades de pointes ventricular tachycardia and 4 of 8 episodes of ventricular tachycardia of greater than 10 beats in duration, occurred during the first 4 days of in-hospital therapy.
Fetsch et al conclude that sotalol and quinidine plus verapamil are more effective than placebo in preventing recurrent atrial fibrillation after cardioversion in patients with persistent atrial fibrillation. It appeared that quinidine plus verapamil was slightly more effective than sotalol in preventing recurrent, persistent atrial fibrillation. Finally, Fetsch et al noted that all the episodes of torsades de pointes occurred on sotalol, and that the majority of events that might be considered proarrhythmia occurred in the first 4 days of antiarrhythmic drug therapy (Fetsch T, et al. Prevention of Atrial Fibrillation After Cardioversion: Results of the PAFAC Trial. Eur Heart J. 2004;25:1385-1394).
Comment by John P. DiMarco, MD, PhD
The PAFAC Trial is an important study that provides interesting observations that should effect the way we treat atrial fibrillation. Perhaps the most important observation is the high frequency of asymptomatic recurrences of atrial fibrillation. These episodes could be both asymptomatic and self-terminating even in patients who had initially presented with persistent atrial fibrillation. The daily 1 minute ECG transmissions allowed this observation to be made. This high prevalence of asymptomatic atrial fibrillation in patients has obvious implications on the need for continuing anticoagulation in patients, even if they appear to be well clinically and in sinus rhythm.
The second major observation of interest is the apparent favorable interaction between quinidine and verapamil.
The mechanisms responsible for this are uncertain. Although quinidine was formerly the most commonly used drug for maintenance of sinus rhythm in patients with atrial fibrillation, recent concerns about its proarrhythmic potential and its side effect profile have caused it to be less frequently prescribed. Adding verapamil has several potentially beneficial effects. Calcium channel blockers may decrease the atrial remodeling that occurs in association with atrial fibrillation. Calcium channel blockade also inhibits development of the early after depolarizations that are thought to be responsible for torsades de pointes. The opposite effects of quinidine and verapamil on GI motility may balance each other out, making both drugs more tolerable. Finally, verapamil and quinidine may have pharmacokinetic interactions via the cytochrome P450 system that allow more stable therapeutic plasma levels at lower doses. In PAFAC, relatively low doses of quinidine and verapamil appeared to be as successful as sotalol and relatively free of therapy-limiting side effects.
A third major observation is the temporal pattern for the occurrence of proarrhythmia. In this study, two-thirds of the proarrhythmia was seen within the first 4 days. We are unfortunately not provided much information about the clinical characteristics of those who experienced proarrhythmia. It would be important to know if patients with normal ventricular function and no ventricular hypertrophy ever developed this problem. Currently, we always hospitalize patients with left ventricular hypertrophy or congestive heart failure when starting antiarrhythmic drugs. If proarrhythmia occurred in patients without this finding, the data presented here would argue that any patients with structural heart disease should be hospitalized when drugs are begun after cardioversion of atrial fibrillation.
The PAFAC investigators should be congratulated on an excellent, well designed study. Their study confirms the relatively poor efficacy of antiarrhythmic drugs in preventing recurrent atrial fibrillation, but the careful trial design provides data helpful for designing future studies and for managing patients on a day-to-day basis.
Dr. DiMarco, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville, is on the Editorial Board of Clinical Cardiology Alert.