Assessment of the efficacy and safety of antiarrhythmic therapy for chronic atrial fibrillation: observations on the role of trial design and implications of drug-related mortality.

The findings in clinical trials of antiarrhythmic drug efficacy and safety are frequently difficult to compare, since study design often has an important effect on trial outcome. To explore this problem further, we compared three designs--randomized control, nonrandomized control, and uncontrolled--collectively enrolling 2415 patients in 21 trials reporting on the role of quinidine in the prevention of chronic atrial fibrillation. The proportion of patients remaining in sinus rhythm at 3, 6, and 12 months after cardioversion was calculated by means of Kaplan-Meier techniques, and the data were pooled for each trial design. For the randomized control trials the difference in the absolute percentage of patients remaining in sinus rhythm in the quinidine and control groups was 24% at each of the three follow-up intervals. Contrary to findings in the randomized control trials, the magnitude of the treatment benefit in nonrandomized trials was smaller and declined markedly over time. The percentage of patients remaining in sinus rhythm in the uncontrolled trials was intermediate to the percentages in the other two trial designs. When the data from all three trial designs were pooled, the crude mortality rate was 2.0% in quinidine-treated patients and 0.6% in control patients. Sudden cardiac death or ventricular fibrillation was the cause of death in 13 of 19 patients for whom the cause of death was known, highlighting the potential risk of quinidine-induced proarrhythmia. Although quinidine is effective in maintaining sinus rhythm, estimates of the treatment effect vary among trial types.(ABSTRACT TRUNCATED AT 250 WORDS)