Dose-response relations of azimilide in the management of symptomatic, recurrent, atrial fibrillation

We evaluated the efficacy and safety of azimilide, a new class III antiarrh ythmic agent that blocks both the slow and fast components of the cardiac-d elayed rectifier potassium currents in 4 randomized, double-blind, placebo- controlled trials with similar protocols. The purpose of this study was to assess the relation between dose and effect. A total of. 1,380 patients wit h a documented history of symptomatic atrial fibrillation (AF), atrial flut ter, or both, were enrolled. After a 3-day loading period during which the assigned dose was given, twice a day, subjects received placebo or azimilid e (35, 50, 75, 100, or 125 mg once a day) for the duration of the study per iod. The primary end point of the studies was the time to symptomatic arrhy thmia recurrence with a transtelephonic electrocardiogram typical of AF, at rial flutter, or paroxysmal supraventricular tachycardia. For each study, K aplan-Meier estimates of the median time to recurrence were computed for pl acebo and for each azimilide dose. Cox proportional-hazards modeling was us ed to estimate hazard ratios for each active dose. Each. of the 2 highest a zimilide doses (100 and 125 mg/day) significantly prolonged the time to rec urrence of arrhythmia. For the 100 mg/day dose, the hazard ratio was 1.34, 95% confidence interval 1.05 to 1.72; p = 0.02. For the 125 mg/day dose, th e hazard ratio was 1.32, 95% confidence interval 1.07 to 1.62; p = 0.01. Pa tients with a history of either ischemic heart disease or congestive heart failure had a significantly greater treatment effect from azimilide than th ose without it. Torsades de Pointes occurred in 0.9% of patients receiving either of the 2 effective doses. Thus, doses of azimilide <100 mg/day are n ot effective for control of AF, whereas doses of 100 and 125 mg/day are eff ective with an acceptable risk of serious toxicity. (C)2001 by Excerpta Med ica, Inc.