Dose-response relations of azimilide in the management of symptomatic, recurrent, atrial fibrillation
Academic Article
Overview
Research
Identity
Additional Document Info
View All
Overview
abstract
We evaluated the efficacy and safety of azimilide, a new class III antiarrhythmic agent that blocks both the slow and fast components of the cardiac-delayed 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 with a documented history of symptomatic atrial fibrillation (AF), atrial flutter, or both, were enrolled. After a 3-day loading period during which the assigned dose was given twice a day, subjects received placebo or azimilide (35, 50, 75, 100, or 125 mg once a day) for the duration of the study period. The primary end point of the studies was the time to symptomatic arrhythmia recurrence with a transtelephonic electrocardiogram typical of AF, atrial flutter, or paroxysmal supraventricular tachycardia. For each study, Kaplan-Meier estimates of the median time to recurrence were computed for placebo and for each azimilide dose. Cox proportional-hazards modeling was used to estimate hazard ratios for each active dose. Each of the 2 highest azimilide doses (100 and 125 mg/day) significantly prolonged the time to recurrence 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, the hazard ratio was 1.32, 95% confidence interval 1.07 to 1.62; p = 0.01. Patients with a history of either ischemic heart disease or congestive heart failure had a significantly greater treatment effect from azimilide than those 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 not effective for control of AF, whereas doses of 100 and 125 mg/day are effective with an acceptable risk of serious toxicity.
