Vernakalant Hydrochloride for Rapid Conversion of Atrial Fibrillation: A Phase 3, Randomized, Placebo‐Controlled Trial

Background. The present study assessed the efficacy and safety of vernakalant hydrochloride (RSD1235), a novel compound, for the conversion of atrial fibrillation (AF). Methods and results. Patients were randomized in a 2:1 ratio to receive vernakalant or placebo and were stratified by AF duration of 3 hours to 7 days (short duration) and 8 to 45 days (long duration). A first infusion of placebo or vernakalant (3 mg/kg) was given for 10 minutes, followed by a second infusion of placebo or vernakalant (2 mg/kg) 15 minutes later if AF was not terminated. The primary end point was conversion of AF to sinus rhythm for at least 1 minute within 90 minutes of the start of drug infusion in the short-duration AF group. A total of 336 patients were randomized and received treatment (short duration, n=220; long duration, n=116). Of the 145 vernakalant patients, 75 (51.7%) in the short-duration AF group converted to sinus rhythm (median time, 11 minutes) compared with 3 of the 75 placebo patients (4.0%; P<.001). Overall, in the short- and long-duration AF groups, 83 of the 221 vernakalant patients (37.6%) experienced termination of AF compared with 3 of the 115 placebo patients (2.6%; P<.001). Transient dysgeusia and sneezing were the most common adverse effects in vernakalant-treated patients. Four vernakalant-related serious adverse events (hypotension [2 events], complete atrioventricular block, and cardiogenic shock) occurred in 3 patients. Conclusion. Vernakalant demonstrated rapid conversion of short-duration AF and was well tolerated.—Roy D, Pratt CM, Torp-Pedersen C, et al.; Atrial Arrhythmia Conversion Trial Investigators. Vernakalant hydrochloride for rapid conversion of atrial fibrillation: a phase 3, randomized, placebo-controlled trial. Circulation. 2008;117(12):1518–1525. This double-blinded prospective study demonstrated efficacy of vernakalant in converting AF to sinus rhythm when compared with placebo. The highest success rates were inversely proportionate to the duration of the arrhythmia, (62.1% with AF of 3–48 hours, 23.8% with AF of 3–7 days, and 7.9% with AF of 8–45 days), presumably due to atrial electrical remodeling seen with longer durations of AF. The mean time to conversion was 11 minutes, and 74 of the 75 converted patients maintained sinus rhythm at 24 hours. Nonsustained ventricular tachycardia was higher in the placebo group (14.8% vs 6.3%), but this may be in part due to the higher proportion of those in the placebo group using digoxin. Torsade de pointes occurred in 2 patients and was not seen until 32 hours and 16 days of the infusions, though the drug half-life is 2 to 3 hours. Modest increases in QT interval were seen in the trial drug group, but these were resolved by 90 minutes after drug infusion. Heart failure was more common in the placebo and vernakalant group with 8 to 45 days of AF (32% and 24%, respectively) compared with those with a <8-day duration (7% and 10%, respectively). Whether the higher proportion of heart failure patients at baseline in the 8 to 45 days group affected conversion cardioversion rates is unclear. Vernakalant is a novel drug in phase 3 trials that selectively blocks atrial K+ and frequency-dependent Na+ channels, resulting in prolongation of the atrial refractory period with little effect on ventricular refractory periods. Compared with other commonly used antiarrhythmics used in AF (e.g., ibutilide, procainamide, and amiodarone), it is relatively effective, rapid-acting, and apparently well tolerated. Though a small percentage of the trial patients had heart failure, the data suggest that vernakalant could be safely used in converting heart failure with short-duration AF to sinus rhythm, whereas other common antiarrhythmic medications are usually contraindicated for use in this population.