A New Drug for Rapid Conversion of AF
Abstract & Commentary
By John P. DiMarco, MD, PhD Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville Dr. DiMarco is a consultant for Novartis, and does research for Medtronic and Guidant. This article originally appeared in the May 2008 issue of Clinical Cardiology Alert. It was edited by Michael H. Crawford, MD, and peer reviewed by Rakesh Mishra, MD.
Source: Roy D, et al. Vernakalant hydrochloride for rapid conversion of atrial fibrillation: a phase 3, randomized, placebo-controlled trial. Circulation. 2008;117:1518-1525.
Vernakalant is a new investigational anti-arrhythmic drug. The compound is relatively selective, blocking the early-activating potassium channel and the frequency-dependent sodium channel; it has a half-life of two to three hours. This study evaluates the ability of intravenous vernakalant to terminate acute onset atrial fibrillation (AF). Patients with sustained atrial fibrillation, with a duration from three hours to 45 days, were eligible for inclusion. Patients were hemodynamically stable, and had no history of sick sinus syndrome, marked QRS, or QT prolongation, or recent acute coronary syndrome, myocardial infarction, or cardiac surgery. Rate control therapy with AV nodal blocking agents was permitted prior to study drug infusion. Other antiarrhythmic drugs as background therapy were permitted. Patients received a ten-minute infusion of either vernakalant (3 mg/kg) or placebo, followed by a 15-minute observation period. Patients who did not convert received an additional 2 mg/kg dose of vernakalant or matching placebo. A Holter monitor continuously monitored the cardiac rhythm from screening to 24 hours after the last dose of study drug. Electrical cardioversion was permitted in non-responders after two hours. The primary efficacy end point was the proportion of patients who had conversion to sinus rhythm, for at least one minute, within 90 minutes of drug administration. Patients were stratified by the duration of AF into two groups: short duration AF (3 hours to 7 days) and longer duration AF (8-45 days).
A total of 356 patients were randomized to either vernakalant or placebo. Twenty patients were withdrawn after randomization for various reasons. The mean age was approximately 62 years. Two hundred and twenty patients were in the short duration AF group and 116 patients were in the long duration AF group. Hypertension and ischemic heart disease were the most common cardiac diagnoses. Most patients were on some form of AV nodal blocking agent, and approximately 10% were receiving a class I or class III antiarrhythmic drug. In the short duration AF group, 75 of 145 vernakalant patients (51.7%) converted to sinus rhythm within 90 minutes, compared with three of the 75 placebo patients (4%; P < 0.001); patients with AF lasting 3-48 hours had a higher success rate (62.1%). Of the 75 patients who demonstrated conversion, 57 (76%) did so with the initial 3 mg/kg dose. The median time to conversion was 11 minutes, and only 75 of the vernakalant-treated patients who initially converted relapsed to atrial fibrillation within 24 hours. In contrast, only six of the 76 vernakalant patients in the longer duration AF group had termination of atrial fibrillation, compared with zero of the 40 placebo patients. Nineteen vernakalant patients (8.6%) converted to atrial flutter in the first 90 minutes; five patients subsequently converted to sinus rhythm. None of the episodes of atrial flutter were associated with 1:1 AV conduction. During 30-day follow-up, there were three deaths, all in the vernakalant group; however, none of the deaths were considered to be related to study drug. Adverse events were uncommon. There were four serious adverse events that were considered to be possibly or probably related to vernakalant. Two patients developed significant hypotension and one 90-year-old woman had complete heart block after electrical cardioversion 2.5 hours after completion of the second vernakalant infusion. There were no significant increases in ventricular arrhythmias associated with vernakalant, as well as no episodes of torsades de pointe or ventricular fibrillation in either group in the first 24 hours after drug administration. Notable adverse events in the vernakalant group included dysgeusia, sneezing, and nausea. The median duration for all of these adverse events was less than 15 minutes. Vernakalant had no significant effect on heart rate in patients who remained in atrial fibrillation. Vernakalant produced moderate increases in the QRS interval and in the QTc intervals.
Roy and colleagues concluded that vernakalant is an effective agent for rapid conversion of short duration atrial fibrillation. Serious adverse events were uncommon and minor adverse events were of short duration.
Commentary
New or recent onset atrial fibrillation is a common problem in emergency rooms and among hospitalized patients. Although transthoracic cardioversion is highly effective, cardioversion requires anesthesia or sedation and may be complicated by immediate or early recurrence of AF. Current pharmacologic options for acute conversion are limited. Oral flecainide or propafenone may be used in patients with little or no structural heart disease. Intravenous ibutilide is more effective than procainamide, but ibutilide may cause torsades de pointes, and requires careful monitoring. Amiodarone and dofetilide may convert AF; usually, multiple doses are required. In this paper, Roy et al show that vernakalant, a multichannel blocker, is moderately effective and fairly safe when used to convert AF episodes of recent onset. As with other drugs, the efficacy rate is greatest in those with very recent onset, but these patients are frequently seen by physicians since they can become very symptomatic at the start of the episode. Based on the data in this paper, the FDA Cardio-Renal Advisory Committee recently voted in support of the market release of vernakalant for patients with AF. It's likely that it will largely replace ibutilide as the intravenous drug of choice for atrial fibrillation. However, ibutilide may remain the first option for patients with atrial flutter.
Vernakalant is a new investigational anti-arrhythmic drug. The compound is relatively selective, blocking the early-activating potassium channel and the frequency-dependent sodium channel; it has a half-life of two to three hours.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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