Vernakalant Hydrochloride for Rapid Conversion of Atrial Fibrillation - Atrial Arrhythmia Conversion Trial
Currently, ibutilide is the only agent that is Food and Drug Administration approved for acute conversion of atrial fibrillation (AF). Other agents that are frequently used, such as amiodarone, are associated with modest efficacy and frequent side effects. Vernakalant hydrochloride is a newer agent, which showed promising results in a placebo-controlled phase II trial. The goal of this trial was to study the safety and efficacy of vernakalant in acute conversion of AF.
Vernakalant hydrochloride is superior to placebo in acute conversion of AF to sinus rhythm, with an acceptable safety profile.
Patients Enrolled: 336
Mean Follow Up: 30 days
Mean Patient Age: 62.1 years
• Sustained AF for 3 hours to 45 days
• Age ≥18 years
• Body weight 45-136 kg
• Systolic blood pressure >90 mm Hg and <160 mm="">
• Diastolic blood pressure <95 mm="" hg="" mm="">
• Sick sinus syndrome
• QRS >14 msec without a pacemaker
• Ventricular rate <50>
• Uncorrected QT >440 msec
• Typical atrial flutter
• New York Heart Association class IV symptoms of heart failure
• Acute coronary syndromes, myocardial infarction, or cardiac surgery within 30 days before enrollment
• Reversible cause of AF
• End-stage disease
• Previously failed electrical cardioversion
• Uncorrected electrolyte imbalance
• Digoxin toxicity
Proportion of patients with short duration AF (3 hours to 7 days) who had conversion to sinus rhythm for at least 1 minute within 90 minutes of drug administration
• Time to conversion from first exposure to study drug
• Proportion of patients who remain in normal sinus rhythm at 24 hours
• Proportion of patients with AF with duration of 3 hours to 45 days and 8 to 45 days who had restoration to normal sinus rhythm or a paced rhythm
• Serious side effects
Patients with AF received a 10-minute infusion of vernakalant (3.0 mg/kg) or placebo, followed by a 15-minute observation period. If the patient did not convert to sinus rhythm, a second dose of vernakalant (2.0 mg/kg) or placebo was administered. Use of other antiarrhythmic agents and electrical cardioversion was discouraged until at least 2 hours after study drug infusion.
Beta-blockers (59.2%), digoxin (27.1%), class I antiarrhythmic agents (6.5%), and class III antiarrhythmic agents (5.1%)
A total of 330 patients were randomized (221 to vernakalant, and 115 to placebo). Patients were stratified into AF of short duration (3 hours to 7 days, median 28.3 hours; n = 220) and long duration (7 to 45 days, median 562 hours; n = 116). Baseline characteristics were similar between the two groups.
Efficacy: More patients converted to sinus rhythm (for at least 1 minute) within 90 minutes in the vernakalant group (37.6%) compared with the placebo group (2.6%) (p
Safety: There were three deaths (1.4%) in the vernakalant group at 30 days, and none in the placebo group. Hospitalization for recurrent AF occurred in 5.9% of patients in the vernakalant group, compared with 12.2% in the placebo group. Treatment-related side effects were more common with vernakalant compared with placebo: dysgeusia (29.9% vs. 0.9%), sneezing (16.3% vs. 0%), paresthesias (10.9% vs. 0%), nausea (9.0% vs. 0.9%), and hypotension (6.3% vs. 3.5%). Vernakalant also prolonged QRS and QTc intervals significantly at the end of the 10-minute infusion, compared with placebo. However, the incidence of all ventricular arrhythmias was 9.0% for vernakalant and 17.4% for placebo; torsades de pointes was noted in two patients in the vernakalant group (0.9%) and none in the placebo group (0%).
The results of this intriguing clinical trial indicate that vernakalant hydrochloride, an atrial-selective, early-activating K+ and frequency-dependent Na+ channel blocker, may be a novel alternative to existing agents for acute conversion of AF to sinus rhythm, especially if it is of relatively short duration. Treatment-related side effects were fairly common, although the incidence of ventricular arrhythmias was similar to placebo. The incidence of torsades de pointes was
Larger clinical studies on the safety and efficacy of this agent, especially in comparison with currently used medications, are necessary. Further studies will also need to study other patient populations with AF, such as those who have had electrical cardioversion or ablations (percutaneous or surgical) before.
Roy D, Pratt CM, Torp-Pedersen C, et al., on behalf of the Atrial Arrhythmia Conversion Trial Investigators. Vernakalant hydrochloride for rapid conversion of atrial fibrillation: a phase 3, randomized, placebo-controlled trial. Circulation 2008;117:1518-25.
Keywords: Nausea, Paresthesia, Body Weight, Electric Countershock, Hypotension, Blood Pressure, Torsades de Pointes, United States Food and Drug Administration, Sneezing, Dysgeusia, Pyrrolidines, Atrial Fibrillation, Sulfonamides
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