A Randomized, Placebo-Controlled Study of Vernakalant (Oral) for the Prevention of Atrial Fibrillation Recurrence After Cardioversion

Abstract

Background-Vernakalant, a relatively atrial-selective antiarrhythmic drug, has previously demonstrated efficacy for the acute conversion of atrial fibrillation (AF) to sinus rhythm. This study was designed to determine the most appropriate oral dose of vernakalant for the prevention of AF recurrence postcardioversion. Methods and Results-Patients with nonpermanent AF were randomized to 150, 300, or 500 mg vernakalant or placebo twice daily for up to 90 days. The efficacy analysis was conducted on 605 of 735 patients who entered the maintenance phase on day 3 after cardioversion. The time to the first recurrence of symptomatic sustained AF was significantly longer in the 500 mg vernakalant group, with a median of Ͼ90 days versus 29 days in the placebo group (hazard ratio, 0.735; Pϭ0.0275). No significant effect was seen at the lower doses. The percent of patients in sinus rhythm at day 90 was 41%, 39%, and 49% in the 150-mg (nϭ147), 300-mg (nϭ148), and 500-mg (nϭ150) vernakalant groups, respectively, compared with 36% in the placebo group (nϭ160). There were no vernakalant-related proarrhythmic events. Related serious adverse events occurred in 2 patients in the 150-mg vernakalant group and in 1 patient in each of the other groups. Conclusions-Vernakalant, 500 mg twice daily, appears to be effective and safe for the prevention of AF recurrence after cardioversion. The absence of proarrhythmia and favorable safety profile is an important finding for the drug. Key Words: antiarrhythmia agents Ⅲ arrhythmia Ⅲ cardioversion Ⅲ prevention Ⅲ vernakalant M aintenance of sinus rhythm is a necessary goal in many patients with paroxysmal or persistent atrial fibrillation (AF). In the Euro Heart Survey, 1 77% of patients with paroxysmal or persistent AF received pharmaceutical rhythm control therapy. Currently available antiarrhythmic drugs have important limitations. The most effective compound, amiodarone, is associated with severe noncardiac side effects. 2,3 Class 1C antiarrhythmics and sotalol are associated with risks of proarrhythmia, which limit their use. 4 Finally, the newly registered dronedarone was significantly inferior to amiodarone for the composite primary end point of time to first AF recurrence or premature study drug discontinuation (due to intolerance or lack of efficacy). 5 Thus, there is a continued need to develop safe and efficacious antiarrhythmic drugs. Clinical Perspective on p 643Vernakalant represents a novel class of antiarrhythmics being developed for conversion as well as maintenance of sinus rhythm after conversion. The electrophysiological properties differ from currently available compounds. Vernakalant has relative atrial specificity and targets early-activating and acetylcholine-activated potassium channels and has a weak effect on sodium channels in atria and ventricles. 6 -8 Vernakalant slows conduction at rapid pacing rates and prolongs atrial refractoriness. The intravenous formulation has been demonstrated to rapidly convert recent onset AF to sinus rhythm in several clinical trials...

Comparison of electrophysiological and antiarrhythmic effects of vernakalant, ranolazine, and sotalol in canine pulmonary vein sleeve preparations

“…45 An oral formulation of vernakalant for the prevention of AF recurrence post-cardioversion is under investigation. 46 Our data suggest that the clinical efficacy demonstrated for vernakalant can be partly explained by suppression of triggered activity responsible for the induction of AF and other atrial arrhythmias. The effects of vernakalant to induce post-repolarization refractoriness in PV, as in other atrial tissues (Burashnikov and Antzelevitch, unpublished observation), also points to a mechanistic rationale for rhythm control utility in the chronic management of AF.…”

Future Perspectives in the Pharmacological Treatment of Atrial Fibrillation and Ventricular Arrhythmias in Heart Failure

“…Following intravenous administration, vernakalant effectively converted AF to sinus rhythm in recent onset and postoperative AF [305][306][307]. In a recent clinical trial oral vernakalant was found to be effective for maintaining sinus rhythm following cardioversion of AF [308]. Vernakalant does not exhibit proarrhythmic effects in dogs with chronic atrioventricular block, a model featuring I Ks downregulation, bradycardia and increased susceptibility to arrhythmias [309].…”

“…Vernakalant does not exhibit proarrhythmic effects in dogs with chronic atrioventricular block, a model featuring I Ks downregulation, bradycardia and increased susceptibility to arrhythmias [309]. No proarrhythmic adverse effects were found in a rabbit proarrhythmia model [310] or in a recent clinical trial [308]. In AF associated with HF, vernakalant appears to be less effective for cardioversion and increased incidence of serious hypotensive episodes and ventricular arrhythmias were detected in patients with left ventricular dysfunction [311].…”

Safety and efficacy of pharmacological cardioversion of atrial fibrillation using intravenous vernakalant, a new antiarrhythmic drug with atrial selectivity

“…form of vernakalant given for conversion of AF [12][13][14][15], but yet only one such Phase II study evaluating the oral form of vernakalant is published [16].…”