Randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a single oral dose of vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm: RESTORE SR

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• 作者：Jonathan P. Piccini ; MD ; MHS ; FHRS^* ; ^{jonathan.piccini@duke.edu" class="auth_mail" title="E-mail the corresponding author} ; Edward L.C. Pritchett ; MD^* ; Beth A. Davison ; PhD^&dagger ; ; Gad Cotter ; MD^&dagger ; ; Laura E. Wiener ; MS^&Dagger ; ; Gary Koch ; PhD^&Dagger ; ; Gregory Feld ; MD ; FHRS^§ ; ; Albert Waldo ; MD ; PhD ; FHRS^║ ; Isabelle C. van Gelder ; MD ; PhD^¶ ; ; A. John Camm ; MD ; FHRS^# ; Peter R. Kowey ; MD^** ; Julie Iwashita ; BA^&dagger ; &dagger ; ; Howard C. Dittrich ; MD^&dagger ; &dagger ;
• 关键词：Atrial fibrillation ; Antiarrhythmic ; Vanoxerine ; Cardioversion ; Clinical trial
• 刊名：Heart Rhythm
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：13
• 期：9
• 页码：1777-1783
• 全文大小：600 K

文摘

Vanoxerine is an oral, 1,4-dialkylpiperazine derivative antiarrhythmic drug being evaluated for pharmacological cardioversion of atrial fibrillation (AF).

Objective

The purpose of this study was to evaluate the safety and efficacy of vanoxerine for the restoration of sinus rhythm in subjects with recent onset AF or atrial flutter (AFL).

Methods

RESTORE SR (randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a single oral dose of vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm) was a prospective, multinational, randomized, double-blind, placebo-controlled trial that randomized subjects to a single oral dose of vanoxerine 400 mg or placebo (2:1 allocation).

Results

A total of 41 subjects were randomized in the study (placebo [n = 15] and vanoxerine [n = 26]). The study was terminated prematurely because of safety concerns. Overall, 61% (23 of 38) of the treated cohort had a history of AF/AFL and 66% (27 of 41) had structural heart disease (SHD). The primary efficacy end point—conversion to sinus rhythm through 24 hours—occurred in 20% (3 of 15) in the placebo arm vs 69% (18 of 26) in the vanoxerine arm (P = .0024). The mean length of stay was 4.2 ± 2.9 days in the placebo arm vs 4.7 ± 3.2 days in the vanoxerine arm (P = .6561). The primary safety end point (all-cause death, ventricular fibrillation/tachycardia requiring intervention, or torsades de pointes) occurred in no patient in the placebo arm vs 11.5% (3 of 26) in the vanoxerine arm. All 3 patients had torsades de pointes and underlying SHD.

Conclusion

Vanoxerine is an oral, mixed ion channel blocker with I_Kr, I_Na, and L-type calcium channel activity. While oral therapy with 400 mg of vanoxerine appears effective for the termination of recent onset AF/AFL, its use was associated with a significant risk of ventricular proarrhythmia in patients with SHD.