Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia A Randomized Clinical Trial

IMPORTANCE Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by polymorphic ventricular tachycardia with physical or emotional stress, for which current therapy with beta-blockersis incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release-the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT-but has never been assessed prospectively. OBJECTIVE To determine whether flecainide dosed to therapeutic levels and added to beta-blocker therapy is superior to beta-blocker therapy alone for the prevention of exercise-induced arrhythmias in CPVT. DESIGN, SETTING, AND PARTICIPANTS This investigator-initiated, multicenter, single-blind, placebo-controlled crossover clinical trial was conducted from December 19, 2011, through December 29, 2015, with a midtrial protocol change at 10 US sites. Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator underwent a baseline exercise test while receiving maximally tolerated beta-blocker therapy that was continued throughout the trial. Patients were then randomized to treatment A (flecainide or placebo) for 3 months, followed by exercise testing. After a 1-week washout period, patients crossed over to treatment B (placebo or flecainide) for 3 months, followed by exercise testing. INTERVENTIONS Patients received oral flecainide or placebo twice daily, with the dosage guided by trough serum levels. MAIN OUTCOMES AND MEASURES The primary end point of ventricular arrhythmias during exercise was compared between the flecainide and placebo arms. Exercise tests were scored on an ordinal scale of worst ventricular arrhythmia observed (0 indicates no ectopy; 1, isolated premature ventricular beats; 2, bigeminy; 3, couplets; and 4, nonsustained ventricular tachycardia). RESULTS Of 14 patients (7 males and 7 females; median age, 16 years [interquartile range, 15.0-22.5 years]) randomized, 13 completed the study. The median baseline exercise test score was 3.0 (range, 0-4), with no difference noted between the baseline and placebo (median, 2.5; range, 0-4) exercise scores. The median ventricular arrhythmia score during exercise was significantly reduced by flecainide (0 [range, 0-2] vs 2.5 [range, 0- 4] for placebo; P < .01), with complete suppression observed in 11 of 13 patients (85%). Overall and serious adverse events did not differ between the flecainide and placebo arms. CONCLUSIONS AND RELEVANCE In this randomized clinical trial of patients with CPVT, flecainide plus beta-blocker significantly reduced ventricular ectopy during exercise compared with placebo plus beta-blocker and beta-blocker alone.