Ce-452779-3 randomized placebo-controlled trial of flecainide in patients with arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited arrhythmia disorder with a high risk of ventricular tachycardia (VT) or ventricular fibrillation (VF), and implantable cardioverter defibrillators (ICD) remain the palliative therapy of choice. We conducted an NIH-funded pilot clinical trial hypothesizing flecainide administration is more effective than placebo in reducing the burden of ventricular premature beats (VPBs) in ARVC patients. The study was designed as a randomized double-blinded placebo-controlled crossover trial in ARVC patients with administration of 100 mg bid of flecainide or matching placebo for 4 weeks each with a washout period. The primary specific aim was to determine whether flecainide administration is associated with a significant reduction of number of VPBs in comparison to placebo, measured on 7-day Zio-Patch ECG monitoring. Inclusion criteria required ARVC diagnosis with the 2010 ARVC Task Force Criteria at the age of at least 18 years, implanted ICD, and over 500 VPBs on a diagnostic 24-hour Holter recording. Patients were required to be treated with beta-blockers. Patients on other antiarrhythmic treatment required washout with reconfirmation of over 500 VPBs per 24 hour off antiarrhythmic medication. The effect of flecainide on log2(VPB rate) was analyzed using a weighted linear mixed effects analysis of variance model with fixed effects for treatment and period and a random effect for subject, with wights proportional to teh Zio-Patch monitoring time. There were 22 patients with ARVC and an ICD enrolled with a mean age 45+/-13 years, including 12 females. There were 19 patients with at least one Zio-Patch recording and 17 with both recordings. The Table includes details of arrhythmias on placebo and on flecainide. The mean and median number of VPBs/day was significantly lower on flecainide than placebo. At least 50% reduction in VPBs/day was observed in 79% and at least 75% reduction in 53% of patients. The primary analysis showed that flecainide reduced the VPB rate by 72% (p < 0.0001, 95% CI: 56-82%), adjusted for the period effect. There were 2 subjects with pro-arrhythmic response, but flecainide was safe for most of study patients. This is the first randomized clinical trial testing antiarrhythmic management in ARVC patients. Flecainide signficantly reduced the VPB rate and NSVT/VT/VF rate supporting clinical use of this medication in ARVC patients.