Pilot Randomized Trial with Flecainide in ARVC Patients

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Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited arrhythmia disorder with high risk of ventricular tachycardia or fibrillation, and implantable cardioverter defibrillator remains as palliative therapy of choice. Antiarrhythmic therapy with different agents including beta-blockers, sotalol and amiodarone are usually not effective in reducing risk of arrhythmic events. Recent experimental data using a novel murine model with cardiac-specific tamoxifen induced PKP2 deficiency indicated that enhanced triggered activity and increased sarcoplasmic reticulum (SR) calcium release via RyR2 channels could contribute to adrenergic-induced arrhythmias in the setting of ARVC. This study also reported that flecainide effectively prevented the arrhythmias observed in the experimental animals. Separate preclinical and anecdotal clinical reports also suggest that flecainide, likely through a block of the RyR2 receptor, may be a promising antiarrhythmic approach in ARVC. Furthermore, in a small randomized trial flecainide was effective in reducing ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia, a condition linked to RyR2 mutations causing increased SR release and triggered arrhythmias. These results provide a strong rationale for the implementation of a definitive randomized clinical trial to determine whether flecainide will reduce life-threatening VT/VF episodes in high-risk ARVC patients; however before conducting such a large study a pilot project focused on antiarrhythmic effects of flecainide therapy and its safety in ARVC patients is needed. Therefore, we propose to conduct a pilot study designed as randomized double-blinded placebo-controlled crossover trial with administration of 100 mg bid of Flecainide or matching placebo for 4 weeks each with a washout period. Study population will include 38 ARVC patients diagnosed with the 2010 ARVC Task Force Criteria who are at least 21 years old, have implanted ICD, and show at least 500 VPBs in a 24-hour Holter recording. Primary specific aim of this pilot trial is to determine whether Flecainide administration is associated with a significant reduction of number of ventricular ectopic beats (VEBs) in ARVC patients with ICDs. Secondary specific aims are: 1) to assess safety of flecainide administration with particular emphasis on proarrhythmic response; 2) to assess effects of flecainide on burden of VT runs in 7-day ECG recordings; 3) to assess effects of flecainide on burden of atrial premature beats in 7-day recordings; 4) to demonstrate feasibility of enrollment of rare inherited arrhythmia ARVC patients in a randomized study in the light of planned future large clinical trial with VT/VF/death as endpoint.