Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia

Abstract

Objectives: This study evaluated the efficacy and safety of flecainide in addition to conventional drug therapy in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT).

Background: CPVT is an inherited arrhythmia syndrome caused by gene mutations that destabilize cardiac ryanodine receptor Ca(2+) release channels. Sudden cardiac death is incompletely prevented by conventional drug therapy with β-blockers with or without Ca(2+) channel blockers. The antiarrhythmic agent flecainide directly targets the molecular defect in CPVT by inhibiting premature Ca(2+) release and triggered beats in vitro.

Methods: We collected data from every consecutive genotype-positive CPVT patient started on flecainide at 8 international centers before December 2009. The primary outcome measure was the reduction of ventricular arrhythmias during exercise testing.

Results: Thirty-three patients received flecainide because of exercise-induced ventricular arrhythmias despite conventional (for different reasons, not always optimal) therapy (median age 25 years; range 7 to 68 years; 73% female). Exercise tests comparing flecainide in addition to conventional therapy with conventional therapy alone were available for 29 patients. Twenty-two patients (76%) had either partial (n = 8) or complete (n = 14) suppression of exercise-induced ventricular arrhythmias with flecainide (p < 0.001). No patient experienced worsening of exercise-induced ventricular arrhythmias. The median daily flecainide dose in responders was 150 mg (range 100 to 300 mg). During a median follow-up of 20 months (range 12 to 40 months), 1 patient experienced implantable cardioverter-defibrillator shocks for polymorphic ventricular arrhythmias, which were associated with a low serum flecainide level. In 1 patient, flecainide successfully suppressed exercise-induced ventricular arrhythmias for 29 years.

Conclusions: Flecainide reduced exercise-induced ventricular arrhythmias in patients with CPVT not controlled by conventional drug therapy.

Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Ventricular arrhythmia score per patient at the baseline exercise test on standard therapy and at the first exercise test on the final (stable) flecainide dose in the entire cohort (n=29; panel A), and in the patients who were treated with a first-line β-blocker at an optimal dose (N=15, panel B)

NSVT indicates nonsustained ventricular tachycardia; VPB, ventricular premature beat. The number of patients in each ventricular arrhythmia category and change of ventricular arrhythmia category is shown. The line thickness indicates the number of patients, a dotted line represents one patient. The median time interval between the two tests is shown. All exercise tests were on an unchanged β-blocker dose.

Figure 2. Ventricular arrhythmia score per patient at the baseline exercise test and at the previous exercise test on the same standard therapy dose (panel A), and at the first and second exercise test on the final (stable) flecainide dose (panel B)

The number of patients in each ventricular arrhythmia category and change of ventricular arrhythmia category is shown. The line thickness indicates the number of patients, a dotted line represents one patient. The median time interval between the two tests is shown. The standard therapy exercise tests were on the same β-blocker +/− Ca2+ channel blocker doses. All exercise tests on flecainide were on the same, stable flecainide dose in combination with an unchanged or lower β-blocker dose. The sinus rate at maximal exercise at the first and second exercise test on flecainide was not significantly different (140±19 vs. 144±20; p=0.245). However, the two patients with a ventricular arrhythmia score of 4 and 3 at the second exercise test did reach a significantly higher maximum sinus rate as compared with the first exercise test (increase of 32 and 19 beats per minute, respectively).

Figure 3. Dose-dependence of flecainide in eight CPVT patients who had an increase inflecainide dose

VPB indicates ventricular premature beat; NSVT, nonsustained ventricular tachycardia. The number of patients in each ventricular arrhythmia category and change of ventricular arrhythmia category (X-axis) at the last exercise test on the starting flecainide dose (96±28 mg; range 50 to 150 mg) and at the first exercise test on the final (stable) flecainide dose (178±78 mg; range 100 to 300 mg) is shown. The line thickness indicates the number of patients, a dotted line represents one patient. The median time interval from the start of flecainide therapy is displayed. All exercise tests were on an unchanged β-blocker dose.