Add-on Tx Cuts Exercise-Induced Arrhythmia in Genetic CPVT

— Flecainide helps in catecholaminergic polymorphic ventricular tachycardia

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For catecholaminergic polymorphic ventricular tachycardia (CPVT), adding flecainide (Tambocor) reduced ventricular arrhythmia with exercise for patients in whom ectopy persists despite maximal beta-blocker use, the first randomized trial in the condition showed.

Median ventricular arrhythmia score during exercise was 0 with flecainide versus 2.5 with placebo (P<0.01) on a scale in which 0 is no ectopy, 2 indicates premature ventricular contractions in a bigeminal pattern, and 3 represents ventricular couplets.

Complete exercise-induced ventricular arrhythmia suppression occurred in 11 of the 13 patients with the rare genetic arrhythmia syndrome who completed the trial (85%), Prince Kannankeril, MD, of the Monroe Carell Jr. Children's Hospital at Vanderbilt in Nashville, Tenn., and colleagues reported online in JAMA Cardiology.

"Reduction of exercise-induced arrhythmias is a clinically relevant outcome because persistence of ventricular arrhythmias in the form of couplets or nonsustained ventricular tachycardia (NSVT) on exercise testing has been associated with subsequent cardiac events in CPVT," the researchers wrote, although acknowledging that it wasn't their first choice endpoint.

The single-blind, crossover trial had a mid-trial protocol change of primary endpoint from ventricular tachycardia or appropriate ICD therapy to what had been the secondary endpoint -- degree of ventricular arrhythmias induced on exercise testing -- due to poor enrollment that would have left the primary underpowered.

For the originally intended primary outcome, three instances of ICD therapy for VT occurred in two participants. One participant received an appropriate shock during each arm of the study. The other had an appropriate shock after 284 days of flecainide. Exercise testing for this patient showed couplets at baseline, nonsustained ventricular tachycardia with placebo, and bigeminy with flecainide.

Part of the enrollment problem appeared to be rapid uptake of flecainide based on open-label data with no real placebo comparison, the researchers noted, pointing to lack of any prior randomized trials and the level C (expert opinion) evidence for the class IIA recommendation the drug has.

"Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release -- the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT -- but has never been assessed prospectively," they wrote.

The trial included adults and children with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator with exercise-induced arrhythmia despite maximally-tolerated beta-blocker, which was continued throughout the trial. Patients were then randomized to a first treatment round of flecainide or placebo for 3 months, then another 3 months on other treatment after washout.

One patient withdrew after the first arm of treatment due to pregnancy. The median baseline exercise test score was 3. The flecainide dose (guided by trough serum levels) was a median of 150 mg, with a range of 100 to 200 mg, twice daily.

Overall and serious adverse events did not differ between the flecainide and placebo arms. There wasn't any proarrhythmia or worsening of ventricular arrhythmia seen during exercise in the trial.

Disclosures

The study was supported by the National Heart, Lung and Blood Institute.

Kannankeril and co-authors disclosed no relevant relationships with industry.

Primary Source

JAMA Cardiology

Source Reference: Kannankeril PJ, et al "Efficacy of flecainide in the treatment of catecholaminergic polymorphic ventricular tachycardia: A randomized clinical trial" JAMA Cardiol 2017; DOI:10.1001/jamacardio.2017.1320.