Effect of Ranolazine on Ventricular Tachyarrhythmia Burden

Ranolazine is an antianginal and anti-ischemic drug with antiarrhythmic properties related mainly to the inhibition of the late sodium current and the delayed rectifier potassium current associated with action potential prolongation. The RAID (Ranolazine Implantable Cardioverter-Defibrillator) randomized, double-blind, placebo controlled clinical trial found that ranolazine did not significantly reduced the incidence of first VT or VF or death (HR=0.84; p=0.117) in comparison to placebo in 1,012 high-risk patients with an ICD and cardiomyopathy (JACC 2018;72:636-45). However, the study showed that ranolazine administration is associated with a significant reduction in recurrent VT or VF requiring appropriate ICD therapy without evidence for increased mortality (prespecified secondary endpoint). In this secondary analysis, RAID investigators aimed to: 1) evaluate the effect of ranolazine by the degree of ventricular tachyarrhythmia (VTA) burden; 2) evaluate the predictors for increased VTA burden; and 3) identify groups of patients in whom treatment with ranolazine would result in the greatest benefit.

There were 742 (73.3%) patients with no VTA, 93 (9.2%) patients with 1 VTA episode, 92 (9.1%) patients with 2-5 VTA episodes, and 85 (8.4%) with ≥6 VTA episodes. Multivariate analysis identified 7 factors associated with increased VTA burden: history of VTA, age ≥65 years, New York Heart Association functional class ≥III, QRS complex (≥130 ms), low ejection fraction (<30%), atrial fibrillation (AF), and concomitant antiarrhythmic drug (AAD) therapy. Ranolazine significantly reduced VTA burden in patients without concomitant AAD therapy (HR [HR]: 0.68; P < 0.001), whereas no effect was seen in patients concomitantly treated with AADs (HR: 1.33; P= 0.16); P=0.003 for interaction. A similar effect was seen regarding baseline atrial fibrillation, ranolazine was reducing VTA burden in those without atrial fibrillation and had no effect in atrial fibrillation patients. In patients with CRT-D, ranolazine treatment was associated with a 36% risk reduction for VTA recurrence (HR: 0.64; P < 0.001), whereas among patients with ICDs no significant effect was observed (HR: 0.94; P=0.57); P=0.047 for interaction.

This secondary analysis from RAID trial further extends findings from the primary paper demonstrating that in patients with high risk for VTA, ranolazine is effective in reducing VTA burden, with significantly greater effect in CRT-treated patients, those without AF, and those not treated with concomitant AADs. In patients already on AADs or those with AF, the addition of ranolazine did not affect VTA burden. These findings must be interpreted with a caution since the primary endpoint of first VT/VF/death showed only trend but did not meet statistical significance although prespecified secondary endpoint of recurrent VT was met and this recent analyses confirms it in more details.