Synergistic Effect of the Combination of Ranolazine and Dronedarone to Suppress Atrial Fibrillation

Abstract

Objectives The aim of this study was to evaluate the effectiveness of a combination of dronedarone and ranolazine in suppression of atrial fibrillation (AF). Background Safe and effective pharmacological management of AF remains one of the greatest unmet medical needs. Methods The electrophysiological effects of dronedarone (10 μmol/l) and a relatively low concentration of ranolazine (5 μmol/l) separately and in combination were evaluated in canine isolated coronary-perfused right and left atrial and left ventricular preparations as well as in pulmonary vein preparations. Results Ranolazine caused moderate atrial-selective prolongation of action potential duration and atrial-selective depression of sodium channel–mediated parameters, including maximal rate of rise of the action potential upstroke, leading to the development of atrial-specific post-repolarization refractoriness. Dronedarone caused little or no change in electrophysiological parameters in both atrial and ventricular preparations. The combination of drone-darone and ranolazine caused little change in action potential duration in either chamber but induced potent use-dependent atrial-selective depression of the sodium channel–mediated parameters (maximal rate of rise of the action potential upstroke, diastolic threshold of excitation, and the shortest cycle length permitting a 1:1 response) and considerable post-repolarization refractoriness. Separately, dronedarone or a low concentration of ranolazine prevented the induction of AF in 17% and 29% of preparations, respectively. In combination, the 2 drugs suppressed AF and triggered activity and prevented the induction of AF in 9 of 10 preparations (90%). Conclusions Low concentrations of ranolazine and dronedarone produce relatively weak electrophysiological effects and weak suppression of AF when used separately but when combined exert potent synergistic effects, resulting in atrial-selective depression of sodium channel–dependent parameters and effective suppression of AF. (J Am Coll Cardiol 2010;56:1216–24)

Impact of ranolazine on ventricular arrhythmias – A systematic review

“…Additionally, ranolazine can be used on top of class III drugs as it has been shown that it does not cause pro‐arrhythmia despite a marked effect on ventricular repolarization 48, 49, 50. The beneficial role of ranolazine has also been demonstrated by experimental and human studies in atrial arrhythmias 10, 44, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61…”

Status of Antiarrhythmic Drug Development for Atrial Fibrillation

“…However, the combination has been shown to have a dramatic effect beyond what would be expected by adding the effects of the 2 drugs. 51 This synergistic effect allows for lower dosing of dronedarone, thereby reducing its effect on cardiac contractility. In addition, the slowly activating delayed rectifier K+ current (I Ks ) becomes more dominant at high frequencies.…”

Atrial Fibrillation: Current Problems and Prospects of Medical Care, Treatment and Prevention

“…Использование комбинации низких доз дронедарона и ранолазина для профилактики ре-цидива ФП изучалось в РКИ HARMONY (2014). В на-стоящее время ранолазин показан для лечения ста-бильной стенокардии, при этом подтверждена его способность предупреждать возникновение ФП, про-являя синергичный эффект при сочетании с амиода-роном или дронедароном [49]. Оба препарата пока не зарегистрированы в РФ [12].…”