Comparison of Effectiveness of Ranolazine Plus Metoprolol Combination vs. FlecainidE pluS Metoprolol Combination in ATrial Fibrillation Recurrences FOllowing PhaRmacological or Electrical CardioverSion of AtRial Fibrillation

Overview

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice with a prevalence reaching 5% in patients older than 65 years and an incidence that increases progressively with age.1 According to the most recent guidelines, class Ic anti-arrhythmic drugs are considered the first line treatment in patients without significant structural heart disease. Flecainide is effective in preventing AF recurrences in 31-61% of cases according to different studies.2-5 A recent study showed that the combination of Flecainide and Metoprolol improves effective rhythm control in patients with persistent symptomatic AF compared to Flecainide or Metoprolol alone.6 In contrast, the combination of Flecainide and Metoprolol conferred no significant benefit over Flecainide alone in patients with paroxysmal AF. This suggests different underlying mechanisms for paroxysmal and persistent AF. Pulmonary veins are likely the main focus triggering paroxysmal AF while in persistent AF the role of pulmonary veins is less important.

Ranolazine (RN) is a novel antianginal agent with increasingly appreciated antiarrhythmic properties that can suppress ventricular and supraventricular arrhythmias including AF. The antiarrhythmic actions of RN are mainly attributed to its ability to block INa, INaL, and the rapidly activating delayed rectifier potassium current (IKr).7 In experimental studies, RN proved very effective in suppressing late phase 3 early afterdepolarization and delayed afterdepolarization mediated triggered activity in pulmonary vein sleeves.8 RN was shown very effective in suppressing persistent, vagally mediated AF in animal models.9 Clinical evidence of an AF-suppressing effect of RN comes mainly from small caliber studies. Murdock et al, reported a high conversion rate (72%) after administration of 2,000 mg of RN (in a "pill-in-the-pocket" fashion) in patients with short lasting (\<48 hours) new onset paroxysmal AF.10 Our group demonstrated both the superior efficacy and the accelerated action of the combined therapy of Amiodarone with RN compared to Amiodarone alone in patients with paroxysmal AF. Notably, the efficacy benefit of this combination was more pronounced in patients with dilated left atria which is also more likely to occur in cases of persistent AF.11, 12 In a prospective, randomized, double-blind, placebo-control phase II study, different doses of RN were tested in the prevention of AF recurrence after successful electrical cardioversion. Despite the fact that the study did not reach its primary end-point since none of the individual doses of RN significantly delayed the time to first AF recurrence as compared with placebo, an antiarrhythmic efficacy for the two higher doses of RN (500 and 750mg bd) was strongly suggested. The same study confirmed the safety of RN with no evidence for proarrhythmia.13 Notably, beta-blockers were used in less than 50% of patients studied in this study. Although the efficacy of beta-blockers in the maintenance of sinus rhythm is low, the addition of a beta-blocker to an antiarrhythmic agent that exerts its action by inhibiting inward Na+ current like RN and Flecainide may represent an interesting approach in preventing AF relapse. Various laboratory studies have demonstrated that inward Na+ current could be modulated by beta-adrenergic receptors in a variety of cell lines.14, 15 In this context, the beta-blocking activity of Amiodarone or Dronedarone may account for the successful combination with RN in suppressing AF in either experimental or clinical studies.