Combined Actions of Ivabradine and Ranolazine Reduce Ventricular Rate During Atrial Fibrillation.

VERRIER, RICHARD L.; SILVA, ANA F.G.; BONATTI, RODOLFO; BATATINHA, JULIO A.P.; NEARING, BRUCE D.; LIU, GONGXIN; RAJAMANI, SRIDHARAN; ZENG, DEWAN; BELARDINELLI, LUIZ

Drug Combination Reduces Ventricular Rate in AF Introduction Ventricular rate during atrial fibrillation (AF) can be reduced by slowing atrioventricular (AV) node conduction and/or by decreasing dominant frequency of AF. We investigated whether combined administration of ivabradine and ranolazine reduces ventricular rate during AF. Methods and Results Ivabradine (maximum clinical dose, 0.25 mg/kg, and 0.10 mg/kg, i.v.) and ranolazine (2.4 mg/kg, i.v., bolus followed by 0.135 mg/kg/min) were studied in an anesthetized pig (N = 16) model of AF. Combined administration of 0.25 mg/kg ivabradine with ranolazine reduced ventricular rate during AF by 51.9 ± 9.7 beats/min (23%, P = 0.017) and dominant frequency of AF by 2.8 ± 0.5 Hz (32%, P = 0.005). It increased PR (P = 0.0002, P = 0.0007) and A-H intervals (P = 0.047, P = 0.002) during pacing at 130 and 180 beats/min, respectively, to a greater degree than additive effects of single agents. Combined administration of 0.1 mg/kg ivabradine with ranolazine exceeded additive effects of single agents on A-H intervals and dominant frequency of AF. Moreover, ranolazine potentiated low-dose ivabradine's reduction in ventricular rate, as combined administration more than doubled effects of the higher ivabradine dose alone and was similar to the combination with the higher dose. Neither drug nor their combination affected contractility (left ventricular [LV] dP/dt), QT or His-ventricular (H-V) intervals, or mean arterial pressure during sinus rhythm or AF. Conclusion Combined administration of ivabradine and ranolazine at clinically safe levels decreases ventricular rate during AF by reducing AV node conduction and AF dominant frequency without QT prolongation or depression in contractility. Targeting these actions offers intrinsic advantages over conventional nodal agents, which can reduce contractility.

ANALYSIS of variance; ANIMAL experimentation; ATRIAL fibrillation; CARDIAC catheterization; CARDIOVASCULAR agents; COMBINATION drug therapy; ELECTRIC stimulation; ELECTROCARDIOGRAPHY; ELECTROPHYSIOLOGY; GUINEA pigs; HEART beat; HEMODYNAMICS; PIPERAZINE; RESEARCH funding; STATISTICS; SWINE; T-test (Statistics); DATA analysis; REPEATED measures design; DATA analysis software; DESCRIPTIVE statistics

Journal of Cardiovascular Electrophysiology, 2015, Vol 26, Issue 3, p329

1045-3873

Academic Journal

10.1111/jce.12569