CE-452779-1 IVABRADINE FOR CONTROLLING HEART RATE IN PERMANENT ATRIAL FIBRILLATION: RESULTS OF THE TRANSLATIONAL CLINICAL TRIAL BRAKE-AF

Abstract

Ivabradine has been postulated to reduce the ventricular rate in atrial fibrillation. However, the mechanisms responsible for that reduction and its performance as rate-control drug are not known To evaluate the mechanism of inhibition of atrioventricular conduction produced by ivabradine and to determine its efficacy and safety compared with digoxin in permanent atrial fibrillation The effects of ivabradine in atrioventricular nodal and ventricular cells were studied by in-vitro whole-cell patch-clamp experiments . Changes in If, INa, ICaL, ICaT, IKs, IKr, and IK1 conductances were integrated in mathematical simulations of nodal and ventricular action potentials. In parallel, a multicenter, randomized, open-label, phase III clinical trial compared ivabradine (5mg BID increased to 7.5mg BID after one month) versus digoxin (0.10-0.25mg QD adjusted by serum levels) for uncontrolled permanent atrial fibrillation despite beta-blockers or calcium channel blockers. Primary efficacy and safety endpoints were the reduction of the mean daytime heart rate at 3 months and a combination of syncope, clinically significant bradycardia or serious drug-related adverse events, respectively. The primary efficacy endpoint was evaluated by intention to treat using the O'Brien–Fleming method. Safety endpoints were evaluated with χ2 or Fisher’s exact tests Ivabradine 1 μM inhibited If and IKr by 28.9% and 22.8% (P<0.05) respectively. INa and ICaL were also reduced but only at 10 μM. Ivabradine slowed the firing frequency of a modelled human AV nodal action potential by 10.6% and induced a minimal prolongation of the ventricular action potential. The clinical trial randomized 35 patients to ivabradine and 33 to digoxin. Mean daytime heart rate decreased by 11.6 bpm (-11.5%) in the ivabradine arm (p=0.02) Vs 19.6 (-20.6%) in the digoxin arm (p<0.001) however, the non-inferiority margin of efficacy was not met (Z:-1.95; p=0.97). Primary safety endpoint occurred in 3 (8.6%) patients on ivabradine and in 8 (24.2%) on digoxin (p=0.10). Therapeutic adherence was lower in the digoxin arm (78.8% vs. 97.1%; p=0.02) Ivabradine produced a discrete heart rate reduction in patients with permanent atrial fibrillation. Compared with digoxin, ivabradine was less effective, better tolerated and had a similar rate of serious adverse events.The inhibition of If in the AV node seems the main mechanism responsible for the ivabradine-induced heart rate reduction in atrial fibrillation.