Antianginal and Antiischemic Effects of Ivabradine, an I _f Inhibitor, in Stable Angina

Abstract

Background-Heart rate reduction should benefit patients with chronic stable angina by improving myocardial perfusion and reducing myocardial oxygen demand. This study evaluated the antianginal and antiischemic effects of ivabradine, a new heart rate-lowering agent that acts specifically on the sinoatrial node. Methods and Results-In a double-blind, placebo-controlled trial, 360 patients with a Ն3-month history of chronic stable angina were randomly assigned to receive ivabradine (2.5, 5, or 10 mg BID) or placebo for 2 weeks, followed by an open-label 2-or 3-month extension on ivabradine (10 mg BID) and a 1-week randomized withdrawal to ivabradine (10 mg BID) or placebo. Primary efficacy criteria were changes in time to 1-mm ST-segment depression and time to limiting angina during bicycle exercise (exercise tolerance tests), performed at trough of drug activity. In the per-protocol population (nϭ257), time to 1-mm ST-segment depression increased in the 5 and 10 mg BID groups (PϽ0.005); time to limiting angina increased in the 10 mg BID group (PϽ0.05). Deterioration in all exercise tolerance test parameters occurred in patients who received placebo during randomized withdrawal (all PϽ0.02) but not in those still receiving ivabradine. No rebound phenomena were observed on treatment cessation. Conclusions-Ivabradine produces dose-dependent improvements in exercise tolerance and time to development of ischemia during exercise. These results suggest that ivabradine, representing a novel class of antianginal drugs, is effective and safe during 3 months of use; longer-term safety requires additional assessment.

If channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities

“…Thus, at least in the mouse, the selective HR-lowering activity of ivabradine appears independent of autonomic nervous activity that might alter HR levels and its sensitivity to drugs. This is in keeping with previous reports that ivabradine reduces HR in dogs and in patients with documented stable angina both at rest and during exercise (Monnet et al, 2001;Colin et al, 2002;Borer et al, 2003), unlike b-antagonists that lower HR largely depending on the level of sympathetic tone (Colin et al, 2002).…”

“…An increase in heart rate (HR) is a common occurrence in cardiac pathophysiology, particularly in heart failure, mediated by b-adrenergic receptors (bARs) following activation of the sympathetic nervous system (Cohn, 1990;Kaye et al, 1995;Borer et al, 2003). Although an elevated HR may initially compensate for insufficient cardiac output, sustained tachycardia usually leads to adverse haemodynamic consequences.…”

“…Previous studies have established the selective HR-reducing activity of ivabradine devoid of negative inotropic effect in various species, including the rat, pig, dog and human, when given intravenously (Thollon et al, 1994;Simon et al, 1995;Monnet et al, 2001;Colin et al, 2002;Camm & Lau, 2003) or orally (Borer et al, 2003). Antianginal and anti-ischaemic effects of ivabradine have been demonstrated in patients with stable angina (Borer et al, 2003).…”

“…Previous studies have established the selective HR-reducing activity of ivabradine devoid of negative inotropic effect in various species, including the rat, pig, dog and human, when given intravenously (Thollon et al, 1994;Simon et al, 1995;Monnet et al, 2001;Colin et al, 2002;Camm & Lau, 2003) or orally (Borer et al, 2003). Antianginal and anti-ischaemic effects of ivabradine have been demonstrated in patients with stable angina (Borer et al, 2003). Although ivabradine is able to reduce HR under conditions of exercise (Simon et al, 1995;Monnet et al, 2001;Colin et al, 2002;Borer et al, 2003), there has been limited information on the efficacy of ivabradine in HR reduction under other conditions of enhanced sympathoadrenergic activity, a situation commonly seen under diseased conditions.…”

“…Antianginal and anti-ischaemic effects of ivabradine have been demonstrated in patients with stable angina (Borer et al, 2003). Although ivabradine is able to reduce HR under conditions of exercise (Simon et al, 1995;Monnet et al, 2001;Colin et al, 2002;Borer et al, 2003), there has been limited information on the efficacy of ivabradine in HR reduction under other conditions of enhanced sympathoadrenergic activity, a situation commonly seen under diseased conditions. In this study, we have investigated the effects of oral ivabradine on HR in the mouse with enhanced sympathoadrenergic activity due to (1) stress-evoked sympathetic activation, (2) cardiac specific overexpression of b 2 AR and (3) b-agonist stimulation.…”