RESUMO
An elevated heart rate is an established marker of cardiovascular risk. Previous analyseshave suggested that ivabradine, a heart-ratereducing agent, may improve outcomesin patients with stable coronary artery disease, left ventricular dysfunction,and a heart rate of 70 beats per minute or more.METHODSWe conducted a randomized, double-blind, placebo-controlled trial of ivabradine,added to standard background therapy, in 19,102 patients who had both stablecoronary artery disease without clinical heart failure and a heart rate of 70 beats perminute or more (including 12,049 patients with activity-limiting angina [class ≥II onthe Canadian Cardiovascular Society scale, which ranges from I to IV, with higherclasses indicating greater limitations on physical activity owing to angina]). Werandomly assigned patients to placebo or ivabradine, at a dose of up to 10 mg twicedaily, with the dose adjusted to achieve a target heart rate of 55 to 60 beats perminute. The primary end point was a composite of death from cardiovascularcauses or nonfatal myocardial infarction.RESULTSAt 3 months, the mean (±SD) heart rate of the patients was 60.7±9.0 beats per minutein the ivabradine group versus 70.6±10.1 beats per minute in the placebo group.After a median follow-up of 27.8 months, there was no significant difference betweenthe ivabradine group and the placebo group in the incidence of the primaryend point (6.8% and 6.4%, respectively; hazard ratio, 1.08; 95% confidence interval,0.96 to 1.20; P=0.20), nor were there significant differences in the incidences ofdeath from cardiovascular causes and nonfatal myocardial infarction. Ivabradinewas associated with an increase in the incidence of the primary end point amongpatients with activity-limiting angina but not among those without activity-limitingangina (P=0.02 for interaction). The incidence of bradycardia was higher with ivabradinethan with placebo (18.0% vs. 2.3%, P<0.001)...