Heart rate modulation in stable ischemic heart disease: what we have learned from the SIGNIFY study?

Abstract

Elevated heart rate is a marker of cardiovascular risk in patients with stable coronary artery disease. The addition of ivabradine to standard therapy to reduce heart rate did not improve outcomes in the recent SIGNIFY trial. Moreover, a significant interaction between the effect of ivabradine among subgroups with and without angina with a worse outcome in patients in CCS class >II at baseline was detected. The explanation for this surprising finding despite a significant reduction in angina and myocardial revascularization procedures is uncertain. A J-curve for heart rate was not demonstrated. We speculate a significant interference on adverse events (mainly atrial fibrillation and consequently acute coronary syndromes) and on the outcome of unfavorable interactions between ivabradine and diltiazem, verapamil and strong inhibitors of CYP3A4 (4.6% of the total population). Excluding this subgroup, there are no significant changes in outcomes between the two treatment groups (ivabradine and placebo). In conclusion, heart rate is a marker of risk but is not a risk factor and/or a target of therapy in patients with stable coronary artery disease and preserved ventricular systolic function. Standard doses of ivabradine are indicated for treatment of angina as an alternative or in addition to beta-blockers, but should not be administered in association with CYP3A4 inhibitors or heart rate-lowering calcium antagonists.