Ivabradine reduces heart rate without affecting blood pressure or left ventricular systolic performance. Given studies demonstrating a relationship between heart rate and cardiovascular risk, modifying heart rate with ivabradine may reduce risk in patients with coronary disease. In the Study Assessing the Morbidity–Mortality Benefits of the I_f Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) trial, patients with coronary artery disease, a heart rate of 70 bpm or more, and without heart failure, were studied to assess whether they would benefit from ivabradine. In this large international randomized controlled trial,19102 eligible patients were randomized to placebo or ivabradine up to 10mg twice daily (mean dose 8.2±1.7 mg twice daily) in addition to standard therapy that included beta-blockers in over 80% of patients. The dose of ivabradine was titrated to achieve a resting heart rate between 55 and 60 bpm and the primary end-point was a composite of death from cardiovascular causes or nonfatal myocardial infarction. At a median follow-up of 27.8 months, there was no significant difference between ivabradine and placebo in the incidence of cardiovascular death or non-fatal myocardial infarction (6.8% and 6.4%, respectively; HR 1.08; 95% CI, 0.96 to 1.20; P=0.20). Ivabradine was associated with an increased rate of adverse events, including symptomatic bradycardia (7.9%, vs. 1.2%; p<0.001) and atrial fibrillation (5.3% vs. 3.8%; p<0.001).

Conclusion: In patients with stable coronary artery disease, the addition of ivabradine to standard therapy did not reduce rates of cardiovascular death or non-fatal myocardial infarction and increased rates of adverse events. These findings also highlight that heart rate is likely a marker, rather than a mediator, of cardiovascular risk.

Summarized by Hussain Contractor and Steven M. Bradley

Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R; SIGNIFY Investigators. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014 Sep 18;371(12):1091-9.