Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY trial): a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart failure

Am Heart J. 2013 Oct;166(4):654-661.e6. doi: 10.1016/j.ahj.2013.06.024. Epub 2013 Sep 17.


Background: Elevated heart rate in stable coronary artery disease (CAD) is associated with worse outcomes, particularly increased risk of myocardial infarction. Heart rate reduction with the If inhibitor ivabradine confers symptomatic benefits in angina pectoris and reduces coronary events in patients with stable CAD and left ventricular (LV) systolic dysfunction, with a resting heart rate of ≥70 beats/min. The SIGNIFY trial is testing the hypothesis that heart rate reduction using ivabradine reduces mortality and cardiovascular events in patients with stable CAD, but without clinical heart failure.

Methods: The SIGNIFY trial is a randomized, double-blind, parallel-group, placebo-controlled, event-driven study in patients with stable CAD (1,139 centers, 51 countries). Participants are 55 years or older, with stable CAD and an LV ejection fraction >40%, in sinus rhythm, with a baseline resting heart rate of ≥70 beats/min, and with at least 1 additional cardiovascular risk factor. At inclusion, patients receive ivabradine 7.5 mg twice a day or matching placebo, which is adjusted at every visit to a heart rate target of 60 beats/min. Participants should receive the best possible background treatment for stable CAD. The primary end point is a composite of cardiovascular death or nonfatal myocardial infarction.

Results: Recruitment lasted from October 2009 to April 2012. The SIGNIFY trial has recruited 19,102 patients (age 65.0 ± 7.2 years, resting heart rate 77.2 ± 7.0 beats/min, 72% male) with no evidence for LV dysfunction (ejection fraction 56.5% ± 8.6%).

Conclusion: The SIGNIFY trial will shed further light on the role of heart rate lowering with ivabradine in patients with stable CAD without clinical heart failure. The study is expected to end in 2014.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Benzazepines / administration & dosage*
  • Coronary Artery Disease / diagnostic imaging
  • Coronary Artery Disease / drug therapy*
  • Coronary Artery Disease / epidemiology
  • Cyclic Nucleotide-Gated Cation Channels
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Global Health
  • Heart Failure
  • Heart Rate / drug effects*
  • Humans
  • Ivabradine
  • Male
  • Middle Aged
  • Morbidity / trends
  • Radiography
  • Retrospective Studies
  • Stroke Volume / physiology
  • Survival Rate / trends
  • Treatment Outcome
  • Ventricular Function, Left / drug effects*
  • Ventricular Function, Left / physiology


  • Benzazepines
  • Cyclic Nucleotide-Gated Cation Channels
  • Ivabradine

Associated data

  • ISRCTN/ISRCTN61576291