Study Assessing the Morbidity–Mortality Benefits of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease | Clinical Trial - SIGNIFY


The goal of the trial was to evaluate treatment with ivabradine compared with placebo among patients with stable coronary artery disease without clinical heart failure.


Ivabradine will reduce adverse cardiovascular events.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • Participants were at least 55 years of age with documented stable coronary artery disease, no evidence of clinical heart failure, and resting heart rate at least 70 bpm.
  • Participants were required to have at least one additional major adverse characteristic:
    - CCS angina class ≥2
    - Evidence of myocardial ischemia within the last year
    - Hospital discharge within the last year for a major coronary event
  • Or at least two minor adverse characteristics:
    - High-density lipoprotein cholesterol <40 mg/dl
    - Low-density lipoprotein cholesterol >160 mg/dl
    - Type 1 or 2 diabetes
    - Peripheral arterial disease
    - Current smoking
    - Age ≥70 years

    Number of enrollees: 19,102
    Duration of follow-up: median 27.8 months
    Mean patient age: 65 years
    Percentage female: 27%
    Ejection fraction: 56%


  • Left ventricular ejection fraction ≤40%
  • Unstable cardiovascular condition

Primary Endpoints:

  • Cardiovascular death or MI

Secondary Endpoints:

  • Cardiovascular death
  • MI

Drug/Procedures Used:

Participants with stable coronary artery disease without clinical heart failure and resting heart rate >70 bpm were randomized to ivabradine, up to 10 mg twice daily (n = 9,550) versus placebo (n = 9,552). The study drug was titrated to achieve a target heart rate of 55-60 bpm.

Concomitant Medications:

  • Aspirin: 92%
  • Statin: 92%
  • Beta-blocker: 83%
  • Angiotensin-converting enzyme inhibitor: 60%
  • Angiotensin-receptor blocker: 23%

Principal Findings:

Overall, 19,102 patients were randomized. The median age was 65 years, 27% were women, mean heart rate was 77 bpm, mean systolic blood pressure was 131 mm Hg, 24% were current smokers, 73% had a prior myocardial infarction (MI), 68% had prior coronary revascularization, 21% had peripheral arterial disease, and 43% had diabetes.

At 3 months, the mean heart rate was 60.7 bpm in the ivabradine group versus 70.6 bpm in the placebo group. The difference in heart rate was maintained for the duration of the study. Permanent discontinuation of the study drug occurred in 20.6% of the ivabradine group versus 14.5% of the placebo group. The predominant reason for drug discontinuation was bradycardia (symptomatic and asymptomatic). There was minimal change in beta-blocker therapy in either group during the course of the study.

At a median of 27.8 months, the primary outcome of cardiovascular death or MI occurred in 6.8% vs. 6.4% (p = 0.20). Patients with significant angina symptoms (Canadian Cardiovascular Society [CCS] ≥2) appeared to be harmed by ivabradine (p for interaction = 0.02).

Cardiovascular death: 3.4% vs. 3.2% (p = 0.25), respectively
MI: 3.7% vs. 3.5% (p = 0.60), respectively
Hospitalization for heart failure: 2.3% vs. 1.9% (p = 0.07), respectively


Among patients with stable coronary artery disease without clinical heart failure, the use of ivabradine, in addition to standard medical therapy, did not reduce adverse cardiovascular events compared with placebo. Previous studies examining ivabradine include the SHIFT and BEAUTIFUL trials. The SHIFT trial documented a reduction in adverse events (cardiovascular mortality or heart failure hospitalization) with ivabradine among participants with moderate to severe chronic heart failure and resting heart rate ≥75 bpm. The BEAUTIFUL trial examined participants with stable coronary disease and left ventricular dysfunction. There was no reduction in the primary efficacy outcome; however, among those with heart rate ≥70 bpm, ivabradine was associated with less MI and coronary revascularization procedures. The reason for the lack of benefit from ivabradine in the current trial is unknown.

Moreover, the finding of possible harm among patients with more significant angina symptoms needs to be interpreted with caution. While elevated heart rate is a poor prognostic marker, it may not be a good modifiable target on which to improve outcomes.


Fox K, Ford I, Steg PG, et al., on behalf of the SIGNIFY Investigators. Ivabradine in Stable Coronary Artery Disease Without Clinical Heart Failure. N Engl J Med 2014;Aug 31:[Epub ahead of print].

Editorial: Ohman EM, Alexander KP. The Challenges With Chronic Angina. N Engl J Med 2014;Aug 31:[Epub ahead of print].

Presented by Dr. Kim Fox at the European Society of Cardiology Congress, Barcelona, Spain, August 31, 2014.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Implantable Devices, Acute Heart Failure

Keywords: Coronary Artery Disease, Myocardial Infarction, Heart Failure, Peripheral Arterial Disease, Blood Pressure, Bradycardia, Heart Rate, Ventricular Dysfunction, Left, Diabetes Mellitus, Benzazepines, ESC Congress

< Back to Listings