morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left-ventricULar dysfunction - BEAUTIFUL — Presented at ESC 2008


The goal of the trial was to evaluate treatment with the sinoatrial node inhibitor, ivabradine, compared with placebo in patients with stable coronary artery disease and left ventricular dysfunction.


Ivabradine will improve cardiac death and morbidity.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patients Screened: 12,138
Patients Enrolled: 10,917
NYHA Class: I, 15%; II, 61%; III, 23%
Mean Follow Up: Median 19 months
Mean Patient Age: 65 years
Female: 17
Mean Ejection Fraction: 32

Patient Populations:

  • Patients at least 55 years of age (or at least 18 years of age if diabetic) in sinus rhythm at a rate of at least 60 bpm
  • Coronary artery disease documented by previous myocardial infarction, percutaneous or surgical coronary revascularization, or coronary angiogram with at least one coronary stenosis at least 50% narrowed
  • Left ventricular ejection fraction <40% and end-diastolic dimension >56 mm
  • Angina and heart failure symptoms required to be stable for at least 3 months, with the use of optimized cardiac medications for at least 1 month


  • Myocardial infarction or coronary revascularization within the previous 6 months
  • Stroke or transient ischemic attack within the previous 3 months
  • Implanted pacemaker, cardioverter, or defibrillator
  • Valvular disease likely to need surgery within 3 years
  • Sick sinus syndrome, sinoatrial block, congenital long QT, or complete atrioventricular block
  • Severe or uncontrolled hypertension
  • New York Heart Association class IV
  • Current use of CYP P450 3A4 inhibitors

Primary Endpoints:

Composite of cardiovascular death, hospital admission for myocardial infarction, or for new onset or worsening heart failure

Secondary Endpoints:

  • All-cause mortality
  • Cardiovascular mortality
  • Composite of hospital admission for fatal and nonfatal myocardial infarction or unstable angina
  • Coronary revascularization
  • Hospital admission for heart failure
  • Hospital admission for myocardial infarction

Drug/Procedures Used:

Patients with stable coronary artery disease and left ventricular dysfunction were randomized to ivabradine (n = 5,479) or placebo (n = 5,438).

Concomitant Medications:

The dose of ivabradine was 5 mg twice daily for 2 weeks, and then titrated to 7.5 mg twice daily if the heart rate was greater than 60 bpm. The dose was decreased or stopped if the heart rate was less than 50 bpm.

Among the participants, the use of aspirin was 94%, statins 74%, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers 90%, beta-blockers 87%, nitrates 43%, diuretics 59%, and anti-aldosterone agents 27%.

Principal Findings:

Among the participants, the mean left ventricular ejection fraction was 32%, body mass index was 28.5 kg/m2, history of myocardial infarction 88%, and previous coronary revascularization 52%. The mean heart rate at enrollment was 71.6 bpm and the mean systolic blood pressure was 128 mm Hg. There were 28% of participants that discontinued ivabradine, compared with 16% of controls. Medication was discontinued due to bradycardia in 13% of the ivabradine group versus 2% of the control group. Serious adverse events occurred in 22.5% of the ivabradine group, compared with 22.8% of the control group (p = 0.70).

The difference in the mean heart rate (placebo minus ivabradine) at 12 months was 6.4 bpm and 5.6 bpm at 24 months. Among patients with a baseline heart rate greater than 70 bpm, the mean difference was 7.9 bpm at 12 months and 6.9 bpm at 24 months.

The primary outcome, composite of cardiovascular death, hospital admission for myocardial infarction, or for new onset or worsening heart failure occurred in 15.4% of the ivabradine group versus 15.3% of the placebo group (p = 0.94). Among patients with a baseline heart rate greater than 70 bpm, the primary outcome occurred in 17.2% versus 18.5% (p = 0.17), respectively.

All-cause mortality occurred in 10.4% versus 10.1%, cardiovascular death occurred in 8.6% versus 8.0%, hospitalization for myocardial infarction occurred in 3.6% versus 4.2%, hospitalization for heart failure occurred in 7.8% versus 7.9%, and coronary revascularization occurred in 2.8% versus 3.4% (p = not significant for all outcomes), respectively. There was no difference in the secondary outcomes among patients with a baseline heart rate ≥70 bpm, except for hospitalization for myocardial infarction (3.1% vs. 4.9%, p = 0.001) and coronary revascularization procedures (2.8% vs. 4.0%, p = 0.016).


Ivabradine produces a sustained reduction in heart rate over long-term follow-up. Among patients with stable coronary artery disease and left ventricular dysfunction, the use of ivabradine does not improve cardiac outcomes compared with placebo. However, among patients with a baseline heart rate ≥70 bpm, ivabradine did reduce the incidence of hospitalization for myocardial infarction and subsequent coronary revascularization procedures. Ivabradine was well tolerated, with a similar rate of adverse events compared with control.

The motivation for the use of this agent was the ability of ivabradine to reduce heart rate without affecting blood pressure, contractility, or ventricular depolarization. It remains to be seen if ivabradine would have produced different results in a population with a higher resting heart rate (i.e., 80-100 bpm).


Fox K, Ford I, Steg G, Tendra M, Ferrari R, on behalf of the BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:807-16.

The BEAUTIFUL Study: Efficacy of Ivabradine in Reduction of Cardiovascular Events Among Patients With Stable Coronary Artery Disease and Left Ventricular Dysfunction. Presented by Dr. Kim Fox at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Implantable Devices, EP Basic Science, Acute Heart Failure

Keywords: Myocardial Infarction, Follow-Up Studies, Blood Pressure, Sinoatrial Node, Heart Rate, Benzazepines, Body Mass Index, Coronary Stenosis, Heart Failure, Stroke Volume, Bradycardia, Ventricular Dysfunction, Left, Diabetes Mellitus, Cardiotonic Agents

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