MUNICH — The antianginal drug ivabradine reduced acute myocardial infarctions and need for coronary revascularization in patients with coronary artery disease, left ventricular dysfunction, and a resting heart rate of 70 beats per minute or more in the 11,000-patient BEAUTIFUL trial.
“This study will have important implications, I think, for how we manage our patients with coronary disease,” Dr. Kim Fox said at the annual congress of the European Society of Cardiology.
BEAUTIFUL (Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Disease and Left-Ventricular Dysfunction) also convincingly established for the first time in a large prospective study that resting heart rate is an important prognostic risk factor in coronary artery disease patients with left ventricular systolic dysfunction, and that a rate in excess of 70 beats per minute (bpm) is an independent predictor of increased risk of coronary, but not heart failure, events, said Dr. Fox, chair of the BEAUTIFUL executive committee, professor of clinical cardiology at Imperial College, London.
BEAUTIFUL randomized 10,917 patients with coronary artery disease (CAD) and a left ventricular ejection fraction below 40% in double-blind fashion to ivabradine at a target dose of 7.5 mg twice daily, or placebo, on top of standard evidence-based background medications, including β-blockers in 87% and an ACE inhibitor or angiotensin II receptor blocker in 90%. All patients were in sinus rhythm. More than 4,000 had diabetes. The mean baseline resting heart rate was 71.6 bpm.
At a median follow-up of 19 months, ivabradine had no impact on the primary composite end point of cardiovascular death, hospitalization for acute MI, or hospitalization for heart failure. The lack of benefit was due to ivabradine's neutral effect on heart failure-related events.
In contrast, heart rate-lowering via ivabradine proved to have a significant protective effect against ischemic events among the 5,392 patients with a baseline resting heart rate of at least 70 bpm. Coronary events were a prespecified secondary end point in BEAUTIFUL, and ivabradine variously reduced the risk of such events by 22%–36%, compared with maximal background medical therapy (see box). The drug was extremely well tolerated, with a side effect profile similar to placebo.
Dr. Roberto Ferrari, a member of the trial's executive committee, said a key take-home message of BEAUTIFUL is that resting heart rate matters.
Indeed, resting heart rate is a low-tech, yet highly informative prognostic indicator that now should be measured routinely in patients with coronary disease. And as BEAUTIFUL has shown, a rate of 70 bpm or more despite optimal medical therapy in patients with left ventricular systolic dysfunction is a red flag. It was associated with a 34% greater risk of cardiovascular death than a resting heart rate below 70 bpm, along with a 38% increased rate of coronary revascularization, a 46% increase in MI, and a 53% greater risk of hospitalization for heart failure, said Dr. Ferrari of the University of Ferrara (Italy).
Ivabradine is not available in the United States. It was approved by the European Medicines Agency in 2005 for the treatment of stable angina in patients with normal sinus rhythm who cannot tolerate β-blockers, and is marketed as Procoralan by Servier, which funded the BEAUTIFUL study. All of the executive committee members received research grants and fees from the company.
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