Ivabradine Reduces Incidence Of Coronary Artery Disease Outcomes In Patients With High Heart Rate (Beautiful Study)

Main Category: Cardiovascular / Cardiology
Article Date: 31 Aug 2008 - 4:00 PDT

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Use of the heart-rate lowering drug ivabradine can reduce the incidence of cardiovascular disease and death in patients with coronary artery disease and a high heart rate. These are the conclusions of the first of two Articles (the BEAUTIFUL study) published early Online and in an upcoming edition of The Lancet; the second Article concludes higher resting heart rate in patients with coronary artery disease is a strong independent risk factor for death, heart attack and heart failure. Both Articles are being presented at the European Society of Cardiology meeting in Munich.

Ivabradine specifically inhibits electric currents in the sinoatrial node, which controls heart rate, but does not affect other aspects of cardiac function. Professor Kim Fox, Royal Brompton Hospital, London, UK, and colleagues from the BEAUTIFUL investigation team did a randomised controlled trial to test whether lowering heart rate with this drug reduces cardiovascular death and disease in 10 917 patients with coronary artery disease and left-ventricular dysfunction. All patients received regular cardiovascular medicine, and in addition to this 5 479 patients received 5 mg ivabradine, with the intention of increasing to 7•5 mg twice a day, while 5438 received matched placebo. The trial's primary endpoint was a composite of death, admission to hospital for heart attack, or admission to hospital for new or worsening heart failure.

The researchers found patients had a mean heart rate of about 70 beats per minute (bpm). Ivabradine reduced heart rate by 6 bpm at 12 months. Most patients (87%) received β blockers in addition to the study drugs, but this did not cause any safety issues. Ivabradine had no effect on the primary endpoint for patients, and serious adverse events were as likely in both Ivabradine (22•5%) and placebo (22•8%) patients. However, when looking at a specific sub-group of patients with a heart rate of above 70 bpm at the start of the study, Ivabradine again had no effect on the primary outcome for these patients, but did reduce coronary secondary outcomes, namely admission to hospital for fatal and non-fatal heart attack (36% reduced risk) and coronary revascularisation* (30% reduced risk). Both of these risk reductions were statistically significant. The authors conclude: "Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater."

In the second Article, the researchers did a sub-group analysis of the placebo group of the BEAUTIFUL study, to test the hypothesis that raised resting heart rate at the start of the study was a marker for subsequent cardiovascular death and disease. Mathematical modeling was used to work out the likelihood of these outcomes for patients with a heart rate of above 70 bpm (2693 patients) and below 70 bpm (2745).

They found that in the above 70 bpm group, patients had increased risk of cardiovascular death (34%), admission to hospital for heart failure (53%), admission to hospital for heart attack (46%), and coronary revascularisation (38%). Analysis revealed that for every increase of 5 bpm, there were increases in cardiovascular death (8%), admission to hospital for heart failure (16%), admission to hospital for heart attack (7%) and coronary revascularisation (8%). The authors conclude: "Elevated heart rate was a strong independent risk factor in patients with coronary artery disease and left-ventricular dysfunction. This was observed on top of a high level of background treatment, including β blockers, in our patient population. Heart rate should be assessed as a prognostic marker and to guide optimum medical treatment in this patient population."

In an accompanying Comment, Dr Jan-Christian Reil and Professor Michael Böhm, Universitätsklinikum des Saarlandes, Germany, say: "The BEAUTIFUL study has valuable lessons for clinical practice and illustrates the importance of individual decision-making. It remains to be seen whether or not the concept of the slower the better holds true."

*Coronary revascularisation covers both balloon angioplasty and coronary artery bypass graft surgery.

The Lancet