Elsevier

The Lancet

Volume 372, Issue 9641, 6–12 September 2008, Pages 807-816
The Lancet

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Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(08)61170-8Get rights and content

Summary

Background

Ivabradine specifically inhibits the If current in the sinoatrial node to lower heart rate, without affecting other aspects of cardiac function. We aimed to test whether lowering the heart rate with ivabradine reduces cardiovascular death and morbidity in patients with coronary artery disease and left-ventricular systolic dysfunction.

Methods

Between December, 2004, and December, 2006, we screened 12 473 patients at 781 centres in 33 countries. We enrolled 10 917 eligible patients who had coronary artery disease and a left-ventricular ejection fraction of less than 40% in a randomised, double-blind, placebo-controlled, parallel-group trial. 5479 patients received 5 mg ivabradine, with the intention of increasing to the target dose of 7·5 mg twice a day, and 5438 received matched placebo in addition to appropriate cardiovascular medication. The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure. We analysed patients by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00143507.

Findings

Mean heart rate at baseline was 71·6 (SD 9·9) beats per minute (bpm). Median follow-up was 19 months (IQR 16–24). Ivabradine reduced heart rate by 6 bpm (SE 0·2) at 12 months, corrected for placebo. Most (87%) patients were receiving β blockers in addition to study drugs, and no safety concerns were identified. Ivabradine did not affect the primary composite endpoint (hazard ratio 1·00, 95% CI 0·91–1·1, p=0·94). 1233 (22·5%) patients in the ivabradine group had serious adverse events, compared with 1239 (22·8%) controls (p=0·70). In a prespecified subgroup of patients with heart rate of 70 bpm or greater, ivabradine treatment did not affect the primary composite outcome (hazard ratio 0·91, 95% CI 0·81–1·04, p=0·17), cardiovascular death, or admission to hospital for new-onset or worsening heart failure. However, it did reduce secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0·64, 95% CI 0·49–0·84, p=0·001) and coronary revascularisation (0·70, 95% CI 0·52–0·93, p=0·016).

Interpretation

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.

Funding

Servier, France.

Introduction

Patients with stable coronary artery disease have high event rates, despite modern treatments.1, 2 Patients with left-ventricular systolic dysfunction have even higher rates of mortality.1, 3, 4 A high resting heart rate is a potentially modifiable cardiovascular risk factor, both in the general population5 and in patients with cardiovascular disease.6, 7, 8 Large studies with long-term follow-up have shown that a high heart rate is an independent predictor of all-cause and cardiovascular mortality in coronary artery disease patients, irrespective of the presence of hypertension.9, 10 Lowering heart rate could reduce mortality and cardiovascular events, but this has not been formally tested, because existing agents that lower heart rate, such as β blockers and non-dihydropyridine calcium channel blockers, have other cardiovascular actions that confound the results.

Ivabradine is a specific inhibitor of the If current in the sinoatrial node.11 As a result, it is a pure heart-rate-lowering agent in patients with sinus rhythm. Ivabradine does not affect blood pressure,12 myocardial contractility,13 intracardiac conduction, or ventricular repolarisation.14 Treatment with ivabradine therefore provides an opportunity to assess the effects of lowering heart rate without directly altering other aspects of cardiac function. Ivabradine is an agent that effectively prevents myocardial ischaemia and treats symptoms in patients with chronic stable angina pectoris.15, 16

We designed the BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left-ventricULar dysfunction) trial to assess whether the addition of ivabradine to standard treatment to lower heart rate can reduce cardiovascular death and morbidity. We selected patients with both stable coronary artery disease and impaired left-ventricular function since reduction of heart rate is thought to contribute to the beneficial effects of β blockers in patients who have systolic dysfunction.

Section snippets

Patients

We did a randomised, double-blind, placebo-controlled, parallel-group trial in 781 centres in 33 countries. Patients were screened between December, 2004, and December 2006. Details of the design17 and the baseline characteristics of the study population18 have been published. The trial was approved by the appropriate ethics committees at all participating centres, according to their national guidelines. We obtained written informed consent from all patients before assessment.

Patients eligible

Results

Figure 1 shows the trial profile. Between December, 2004, and December, 2006, 12 473 patients were assessed for entry into the study. 335 were excluded, and 12 138 were screened. 1221 were excluded at this stage. 10 917 eligible patients were enrolled. The first was included in January, 2005. 5479 patients were randomly assigned to receive ivabradine and 5438 to receive placebo. Ten patients (two allocated to ivabradine and eight to placebo) did not start study medication. The median duration

Discussion

Ivabradine treatment was associated with a placebo-corrected reduction in heart rate of 6 bpm at 12 months and 5 bpm at 24 months. Ivabradine did not affect the primary composite endpoint of cardiovascular death, admission to hospital for acute myocardial infarction, or admission to hospital for new-onset or worsening heart failure in any of the subgroups analysed (figure 4). Most patients received treatments recommended by guidelines, at comparable rates to those achieved in patients with

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