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