Rationale of the BEAUTIFUL Study
What is the rationale of this trial?
Impact of elevated resting heart rate on cardiovascular and all-cause mortality- Elevated heart rate has been shown to be associated with an increased risk of all-cause mortality, cardiovascular mortality, and development of cardiovascular disease in the general population, but also in hypertensives, diabetics, and those with preexisting coronary artery disease1-7
- A large study of CASS8 registry on 24, 913 patients with a follow-up of 14.1 years has extended our understanding of the prognostic importance of heart rate in patients with stable coronary artery disease. All-cause and cardiovascular mortality and cardiovascular rehospitalizations were increased in patients with increased heart rate. This association between heart rate and total mortality was observed in all analyzed subgroups.
Expected prevention benefits from resting heart rate reduction- There is good evidence that the beneficial effects of beta-blockers on survival after acute myocardial infarction or in heart failure are related to heart rate9 reduction. Experimental and clinical data have demonstrated that heart rate reduction is the main mechanism of reducing ischemia, improving left ventricular function, and reducing post myocardial infarction mortality.
- A significant association between heart rate reduction and mortality in patients receiving β-blockers following myocardial infarction was seen in a review of 11 long-term randomized, controlled trials.10 Each 10 bpm (beats per minute) reduction in heart rate is associated with a cardiovascular mortality reduction of 30%.10
Unmet need for optimal heart rate control
- Resting heart rate may not be sufficiently controlled. In one study of data compiled in the Duke Databank for Cardiovascular Disease, patients with coronary artery disease had a mean heart rate of 70 b.p.m despite use of beta-blockers by 61% of patients.11
- In addition, an assessment of long-term compliance12 revealed that 30 days after myocardial infarction, 58% of patients received beta-blockers. However, five years later only 58% of those who had started beta-blocker treatment were still on therapy. In addition, prescribed doses were generally ≤ 50% of those used in clinical trials. This inability of reaching the target heart rate is, in the majority of cases, related to beta-blockers’ side effects. This poor heart rate control, use of low doses, and poor compliance with traditional heart rate–lowering agents highlight the need to improve the management of heart rate in coronary artery disease patients.
Why recruit coronary artery disease patients with left ventricular dysfunction in the BEAUTIFUL study?
- Although the prognosis of patients with coronary artery disease has been greatly improved by advances in cardiovascular treatment, the presence of left ventricular dysfunction still has a dramatic and negative effect on survival.13-15
- In the CASS registry, for example, 12-year survival rates for patients with at least 1 diseased vessel dropped from 73% in patients with ejection fractions of 50-60% to 21% in patients with ejection fractions ≤ 34%.
- Heart rate reduction is a key factor for improvement of left ventricular function16. Current heart rate–lowering therapies, however, have collateral effects that may not be adequate in patients with left ventricular dysfunction.
Why choose Ivabradine for the BEAUTIFUL study?
- Given the high level of evidence of the benefits of heart rate reduction per se on cardiovascular and total mortality, it is of high interest to assess the benefits of a pharmacological agent acting only through heart rate reduction.
- However, traditional heart rate–reducing agents also reduce myocardial contractility, which might be particularly deleterious when ventricular function is already impaired. In that case the negative inotropic effect of beta-blockers is inadequate.
- Ivabradine, the first If inhibitor, provides a pure heart rate reduction ie, heart rate reduction without impairing other cardiac function parameters. Unlike other traditional heart rate–reducing agents, experimental and clinical data support the concept that the pure heart rate reduction induced by Ivabradine is beneficial in the case of ventricular dysfunction. Ivabradine improves left ventricular function and increases stroke volume, thus preserving cardiac output, in a rat model of cardiac failure.17
- A preliminary study in patients with coronary artery disease and moderate left ventricular dysfunction has suggested that Ivabradine has beneficial effects on left ventricle geometry in patients with left ventricular dysfunction.18
- These results may be linked to modifications of left ventricular structure, as demonstrated by the reduction of cardiac collagen accumulation and the persistence of the improvement in left ventricular function after interruption of long-term treatment.
References
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13. Burns R J, Gibbons R J, et al. The relationships of left ventricular ejection fraction, end-systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis. J Am Coll Cardiol. 2002;39(1):30-36.
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15. The Multicenter Postinfarction Research Group. Risk stratification and survival after myocardial infarction. N Engl J Med. 1983;309:331-336.
16. Thackray SD, Ghosh, JM et al. The effect of altering heart rate on ventricular function in patients with heart failure treated with beta-blockers. Am Heart J. 2006;152:713 e9-13.
17. Mulder P, Barbier S, et al. Long-term heart rate reduction induced by the selective I(f) current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation 2004;109:1674-1659.
18. Jondeau G, Koresicki, J et al. Effect of ivabradine in patients with left ventricular systolic dysfunction and coronary artery disease. Eur Heart J 2004;25:451.