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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Overview of large morbidity/mortality trials with ivabradine: focus on the BEAUTIfUL study

Philippe Gabriel Steg

Centre Hospitalier Bichat-Claude Bernard, Université Denis Diderot, Paris VII, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

Corresponding author. Tel: +33 1 40 25 86 68. E-mail address: gabriel.steg{at}bch.aphp.fr


   Abstract
Top
 Abstract
Rationale for the BEAUTIfUL...
 BEAUTIfUL: design and methods
 Patient population
 References
 
Heart failure and left ventricular dysfunction complicating coronary artery disease (CAD) are associated with a poor prognosis. Beta-blockers have been shown to be beneficial for survival in these conditions, a benefit that is mediated, in part, through slowing of the heart rate. In addition, since heart rate is one of the major determinants of myocardial oxygen consumption, its lowering is associated with relief of ischaemia and anginal symptoms, and indeed, slowing the heart rate with beta-blockers is associated with effective relief of ischaemia. Therefore, in left ventricular dysfunction complicating CAD, there is potentially a major role for slowing the heart rate. Although effective, beta-blockers may not always achieve optimal heart rate lowering or may not be well tolerated. Ivabradine, a selective heart rate-lowering agent, is being tested compared with placebo, in addition to standard therapy (including beta-blockers, if tolerated) in the large morbidity/mortality BEAUTIfUL trial. This study was established to test the superiority of ivabradine compared with placebo as an adjunct to conventional therapy in the reduction of a composite endpoint of cardiovascular mortality, acute myocardial infarction (requiring hospital admission), and new or worsening heart failure (requiring hospital admission) in patients with stable CAD, in sinus rhythm, and with left ventricular dysfunction. Approximately 11 000 patients with evidence of CAD, a sinus rhythm of ≥60 bpm, and an ejection fraction of 39% or less were enrolled. In a randomized, double-blind fashion, patients are receiving ivabradine 5 mg twice daily titrated to 7.5 mg twice daily after 2 weeks, or matching placebo, in order to target a heart rate of <60 bpm. Holter electrocardiography, echocardiography, and NT-proBNP substudies are also planned.

The BEAUTIfUL trial will be an important step in determining the clinical importance of heart rate on the outcome of patients with CAD and left ventricular dysfunction.

Key Words: Coronary artery disease • Heart rate • Ivabradine • Left ventricular dysfunction • Randomized clinical trial


   Rationale for the BEAUTIfUL trial
Top
 Abstract
 Rationale for the BEAUTIfUL...
BEAUTIfUL: design and methods
 Patient population
 References
 
Important advances have been made in the management of coronary artery disease (CAD), not only in terms of very substantial improvement in the short- and long-term outcomes in patients with acute coronary syndromes,1 but also in terms of improved secondary prevention.2,3 However, even with contemporary therapy, cardiovascular event rates remain high in stable outpatients with CAD.4 In the REduction of Atherothrombosis for Continued Health (REACH) international cohort of stable outpatients collected in 2003–2004, cardiovascular mortality at 1 year in the subset of 38 602 patients with CAD was 1.93%, and the composite endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 4.52% of the patients.4 Among the factors that strongly impact on prognosis in CAD, left ventricular function is an important one. In patients with acute coronary syndromes, the presence of heart failure is a very strong predictor of increased hospital and post-discharge mortality.5 After acute myocardial infarction, the presence of left ventricular dysfunction, with or without overt clinical heart failure, is also a very strong predictor of mortality.6

Beta-blockers have been shown to be beneficial both during7 and after8 acute myocardial infarction in terms of a reduction in mortality and sudden death. In addition, beta-blockers have also been shown to reduce mortality in patients with congestive heart failure, and the greatest benefits have been derived by patients with the greatest reduction in resting heart rate.9 The combined benefits of beta-blockers on prevention of ischaemia and survival in heart failure suggest that heart rate lowering may be of particular benefit in patients with ischaemic heart disease and left ventricular dysfunction. However, beta-blockers are not universally prescribed or tolerated at full doses in these patients,10–12 often because of contraindications related to asthma, hypotension, or conduction disorders, or because of poor tolerance due to the negative inotropic effects, hypotensive effects, or side effects such as erectile dysfunction.

Heart rate is one of the major determinants of myocardial oxygen consumption. As such, it is an important precipitating factor for myocardial ischaemia and anginal symptoms. It is logical then, that some of the most important treatments useful in preventing or treating myocardial ischaemia and angina, such as beta-blockers and some (but not all) calcium channel blockers, act by lowering heart rate. In fact, the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of patients with angina recommend targeting a heart rate of <60 beats per minute (bpm) for patients with stable angina.13

In addition, despite the short-term variability in heart rate, large epidemiologic observational studies have consistently linked resting heart rate with long-term cardiovascular risk in subjects without established cardiovascular disease: the higher the heart rate, the greater the risk of cardiovascular and even all-cause mortality.14 More recently, an analysis of the Coronary Artery Surgery Study (CASS) registry15 also showed the long-term prognostic value of resting heart rate in patients with suspected or proven CAD: 24 913 patients from the CASS registry were followed for a median duration of 14.7 years. All-cause mortality and cardiovascular mortality increased with increasing heart rate, and this persisted after adjustment for multiple baseline clinical variables.

All these data suggest that a pure heart rate-lowering agent that is devoid of negative inotropic or hypotensive properties may be useful in patients with CAD and left ventricular dysfunction. Ivabradine is the first agent in a new class of heart rate-lowering agents that act specifically on the sinus node by selective inhibition of the If current responsible for the cardiac pacemaker.16 It has no action on other cardiac ionic currents,17 and does not compromise inotropism or affect blood pressure or the electrophysiological properties of the heart. In stable angina patients, ivabradine reduces resting heart rate.

Since ivabradine selectively lowers heart rate, it is a potent anti-anginal agent: it leads to dose-dependent improvements in exercise tolerance and prevention of exercise-induced ischaemia.18 It produces similar effects to those of atenolol, as measured in a recent randomized double-blind comparison with atenolol (Figure 1).19 It is a safe agent, with no impact on atrioventricular conduction or QT corrected interval and no negative inotropic properties, and it can be safely co-administered with other therapies usually prescribed in these patients, including beta-blockers. It has been tested in patients with left ventricular systolic dysfunction and CAD: in a double-blind, placebo-controlled trial, 65 patients with CAD, class II New York Heart Association (NYHA) heart failure, and a mean left ventricular ejection fraction of 40% were randomly assigned to ivabradine 10 mg twice daily (bid) or placebo for 3 months.20 As expected, ivabradine was associated with a more marked decrease in heart rate but an increased improvement in the distance walked during the 6 minute walking test. Possibly the most intriguing result of this pilot study was the finding of improved ventricular geometry with ivabradine: after 3 months of therapy, end-diastolic and end-systolic volume were both reduced (albeit non significantly), whereas they remained essentially unchanged in patients receiving placebo. In addition, the impact of ivabradine on volumes appeared to increase as left ventricular ejection fraction decreased: in patients with an initial ejection fraction below 35%, end-diastolic volume decreased by 22 mL in the ivabradine group vs. a 14 mL increase in the placebo group. Corresponding changes with ivabradine and placebo for end-systolic volumes were –24 mL and +9 mL, respectively.


Figure 1
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  		Figure 1 Comparison of the anti-anginal effects (total exercise duration at trough) of ivabradine vs. atenolol in the INITIATIVE trial, reprinted from Tardif JC et al.19

 

   BEAUTIfUL: design and methods
Top
 Abstract
 Rationale for the BEAUTIfUL...
 BEAUTIfUL: design and methods
Patient population
 References
 
The BEAUTIfUL study has been established to test the superiority of ivabradine compared with placebo as an adjunct to conventional therapy in the reduction of the composite endpoint of cardiovascular mortality, acute myocardial infarction (requiring hospital admission), and new or worsening heart failure (requiring hospital admission) in patients with stable CAD, in sinus rhythm, and with left ventricular dysfunction.21


   Patient population
Top
 Abstract
 Rationale for the BEAUTIfUL...
 BEAUTIfUL: design and methods
 Patient population
References
 
To be enrolled in the trial, non-diabetic patients had to be ≥55 years of age and diabetic patients had to be ≥18 years of age (regardless of the type of diabetes), with evidence of CAD (documented by a previous myocardial infarction ≥6 months before randomization, previous percutaneous coronary intervention or coronary artery bypass graft, or angiographic evidence of at least 50% narrowing of ≥1 major coronary artery). Patients had to be in sinus rhythm with a resting heart rate of at least 60 bpm on a recent ECG, with a left ventricular ejection fraction of ≤39% on recent echocardiography and left ventricular dilatation (short axis diameter >56 mm). They had to have been stable for at least 3 months with regard to symptoms of angina and heart failure, and had to have been receiving appropriate and stable doses of conventional cardiovascular medications. Finally, all patients had to provide written informed consent.

The main exclusion criteria were recent events or revascularizations, presence of a pacemaker or cardioverter/defibrillator, valvular disease likely to require surgery within the next 3 years, sick sinus syndrome, sinoatrial block, congenital long QT syndrome, complete atrioventricular block, severe or uncontrolled hypertension, class IV NYHA heart failure symptoms, or severe liver or renal disease.

Importantly, background cardiovascular therapy had to be considered as optimal, with consideration given to beta-blockers, statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and antiplatelet drugs.

Following enrolment, after a run-in period of 2 weeks, patients have a baseline evaluation and are randomized, with visits scheduled at 2 weeks, 1, 3, and 6 months, and every 6 months thereafter.

Ivabradine (or matching placebo) is started at 5 mg twice daily, and up-titrated to 7.5 mg twice daily 2 weeks after inclusion, provided that resting heart rate is ≥60 bpm. The dose scheme is presented in Figure 2. A substantial fraction of trial participants will have been on beta-blockers before inclusion into the study, and importantly, beta-blockers may be administered after inclusion as clinically indicated, although they should be introduced in progressive doses. It is therefore expected that a substantial fraction of participants will be on beta-blockers as well as blinded therapy.


Figure 2
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  		Figure 2 Titration scheme for ivabradine in the BEAUTIfUL trial, reprinted from Fox K. et al21

 
The primary endpoint of the study is the composite of cardiovascular death, hospitalization for acute myocardial infarction, and hospitalization for new onset or worsening heart failure. Secondary endpoints include (i) the composite of hospitalizations for acute coronary syndromes, heart failure, and coronary revascularization; (ii) mortality due to CAD; (iii) all-cause mortality; (iv) individual components of the primary and secondary endpoints. Tertiary endpoints are the development of new-onset diabetes and the metabolic syndrome, and changes in left ventricular ejection fraction, fractional shortening, and end-diastolic dimension.

An endpoint validation committee will adjudicate major events within the trial and the safety of the trial will be monitored by a data monitoring committee.

The planned number of patients is 9650, with an expected number of primary endpoints of 950. The study has 90% power to detect a 19% relative reduction in the risk of the primary composite endpoint, assuming an event incidence of 11% at 2.25 years in the placebo group and an incidence of non-cardiovascular death of 1% in both groups. An amendment has been introduced in order to ensure that the last included patients are treated for at least 12 months. To enrol this large number of patients, 780 sites in 33 countries across 4 continents are participating in the study, which is therefore providing a large population from across a broad range of medical practice patterns. In addition to the main trial, several important substudies are nested within BEAUTIfUL. A Holter substudy will involve approximately 700 patients, who will undergo 24 h Holter ECG monitoring at baseline, and 1 and 6 months, therefore providing important information on the actual heart rate in ambulatory patients and additional data on the safety of ivabradine in the context of patients with stable CAD and left ventricular dysfunction. Another substudy will focus on echocardiography and NT-proBNP serum concentrations, and should allow assessment of the effects of ivabradine on left ventricular dimensions and function simultaneously, with correlations to NT-proBNP. Measurements are planned at baseline, 3 and 12 months with central assessment of echocardiographic recordings and cardiac biomarkers.

If the results are positive, i.e. if ivabradine achieves the expected reduction in event rates in comparison with placebo on top of standard therapy, it is likely to have a major impact on clinical practice. Given the specific mode of action of ivabradine, a selective heart rate-lowering agent, it would be the first direct test of the importance of heart rate in the secondary prevention of cardiovascular events (whereas almost all previous evidence regarding the link between heart rate and outcomes has been observational). It would also represent a substantial extension of the established clinical benefits of ivabradine, from the control of anginal symptoms to improved cardiovascular morbidity and mortality.

Conflict of interest: none declared.


   References
Top
 Abstract
 Rationale for the BEAUTIfUL...
 BEAUTIfUL: design and methods
 Patient population
 References
 

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