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There is increasing evidence to suggest that resting heart rate is a strong predictor of total and cardiovascular mortality in patients with coronary artery disease (CAD) and in post-myocardial infarction (MI) patients.^1-3 Recent data have shown that heart rate reduction in post-MI patients could reduce the cardiovascular events.⁴

Among current therapeutic options, β-blockers decrease heart rate and are able to reduce mortality and sudden cardiac death, particularly in post-MI patients and in patients with heart failure.^3,5-7 Experimental and clinical data demonstrate that heart rate reduction is an important mediator of the effects of β-blockers on ischemia, LV function, and reduction in post-MI mortality.^4,7 However, despite the wide availability of β-blockers, resting heart rate may not be sufficiently lowered.⁸ Furthermore, adherence to β-blockers is far from perfect because of their side effects (impotence, drop in blood pressure).^9-11

Based on these important considerations, it has been estimated that further heart rate lowering could be beneficial in patients with CAD and particularly those with LVD. CAD patients with associated LVD were chosen because left ventricular dysfunction (LVD) has a dramatic and negative effect on survival.^12,13 Ivabradine, an I_f inhibitor that provides pure heart rate reduction, was chosen for this strategy.^14-16 In clinical trials, ivabradine has been shown to produce dose-dependent improvements in ischemia and its tolerability is excellent even in patients with LVD.^17-19

Thus, the BEAUTIFUL trial was designed to assess the morbidity-mortality benefits of pure heart rate reduction with ivabradine above and beyond conventional treatment in CAD patients with associated LVD.²⁰

Ivabradine was chosen as treatment because it met the criteria as an efficient pure heart rate–lowering agent with good tolerability.

Ivabradine selectively lowers heart rate leading to powerful anti-ischemic efficacy

Ivabradine acts specifically on the sinoatrial node and lowers heart rate by selective inhibition of the I_f pacemaker current without affecting other cardiac ionic currents.^14-16 Moreover, unlike β-blockers, ivabradine fully preserves myocardial contractility and relaxation and thereby increases the diastolic perfusion time.²¹ During exercise, the alpha receptor–mediated coronary vasoconstriction observed with β-blockers is not observed with ivabradine, which can result in increased coronary blood flow during exercise.²² This results in an optimal myocardial oxygen supply.
The clinical benefits of pure heart rate reduction with ivabradine have been assessed in a large research program. The antianginal and anti-ischemic efficacy of ivabradine has also been compared with that of β-blockers and calcium channel blockers.
In patients with LVD, preliminary analysis of a 3-month trial demonstrated improved myocardial performance with ivabradine.²³ These effects are consistent with those observed in experimental models.²⁴

Ivabradine is safe and well tolerated

In clinical trials including more than 5000 patients, the tolerability of ivabradine has been excellent.^18,19,25 The main adverse event (minor visual symptoms) was transient and well tolerated. No effects on blood pressure, atrioventricular conduction, or QT interval have been noted.
Combination of ivabradine with beta-blockers, ACE inhibitors, angiotensin II antagonists, diuretics, short and long acting nitrates, HMG CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetics, aspirin, and other anti-platelet agents has been found to be safe.²⁶

BEAUTI_fUL is a large, double-blind, randomized, placebo-controlled trial.²

After a 2-week run-in period, patients were randomized to take ivabradine 5 mg bid or placebo. If after 2 weeks of treatment with 5 mg bid, a patient’s heart rate was ≥60 bpm, he or she was switched to 7.5 mg bid.²⁰ If, on the other hand, the patient’s heart rate dropped below 50 bpm or if the patient showed signs of bradycardia, the patient’s enrollment was discontinued. At each study visit, a similar assessment was performed. The goal was to maintain a heart rate between 50 and 60 bpm for 18 to 36 weeks for each patient. The primary end point is a composite of cardiovascular death and hospitalization for acute MI or new-onset or worsening heart failure.

Patients were included if they were ≥55 years of age.
Patients with type 1 or 2 diabetes could be enrolled if they were ≥18 years of age.
Patients needed to have documented stable CAD, a resting sinus rate ≥60 bpm, a left ventricular ejection fraction =39%, and a left ventricular end-diastolic diameter >56 mm.

In the BEAUTIFUL study, 10 917 patients were recruited in 781 centers in 33 countries.²⁷ Based on the preliminary analysis, the mean age is 65 years, 83% are male, 88% of patients have a history of MI, and the mean ejection fraction is 32.3%.
13.8% (1507 patients) of the randomized patients had limiting angina at baseline.³¹

Diabetes mellitus is present in 37% of patients and metabolic syndrome in 40% of patients. The mean heart rate was 71.6 bpm. A large proportion of patients are taking β-blockers (87%). Other/additional medications include antithrombotics (94%), which include mainly aspirin (84%), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers (89%), and lipid-lowering drugs (76%). According to the most recent European Society of Cardiology guidelines, these patients, at baseline, can be considered as optimally and adequately treated.²⁸ Thus, any benefit obtained with ivabradine would be beyond the benefits of these ‘established’ preventive therapies.

The most important findings from the BEAUTIFUL study¹ are:

• Coronary patients with associated left ventricular dysfunction (LVD), who have heart rate more than 70 bpm have a significantly higher risk of cardiovascular death, myocardial infarction and heart failure (p=0.006). This is independent of all other risk factors or concomitant treatments.

• In these patients (HR > 70 bpm) the use of Procoralan results in a significant reduction of the most important coronary events like myocardial infarction by 36% (p=0.001) and coronary revascularisation by 30% (p=0.016). These results make Procoralan the only antianginal treatment to reduce myocardial infarction and revascularisation even when the patients are already treated with the recommended optimal preventive therapy.

• In all angina patients with left ventricular dysfunction (LVD), ivabradine reduces the primary end point of cardiovascular death, hospitalization for myocardial infarction, and heart failure by 24%. These results are even more impressive in angina patients with a resting heart rate >70 bpm, reducing the most important coronary events like the risk of myocardial infarction (fatal or nonfatal) by 73% and the need for revascularization by 59 %. These results make Procoralan the first and only antianginal treatment to significantly improve the cardiovascular prognosis of all angina patients, with even more pronounced benefit in those with a heart rate >70 bpm.³¹


1. Fox et al. Lancet. In press

BEAUTIFUL has 3 main implications:

- The BEAUTIFUL study reinforces the importance of heart rate as a prognostic risk factor. These results should encourage the clinicians to measure heart rate in all coronary patients and, moreover, the level of heart rate should now guide the treatment decisions for coronary patients.²⁹

- The second clinical implication is that for coronary patients with associated LVD and with a heart rate more than 70 bpm, Procoralan should be used, irrespective of the background therapy to reduce the risk of the most important coronary events like myocardial infarction and revascularization.³⁰

- New analysis of the BEAUTIFUL study in angina patients shows that Procoralan is the first and only antianginal treatment to significantly improve the cardiovascular prognosis of all angina patients by reducing the risk of the most important coronary events like myocardial infarction and revascularization. This is irrespective of the background therapy and the benefit is even more pronounced in those with a heart rate >70 bpm. Thus, Procoralan should be used in all angina patients, symptomatic or with a positive exercise tolerance test, to improve their prognosis and reduce their symptoms.³¹