News:BEAUTIFUL study fails to meet primary endpoint but demonstrates that heart rates can safely be reduced with Ivabradine

August 31, 2008 By Alexandra M. Palmer [mailto:apalmer@perfuse.org]

The goal of this trial was to assess the morbidity-mortality benefits of the heart rate-lowering agent Ivabradine (Procoralan®) on top of current preventive therapy in CAD patients with left ventricular dysfunction. The primary endpoint was a composite one, consisting of cardiovascular mortality, hospital admission for acute myocardial infarction and hospitalization for new-onset or worsening heart failure. Secondary endpoints included the composite of hospitalization for acute coronary syndrome, for new-onset or worsening heart failure, or coronary revascularization, mortality due to CAD and all-cause mortality.

BEAUTIFUL was a randomized, double-blind, placebo-controlled, multicenter, international, 2-arm study which recruited 10,917 patients at 781 centers in 33 countries across 4 continents. The parallel-group study consisted of patients who presented with CAD and left ventricular ejection fraction <40%. Most patients were already being administered the following optimal therapies: antiplatelet agents (94%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (91%), β-blockers (87%), and lipid-lowering agents (76%). On top of these recommended guidelines medications, patients were randomized to 5 mg Ivabradine twice daily (n=5,479) or matching placebo (n=5,438). After 2 weeks of this treatment regimen, patients with a resting heart rate ≥ 60 bpm received the target dose of 7.5 mg Ivabradine twice daily (or matching placebo).

The duration of follow-up was a median of 19 months, at which time Ivabradine had safely reduced heart rate by 6 beats per minute, but had no significant affect on the reduction of the primary composite endpoint (HR = 0.91, p = 0.17). In a pre-specified subgroup of patients with a heart rate > 70 at baseline, Ivabradine treatment did significantly reduce the following secondary endpoints: risk of hospitalization for fatal and non-fatal myocardial infarction by 36% (HR = 0.64, p=0.001) and the risk of coronary revascularization by 30% (HR = 0.70, p=0.016). In this same pre-specified subgroup, there was no reduction in cardiovascular death (HR 1.02, p=0.82) or hospitalization for congestive heart failure (HR 0.97, p=0.76).

The findings of the study are limited by the fact that beta-blocker use was slightly higher among patients with heart rates < 70 bpm (90% vs 84%), a finding that may account at least in part for the larger effect of Ivabradine in the higher-heart-rate group.

BEAUTIFUL suggests that among patients with heart rates ≥ 70 bpm, the heart rate and some CV events can safely be reduced by using Ivabradine on top of background therapy. These outcomes are provocative, but should be viewed as hypothesis generating, and cannot be applied to individuals with CAD and normal ejection fractions, as the study consisted of people with impaired LV function.

Mode of action
Ivabradine acts on the If (f is for "funny", so called because it had unusual properties compared with other current systems known at the time of its discovery) ion current, which is highly expressed in the sinoatrial node. If is a mixed Na+–K+ inward current activated by hyperpolarization and modulated by the autonomic nervous system. It is one of the most important ionic currents for regulating pacemaker activity in the sinoatrial (SA) node. Ivabradine selectively inhibits the pacemaker If current in a dose-dependent manner. Blocking this channel reduces cardiac pacemaker activity, slowing the heart rate and allowing more time for blood to flow to the myocardium.

Uses
Ivabradine was approved by the European Medicines Agency in 2005. It is indicated for the symptomatic treatment of stable angina pectoris in patients with normal sinus rhythm, who have a contraindication to or intolerance to beta blockers. It has been shown to be non-inferior to the beta-blocker atenolol for this indication and amlodipine.

Apart from angina, it is also being used off-label in the treatment of inappropriate sinus tachycardia.

Dosage
A dose of 5 mg twice daily is recommended initially; after 1 month, it is recommended to increase to 7.5 mg twice daily to get the optimal efficacy linked to heart rate reduction. Given limited experience in the elderly, the manufacturer recommends a starting dose of 2.5 mg.

Adverse effects
14.5% of all patients taking ivabradine experience luminous phenomena (by patients described as sensations of enhanced brightness in a fully maintained visual field). This is probably due to blockage of I h ion channels in the retina which are very similar to cardiac If. These symptoms are mild, transient, fully reversible and non-severe. In clinical studies about 1% of all patients had to discontinue the drug because of these sensations, which occurred on average 40 days after commencement of the drug.

Bradycardia (unusually slow heart rate) occurs at 2% and 5% for doses of 7.5 and 10 mg respectively (compared to 4.3% in atenonol). 2.6-4.8% reported headaches. Other common adverse drug reactions (1–10% of patients) include first-degree AV block, ventricular extrasystoles, dizziness and/or blurred vision.

Contraindications
Ivabradine is contraindicated in sick sinus syndrome, and cannot be used concominantly with inhibitors of CYP3A4 such as azole antifungals (such as ketoconazole), macrolide antibiotics, nefazodone and the anti-HIV drugs nelfinavir and ritonavir.