Ivabradine for patients with stable CAD and left-ventricular systolic dysfunction

According to findings from a Phase III trial published early online in the Lancet, ivabradine does not improve cardiac outcomes in patients with stable coronary artery disease (CAD) and left-ventricular systolic dysfunction (LVD).

The authors note that high heart rate has been shown to be an independent predictor of mortality in CAD patients; lowering heart rate could therefore reduce mortality and cardiovascular events, but this has not been tested as current agents (e.g. beta-blockers) have other cardiovascular actions that would confound the results.  Ivabradine is a selective sinus node inhibitor which decreases resting heart rate – it has no effect on blood pressure, myocardial contractility, intracardiac conduction, or ventricular repolarisation.  They therefore designed this trial (BEAUTIFUL - morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left-ventricULar dysfunction) to see whether the addition of ivabradine to standard treatment to lower heart rate could reduce cardiac death and mortality in patients with CAD and LVD.

A total of 10,917 adults (over 55 years or over 18 years if diabetic) with CAD and a left ventricular ejection fraction of <40% were randomised to double-blind treatment with ivabradine (n=5,479; 5mg initially, increasing up to 7.5mg twice daily) or placebo (n=5,438).  For inclusion, patients had to be in sinus rhythm, have a resting heart rate of at least 60bpm, and have been stable in terms of angina and/or heart failure symptoms for the previous three months (and on stable doses of conventional cardiovascular medicine for the previous one month – this was continued during the study).  Treatment was reduced/ discontinued if the heart rate fell below 50bpm and/or in the presence of symptoms of bradycardia.  The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure (intention-to-treat analysis).

The mean age of the group was 65 years, and 83% were male.  The mean heart rate at baseline was 71.6 bpm, and the mean LVEF was 32.4%. A total of 94% patients were receiving aspirin or an anticoagulant, 87% a beta-blocker; 74% statins, and 90% an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (no statistically significant differences between the two groups). 

After a median follow-up of 19 months, the main findings were as follows:

• The mean difference between the treatment groups (placebo minus ivabradine) in change from baseline resting heart rates was 7.2 bpm (95% CI 6.8–7.5) at 6 months, 6.4 bpm (6.0–6.8) at 12 months, 6.0 bpm (5.6–6.5) at 18 months, and 5.6 bpm (5.1–6.2) at 24 months
• The primary endpoint occurred in 844 patients (15.4%) in the ivabradine group and 832 (15.3%) in the placebo group (hazard ratio [HR] 1.00, 95% CI 0.91–1.1, p=0.94)
• In a pre-specified subgroup of patients with a heart rate of ≥70bpm, there was no effect of ivabradine on the primary endpoint (hazard ratio 0.91, 95% CI 0.81–1.04, p=0.17) but it was found to reduce the incidence of the following secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0.64, 95% CI 0.49–0.84, p=0.001) and coronary revascularisation (0.70, 95% CI 0.52–0.93, p=0.016).

The authors suggest that ivabradine could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater.  This trial was however not powered to test for statistically significant differences in this subgroup for the secondary endpoints; these findings would need confirmation in a prospective study.

Lancet, published early online 31 August 2008; DOI:10.1016/S0140-6736(08)61170-8 (main study, link to abstract); Lancet, published early online 31 August 2008;