BEAUTIFUL – no go for go slow with ivabradine

Ivabradine is a pure heart-rate lowering agent that is a specific inhibitor of the If current in the sino-atrial node; currently it is licenced for the treatment of angina.  The BEAUTIFUL (morbidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left-ventricUlar dysfunction) trial aimed to determine if heart rate lowering with ivabradine could reduce cardiovascular death and mortality in patients with stable coronary artery disease and impaired systolic function (<40%), as several studies have demonstrated that a high heart rate is an independent predictor of both cardiovascular and all-cause mortality.

10,917 eligible patients were enrolled in a randomised, double-blind, placebo-controlled, parallel-group manner.  5479 patients received 5mg ivabradine, with the intention of increasing to the target dose of 7.5mg twice a day, and 5438 received matched placebo in addition to their other cardiac medications.  The primary endpoint was a composite of cardiovascular death, and admission to hospital for new onset or worsening heart failure.
Mean heart rate at baseline was 71.6 (SD 9.9) beats per minute (bpm); over a median follow-up of 19 months ivabradine reduced heart rate by 6bpm (SE 0.2) at 12 months, corrected for placebo.  Of note, 87% patients were concomitantly taking beta-blockers, but no safety concerns were noted.  Ivabradine did not affect the primary composite endpoint (HR 1.00, p=0.94), and 1233 patients (22.5%) in the treatment group had serious events, compared to 1239 (22.8%) in the control group (p=0.17). Treatment did reduce the secondary endpoints of non-fatal myocardial infarction (HR 0.64, p=0.001) and coronary revascularisation (HR 0.70, p=0.016).
Thus although the study failed to reach its primary outcome, the data acquired seems to demonstrate the safety of giving ivabradine, even in combination with a beta-blocker.  Although a direct comparison between these two drugs would be useful, it would be hard to justify ethically; further knowledge on the role of ivabradine in a heart failure population will be gained from the forthcoming SHIFT trial (Systolic Heart failure treatment with the If-inhibitor ivabradine Trial).
•    Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 2008; DOI:10.1016/S0140-6736(08)61170-8. Available at: http://www.thelancet.com.
•    Reil JC, Böhm M. BEAUTIFUL results-the slower, the better? Lancet 2008; DOI:10.1016/S0140-6736(08)61172-1. Available at: http://www.thelancet.com.