Ivabradine and the SIGNIFY conundrum

This editorial refers to ‘Bradycardia and atrial fibrillation in patients with stable coronary artery disease treated with ivabradine: an analysis from the SIGNIFY study’[†][1], by K. Fox et al ., on page 3291. Stable angina is a prevalent and disabling condition that occurs in 10–14% of those aged 65–84 years,1 with population studies suggesting that almost a third of affected patients experience an angina episode at least once a week.2 Treatment focuses upon the alleviation of angina symptoms and the prevention of cardiac events. Although the development of cardioprotective agents has received considerable attention in recent years, there has been less progress with novel antianginal agents. Ivabradine is a novel antianginal agent that inhibits the sinus node If channel to produce a dose-dependent bradycardia and thus anti-ischaemic effects without significant direct effects on vasomotor tone, blood pressure, or myocardial contractility. Previous studies have shown it to be superior to placebo and non-inferior to first-line antianginal agents (beta-blockers and calcium channel blockers).1 However like the first-line agents, its cardioprotective benefit in patients with stable angina has not been confirmed,3,4 although its benefit in heart failure is well supported.5 The BEAUTIFUL3 and SIGNIFY4 studies evaluated the cardioprotective effects of ivabradine in patients with coronary artery disease with3 and without4 left ventricular systolic dysfunction, who had resting sinus rhythm rates ≥70 b.p.m. Although neither study reported an overall cardioprotective benefit, a post-hoc analysis of the BEAUTIFUL study observed a 42% reduction in myocardial infarct hospitalizations amongst patients with symptom-limiting angina.6 Consequently a pre-specified subgroup analysis of patients with Canadian Cardiovascular Society Class II–IV … [1]: #fn-2