Level 1: Likely reliable evidence

Ivabradine is a novel agent that lowers heart rate by inhibiting the I(f) current in the sinoatrial node. The SHIFT trial evaluated the drug’s efficacy in 6,558 patients with symptomatic chronic heart failure (Lancet. 2010;376:875-885). Patients in sinus rhythm (heart rate ≥70 beats per minute) and with a left-ventricular ejection fraction ≤35% were randomized to ivabradine 2.5-7.5 mg twice daily vs. placebo and followed for a median of 22.9 months. All patients had been admitted to a hospital for heart failure within one year and were on stable treatment for at least four weeks, including beta blockers if tolerated. About 90% of the patients were on beta blockers at baseline, but only 26% were taking their target beta-blocker dose.

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In the ivabradine group, heart rates were reduced by 11 beats per minute at 28 days and by nine beats per minute at one year compared with placebo (P <0.05). Ivabradine was associated with reduced heart failure mortality (3% vs. 5%, P=0.014, NNT 50) and reduced all-cause hospital admission (38% vs. 42%, P=0.003, NNT 25). The ivabradine group also had lower hospitalization rates for worsening heart failure (16% vs. 21%, P <0.0001, NNT 20) and for any cardiovascular cause (30% vs. 34%, P=0.0002, NNT 25). Differences in all-cause mortality (16% vs. 17%) and total cardiovascular mortality (14% vs. 15%) were not significant. The ivabradine group had higher rates of bradycardia and visual adverse effects.

Ivabradine is approved for the management of stable angina in Europe, India, and Australia but is not available in the United States or Canada.