Ivabradine in Stable Coronary Artery Disease Without Clinical Heart Failure

Study Questions:

In patients with stable coronary artery disease and without clinical heart failure, does ivabradine (which inhibits the If pacemaker current in the sinoatrial node and reduces the heart rate) improve outcomes?


SIGNIFY (Study Assessing the Morbidity–Mortality Benefits of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease) was a randomized, double-blind, placebo-controlled trial of patients with stable coronary artery disease, no evidence of clinical heart failure, sinus rhythm, and resting heart rate of 70 bpm or more on two consecutive electrocardiographic readings. Patients with an ejection fraction ≤40% were excluded. Following a 2- to 4-week placebo run-in phase, patients were randomized to receive ivabradine at a dose of 7.5 twice daily or matching placebo. Target heart rate was 55-60 bpm, and the dose of ivabradine could be adjusted to 5.0, 7.5, or 10.0 mg twice daily accordingly. The primary endpoint was a composite of death from cardiovascular causes of nonfatal myocardial infarction.


A total of 19,102 patients underwent randomization (9,550 assigned to ivabradine, 9,552 assigned to placebo). 63.1% of patients had activity-limiting angina (i.e., Canadian Cardiovascular Society class ≥2). After a median follow-up of 27.8 months, there was no significant difference between the ivabradine and placebo groups in the incidence of the primary composite endpoint (6.8% and 6.4%, respectively; hazard ratio, 1.08; 95% confidence interval, 0.96-1.20; p = 0.20). In subgroup analyses, ivabradine was associated with an increase in the incidence of the primary endpoint among patients with activity-limiting angina, but not those without such angina (p = 0.02 for interaction).


Ivabradine, in addition to standard guideline-based medical therapy, does not reduce death from cardiovascular causes of nonfatal myocardial infarction in patients with stable coronary artery disease without clinical heart failure and resting heart rate >70 bpm.


Although other studies have suggested that ivabradine improves clinical outcomes in patients with heart failure, the current analysis provides convincing evidence that this is not the case in patients with stable coronary artery disease free of heart failure. And, while the results of the primary analysis were not significant, the interaction between study treatment and the presence of angina at baseline warrants careful consideration in patients with activity-limiting angina, and perhaps this therapy (to whom it is available) is best avoided in this subgroup. In an accompanying editorial, Ohman and Alexander remind us that the trial of ivabradine in heart failure demonstrated that more than half of patients were receiving inadequate doses of beta-blockade. It would be important to further characterize the dosing of beta-blockade in patients with stable coronary artery disease, as this too could be a therapeutic opportunity.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Implantable Devices, EP Basic Science, Acute Heart Failure

Keywords: Myocardial Infarction, Follow-Up Studies, Heart Failure, Sinoatrial Node, Confidence Intervals, Electrocardiography, Angina Pectoris, Heart Rate, Benzazepines

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