SIGNIFY: Ivabradine in Patients With Stable CAD Without CHF

The addition of ivabradine to standard background therapy to reduce heart rate did not improve outcomes in patients with stable coronary artery disease without clinical heart failure, according to results from the SIGNIFY Trial presented Aug. 31 at ESC Congress 2014 and simultaneously published in the New England Journal of Medicine.

Additional Resources
  • ESC Congress 2014 Meeting Coverage
  • SIGNIFY Trial Summary
  • The trial randomly assigned 19,102 patients with stable coronary artery disease without clinical heart failure and a heart rate of 70 beats per minute or more to ivabradine or placebo. The dose was adjusted to achieve a target heart rate of 55-60 beats per minute. At three months, the mean heart rate of patients in the ivabradine group was about 60.7 beats per minute, compared to roughly 70.6 beats per minute in the placebo group.

    After a median follow up of 27.8 months, study investigators noted no significant differences in the incidences of death from cardiovascular causes and nonfatal myocardial infarction between the two groups. Among patients with activity-limiting angina, there was an increase in the primary incidence of death from cardiovascular-related diseases or nonfatal myocardial infarction in those taking ivabradine, however. The incidence of bradycardia was also higher in this group as compared to placebo.

    "Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, these results suggest that an elevated heart rate is only a marker of risk – but not a modifiable determinant of outcomes – in patients who have stable coronary artery disease without clinical heart failure," the investigators write.

    "What action should physicians who have ivabradine available to them take on the basis of this subgroup finding," ask E. Magnus Ohman, MD, FACC, and Karen P. Alexander, MD, FACC, in a related editorial comment. "Our recommendation is to exercise caution among patients with more severe forms of angina and to consider adjusting beta-blocker doses to effective levels before initiating ivabradine. The experience from the trial of ivabradine in heart failure suggests that nearly 60 percent of patients were receiving inadequate doses of beta-blockers and that the majority of benefit with ivabradine was among patients who could not take beta-blockers or who were taking a lower dose. Whether this holds true for patients with angina is unknown, but this cautious approach may be reasonable until we understand this finding better."

    Keywords: Coronary Artery Disease, Myocardial Infarction, Follow-Up Studies, Heart Failure, Bradycardia, Heart Rate, Benzazepines

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