Adding ivabradine to standard background therapy did not improve outcomes in a large, randomized, placebo-controlled trial of more than 19,000 patients who had stable coronary artery disease without clinical heart failure.

At 3 months, the mean heart rate was 60.7 beats per minute in 9,550 patients in the Study Assessing the Morbidity-Mortality Benefits of the I_f Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) who were assigned to receive ivabradine, compared with 70.6 beats per minute in 9,552 patients who received placebo. At a median of 27.8 months, the percentage of patients reaching a composite endpoint of death from cardiovascular causes or nonfatal myocardial infarction was 6.8% and 6.4% in the groups, respectively (hazard ratio,1.08), Dr. Kim Fox of Royal Brompton Hospital, London and colleagues reported at the 2014 European Society of Cardiology Congress.

The differences between the ivabradine and placebo groups were not statistically significant, but ivabradine was associated with a nonsignificant increase in the incidence of the primary end point in patients with Canadian Cardiovascular Society class II angina or higher (7.6% vs. 6.5%, hazard ratio, 1.18), the investigators said.

The findings were simultaneously published online Aug. 31 in the New England Journal of Medicine (N. Engl. J. Med 2014 Aug. 30[doi:10.1056/NEJMoa1406430].

Study participants, who were recruited from 1,139 centers in 51 countries between October 12, 2009 and April 30, 2012, were at least 55 years of age with documented and treated stable coronary artery disease, but no evidence of clinical heart failure. They also had to be in sinus rhythm, have a resting heart rate of 70 beats per minute or more on two consecutive readings, and have at least one major or two minor adverse prognostic factors.

All patients completed a 2- to 4-week placebo run-in phase then were randomized to ivabradine at a dose of 7.5 mg twice daily (or 5 mg twice daily for those over age 74 years) or placebo in addition to stable background therapy prescribed according to contemporary guidelines. Dosing was adjusted as needed to 5, 7.5, or 10 mg twice daily based on heart rate and bradycardia. The target heart rate was 55-60 beats per minute, and the mean study-drug dose throughout the trial was 8.2 mg twice daily in the ivabradine group, and 9.5 mg twice daily in the placebo group.

Adverse events occurred in significantly more patients in the ivabradine group (73.3% vs. 66.9%). Bradycardia, in particular, was increased in the ivabradine group (7.9% vs. 1.2% for symptomatic bradycardia, and 11.0% vs. 1.3% for asymptomatic bradycardia. Atrial fibrillation and phosphenes were also increased in the ivabradine group (5.3 vs. 3.8% and 5.4% vs. 0.5%, respectively).

Serious adverse events were also significantly more common in the ivabradine group, with 37.6% and 35.4% of patients in the groups, respectively, experiencing a serious adverse event. These events were classified as cardiac disorders in 19.0% and 16.7% of patients in the groups, respectively.

The SIGNIFY findings contrast with those from previous post hoc analyses that suggested ivabradine improves outcomes in patients with stable coronary artery disease.

"In addition, in patients with heart failure, the reduction in heart rate with ivabradine has been shown to improve clinical outcomes, beyond the improvements observed with beta-blockers," the investigators said.

In fact, on the basis of findings from the phase III Systolic Heart Failure Treatment with the I_f Inhibitor Ivabradine Trial (SHIFT), the U.S. Food and Drug Administration recently granted priority review designation for ivabradine for the treatment of chronic heart failure.

Ivabradine lowers heart rate without affecting blood pressure or left ventricular systolic function, by inhibiting the I_f, or pacemaker, current in the sinoatrial node. It is approved in numerous countries outside the United States and is used for reducing angina symptoms and for chronic heart failure.

A number of hypotheses may explain the SIGNIFY findings.

"It is possible that ivabradine decreased the heart rate too much or that there may be a J-shaped curve for the relationship between heart rate and outcome," the investigators said, explaining that "ivabradine may have unintended effects (e.g., adjustment of the doses of other heart-rate lowering agents) that may have affected the potential benefits of the lowering of heart rate with ivabradine."

Further, heart rate-reducing antianginal agents may have no effect on outcomes in patients with stable coronary artery disease, they said.

The findings may also reflect the fact that an elevated heart rate is due to different pathophysiological mechanisms in those with heart failure and those with stable coronary artery disease, they noted.

"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," they concluded.

This study was funded by Servier. Dr. Fox reported receiving personal fees and/or nonfinancial support from Servier, AstraZeneca, TaurX, Armgo, Broadview Ventures, and CellAegis. She also is director of Heart Research Lt. and Vesalius Trials Ltd. Detailed disclosures for all study authors are available at NEJM.org.

SIGNIFY: Ivabradine no help in stable CAD