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SIGNIFY: Ivabradine no help in stable CAD

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Ivabradine risky in severe angina

The increased incidence of the primary endpoint among patients with Canadian Cardiovascular Society Class II or higher levels of angina in the SIGNIFY trial was surprising and warrants further study to ascertain whether this angina subgroup is one in which caution should be exercised.

In the meantime, caution should indeed be exercised with respect to the use of ivabradine (by physicians who have access to the drug) in those with more severe forms of angina, and adjustment of beta-blocker doses to effective levels should be considered before initiating ivabradine.

The experience from the trial of ivabradine in heart failure suggests that nearly 60% 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 a cautious approach may be reasonable pending better understanding of the matter.

More therapies are needed for patients with chronic angina – particularly in the United States, both to improve symptoms and to improve quality of life.

What we may need to consider is the level at which an individual patient might be willing to trade some potential risk of major nonfatal cardiovascular events for less angina and a better quality of life.

Dr. E. Magnus Ohman and Dr. Karen P. Alexander of Duke University, Durham, N.C., made these remarks in an accompanying editorial (N. Engl. J. Med. 2014, Aug. 31[doi: 10.1056/NEJMe1409369]). Dr. Ohman reported receiving grant support and/or consulting fees from Abiomed, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Janssen, Pozen, Sanofi Aventis, The Medicines Company, and WebMD. Dr. Alexander reported receiving grant support from Gilead.




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 If 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 If 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 If, 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.


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