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SIGNIFY: Ivabradine did not improve outcomes in stable CAD
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BARCELONA, Spain — The addition of ivabradine to standard background therapy to reduce heart rate did not improve outcomes in patients with stable CAD without clinical HF enrolled in the SIGNIFY trial.
Previous research suggested that ivabradine (Procoralan, Servier) might improve outcomes in patients with CAD, left ventricular dysfunction and a heart rate ≤70 bpm. SIGNIFY was a randomized, double blind, placebo-controlled trial of 19,102 patients (mean age, 65 years; 72.4% men) with stable CAD without clinical HF and a heart rate ≥70 bpm. Patients were randomly assigned placebo (n=9,552) or ivabradine up to 10 mg twice daily, with dose adjustment to achieve a target heart rate of 55 bpm to 60 bpm (n=9,550).
According to results presented at ESC Congress by Kim Fox, MD, from Imperial College and Royal Brompton Hospital, London, mean heart rate was reduced to 60.7 bpm in the ivabradine group compared with 70.6 bpm in the placebo group at 3 months. The difference in mean heart rate between the groups was maintained for the duration of the study, he said during his presentation.
Kim Fox
The primary endpoint was a composite of death from CV causes and nonfatal MI. After a mean follow-up of 27.8 months, the incidence of the primary endpoint was 6.8% in the ivabradine group vs. 6.4% in the placebo group (HR=1.08; 95% CI, 0.96-1.2; P=.2). The researchers also reported no difference in the individual components of the primary endpoint (death from CV causes: HR=1.1; 95% CI, 0.94-1.28; P=.25; nonfatal MI: HR=1.04; 95% CI, 0.9-1.21; P=.6). The ivabradine and placebo groups also had a similar rate of death from any cause (HR=1.06; 95% CI, 0.94-1.21; P=.35) and incidence of sudden death (201 cases vs. 202 cases, respectively).
The researchers also evaluated the effect of ivabradine vs. placebo in specific subgroups. “In the subgroup of patients with angina (Canadian Cardiovascular Society class ≥II [63.1% of population]), there appeared to be an increase in CV death or nonfatal MI,” Fox said.
The incidence of the primary endpoint in the subgroup with activity-limiting angina was 7.6% for the ivabradine group vs. 6.5% for the placebo group (HR=1.18; 95% CI, 1.03-1.35; P=.02). The same trend was not observed in patients without angina or in those with CCS class I angina (HR=0.89; 95% CI, 0.74-1.08; P=.25). In the subgroup of patients with CCS class ≥II angina, 24% of those assigned ivabradine experienced improvement in CCS class at 3 months vs. 18.8% of those assigned placebo (P=.01).
“Lowering heart rate with ivabradine in CAD patients without clinical HF does not reduce the risk for CV death or nonfatal MI. … We were surprised by the findings in patients with angina. The results were immediately reported to the European Medicines Agency, [which is] now looking into the data so they can advise patients as to what they should be doing [with ivabradine],” he said.
In an accompanying editorial in The New England Journal of Medicine, E. Magnus Ohman, MB, and Karen P. Alexander, MD, wrote, “Although this is a subgroup of an overall neutral trial, it is a group of more than 12,000 patients, who were studied where the therapy is approved and in use outside the United States.” They noted that it would be of “paramount importance to analyze the SIGNIFY trial in greater detail to better define what drove the outcomes among patients with severe angina who had been randomly assigned to ivabradine.”
The mean dose of ivabradine in the study was 8.2 mg twice daily, which is higher than that typically used in clinical practice today, Fox said. In addition, most patients were already receiving standard therapy, most commonly antiplatelet therapy or anticoagulants (97.7%), statins (92.2%), beta-blockers (83.1%) and ACE inhibitors (59.3%). – by Katie Kalvaitis
For more information:
Fox K. Hot Line II. Coronary Artery Disease and Lipids. Presented at: the European Society of Cardiology Congress; Aug. 30-Sept. 3, 2014; Barcelona, Spain.
Fox K. N Engl J Med. 2014;doi:10.1056/NEJMoa1406430.
Ohman EM. N Engl J Med. 2014;doi:10.1056/NEJMe1409369.
Disclosure: The study was supported by Servier. Fox reports receiving grants and honorarium from Servier. See the NEJM study and editorial for other relevant financial disclosures.