• Cardiology Clinical Trials
• Cardiology
• Coronary Artery Disease

• Cardiology Clinical Trials
• Coronary Artery Disease

Kim M. Fox, MD, Imperial College, London, United Kingdom, reported the results of the Study Assessing the Morbidity-Mortality Benefits of the I _f Inhibitor Ivabradine in Patients With Coronary Artery Disease Without Heart Failure [SIGNIFY; Fox K et al. N Engl J Med. 2014]. The study found that treatment with ivabradine did not reduce the risk of cardiovascular (CV) death or nonfatal myocardial infarction (NFMI). However, in patients with Canadian Cardiovascular Society (CCS) class II or greater angina at baseline, ivabradine increased the risk of CV death or myocardial infarction (MI).

The BEAUTIFUL study [Fox K et al. Lancet. 2008] also tested ivabradine in patients with stable coronary artery disease (CAD) and left ventricular systolic dysfunction. In the overall study population, the primary outcome of hospitalization for fatal and NFMI was not reduced with ivabradine versus placebo on top of standard therapy. However, ivabradine appeared to reduce the rate of the primary outcome in the patients with a heart rate ≥ 70 beats per minute (bpm). Ivabradine is currently approved in the European Union for use in patients with CAD and patients with heart failure and who are either intolerant of beta-blockers or are inadequately controlled despite treatment with beta-blockers.

SIGNIFY—a prospective, international, double-blind study—enrolled patients aged ≥ 55 years with stable CAD and ≥ 1 other CV risk factor, including CCS class ≥ II angina, a left ventricular ejection fraction (LVEF) > 40%, and a heart rate ≥ 70 bpm [Fox K et al. N Engl J Med. 2014], to further test the hypothesis that ivabradine improved outcomes in patients with elevated resting heart rate. A higher-dose regimen of ivabradine, a drug known to have a specific and direct effect on heart rate alone, was used to obtain maximum heart rate reduction in SIGNIFY. After a 14- to 30-day run-in, patients were randomized to ivabradine (7.5 mg, BID; n = 9550) or placebo (n = 9552), and the drug was uptitrated as tolerated to a maximum of 10 mg (BID) to obtain a target a heart rate of 55 to 60 bpm.

The study patients were mostly men (73%) aged 65 years with a LVEF (56%) and with a high frequency of prior MI (73%) and other risk factors. They were receiving optimal CV medical therapy [Gibbons RJ et al. J Am Coll Cardiol. 2003; Fox K et al. Eur Heart J. 2006]. The median follow-up was 27.8 months.

The baseline resting heart rate was 77 bpm in both groups. The mean reduction in heart rate was 9.7 bpm with ivabradine versus placebo. Prof Fox noted that the reduction in heart rate was less than what they had anticipated.

The incidence of the primary composite outcome of CV death or NFMI was similar with ivabradine (3.03% per year) and placebo (2.82%; P = .20), as was the incidence of its components (Table 1).

In the overall study population, the incidence of adverse events was higher with ivabradine versus placebo (73% vs 66.9%; P < .001). Symptomatic and asymptomatic bradycardia occurred in about 19% of patients in the ivabradine group versus about 2.5% in the placebo group. Atrial fibrillation occurred in 5.3% and 3.8% of the ivabradine and placebo groups, respectively. Importantly, the total incidence of life-threatening arrhythmias—ventricular tachycardia, ventricular fibrillation, and Torsades de pointes—was infrequent (≤ 0.9%).

In the prespecified analysis of patients with angina CCS class ≥ II (n = 12 049), there was a significant increase of 18% in the composite of CV death and MI, and a similar nonsignificant trend was seen for the components of the primary outcome (Table 2). Prof Fox noted that this is the population in which the research group anticipated finding the maximum benefit with a lower heart rate. In the angina population, ivabradine improved symptoms, with a greater improvement in CCS class at 3 months (24.8% vs 19.4% with placebo; P < .01). The need for elective coronary revascularization was not significantly reduced with ivabradine versus placebo (HR, 0.82; P = .06).

In summary, in the absence of clinical heart failure in patients with stable CAD, lowering the heart rate with ivabradine did not prevent the progression of CAD, stated Prof Fox, and in patients with angina at baseline, there was an increase in CV death or NFMI. The results of this study has led a review by the European Medical Agency that is ongoing to determine what, if any, further action is needed.

• © 2014 MD Conference Express®