November 24th, 2014

European Review Confirms Increased Risk with Ivabradine

Following a review provoked by troubling findings that emerged from a large clinical trial, the European Medicines Agency (EMA) is making several recommendations intended to lower the risk of heart problems linked to the heart-rate-lowering drug ivabradine. The drug is marketed by Servier in Europe under the brand names of Corlentor and Procoralan and is indicated for the treatment of heart failure and stable angina. The drug is not available in the U.S. but is under development by Amgen for the indication of heart failure.

The review by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) concluded that ivabradine “should only be started if the patient’s resting heart rate is at least 70 beats per minute.” The drug should only be used for the symptomatic relief of angina because it “has not been shown to provide benefits such as reducing the risk of heart attack or cardiovascular death.”

The committee also recommended that ivabradine should not be prescribed along with verapamil or diltiazem, drugs that also lower the heart rate. In addition, patients taking ivabradine should be monitored for atrial fibrillation and if AF develops the physician should re-evaluate treatment with ivabradine.

Concern about ivabradine emerged earlier this year due to results of the very large SIGNIFY study testing a high dose of ivabradine in more than 19,000 patients with stable angina. Although the overall results were neutral, troubling findings occurred in the very large subgroup (more than 12,000 patients) with symptomatic angina. The EMA review concluded that in these patients ivabradine, compared with placebo, had a small but significant increase in the risk of CV death and nonfatal MI (3.4% vs 2.9% yearly incidence rates) and a substantially higher risk of bradycardia (17.9% vs. 2.1%). Also, the rate of AF was 5.3% in the ivabradine group compared with 3.8% in the placebo group. The EMA also examined additional data that confirmed the increased risk of AF in ivabradine patients.

The EMA said that the higher than recommended dose of ivabradine used in SIGNIFY “did not fully explain the findings.” But it repeated its guidance that the initial dose of ivabradine for angina should be no greater than 5 mg twice a day and  that the maximum dose should not exceed 7.5 mg twice a day.



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