European Medicines Agency Recommends Closer Monitoring of Ivabradine-Treated Patients

November 07, 2014

LONDON, UK — The European Medicines Agency (EMA), following a review by the Pharmacovigilance Risk Assessment Committee (PRAC), is making new recommendations on the use ivabradine (Corlentor/Procoralan, Servier) for the treatment of patients with symptoms of angina[1].

The review is based on "surprising" data that came to light from the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY).

As reported by heartwire , a prespecified analysis showed ivabradine to be associated with an increase in the combined end point of death or nonfatal MI in a subgroup of more than 12 000 patients with symptomatic angina (Canadian Cardiovascular Society class 2–4), one of the approved indications for the drug in Europe.

SIGNIFY was published in the New England Journal of Medicine this past August and presented at the European Society of Cardiology 2014 Congress in Barcelona, Spain. The results showed that adding ivabradine to standard therapy had no effect, overall, on cardiovascular events in the placebo-controlled trial of more than 19 000 patients with stable coronary artery disease. Treatment with the drug did produce an average 10-beat-per-minute reduction in heart rate compared with placebo when measured after the trial's third month.

The EMA's PRAC review noted that patients in SIGNIFY were treated with as much as 20 mg of ivabradine daily (10 mg twice per day), a dose that is higher than the currently authorized maximum daily dose (7.5 mg twice a day). While the PRAC does not believe the higher dose fully explains the findings, "the committee reiterated that the starting dose for angina should not exceed 5 mg twice a day and that the maximum dose should not exceed 7.5 mg twice a day."

The PRAC reminds physicians that when ivabradine is prescribed for angina, "it should be used only to alleviate symptoms, as the available data do not indicate that the medicine provides benefits on outcomes such as reducing heart attack or cardiovascular death."

In its evaluation, thhe PRAC also concluded that patients treated with ivabradine are at an increased risk of developing atrial fibrillation compared with control-treated patients. Although the increased risk appears modest (4.86% vs 4.08%), the committee recommends that physicians monitor patients for the arrhythmia.

Finally, the committee notes that bradycardia risk is significantly elevated with ivabradine. Given the increased risk—in SIGNIFY, 17.9% developed bradycardia compared with 2.1% of the placebo-treated patients—the PRAC recommends physicians check baseline heart rate before starting treatment or when the dose is adjusted.

Ivabradine is approved in the European Union but is not available in the US. The Food and Drug Administration is currently reviewing ivabradine as a potential treatment of patients with chronic heart failure based on data from the SHIFT study.


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