Ivabradine (Corlanor) – Mixed Results in Clinical Trials

The next issue of The Medical Letter (1469; May 25, 2015) will include an article on ivabradine (Corlanor – Amgen), a new drug for treatment of heart failure. The FDA-approved indication for its use is actually much more complicated. It specifies that the drug is approved to reduce the risk of hospitalization for worsening heart failure in adult patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction (LVEF) < 35% who are in sinus rhythm with resting heart rate > 70 beats per minute and either are on maximally tolerated doses of beta blockers or have a contraindication to beta blocker use. And have one blue eye and one brown eye (just kidding).

The FDA has tended, in recent years, to restrict the indications for new drugs to the types of patients enrolled in the pivotal clinical trials on which approval was based. But the degree of specificity in the labeling of ivabradine suggests that the agency had some serious reservations about the decision to permit its marketing in the US, even though the drug has been available in other countries for as long as 10 years (as Procorolan, and others).

One reason for concern could have been the mixed results reported in clinical trials. The pivotal study (SHIFT) was conducted in patients who more or less fit the specifications in the labeling except that they were not required to be on maximally tolerated doses of beta blockers or to have a contraindication to their use. Anyway, the investigators found that the drug reduced hospital admissions for worsening heart failure and deaths due to heart failure, but not cardiovascular deaths overall. And in patients who were receiving at least 50% of the target dose of a beta blocker (closer to the labeled indication), deaths due to heart failure were not significantly reduced either.

In 2 other clinical trials of ivabradine described in our article, one in patients with stable coronary artery disease without clinical heart failure and the other in patients with stable coronary artery disease and left ventricular dysfunction, ivabradine did not improve clinical outcomes. And in one of the trials, it significantly increased the rate of either cardiovascular death or nonfatal MI in patients with more than minimal (CCS class II or higher) angina pectoris. Which is really interesting, because Procorolan and other international brands of ivabradine are approved for use not only in heart failure but also for patients with stable coronary disease.

So it’s not difficult to see why the FDA might have had reservations about approving ivabradine. And there’s more to it, of course. To get the complete picture, and to find out our recommendations for use of ivabradine, take a look at our upcoming issue.

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