FDA approves ivabradine for treatment of HF

Jay N. Cohn, MD

The approval of ivabradine as a tool for managing chronic HF recognizes the effectiveness of the drug in reducing morbid events, particularly HF hospitalizations, in patients already treated with optimal therapy approved for HF. The dilemma for the practitioner, however, is how to know which patients should receive the drug. Approved labeling for the drug identifies patients with heart rates above 70 while taking maximally tolerated doses of a beta-blocker. Based on guidelines, these patients should also be receiving an ACE inhibitor or an angiotensin receptor blocker in standard doses. Should ivabradine be routinely added to this background therapy? Or should it be reserved for patients whose left ventricular ejection fraction or left ventricular chamber size remains grossly abnormal, thus perhaps placing them at high risk? The pivotal study and the labeling give no clues to individual management. Eventually, the drug may find a place as a substitute for a beta-blocker, but that is currently outside of labeling.

These are the complexities of clinical management derived from trials in which drugs are layered on in sequence in clinical trial design. The benefit, while statistically significant in a population, clearly does not apply to every patient.  More data are needed to aid in the medical decision-making process, especially when the new drug will be expensive and existing therapy is cheap.

James B. Young, MD

A recent state-of-the-art review on CV drug development by Christopher B. Fordyce, MD, MSc, and colleagues in the Journal of the American College of Cardiology (2015;65:1567-1582) led with the question: “Is it dead or just hibernating?” At the least, we are in a serious doldrum. Indeed, it seems that nothing really new for HF has been FDA-approved in a long time. Perhaps one or two are close (LCZ698, an angiotensin receptor blocker/neprilysin inhibitor the most often cited example) and many new ideas keep popping up with none getting very far, it seems to me. 

Thus, the news that the FDA has approved ivabradine for select HF patients is welcomed with a great deal of interest and some enthusiasm. Perhaps it is not really a new drug, as it has been available in the European Union for several years. As evidence mounted supporting benefits and safety of ivabradine in well-designed and well-conducted clinical trials supervised by a cadre of extraordinary HF trial gurus, Amgen obtained the product and brought it to the FDA for data review and approval. There was speculation about what the agency would do, particularly whether they would ask the sponsor for additional clinical trial data from studies that were primarily done in North America. There has been some queasiness about the FDA relying solely on data from clinical trials done, for the most part, outside of the U.S. That did not appear to happen and the drug was approved for use in the U.S., but in a very narrow population: patients with HF with reduced ejection fraction (EF < 35%) who have “stable” but symptomatic HF while being in sinus rhythm on a maximally tolerated beta-blocker dose with resting heart rate 70 beats per minute or better. The indication is “reducing the risk of hospitalization for decompensated heart failure.”

Ivabradine is an intriguing agent with a mechanism of action that is different than other “guideline-endorsed” HF drugs. It is said to inhibit the “funny current” of the sinus note which slows the rate of depolarization and, thus, decreases heart rate. The agent seems well tolerated, but did cause a slight excess of atrial fibrillation and bradycardia. It is priced at $375/month and must be taken twice daily. 

What we have is a promising and novel approach to HF patient management that might decrease hospitalizations, but will face substantial challenges. Arguments will be made that the favorable economics of decreasing admissions for HF decompensation will make up for the anticipated $4,500/year annual cost, but that is likely going to be a hollow case for the many patients responsible for significant portions of their medication costs. Also, the twice-daily administration requirement could be burdensome and add to the polypharmacy challenges already apparent in this patient population. Nonetheless, the approval of ivabradine is a very positive story for patients and caregivers, and we hope that more data comes available about the drug’s impact on the spectrum of heart failure morbidity and mortality.