Given that ivabradine works exclusively by lowering heart rate, specifically targeting the heart-rate controlling “funny” (If) current of the sinus node, the use of beta-blockers by study patients received extra scrutiny, with 89% of enrolled patients receiving a beta-blocker, and with 56% receiving at least half of their target beta-blocker dosage and 26% getting the complete, recommended dosage. In addition, more than 90% of patients received an ACE inhibitor or an angiotensin receptor blocker.
Patients in the study received the highest background dose of a beta-blocker in a heart failure trial outside of a beta-blocker study,” said Dr. Swedberg. “We think they had the best treatment available. This is the best we can achieve today with a beta-blocker.” All patients in SHIFT began a beta-blocker, and only those who were completely intolerant of the drug came off it. The added heart-rate reduction that ivabradine provided on top of the beta-blocker “saved energy in a compromised myocardium,” he explained.
“We encouraged up-titration [of beta-blockers] as much as possible,” Dr. Komajda said.
“It’s unlikely that use of higher beta-blocker doses in SHIFT would have caused a further reduced heart rate. In the real world, clinicians are unable to increase doses of beta-blockers to target levels because of actual or perceived side effects,” Dr. Anand said.
“There are adverse effects from beta-blockers. Sometimes you can’t push high doses,” said Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia. Ivabradine “supplements the titration of a beta-blocker when you run out of room because of side effects,” he said in an interview. Dr. Bove said that the 50% prevalence of a heart rate of 77 bpm or greater in the SHIFT patients reasonably reflected the rate in average heart failure patients of the type enrolled, and was a rate indicating inadequately controlled heart failure. Among similar patients who were managed in a more intensive, closely monitored program, perhaps 25% would have such an elevated heart rate and would be good candidates for ivabradine treatment, he said in an interview.
Dr. Anand recommended excluding heart failure patients with atrial fibrillation from ivabradine treatment, but despite that, he estimated that roughly 40% of all heart failure patients with left ventricular systolic dysfunction who were on current, standard-of-care therapy might benefit from the addition of ivabradine to their regimen.
SHIFT was sponsored by Servier Laboratories, which markets ivabradine in Europe under the name Procoralan for the treatment of patients with chronic stable angina. Ivabradine does not have an approved indication from the U.S. Food and Drug Administration. Dr. Komajda and Dr. Swedberg have received fees and research grants from Servier, and two of their coauthors on the study are employees of Servier. Dr. Pitt has received honoraria from and has been a consultant to Merck & Co., Novartis, and Pfizer Inc. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems. Dr. Anand has served on an advisory board for and received research grants from Corventis Inc.