BARCELONA – The time is right for a placebo-controlled, randomized trial of ivabradine in patients with heart failure with reduced ejection fraction who are unwilling or unable to take a beta-blocker as recommended in the guidelines, John G.F. Cleland, MD, asserted at the annual congress of the European Society of Cardiology.
He cited as the rationale for such a study a new post-hoc analysis of data from the SHIFT trial showing that ivabradine (Corlanor) significantly reduced both cardiovascular and all-cause mortality, as well as hospitalizations for heart failure, in the subset of study participants who weren’t on beta-blocker therapy.
“This is a post-hoc analysis of a study that’s been completed. This is not enough information to change a guideline, but it’s enough information that it requires validation in a new study,” observed Dr. Cleland, professor of cardiology at the University of Glasgow.
“I think there would be ethical equipoise,” he added. “If patients are unwilling or unable to take a beta-blocker, or their cardiologist feels it’s not in their best interest, then I certainly think a placebo-controlled trial would not only be appropriate, but there’s also an onus on the cardiology community to do such a trial.”
Ivabradine slows heart rate by a unique mechanism that doesn’t involve blockade of adrenergic receptors. In the SHIFT trial (Lancet. 2010 Sep 11;376:875-85), more than 6,500 patients with heart failure with reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate greater than 70 bpm were randomized to ivabradine or placebo on top of guideline-directed medical therapy for heart failure. During a median 23 months of follow-up, heart failure hospitalizations were significantly reduced by 26% in the ivabradine group, although cardiovascular deaths were not significantly affected.
As a result of the SHIFT findings, the drug was approved with an indication for use only in combination with a beta-blocker in patients with HFrEF whose on-treatment heart rate exceeds 70 bpm. Ivabradine is not currently recommended as an alternative to beta-blocker therapy. However, in real-world clinical practice a large number of heart failure patients are not managed with a beta-blocker, the cardiologist noted.
His post-hoc analysis focused on the 685 SHIFT participants who were not on a beta-blocker at randomization. During follow-up, there were 93 deaths among patients who were on placebo and only 71 in those randomized to ivabradine, for a statistically significant 30% reduction in all-cause mortality. Cardiovascular mortality was reduced to a similar extent. These hazard ratios remained similar after adjusting for differences in heart rate and other clinical characteristics.
“Beta-blockers are a highly effective therapy for heart failure with reduced ejection fraction, but the mechanism of benefit remains uncertain. It might simply be due to heart rate reduction. And I would point out that we have no evidence of a dose response for beta-blockers: It may well be that you get most of the effect of a beta-blocker with the lowest dose. Titrating to the full dose of a beta-blocker might only be helpful in that it lowers your heart rate. I would argue that 6.25 mg/day of carvedilol plus ivabradine might be as good as 50 mg twice daily of carvedilol but with much higher patient acceptability. We don’t know,” said Dr. Cleland.
“This is an interesting, hypothesis-generating analysis, and we need confirmation now that ivabradine reduces mortality in heart failure patients who are unwilling or unable to take a beta-blocker,” he concluded.
The SHIFT trial was sponsored by Servier. Dr. Cleland reported serving as a consultant to and receiving research funding from that company and others.
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