Ivabradine makes no dent on mortality in patents with stable CAD

Heart patients taking ivabradine did not experience a higher survival rate over placebo in a trial published online Aug. 31 in the New England Journal of Medicine and presented at the 2014 European Society of Cardiology Congress in Barcelona.  

Ivabradine, like beta-blockers, reduces racing heart rates. An international research team proposed that ivabradine would help patients with stable coronary artery disease (CAD) without clinical heart failure by relieving angina. They designed a randomized, placebo-controlled clinical trial to assess ivabradine in 19,102 patients with stable CAD, no clinical heart failure and heart beats of 70 beats or more per minute.

Ivabradine, at a maximum dose of 10 mg daily, was given in conjunction with standard therapy to 9,550 participants. The primary endpoint was the composite of death from cardiovascular causes or nonfatal MI.

First author Kim Fox, MD, of the Royal Brompton Hospital in London, and colleagues determined that contrary to prior studies using ivabradine, mortality rates were not improved. While ivabradine reduced heart rates more than 10 beats per minute compared to placebo, 6.8 percent of patients on ivabradine and 6.4 percent of patients on placebo experienced nonfatal MI or cardiovascular-related mortality. Taken individually, patients taking ivabradine experienced nonfatal MI (hazard ratio 1.04) or cardiovascular related mortality (hazard ratio 1.1) at statistically similar rates to placebo.

One notable finding among the subgroups was that while ivabradine increased the incidence rate for cardiovascular mortality and nonfatal MI in patients with angina Canadian Cardiovascular Society Class II or higher, 24 percent experienced an improvement in angina class at three months, compared with placebo.

Several reasons were posited by Fox et al as to why this study’s results differed from others, including a hypothesis that heart rate-reducing agents may not have as much effect on stable CAD.

“The benefit observed with lowering the heart rate in patients with stable coronary artery disease may reflect the fact that an elevated heart rate is due to different pathophysiological mechanisms in these two conditions,” Fox et al wrote.

E. Magnus Ohman, MB, and Karen P. Alexander, MD, of Duke University in Durham, N.C., wrote in response that while more angina treatments are needed, findings such as these should encourage caution among physicians who have ivabradine available for use. However, they noted that the success of ivabradine in heart failure patients where beta-blockers were previously unsuccessful should encourage more study of whether the drug could still be useful in other heart conditions.

They also questioned the utility of expecting drugs to reduce the risk of death or MI, as the majority of current treatments have not proven to do either.

Despite success with symptoms of angina, Fox et al wrote, “Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, these results suggest that an elevated heart rate is only a marker of risk – but not a modifiable determinant of outcomes – in patients who have stable coronary artery disease without clinical heart failure.”

This study was funded by Servier.