August 31st, 2014

SIGNIFY Trial Provokes Sound and Fury Over Controversial Drug

The already controversial drug ivabradine just got a little more controversial. The drug, which is marketed by Servier under the brand names of Corlentor and Procoralan, is available in Europe and elsewhere and is used for the treatment of heart failure and stable angina. The drug is not available in the U.S., but it is under development by Amgen for a heart failure indication.

Now a very large new study presented at the European Society of Cardiology meeting in Barcelona and published simultaneously in the New England Journal of Medicine has found no evidence of benefit in a stable angina population. It instead found more adverse events associated with the drug, and even suggested the likelihood of harm in a very large and important trial subgroup. The findings have resulted in an investigation by the European Medicines Agency, placing a cloud over the future status of the drug.

In SIGNIFY (Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabadine in Patients with Coronary Artery Disease) 19,102 patients who did not have heart failure and who had stable coronary artery disease and a heart rate of at least 70 bpm were randomized to ivabradine or placebo.

After 27.8 months of followup, there was no overall difference in the primary endpoint (the composite of cardiovascular death or nonfatal MI), which occurred in 6.8% of the ivabradine group and 6.4% of the placebo group (HR 1.08, CI 0.96-1.20, p=0.20). There were also no significant differences in any other significant outcomes of interest, though there was a trend toward more heart failure hospital admission in the ivabradine group (2.3% versus 1.9%, p=0.07).

After three months of treatment, the mean heart rate fell from 77 to 60 in the ivabradine arm and from 77 to 70 in the placebo arm. This difference was maintained throughout the study.

The study drug was discontinued in 20.6% of patients in the ivabradine group versus 14.5% in the placebo group. In the ivabradine group, asymptomatic bradycardia was the leading cause for discontinuation. There were significantly more adverse events in the ivabradine group than in the placebo group: 73.3% versus 66.9% (p<0.001), including symptomatic bradycardia (7.9% versus 1.2%), asymptomatic bradycardia (11% versus 1.3%), atrial fibrillation (5.3% versus 3.8%) and phosphenes (5.4% versus 0.5%). Serious adverse events occurred in 37.6% versus 35.4% (p=0.0001).

 A Really Big Subgroup

The results were similar across subgroups, with one very large and important exception. Placebo was significantly better than ivabradine in the large (12,049 patient) subgroup of patients who had class II or higher angina. In this subgroup, a primary endpoint event occurred in 7.6% of the ivabradine group versus 6.5% of the placebo group (HR1.18, CI 1.03-1.35).

The authors speculated about the reasons for the finding that ivabradine did not benefit their patient population. It may be that decreasing the heart rate too much is harmful, they said. “It is also possible that heart-rate reducing antianginal agents have no effect on outcomes in patients with stable coronary artery disease.”

The difference in outcomes between the stable angina population of SIGNIFY and the heart failure population of SHIFT “may reflect the fact that an elevated heart rate is due to different pathophysiological mechanisms in these two conditions.” In particular, they pointed to the presence of neurohormonal activation in heart failure and its absence in stable angina. They further noted that the dose used in SIGNIFY was higher than the dose used in SHIFT, the pivotal heart failure trial.

In an accompanying editorial, E Magnus Ohman and Karen Alexander discuss the “surprising finding” in the large subgroup of patients with CCS class II or higher angina. “Although this is a subgroup of an overall neutral trial, it is a group of more than 12,000 patients, who were studied where the therapy is approved and in use outside the United States.”

Where ivabradine is available, they advise physicians to “exercise caution among patients with more severe forms of angina and to consider adjusting beta-blocker doses to effective levels before initiating ivabradine.” Almost 60% of patients in the SHIFT trial received inadequate beta-blockade, and most of the benefit associated with ivabradine in that study was found in people who could not take beta blockers or who were taking low doses of beta blockers. But, they acknowledge, “whether this holds true for patients with angina is unknown, but this cautious approach may be reasonable until we understand this finding better.”

A Cloudy Future

Currently ivabradine has a 2a recommendation in the ESC guideline for treating stable angina. The ESC provided the following response to my request for a clarification about the status of that guideline:

The ESC will await the results of the detailed European Medicines Agency (EMA) review before deciding whether it is necessary to update the recommendations regarding ivabradine in the 2013 ESC guidelines on the management of stable coronary artery disease.

Previous ivabradine studies have demonstrated impressive efficacy in the treatment of chronic stable angina, with no safety or tolerability issues identified that were a cause for concern. It is important to note that some patients in the SIGNIFY study received a dose of ivabradine higher than the currently licensed maximum daily dose. This higher ivabradine dose is not the dose mentioned within the 2013 ESC guidelines on the management of stable coronary artery disease.

Any questions relating to the process or timings of the EMA investigation should be directed to the EMA.


To view all of our coverage from the ESC meeting, go to our ESC.14 Headquarters page.

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