Ivabradine again missed a primary endpoint in SIGNIFY

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Patient-reported outcomes matter

The results of this study suggest that routine self-reported health status measurement would clearly improve our ability to provide patients with optimal therapy, given their own preferences. It is time that patient-reported outcomes, particularly those measured in randomized controlled trials, receive the prominence and recognition they deserve. And while Tendera et al. conducted a subgroup analysis, the significance of these results is no less important. Better familiarity with health-related quality of life measurement tools in clinical practice will also add toward greater understanding and appreciation of health status outcomes as those presented by Tendera et al.

Colleen M. Norris, Ph.D., and Dr. Kevin R. Bainey are at the Mazankowski Alberta Heart Institute at the University of Alberta in Edmonton. They had no disclosures. These comments are taken from their accompanying editorial (Circ Cardiovasc Qual Outcomes. 2015 Dec 22. doi: 10.1161/circoutcomes.115.002412).




Adding ivabradine to standard therapy for stable angina pectoris did not improve self-reported physical limitations, compared with placebo, at 12 months, but seemed to decrease the frequency of angina and help patients feel better about their disease, according to a subgroup analysis of SIGNIFY data.

“The robustness of our results is demonstrated by the low rate of missing data and the good internal consistency and validity of the scales used,” Dr. Michal Tendera of the Medical University of Silesia in Katowice, Poland, and his associates wrote in Circulation: Cardiovascular Quality and Outcomes. “The main limitation is the generalizability of the study findings, because the study enrolled patients in sinus rhythm with a heart rate of at least 70 beats per minute.”

SIGNIFY (Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease) had compared ivabradine or placebo plus standard therapy in more than 19,000 patients who had stable coronary artery disease without clinical heart failure. Ivabradine missed its primary endpoint, a composite of cardiovascular deaths and nonfatal myocardial infarctions (N Engl J Med. 2014;371:1091-9).

Dr. Tendera and his associates subsequently performed a subgroup analysis of 4,187 SIGNIFY patients who had responded to the Seattle Angina Questionnaire. Ivabradine again missed its prespecified primary outcome, the mean change in physical limitation score at 12 months (4.56 points vs. 3.40 points, respectively), the investigators reported (Circ Cardiovasc Qual Outcomes. 2015 Dec 22. doi: 10.1161/circoutcomes.115.00209).

However, ivabradine was associated with significant 12-month improvements in other quality of life measures, most notably the frequency of angina (P less than .001), said the investigators. The difference persisted but was somewhat attenuated at 24 and 36 months (P = .01 and .045, respectively). Ivabradine also beat placebo in terms of mean changes in disease perception at 12 months (10.6 vs. 8.6 points for placebo; P = .006).

In general, patients who scored in the lowest tertile for quality of life at baseline improved the most on ivabradine, indicating that the antianginal drug “has a positive effect on a range of quality of life indices in patients with angina, despite the lack of the long-term effect on physical limitation,” the researchers concluded.

Servier makes ivabradine and funded the study. Dr. Tendera and all six coauthors reported receiving financial compensation, including personal fees, from Servier.

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