The GLAGOV study moves toward demonstration of the clinical benefit of evolocumab. The study shows that combined therapy with statins and evolocumab, versus statins alone, not only achieves better stability of atherosclerotic plaque dimensions but actually results in regression of plaque size. In the study, plaque burden is extrapolated from vessel measurements obtained through IVUS, and nominal changes in PAV and TAV serve as markers for atherosclerosis, but these surrogates cannot be equated to a reduction in cardiovascular events. The GLAGOV trial does explore clinical outcomes such as MI, stroke, unstable angina, coronary revascularization, and death; however, the study is not powered to evaluate the statistical significance of these events. We await sufficiently powered phase 3 clinical trials to determine the clinical benefits of PCSK9 inhibitors on cardiovascular disease.
The GLAGOV trial has several strengths, including its design as an international, double-blind, placebo-controlled, randomized clinical trial. The intervention is simple and the outcomes are clearly defined. The statistical assessment yields significant results. Nonetheless, there are multiple limitations to the study. The lead author has received research support from Amgen, the maker of evolocumab. Amgen also participated in study design and maintenance of trial databases; however, data analysis was conducted by an independent statistician. Additionally, the majority of study participants were white males with very few minority patients despite inclusion of study sites around the globe. The homogeneity of the study cohort makes the data difficult to generalize to a larger population. Similarly, patients who lacked a clinical indication for coronary catheterization and those with uncontrolled diabetes, hypertension, and heart failure were excluded, which further limits application of this study to many patients with atherosclerosis. Another limitation is study attrition; only 87% of participants completed the 78-week IVUS and were included in the data analysis, and results may have differed if those lost to follow-up had completed the trial. Furthermore, study duration was limited to 76 weeks and the magnitude and durability of study outcomes after this time point remain unknown.
Applications for Clinical Practice
Reduction in PAV and TAV are surrogate endpoints and are not indicative of a clinical benefit. Nonetheless, the GLAGOV study demonstrates that evolocumab, when used in conjunction with statins, can promote regression of atherosclerosis greater than treatment with statins alone. More studies are needed to evaluate a clinical benefit of adding evolocumab to the regularly used arsenal of lipid-lowering therapies for the treatment of atherosclerosis. Furthermore, cost-effectiveness of evolocumab has not been shown. In 2015 the yearly wholesale price of evolcumab was $14,350. A cost-effectiveness analysis based on this price estimates that treatment of atherosclerotic coronary vascular disease with evolocumab has a cost of $414,000 per quality-adjusted life year [5]. Evolocumab is well tolerated, but additional studies for cardiovascular and mortality outcomes are needed before it can be considered part of the standard of treatment for coronary artery disease.
—Lauren Brooks, MD, University of Maryland School of Medicine, Baltimore, MD
References
1. Nicholls SJ, Hsu A, Wolski K, et al. Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol 2010;55:2399–407.