Nicolls SJ, Puri S, Anderson, T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients. The GLAGOV randomized clinical trial. JAMA 2016;316:2372–84.
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Study Overview
Objective. To determine if evolocumab, a PCSK9 inhibitor, affects the progression of coronary artery disease in patients treated with statins.
Design. Multicenter, international, double-blind, placebo-controlled, randomized clinical trial.
Setting and participants. 197 community and academic hospitals worldwide enrolled 978 participants who underwent serial intravascular ultrasounds (IVUS) to measure their burden of coronary atherosclerosis. A total of 2628 patients were screened. Patients were considered for inclusion if they were 18 years of age or older and had at least 1 coronary artery stenosis of at least 20% on a clinically indicated catheterization. Additionally, the target vessel had to meet IVUS imaging quality and visibility standards. Participants were required to have been on stable statin therapy for at least 4 weeks with an LDL level of > 80 mg/dL or between 60–80 mg/dL with either 1 major or 3 minor cardiovascular risk factors. Major risk factors were noncoronary atherosclerotic disease, myocardial infarction (MI) or hospitalization for unstable angina within the past 2 years, or type 2 diabetes. Minor risk factors included current tobacco use, hypertension, low HDL-C levels, family history of early coronary disease, hsCRP level of 2 mg/L or greater, and age older than 50 years for men and 55 years for women. Patients with uncontrolled hypertension, uncontrolled diabetes, heart failure, renal insufficiency, or liver disease were excluded.
Intervention. Patients were randomized to either treatment with monthly subcutaneous injections of 420 mg evolocumab or placebo injections for 76 weeks. Participants attended 7 follow-up visits during the study period and then underwent repeat IVUS imaging at the 78th week. Research staff, who were blinded to both treatment status and imaging sequence, collected and assessed target vessel measurements, including the vessel lumen and external elastic membrane dimensions. IVUS imaging has been used in numerous clinical studies and has been shown to be accurate and reliable [1].
Main outcome measures. The primary outcome was the target artery change in percent atheroma volume (PAV) from baseline to week 78. PAV was calculated from IVUS measurements. Nominal change in PAV was then determined by calculating the difference of the PAV at baseline and at week 78.
The secondary measure was the normalized total atheroma volume (TAV). TAV addresses variability in the length of vessel segments and the number of images collected during IVUS catheter pullback. The nominal change in TAV was then determined by the difference at baseline and at week 78.
Additional secondary efficacy endpoints included number of patients with regression of plaque and change in lipid parameters. Safety outcomes were investigated through evaluation of the incidence of adjudicated clinical events, including all-cause mortality, cardiovascular death, MI, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and heart failure requiring hospitalization. Post-hoc analysis compared baseline LDL-C level and change in PAV and regression of PAV. The association between LDL lowering and plaque progression was also assessed post hoc.