Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial

Abstract

Aims: Despite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains. Icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, added to a statin was shown to reduce initial CV events by 25% and total CV events by 32% in the REDUCE-IT trial, with the mechanisms of benefit not yet fully explained. The EVAPORATE trial sought to determine whether IPE 4 g/day, as an adjunct to diet and statin therapy, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in statin-treated patients.

Methods and results: A total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis as documented by MDCT (one or more angiographic stenoses with ≥20% narrowing), be on statin therapy, and have persistently elevated triglyceride (TG) levels. Patients underwent an interim scan at 9 months and a final scan at 18 months with coronary computed tomographic angiography. The pre-specified primary endpoint was change in low-attenuation plaque (LAP) volume at 18 months between IPE and placebo groups. Baseline demographics, vitals, and laboratory results were not significantly different between the IPE and placebo groups; the median TG level was 259.1 ± 78.1 mg/dL. There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061). There were significant differences in rates of progression between IPE and placebo at study end involving other plaque volumes including fibrous, and fibrofatty (FF) plaque volumes which regressed in the IPE group and progressed in the placebo group (P < 0.01 for all). When further adjusted for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups remained significantly different, P < 0.01. Only dense calcium did not show a significant difference between groups in multivariable modelling (P = 0.053).

Conclusions: Icosapent ethyl demonstrated significant regression of LAP volume on MDCT compared with placebo over 18 months. EVAPORATE provides important mechanistic data on plaque characteristics that may have relevance to the REDUCE-IT results and clinical use of IPE.

Keywords: Atherosclerosis; Cardiac CT; Coronary artery disease; Prevention; Progression.

Figure 1

Mean plaque progression for each type of plaque composition measured on cardiovascular CT for the icosapent ethyl and placebo groups (icosapent ethyl group, n = 31 and placebo group, n = 37) after multivariable adjustment. Univariable analysis and multiple linear regression were used to examine the change in plaque levels between the cohorts. Multivariable models were adjusted by age, sex, diabetes status, hypertension, and baseline triglyceride levels. All statistical analyses report two-sided P-values for the outcomes. A P-value <0.048 was considered significant for the outcomes.

Figure 2

54 year old male with history of diabetes, hypertension, and hyperlipidaemia on optimal statin therapy randomized to icosapent ethyl and followed for 18 months. Figures (C and D) demonstrate significant regression of LAP (in red) compared with baseline (A and B). (A, B) Coronary Segmentation model of proximal LAD and quantitative measurement of different plaque types at baseline. (C, D) Coronary Segmentation model of same site in proximal LAD and quantitative measurement of different plaque types at 18-month follow-up. Dense Calcium: white; Necrotic Core or Low-Attenuation Plaque: red; Fibrous Fatty: light green; Fibrous: dark green.