Despite reducing progression and promoting regression of coronary atherosclerosis, statin therapy does not fully address residual cardiovascular (CV) risk. High-purity eicosapentaenoic acid (EPA) added to a statin has been shown to reduce CV events and induce regression of coronary atherosclerosis in imaging studies; however, data are from Japanese populations without high triglyceride (TG) levels and baseline EPA serum levels greater than those in North American populations. Icosapent ethyl is a high-purity prescription EPA ethyl ester approved at 4 g/d as an adjunct to diet to reduce TG levels in adults with TG levels >499 mg/dL. The objective of the randomized, double-blind, placebo-controlled EVAPORATE study is to evaluate the effects of icosapent ethyl 4 g/d on atherosclerotic plaque in a North American population of statin-treated patients with coronary atherosclerosis, TG levels of 200 to 499 mg/dL, and low-density lipoprotein cholesterol levels of 40 to 115 mg/dL. The primary endpoint is change in low-attenuation plaque volume measured by multidetector computed tomography angiography. Secondary endpoints include incident plaque rates; quantitative changes in different plaque types and morphology; changes in markers of inflammation, lipids, and lipoproteins; and the relationship between these changes and plaque burden and/or plaque vulnerability. Approximately 80 patients will be followed for 9 to 18 months. The clinical implications of icosapent ethyl 4 g/d treatment added to statin therapy on CV endpoints are being evaluated in the large CV outcomes study REDUCE-IT. EVAPORATE will provide important imaging-derived data that may add relevance to the clinically derived outcomes from REDUCE-IT.

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.