Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Aims</jats:title> <jats:p>Though statin therapy is known to slow coronary atherosclerosis progression and reduce cardiovascular(CV) events, significant CV risk still remains. In the REDUCE-IT study, icosapent ethyl (IPE) added to statin therapy reduced initial CV events by 25% and total CV events by 30%, but its effects on coronary atherosclerosis progression have not yet been fully investigated. Therefore, this study is to determine whether IPE 4g/d will result in a greater change from baseline in plaque volume measured by serial multidetector computed tomography (MDCT) than placebo in statin-treated patients.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results</jats:title> <jats:p>EVAPORATE is a randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis by coronary computed tomographic angiography CCTA (≥1 angiographic stenoses with ≥20% narrowing), on stable statin therapy with low-density lipoprotein cholesterol levels 40 to 115 mg/dl, and persistently high triglyceride levels (135-499 mg/dL). Patients underwent an interim scan at 9 months and were followed for an additional 9 months with CCTA at 0, 9 and 18 months. Here we present the protocol-specified interim efficacy results.</jats:p> <jats:p>A total of 80 patients were enrolled, with 67 completing the 9-month visit and having interpretable CCTA at baseline and at 9-months (age=57±6 years, male=36, 63%). At the 9-month interim analysis, there was no significant change in low attenuation plaque (LAP) between active and placebo groups (74% vs 94%, p = 0.469). However, there was slowing of total non-calcified plaque (sum of LAP, fibrofatty, and fibrous plaque)(35% v. 43%,p=0.010), total plaque (non-calcified + calcified plaque)(15% v. 26%,p=0.0004), fibrous plaque (17% v. 40%,p=0.011) and calcified plaque (-1% v. 9%,p=0.001), after adjustment by baseline plaque, age, sex, diabetes, baseline triglyceride levels, and statin use.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>EVAPORATE is the first study using CCTA to evaluate the effects of IPE as an adjunct to statin therapy on atherosclerotic plaque characteristics in a high-risk CV population with persistently high TG levels. It provides important mechanistic data in regards to the reduction in CV events in the REDUCE-IT clinical trial.</jats:p> </jats:sec> <jats:sec> <jats:title>Translational Potential</jats:title> <jats:p>Given the robust cardiovascular event reduction seen in clinical trials of Icosapent ethyl, this study demonstrates that one potential mechanism of benefit of this therapy is to slow atherosclerosis progression. This study shows that most coronary plaque types show slowed rates of progression under the influence of statin plus Icosapent ethyl. A translational use of this information would be to potentially use this therapy in addition to statin therapy in cases with presence of significant atherosclerosis.</jats:p> </jats:sec>

Targeting hypertriglyceridemia to mitigate cardiovascular risk: A review

“…A 9-month interim analysis of EVAPORATE showed that icosapent ethyl at 4 g/day did not reduce progression of low attenuation plaque volume (74% vs 94%; P =0.47) or fibrofatty plaque volume (87% vs 25%; P =0.65) versus placebo, respectively (n=30, IPE; n=37, placebo). 74 However, icosapent ethyl did reduce progression of total plaque versus placebo (15% vs 26%; P <0.001). The study is designed to conclude after 18 months of therapy.…”

Effects of Eicosapentaenoic Acid on Arterial Calcification

“…In an ongoing trial, the EVAPORATE study, changes in coronary plaque, including low-attenuation, fibro-fatty, fibrous, calcified and non-calcified plaque, over a period of 9 to 18 months are being examined in patients treated with statins plus a higher dose of EPA, 4 g/day [11]. The results of interim analysis at nine months, which were presented in 2019 AHA Scientific Sessions (Philadelphia, PA), indicated slowed progression of calcified plaque: EPA, 1% decrease vs. placebo, 9% increase, p = 0.001 [126]. These clinical studies were summarized in Table 2.…”

Coronary computed tomography angiography in asymptomatic patients: Still a taboo or precision medicine?

“…New drugs, such as bempedoic acid, a small molecule that inhibits cholesterol synthesis [9], or inclisiran, a new anti-PCSK9 operating as a synthetic small interfering ribonucleic acid (siRNA), are currently being evaluated as additional weapons to be added to our armamentarium [10]. Beyond LDL lowering drugs, anti-inflammatory drugs such as colchicine [11,12], and purified omega 3 fatty acids [13] may add plaque-stabilizing effects, by modifying low-attenuation plaque components, as shown by recent CCTA studies [14,15]. CCTA features suggestive of high-risk individuals for future ACS and sudden death, along with targeted pharmacologic options for plaque stabilization, are summarized in Fig.…”