EVAPORATE Hints at Slowed Plaque Progression With Icosapent Ethyl

The findings might provide a mechanistic explanation for at least some of the CV event reduction seen in REDUCE-IT.

EVAPORATE Hints at Slowed Plaque Progression With Icosapent Ethyl

PHILADELPHIA, PA—Preliminary data suggest that icosapent ethyl (Vascepa; Amarin) slows the progression of atherosclerosis in patients similar to those enrolled in the REDUCE-IT trial, which showed a relative 25% reduction in MACE with the pharmaceutical-grade omega-3 fatty acid formulation among patients with high triglyceride levels.

An interim analysis of EVAPORATE, a study designed to explore a potential mechanism to explain the REDUCE-IT results, showed that after 9 months, patients treated with icosapent ethyl had less progression in multidetector CT-assessed coronary plaque than did those who received placebo, according to Matthew Budoff, MD (Harbor-UCLA Medical Center, Torrance, CA).

Though the difference did not reach statistical significance for the primary endpoint—change in low-attenuation plaque volume—there was significantly less progression in total, fibrous, noncalcified, and calcified plaque in the icosapent ethyl group, Budoff reported here at the American Heart Association (AHA) 2019 Scientific Sessions.

In a mechanistic study like this, Budoff indicated in a media briefing, it’s fair to look at these other outcomes when evaluating the results. “I think it showed a remarkable consistency across almost all of the endpoints, and some of the P values were quite low,” Budoff said, noting that total plaque was a prespecified endpoint and, in fact, was the primary endpoint when the study was initially designed. “So I think that you should look at the range of the endpoints and see that overall we hit statistical significance with four of them, [with] a trend in the right direction for our primary,” he explained.

Stephen Nicholls, MBBS, PhD (Monash University, Melbourne, Australia), who served as a discussant for EVAPORATE, followed that up by saying, “I don’t see this study as a failed study by any stretch. I mean, this is an interim analysis of a study where we’re going to get an opportunity to have another look.” EVAPORATE was planned and powered for an 18-month follow-up, and Nicholls said he suspects all of the endpoints will align at that point.

To TCTMD, Nicholls said “the fact that they overall saw an effect on total plaque is a really important finding because I think in every imaging modality we’ve ever looked at—angiography, ultrasound, invasive imaging, CT—total plaque matters. The more plaque you’ve got, the more progression you’ve got, the more likely you’ll have an event. So when I see that result and see that there is significance in terms of that outcome, that’s a really positive finding for me.”


Budoff said that multidetector CT has the ability to evaluate coronary plaque progression over time, which has been demonstrated in prior studies to be a significant predictor of future CV events.

EVAPORATE was designed to use serial multidetector CT scans at baseline, 9 months, and 18 months to evaluate the impact of icosapent ethyl on plaque progression and potentially provide an explanation for the benefits seen in REDUCE-IT. Investigators enrolled 80 patients who had elevated triglyceride levels (135 to 499 mg/dL), were on stable statin therapy, had LDL-cholesterol levels greater than 40 mg/dL but no higher than 115 mg/dL, and had at least one coronary stenosis of 20% or greater on CT. The entry criteria were similar to those used in REDUCE-IT, Budoff noted.

Patients were randomized to receive icosapent ethyl 4 g/day or placebo for 18 months.

Budoff presented the results of the prespecified 9-month interim analysis, which included 67 patients who completed the third study visit. Mean age was 55.6 in the icosapent ethyl arm and 58.3 in the placebo arm; slightly more than half of participants were men.

At 9 months, median percent change in plaque volume was not significantly reduced with icosapent ethyl relative to placebo when looking at low-attenuation plaque, but it was when looking at several secondary plaque measures. Fibro-fatty plaque, on the other hand, progressed to a greater extent in the icosapent ethyl arm, although the difference was not significant.

Median Percent Change in Plaque Volume at 9 Months


Icosapent Ethyl


P Value

Low-Attenuation Plaque




Fibro-Fatty Plaque




Fibrous Plaque




Calcified Plaque




Noncalcified Plaque




Total Plaque




There were consistent effects across subgroups, including the full spectrum of baseline triglyceride levels, Budoff reported.

The reduction in progression of total plaque, in particular, is important, Budoff said, because that correlates best with total atheroma volume as a marker of future CV events.

The investigators also evaluated plaque progression in the placebo arm, an analysis stemming from concerns raised after the REDUCE-IT results came out about the potential adverse lipid effects of the mineral oil used for that purpose. Compared with a historical cohort of patients who received a cellulose-based placebo, those receiving the mineral-oil placebo in this study had nearly identical plaque progression, “reassuring us that the slowed rates of progression we saw among five of the six markers that we measured were due to benefits of icosapent ethyl and not harms of mineral oil,” Budoff said at the media briefing.

Work Continues

In discussing Budoff’s findings, Nicholls noted that research into omega-3 fatty acids and CV risk has been a journey filled with ups and downs, from early signs of potential benefit to a large body of work yielding disappointing results to recent trials—including JELIS and REDUCE-IT—showing the positive effects of high-dose formulations of eicosapentaenoic acid (EPA).

EPA, he said, has a number of biological properties that should theoretically provide a CV benefit by affecting triglyceride-rich lipoproteins, inflammation, oxidative stress, thrombosis, and arrhythmia. The separation of the event curves in REDUCE-IT, he added, is consistent with studies of other therapies known to have an anti-atherosclerotic effect.

As for how to interpret the findings of EVAPORATE when it missed its primary endpoint, Nicholls said: “Do the results reflect the effect of the intervention? I suspect not. Do they reflect more likely a small underpowered study with an interim analysis at 9 months? I think that is more likely to be the case.”

The apparent effect on slowing total plaque progression is promising, he said, but “it will be critical for the ongoing conductors of this study to ensure that there is maximal retention of patients until final imaging. And what we’ve really learned here is that all plaque features in this study progressed. There was no evaporation. They continued to progress, and that emphasizes the importance of high triglyceride levels driving progressive risk in the statin-treated patient.”

There are remaining questions about whether other high-dose omega-3 fatty acid formulations will have an impact on CV risk, whether other patient groups will benefit, and whether imaging will be used to guide use of these treatments, Nicholls said, concluding that “the only way to answer those questions will be more clinical trials.”

Icosapent ethyl is currently US Food and Drug Administration-approved with an indication for reducing triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia. Late last week, an FDA advisory panel recommend the regulator expand the indication to allow for cardiovascular event reduction claims, based on the REDUCE-IT results.

Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • Budoff M. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: the EVAPORATE study. Presented at: AHA 2019. November 18, 2019. Philadelphia, PA.

  • The EVAPORATE trial is funded by Amarin, which provides study drug and placebo.
  • Budoff reports receiving research funding from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Pfizer, and Regeneron and serving as a speaker for Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Novo Nordisk, Pfizer, Regeneron, and Sanofi Aventis.
  • Nicholls reports receiving research support from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience; consulting fees and honoraria from AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim; and serving as the principal investigator of an ongoing trial of omega-3-carboxylic acids (Epanova).