Interim data study into effects of fish oil on plaque progression shows promising findings

Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides (200-499mg/dl) on Statin Therapy (EVAPORATE Study)

News - Nov. 18, 2019

Presented during the AHA Scientific Sessions 2019 by Matthew J Budoff (Lundquist Inst and UCLA Sch of Med, Torrance, CA) .

Introduction and methods

Plaque progression over time can be assessed with multiple CT angiographies, and it has been used to assess the effect of therapies on atherosclerotic plaque progression.

The REDUCE-IT trial showed that treatment with icosapent ethyl reduced the risk of the primary endpoint of CV death, MI, stroke, coronary revascularization and unstable angina by 25%. The current study was a mechanistic study with the aim of obtaining insight into the mechanism through which icosapent ethyl exerts the beneficial effects seen in REDUCE-IT.

EVAPORATE is a randomized, double-blind, placebo-controlled study to evaluate the effects of icosapent ethyl 4 g/day on atherosclerotic plaque in statin-treated patients with coronary atherosclerosis. Eligible participants had atherosclerosis with at least one stenosis of 20%, but no history of MI, stroke of life-threatening arrythmia within the prior 6 months and no history of CABG. They had fasting TG levels between 150 and 500 mg/dL and LDL-c between 40 and 100 mg/d, and should be on stable statin therapy (±ezetimibe) for ≥4 weeks prior to qualifying measurements for randomization. The primary endpoint was progression rates of low attenuation plaque. After randomization, participants were followed for 18 months. This prespecified interim analysis reports the results after 9 months. 80 Persons were randomized, of whom 30 (75%) completed visit 3 in the icosapent ethyl group and 37 (92.5%) in the placebo group.

Main results

At 9 months, compared with placebo, icosapent ethyl slowed plaque progression by:

  • 21% for low attenuation plaque (median % change: 74 vs. 94 with placebo, P=0.469)
  • 19% for total non-calcified plaque (35 vs. 43%, P=0.010)
  • 42% for total plaque (15 vs. 25%, P=0.0004)
  • 57% for fibrous plaque (17 vs. 40%, P=0.011)
  • 89% for calcified plaque (-1 vs. 9%, P=0.001)
  • Increase in Fibrofatty plaque (87 vs. 25%, P=0.650)

Consistent efficacy was seen across multiple subgroups.

The study also compared the effect of rates of progression of the placebos mineral oil and cellulose. No difference in progression of log transformed total plaque was noted, thus ruling out that the effects seen with icosapent ethyl in EVAPORATE were the result of harmful effects of mineral oil.


This mechanistic study using CT coronary angiography showed that icosapent ethyl as adjunct to statin yielded significant changes in most plaque markers, indicative of slowing of plaque progression at 9 months. The primary endpoint of low attenuation plaque was not significant at this interim timepoint, but the study will continue to 18 months as planned.


Stephen Nicholls was the discussant of the EVAPORATE study. He noted that the study had low statistical power. Although the study did not meet its primary endpoint of change in low attenuated plaque, he did not consider the study a failure. He wondered out loud whether the current results reflect the effect of the intervention and he said that he thinks they mostly reflect an underpowered study. The time frame of the study may also have been too short to demonstrate an effect. It will be critical to ensure maximal retention of patients on study drug until final imaging. The effect on total plaque volume is promising, so results at 18 months will be insightful.

Nicholls also noted that the study shows that all plaque features progressed, which emphasizes the importance of high TG levels and progressive CV risk.

In the discussion it came up that it is important to get icosapent ethyl into the tissues. Profound differences have been described in concentrations in tissues. High enough concentrations are needed for an effect, so dose-effects may be at play when a lack of effect is seen.

The comparison of mineral oil and non-mineral oil placebo was useful, and showed that no adverse effect was observed with the mineral oil placebo when compared with historical controls.

During the discussion, Budoff noted that initially, the idea was to have non-calcified plaque or total plaque as primary endpoint, like in many other studies. But, study design was changed towards having low attenuation plaque as primary endpoint. Had it not been changed, the current analysis would have been positive. But, there is a trend in the right direction for the primary endpoint, plus four other characteristics showed good results. Nicholls expects that these findings are going to align in the 18 months data.

- Our reporting is based on the information provided during AHA Scientific Sessions 2019 -

Watch the video about the EVAPORATE study

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