麻豆传媒

The mechanism behind the cardiovascular benefits of icosapent ethyl (Vascepa) was related to plaque regression and stabilization in people with atherosclerotic cardiovascular disease (ASCVD), according to the final results of .

While people had lower plaque volume over time on statins and icosapent ethyl, the placebo group on statins alone showed continued progression of atherosclerosis from baseline to 18 months:

• Low-attenuation plaque: -17% vs +109% (P=0.0061)
• Non-calcified plaque: -19% vs +9% (P=0.0005)
• Fibro-fatty plaque: -34% vs +32% (P=0.0002)
• Fibrous plaque: -20% vs +1% (P=0.0028)
• Calcified plaque: -1% vs +15% (P=0.0531)
• Total plaque: -9% vs +11% (P=0.0019)

"These data highlight the early and substantial impact of icosapent ethyl on the atherothrombotic burden in the at-risk population," reported Matthew Budoff, MD, of UCLA School of Medicine in Los Angeles, at a late-breaking trial session at the European Society of Cardiology virtual meeting.

EVAPORATE's full 18-month results were simultaneously published online in European Heart Journal.

Investigators previously reported a slowing of plaque progression in the icosapent ethyl arm of the trial in the 9-month interim report.

Now, with the "widening separation of the plaque volumes" by 18 months, the "very early effect" of icosapent ethyl on imaging appears to track its increasing clinical benefit observed over time in REDUCE-IT, Budoff said.

"Markers of plaque burden have been shown to be powerful predictors of ASCVD events, as greater plaque burdens are associated with worse CV outcomes. Vulnerable plaque has been demonstrated to be a combination of LAP [low-attenuation plaque] ... along with spotty calcification, a thin fibrous cap, and positive remodelling," the EVAPORATE group noted.

"The study definitely shows a better outcome on plaque as measured by multidetector CT when comparing icosapent ethyl on plaque progression/regression. It is convincing that the drug reduced plaque volume, which would normally be expected to progress over time," commented Philip Greenland, MD, of Feinberg School of Medicine at Northwestern University in Chicago.

However, there is still "no real understanding of how the drug does what it does clinically," and EVAPORATE does not provide answers as to how icosapent ethyl might reduce plaque volumes, Greenland told 麻豆传媒.

The trial enrolled 80 people at three centers. Eligibility criteria included triglyceride levels 135-499 mg/dL and LDL cholesterol 40-115 mg/dL on statin therapy.

Study participants were randomized to icosapent ethyl 4 g/day (n=40) or mineral oil placebo (n=40). Both groups stayed on statin therapy and were told to maintain a low cholesterol diet.

CT angiography at 18 months was completed by 31 patients in the icosapent ethyl group and 37 in the placebo arm. Of those 68 patients, mean age was 57.4, and 54.4% were men. The two arms shared similar baseline characteristics.

Plaque analysis was performed using semi-automated QAngio CT software.

"There were no significant differences in basic lipid measures of total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels from baseline to follow-up with either therapy," the investigators reported.

This is consistent with icosapent ethyl's "pleiotropic, non-lipid effects," they reasoned. "Icosapent ethyl has been shown to have anti-thrombotic, antiplatelet, anti-inflammatory, anti-oxidant, anti-arrhythmic, and pro-resolving effects which could have beneficial effects on multiple steps of the atherosclerotic pathway."

Previous work suggested that the drug's benefit largely depended on the concentration of omega-3 fatty acid eicosapentaenoic acid, the purity of which sets icosapent ethyl apart from other fish oil products.

A major limitation of EVAPORATE was its small sample size, Budoff acknowledged, though he said the trial was nevertheless powered to detect differences in the primary and various secondary endpoints.

The presenter also addressed prior concerns around mineral oil potentially contributing to plaque progression and adverse events in REDUCE-IT.

The rate of plaque progression was similar between the mineral oil placebo of EVAPORATE and cellulose-based placebo in the Garlic5 study, "so we have high confidence that the benefits seen in this trial with icosapent ethyl represent icosapent ethyl's beneficial effects on atherosclerosis and not harm of mineral oil," he said.

In December, icosapent ethyl received FDA marketing approval for the reduction of cardiovascular risk in adults with elevated triglycerides.

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