EVAPORATE: Early Mechanistic Clues to Vascepa's CV Benefits

Patrice Wendling

November 19, 2019

PHILADELPHIA — Interim results from a study designed to explain the striking results from the REDUCE-IT trial with icosapent ethyl (Vascepa, Amarin) show that the high-dose eicosapentaenoic acid (EPA) therapy slows, but does not reverse, coronary plaque progression.

Among 67 statin-treated patients with high triglycerides, there was no significant difference in the primary endpoint ― change in low attenuated plaque ― between those treated with icosapent ethyl or placebo in the EVAPORATE study.

There was significantly less progression, however, in total, noncalcified, fibrous, and calcified plaque in the icosapent ethyl group on interim CT angiography at 9 months, Matthew Budoff, MD, UCLA School of Medicine, Torrance, California, reported here at the American Heart Association (AHA) Scientific Sessions 2019.

During a media briefing, he explained that the original trial design and all of his prior studies used noncalcified plaque as the primary endpoint, but that the steering committee decided to change the endpoint to low attenuated plaque based on recent Japanese work. Nevertheless, icosapent ethyl showed "remarkable consistency" across almost all of the endpoints.

"I think that you should look at the range of the endpoints and see that, overall, we hit statistical significance for four of them, [with] a trend in the right direction for our primary and, again, it is an interim analysis," Budoff said.

"I don't see this as a failed study by any stretch," discussant for the study, Stephen Nicholls, MD, Monash Heart, Monash University, Melbourne, Australia, said in response. "I mean, this is an interim analysis of a study where we're going to get an opportunity have another look...and I suspect that when we see the 18-month data, they're all going to align and we're going to think there's a nice mechanistic story there."

Several biological functions theoretically explain how EPA reduces cardiovascular events, including its effects on triglyceride-rich lipoproteins, inflammation, oxidative stress, thrombosis, and arrhythmia. The separation of event curves in REDUCE-IT is also consistent with an antiatherosclerotic effect, although there was no clear evidence to suggest the benefit is due to lowering of triglyceride-rich lipoproteins, he noted.

The 25% relative risk reduction in major adverse cardiovascular events among a similar patient population in REDUCE-IT was heralded as a new era in cardiovascular disease prevention. However, some questioned whether potential effects of mineral oil used as the placebo may have meant the benefits of icosapent ethyl were overestimated.

To address this, Budoff and colleagues compared the results of placebo-treated patients in EVAPORATE with historical controls from the prospective, randomized GARLIC5 study, in which a cellulose-based inert placebo was used.

Adjusted multivariate analysis showed no significant differences in rates of progression of total plaque volume (P = .7) or noncalcified plaque volume (P = .5) between the two groups. "So we think this is very reassuring that the benefits seen in the EVAPORATE trial with less plaque progression were associated with the benefits of icosapent ethyl and not a potential harm from mineral oil," Budoff said.

EVAPORATE enrolled 80 patients who had elevated triglycerides (135 to 499 mg/dL) and low-density lipoprotein cholesterol levels (>40 mg/dL to ≤115 mg/dL) on statin therapy and had at least one coronary stenosis of 20% or more on CT angiography. Participants were randomly assigned to icosapent ethyl 4 g/d or placebo for 18 months and underwent follow-up CT angiography at baseline, 9 months, and 18 months.

Among the 67 patients who completed the third visit thus far, there was no difference at 9 months in adjusted median low attenuated plaque progression between the icosapent ethyl and placebo groups (74% vs 94%; P = .469). Fibro-fatty plaque progression was numerically greater with icosapent ethyl (87% vs 25%; P = .650).

Median progression was significantly slower with icosapent ethyl for the four remaining plaque features: total noncalcified (35% vs 43%; P = .010), fibrous (17% vs 40%; P = .011), calcification (–1% vs 9%; P =.001), and total plaque (15% vs 26%; P = .0004).

Efficacy was consistent across multiple subgroups, including baseline triglycerides, Budoff said.

Beneficial effects were observed on a number of secondary endpoints, but it's unclear which one is right, and icosapent ethyl failed to significantly modify the primary endpoint, Nicholls noted in the late-breaking trial session.

"Do the results reflect a failed intervention? I suspect not; it probably reflects the size of the study and the early look at 9 months," he said. "The effect on total plaque volume, however, is promising, as we've heard it consistently associates with cardiovascular risk."

It will be critical to ensure maximal retention of patients on study drug until final imaging is read out at 18 months, he observed. "There was no evaporation of plaque in this study. All plaque features progressed, which again continues to reiterate the importance of high triglyceride levels driving residual cardiovascular risk."

Commenting on the results to theheart.org | Medscape Cardiology, Jennifer Robinson, MD, MPH, director of the Preventive Intervention Center at the University of Iowa, Iowa City, said, "I think we're all struggling with the mechanism. This suggests that slowing atherogenesis is one mechanism, but I'm still not excluding in my mind other mechanisms, like an anticoagulant effect. I think it will have multiple effects that are beneficial."

Going forward, it's going to very interesting to see the results of the ongoing STRENGTH trial with carboxylated EPA/docosahexaenoic acid (Epanova, AstraZeneca), which is supposed to be more bioavailable, she said. "Of course, with the polyunsaturated [corn] oil control, which is the opposite of mineral oil because we think it's beneficial, it will all be very confusing."

Both Epanova and Vascepa are already approved for hypertriglyceridemia. Last week, an advisory committee for the US Food and Drug Administration unanimously recommended Vascepa for approval to reduce cardiovascular events, as an adjunct to statin therapy in patients with elevated triglyceride levels.

Amarin Pharma funded the trial and provided the study drug. Budoff reports research funding from Amarin Pharma, Amgen, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Pfizer, and Regeneron; and serving as a speaker for Amarin Pharma, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Novo Nordisk, Pfizer, Regeneron, and Sanofi Aventis.

Nicholls reports research support from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience; and consulting/honoraria from AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. He also reports being the principal investigator of an ongoing trial of Epanova.

American Heart Association (AHA) Scientific Sessions 2019: Presented November 18, 2019.

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