Icosapent ethyl shows benefit on several plaque characteristics at 9 months: EVAPORATE
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PHILADELPHIA — Interim data using coronary CT angiography demonstrated benefits of icosapent ethyl as an adjunct to statin therapy on several plaque characteristics at 9 months in adults with high triglycerides and coronary atherosclerosis.
These are early data and the EVAPORATE study is continuing to 18 months as planned, Matthew Budoff, MD, professor of medicine at David Geffen School of Medicine at UCLA and investigator at the Lundquist Institute, Torrance, California, said during a press conference at the American Heart Association Scientific Sessions.
Progression of plaque
In a prespecified interim analysis at 9 months, icosapent ethyl (Vascepa, Amarin) 4 g per day, compared with placebo, slowed progression of the primary endpoint of low attenuation plaque by 21%, but this finding did not reach statistical significance (P = .469).
Four other endpoints demonstrated significant slowing of progression: 19% for total noncalcified plaque (P = .01), 42% for total plaque (P = .0004), 57% for fibrous plaque (P = .011) and 89% for calcified plaque (P = .001). Results also showed an increase in fibrofatty plaque (P = .65), according to Budoff. He noted consistent efficacy across multiple subgroups, including baseline triglycerides.
Budoff reported data from 80 patients assigned daily icosapent ethyl or placebo, in addition to statin therapy. The randomized, double-blind, placebo-controlled study enrolled patients aged 45 years and older (mean age, 57 years), with at least one angiographic stenosis of 20%, fasting triglyceride levels of 135 mg/dL to 499 mg/dL, LDL > 40 mg/dL and 115 mg/dL on stable statin therapy with or without ezetimibe, and estimated glomerular filtration rate > 60. CT angiography was performed at baseline and 9 months, and patients will undergo follow-up again at 18 months.
EVAPORATE is a two-look sequential-design study, he said, with interim analysis at 9 months and final analysis at 18 months.
In addition, the researchers looked at placebo progression rates using mineral oil compared with a matched cohort using a cellulose-based placebo.
In REDUCE-IT, as Healio previously reported, the primary endpoint of CV death, nonfatal MI, nonfatal stroke, coronary revascularization or unstable angina occurred less often in the icosapent ethyl group compared with the placebo group (17.2% vs. 22%; HR = 0.75; 95% CI, 0.68-0.83; absolute difference, 4.8%; 95% CI, 3.1-6.5; number needed to treat to prevent one primary endpoint event = 21; 95% CI, 15-33), but some experts questioned whether the results were due to benefit from the drug or harm from the mineral oil placebo.
“There was concern after REDUCE-IT and after the EVAPORATE trial started that mineral oil might have contributed to the harm of that [placebo] cohort rather than benefit of icosapent ethyl because of some adverse lipid effects of mineral oil. ... There were identical rates of progression for total plaque and total noncalcified plaque among the two cohorts, reassuring us that the slow rates of progression we saw among five of the six markers we measured were due to benefits of icosapent ethyl and not harms of mineral oil,” Budoff said.
Looking ahead
Discussing the trial, Budoff noted several limitations, including a shorter follow-up than prior CT angiography studies and a primary endpoint that was not significant at the interim timepoint. He said the original study design focused on noncalcified plaque as the primary endpoint, but it was changed to low attenuation plaque.
Still, he said, results show “a trend in the right direction for our primary [endpoint].”
“I don’t see this study as a failed study, by any stretch,” Stephen J. Nicholls, MBBS, PhD, from South Australian Health and Medical Research Institute, Adelaide, Australia and a discussant for the EVAPORATE study, said during a press conference.
“Icosapent ethyl failed to significantly modify the primary endpoint of the study — change in low attenuated plaque — and we cannot make definitive statements with regard to any change in that parameter accordingly. There were beneficial effects observed on a number of secondary endpoints. We have to ask the question: Which of these is correct?” 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.
“This is an interim analysis of a study where we’re going to get an opportunity to have another look. ... I suspect that when we see the 18-month data, they’re going to align,” Nicholls said. – by Katie Kalvaitis
Reference:
Budoff MJ, et al. Late Breaking Science VI: New Frontiers in Lipid Therapy. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.
Disclosures: Budoff reports he received research funding from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Pfizer and Regeneron and has served on speaker bureaus for Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Pfizer, Regeneron and Sanofi. Nicholls reports he has received research support from Amgen, Anthera, AstraZeneca, Cerenis, Eli Lilly, Esperion, InfraReDx, Liposcience, Novartis, Resverlogix, Roche, Sanofi/Regeneron and The Medicines Company; has received consultant fees/honoraria from Akcea, Anthera, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Merck, Omthera, Resverlogix, Sanofi/Regeneron and Takeda; and is principal investigator of an ongoing trial of Epanova.