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The story of icosapent ethyl (Vascepa) was complicated by recent negative data, but it might be too late to expect clinicians to put a hold on their prescribing while they wait for a more definitive trial that may never happen.

Icosapent ethyl has been lauded for its 25% reduction of major adverse cardiovascular events (MACE) in the REDUCE-IT trial, first reported in 2018.

However, that trial was criticized for its use of mineral oil placebo. The control group unexpectedly showed increases in LDL cholesterol and inflammatory biomarkers from baseline, suggesting that mineral oil was not as inert a comparator as previously thought. Some believe the compound to have unexpected adverse biologic effects that could have falsely magnified the risk reduction associated with the pure eicosapentaenoic acid (EPA) formulation of icosapent ethyl.

A darker shadow was cast over the prescription-grade fish oil product this month when two other formulations of omega-3 fatty acids were shown to have no benefit over corn oil placebo in the STRENGTH and OMEMI trials.

Now, some are calling for another trial to ascertain the actual treatment effect of icosapent ethyl, if it really has one.

"A new cardiovascular outcome trial studying icosapent ethyl is the only way to determine whether the drug actually reduces MACE. Such a trial would need to use a truly neutral placebo, such as corn oil, rather than mineral oil," said STRENGTH's senior investigator Steven Nissen, MD, of the Cleveland Clinic.

"A new trial with a biologically-inert placebo would be helpful," agreed Jennifer Robinson, MD, MPH, of the University of Iowa in Iowa City.

But others were not convinced that a new trial is really needed.

"I don't [think] REDUCE-IT needs to be 're-done.' If REDUCE-IT was in isolation, I would think another trial might be needed to be supportive. But REDUCE-IT was not a one-hit wonder," said Erin Michos, MD, MHS, of Johns Hopkins School of Medicine in Baltimore.

She cited the that found 1.8-g icosapent ethyl daily reduced MACE by 19% among more than 18,000 people in Japan. The open-label trial had been conducted without any placebo, mineral oil or otherwise.

"That is pretty remarkable. Especially considering that there is higher dietary intake of marine omega-3 fatty acids in Japan, so the benefit was on a background of higher fish intake than the typical U.S. population. So the findings from REDUCE-IT just didn't come out of nowhere – it was the second largest randomized cardiovascular outcome trial," according to Michos.

EPA has shown benefit without a mineral oil comparator, so there is no need to do any more studies with this fatty acid, argued Matt Budoff, MD, of UCLA, who advocated an outcomes study of mineral oil vs corn oil instead.

In any case, whether a new icosapent ethyl trial should or should not be conducted may be a moot point: such a trial is unlikely to be funded by manufacturer Amarin given that the drug gained FDA approval for cardiovascular prevention last December only to lose a patent protection appeal this September.

Where does that leave clinicians waiting for a new trial that would take several years to bear results even if attempted? What should one do when a patient meets REDUCE-IT criteria now?

"For patients with high triglycerides and high cardiovascular risk, I recommend optimizing all of the available preventive therapies first, including high dose statins, blood pressure medications, and antiplatelet drugs, if indicated. Weight loss is also helpful at lowering triglycerides," said Nissen.

"For very high risk patients who have persistently high triglycerides despite all other effective treatments, prescription of icosapent ethyl is acceptable, but clinicians should keep in mind that this drug significantly increases the risk of atrial fibrillation," he warned.

REDUCE-IT, STRENGTH, and OMEMI all showed higher rates of atrial fibrillation (Afib) with omega-3 fatty acids. This is consistent with observational data from the literature.

"I think that gives me more pause than the mineral oil concern. Although there was not increased risk of Afib-associated stroke in REDUCE-IT, I think the Afib concern needs further monitoring in post-marketing surveillance," Michos said.

Ultimately, STRENGTH will not change her prescribing patterns, Michos told 番茄社区app: She still prescribes icosapent ethyl to secondary prevention patients and those with type 2 diabetes plus one other risk factor who have high triglycerides despite having LDL cholesterol controlled on a statin.

Part of the explanation for why icosapent ethyl worked in REDUCE-IT but another omega-3 product would fail is that the effects of fatty acids vary by dose and formulation, argued REDUCE-IT lead investigator Deepak Bhatt, MD, MPH, of Brigham and Women's Hospital and Harvard Medical School in Boston.

One theory is that the benefits of the pure EPA in icosapent ethyl can be offset by docosahexaenoic acid (DHA), which may explain why the combination EPA/DHA agents in STRENGTH and OMEMI were no better than placebo.

"EPA and DHA differ in how they insert in lipoprotein particles and cellular membranes, with DHA conferring a lipid membrane disordering effect," whereas EPA confers more membrane stability, Michos noted. "There are also differences in their effects on inflammatory biomarkers, rates of lipid oxidation, and endothelial function."

Robinson also suggested that corn oil placebo may have modest cardiovascular benefits masking any modest benefits from EPA/DHA.

Additionally, if an omega-3 fatty acid is prepared, processed, or packaged in a way that leads to oxidation, then it could lose any biological benefits it might have, Bhatt said.

"In STRENGTH, it is possible that carboxylation altered the physical properties of EPA. Such a change in molecular conformation could prevent the membrane stabilization properties of icosapent ethyl that have been postulated to be beneficial," explained Robinson.

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