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A Cleveland Clinic scientist stopped short of saying doctors should take patients off Vascepa, but he said he has questions due to the lack of a "neutral comparator."
Debate over the landmark REDUCE-IT study flared anew today, as scientists presented findings from two new studies that failed to find a prevention benefit for patients taking omega-3 fatty acids.
Results from the American Heart Association Scientific Sessions for the STRENGTH trial, which evaluated omega-3 carboxylic acid in high-risk patients, and the ONEMI trial, studying the effects of omega-3 fatty acids in older heart attack survivors, will no doubt revive many of the questions raised when the REDUCE-IT study found that Vascepa (icosapent ethyl) reduced initial cardiac events by 25% and all events by 30%.
Amarin’s 4-g per day fish oil pill, first approved years ago to treat triglycerides, received FDA approval in December as an add-on therapy to reduce cardiovascular risk.
The AHA published a science advisory saying that prescription omega-3 fish oil supplements may prevent death from heart disease in those who had suffered a heart attack or protect those with heart failure from hospitalization or death. No general population recommendation was given, however.
The omega-3 fatty acid medications tested in REDUCE-IT and STRENGTH are not the same. Vascepa is purified eicosapentaenoic acid (EPA) only, whereas the STRENGTH trial used a therapy containing both EPA and docosahexaenoic acid (DHA). Investigators have noted this distinction repeatedly.
When REDUCE-IT stunned the scientific community, questions were raised about the effect of the mineral oil placebo. Some noted changes in biomarker levels in the placebo group and asked if the placebo was causing cardiac effects, which would make the effects of Vascepa appear more significant.
STRENGTH’s lead author, A. Michael Lincoff, MD, of the Cleveland Clinic, said a corn oil placebo was used in the trial to avoid the “negative control” possibilities that could occur with mineral oil. The trial enrolled more than 13,000 patients in 22 countries but was stopped in January 2020 after six years when results showed it was unlikely to show any benefit for carboxylic acid. (AstraZeneca funded the study.)
Lincoff said no benefit from carboxylic acid occurred even though there was a 269% increase in plasma EPA levels. Notably, the corn oil placebo did not raise cholesterol, ApoB, or high-sensitivity C-reactive protein levels. This, authors noted, suggests “that it was a truly neutral comparator.”
“We believe the questions surrounding the benefit versus risk of fish oil will remain unanswered unless another trial using a neutral placebo such as corn oil is able to definitively show cardiovascular benefits for an omega-3 fatty acid medication,” Lincoff said.
The bottom line was the same in ONEMI, according to principal investigator Are A. Kalstad, MD, of the Center for Clinical Research at Oslo University Hospital in Oslo, Norway. This trial examined how well omega-3 fatty acids do in preventing future events in patients over age 70 who have suffered a heart attack.
“The fact that no indication of any impact from the omega-3 fatty acids were found in this group, along with the results of other recent neutral trials, suggests that omega-3 supplements are ineffective for cardiovascular prevention,” Kalstad said.
Deepak L. Bhatt, MD, the lead investigator for REDUCE-IT and a professor at Harvard Medical School, used his Twitter account to direct followers to a recent supplement on the trial, including an article that examined the mineral oil issue. In an interview, he noted that the FDA approved the use of mineral oil, and when asked if the STRENGTH results are actually an argument in favor of EPA-only therapy, replied, "That's the most obvious and logical conclusion."
"There was no consistent evidence that mineral oil in the amounts used in the REDUCE-IT or Effect of Vascepa on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy (EVAPORATE) trials affects absorption of essential nutrients or drugs, including statins," Bhatt and his co-authors wrote in the European Heart Journal, published by the European Society of Cardiology.
"These results were then considered alongside publicly available data from REDUCE-IT. Based on available evidence, mineral oil does not appear to impact medication absorption or efficacy, or related clinical outcomes, and, therefore, does not meaningfully affect study conclusions when used as a placebo at the quantities used in clinical trials."
JAMA, which published the STRENGTH results, called for a trial comparing Vascepa with corn oil to settle the matter. In an editorial accompanying the study, JAMA Deputy Editor Gregory Curfman, MD, wrote, "Given the current uncertain state of knowledge, neither patients nor physicians can be confident that omega-3 fatty acids have any health benefits, yet in 2019 the global market for omega-3 fatty acids reached $4.1 billion and is expected to double by 2025.
"To resolve the discrepancy between STRENGTH and REDUCE-IT, the FDA should require a postmarketing clinical trial of high-dose icosapent ethyl vs corn oil in patients at risk for cardiovascular events. This is a critical next step to shed further light on this perplexing clinical issue and research question."
Do omega-3 fatty acids have any value? For certain patients with very high cholesterol, yes, Lincoff said. But he stopped short of recommending that doctors halt the drug in patients who are now taking it.
“It’s hard to say ‘take your patients off Vascepa,’ because there is a trial,” Lincoff said. “But I have a high threshold, at this point, to start patients on it.”