Results presented today at the American Heart Association Scientific Sessions involved the STRENGTH trial, which studied omega-3 carboxylic acid in high-risk patients, and the ONEMI trial, which studied the effects of omega-3 fatty acids in recent heart attack survivors over age 70.
In 2017, the AHA issued an a science advisory that said omega-3 fish oil supplements prescribed by clinician may prevent death from heart disease in those who had recently experienced a heart attack, or may prevent death or hospitalization for those with heart heart failure. But the advisory stopped short of recommending the supplements to prevent heart disease in the general population.
Treatments used in REDUCE-IT and STRENGTH have important differences, and so do the placebo tablets used in each trial. Icosapent ethyl contains only eicosapentaenoic acid (EPA), whereas the STRENGTH trial used a therapy containing both EPA and docosahexaenoic acid (DHA). Investigators for REDUCE-IT have pointed out that the 4 g daily dose used in that study is a highly purified form of EPA only, and a recent article argued that DHA may thwart the effects of EPA.
Since the first results appeared, REDUCE-IT investigators have produced follow-up studies showing benefits from icosapent ethyl among specific groups of patients, such as those with diabetes. Earlier in this year’s AHA meeting, Amarin highlighted post-hoc results showing fewer ischemic events in patients following bypass surgery.
But when the first results appeared, some questioned whether the mineral oil placebo used in REDUCE-IT produced cardiac effects—and thus, made it appear that icosapent ethyl was working wonders.
Today, the lead author of STRENGTH, A. Michael Lincoff, MD, professor of medicine and vice chairman for research, Cardiovascular Medicine, Cleveland Clinic, said a corn oil placebo was selected precisely because it would have a neutral effect, unlike mineral oil, which would create a “negative control.”
The STRENGTH trial, which enrolled more than 13,000 patients in 22 countries starting in 2014, was stopped in January 2020 when results showed it was unlikely to show any benefit for carboxylic acid. It was funded by AstraZeneca.
Regarding the use of fish oil-derived medication more broadly, Lincoff said in a statement, “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 lack of benefit for carboxylic acid occurred even though there was a 269% increase in plasma EPA levels. Unlike the mineral oil used in the REDUCE-IT trial, he said, corn oil did not elevate low-density lipoprotein cholesterol or 2 key biomarkers, ApoB or high-sensitivity C-reactive protein, “suggesting that it was a truly neutral comparator.”
A similar result was seen ONEMI. “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,” said Are A. Kalstad, MD, of the Center for Clinical Research at Oslo University Hospital in Oslo, Norway, a principal investigator in the ONEMI trial.
From his Twitter account, Deepak L. Bhatt, MD, the lead investigator for REDUCE-IT and a professor at Harvard Medical School, directed followers to a recent supplement on the trial that featured an article on the mineral oil issue.
"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," the 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."
A discussant for the 2 trials, Alberico Catapano, PhD, said it was important to address the effect of the size the dose of icosapent ethyl, since it is 4 g of pure EPA without DHA. As for the effect of the mineral oil placebo, he said it was unclear whether that would fully explain the difference between the REDUCE-IT and STRENGTH results.
JAMA, which published the STRENGTH findings, called for a new trial.
"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," Deputy Editor Gregory Curfman, MD, wrote.
"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."
Asked about the studies before Sunday's presentation, Lincoff said there are certain patients who should still take omega-3 fatty acids for other reasons, such as those with triglyceride levels above 500 mg/dL. When asked by The American Journal of Managed Care® what clinicians should do if they are currently prescribing icosapent ethyl to patients, he said, the concern is that “none of the Vascepa trials have used neutral comparators.”
“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.”
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