Findings presented today at the American Heart Association’s Scientific Sessions included the STRENGTH study, examining omega-3 carboxylic acid in high-risk patients, and the ONEMI study, examining the effects of omega-3 fatty acids in recent heart attacks were examined at age 70.
In 2017, the AHA issued a scientific recommendation stating that doctor-prescribed omega-3 fish oil supplements prevent death from heart disease in people who have recently had a heart attack or in people with heart failure can. But the recommendation did not stop recommending the dietary supplements for heart disease prevention in the general population.
The treatments used in REDUCE-IT and STRENGTH have important differences, as do the placebo tablets used in each study. Icosapentethyl contains only eicosapentaenoic acid (EPA), while the STRENGTH study uses a therapy that contains both EPA and docosahexaenoic acid (DHA). REDUCE-IT researchers have repeatedly indicated that the 4g daily dose used in this study is only a highly pure form of EPA, and a recent article argues that DHA can thwart EPA’s effects.
Since the first results were published, REDUCE-IT researchers have carried out follow-up studies demonstrating the benefits of icosapentethyl in certain patient groups, such as: B. those with diabetes show. At the start of this year’s AHA meeting, Amarin highlighted post-hoc results showing fewer ischemic events in patients after bypass surgery.
But when REDUCE-IT first showed up, some wondered if the mineral oil placebo used in the study produced cardiac effects – making it appear that icosapent-ethyl works wonders.
Today, STRENGTH lead author A. Michael Lincoff, MD, professor of medicine and vice chairman of research, cardiovascular medicine, Cleveland Clinic said a corn oil placebo was chosen precisely because it would have a neutral effect, unlike mineral oil . which would lead to “negative control”.
The STRENGTH study, which enrolled more than 13,000 patients in 22 countries as of 2014, was stopped in January 2020 when the results showed that no benefit was expected for carboxylic acid. It was funded by AstraZeneca.
Regarding the use of fish oil-derived drugs in a broader sense, Lincoff said in a statement, “We believe the questions about the benefit versus the risk of fish oil will go unanswered unless another study uses a neutral placebo like corn oil can definitely show cardiovascular benefits for an omega-3 fatty acid drug. “
Lincoff said the lack of benefit for carboxylic acid occurred even though plasma EPA levels rose 269%. Unlike the mineral oil used in the REDUCE-IT study, corn oil did not increase low-density lipoprotein cholesterol, nor did two major biomarkers, ApoB or the highly sensitive C-reactive protein, “suggesting it was one is really a neutral comparator product. ”
A similar result was seen ONEMI. “The fact that no evidence of an effect of omega-3 fatty acids was found in this group, along with the results of other more recent neutral studies, suggests that omega-3 supplements are ineffective for cardiovascular prevention,” Are said A. Kalstad, MD, of the Center for Clinical Research at Oslo University Hospital in Oslo, Norway, one of the principal investigators of the ONEMI study.
Deepak L. Bhatt, MD, REDUCE-IT’s lead investigator and professor at Harvard Medical School, directed his followers from his Twitter account to a recent insert about the study that contained an article on petroleum.
“There was no consistent evidence that mineral oil at the levels used in the studies REDUCE-IT or Effect of Vascepa on Coronary Atherosclerosis Progression in Patients with Elevated Triglycerides on Statin Therapy (EVAPORATE) reduced essential nutrient intake or drugs, including statins. “Wrote the authors in the European Heart Journal, published by the European Society of Cardiology.
“These results were then taken into account together with publicly available data from REDUCE-IT. Based on the available evidence, mineral oil does not appear to affect drug absorption or effectiveness or related clinical outcomes and therefore does not materially affect the study’s conclusions when used as a placebo at the amounts used in clinical trials. “
In an interview with the American Journal of Managed Care, Bhatt was asked if the STRENGTH results could indeed support the argument that pure EPA treatment is superior to those combining EPA and DHA. “That is the most obvious and logical conclusion,” he said.
He continued, “It may not be that easy to neutralize EPA with DHA in a 1: 1 ratio. The biology is likely more complex than that. Also, not only may EPA levels in the blood be important, but how the EPA is administered and how tissue levels are achieved, and the formulation tested in STRENGTH may not have been ideal in this regard . “
Bhatt noted that STRENGTH’s first author Stephen J. Nicholls, MD published a study stating that EPA, not DHA, “where is where the action is”. Bhatt confirmed that when AstraZeneca announced the negative topline results for STRENGTH, AstraZeneca contacted investigators and suggested offering study participants the option to receive icosapentethyl instead, as it had just received the new FDA label. His offer was not accepted.
A panelist for the two studies, Alberico Catapano, PhD, said it was important to consider the effect of the dose of icosapentethyl since it is 4g of pure EPA with no DHA. As for the effects of the mineral oil placebo, it was unclear whether this would fully explain the difference between the REDUCE-IT and STRENGTH results.
JAMA, which released the STRENGTH results, requested a new study.
“In view of the current uncertain state of knowledge, neither patients nor doctors can trust that omega-3 fatty acids have any health benefits, but the world market for omega-3 fatty acids reached 4.1 billion US dollars in 2019 and is expected to double by 2025. “Assistant editor Gregory Curfman, MD wrote.
“To address the discrepancy between STRENGTH and REDUCE-IT, the FDA should require a post-marketing clinical trial of high-dose icosapentethyl vs. corn oil in patients at risk for cardiovascular events. This is an important next step in furthering this confusing issue to illuminate. ” clinical problem and research question. “
When asked about the studies before the presentation on Sunday, Lincoff said there are certain patients who should still be taking omega-3 fatty acids for other reasons, such as triglyceride levels above 500 mg / dl. When asked by the American Journal of Managed Care® what clinicians should do if they are currently prescribing icosapentethyl to patients, he said the concern was that “none of the Vascepa studies have used neutral comparators.”
“It’s hard to say, ‘take your patients off Vascepa’ because there’s a study,” Lincoff said. “But at this point I have a high threshold to start patients with.”
Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids compared to corn oil on serious adverse cardiovascular events in patients at high cardiovascular risk: the randomized clinical trial STRENGTH. JAMA. Published online on November 15, 2020. doi: 10.1001 / jama.2020.22258