Questions about the cardiovascular benefit of omega-3 fatty acids and the high-dose eicosapentaenoic acid (EPA) product, icosapent ethyl (Vascepa, Amarin), have resurfaced with the presentation and publication of the STRENGTH trial using a combined high-dose omega-3 fatty acid product.
The STRENGTH trial showed no benefit on cardiovascular event rates of a high-dose combination of EPA and docosahexaenoic acid (DHA) in a new branded product (Epanova, AstraZeneca).
It was announced in January that the trial was being stopped because of a low likelihood of showing any benefit.
Full results were presented today at the virtual American Heart Association (AHA) Scientific Sessions 2020 and simultaneously published online in JAMA.
These results showed similar cardiovascular event rates with the high-dose EPA/DHA product and placebo, with a hazard ratio for the primary endpoint of 0.99. In addition to no benefit, more adverse effects occurred in the active treatment arm, with a higher rate of gastrointestinal adverse events and atrial fibrillation.
“We found no benefit of a high-dose combination of EPA and DHA. Despite a 270% to 300% increase in EPA, the hazard curves for the active and placebo groups were superimposable,” STRENGTH investigator A. Michael Lincoff, MD, Cleveland Clinic, Ohio, told the AHA meeting.
The big question is how the negative results of the STRENGTH trial can be reconciled with the very positive results of the REDUCE-IT trial, which showed an impressive 25% relative risk reduction in major adverse cardiovascular events with the high-dose purified EPA product, icosapent ethyl.
Lincoff proposed several possible explanations for the different results between these two trials, although he cautioned that all explanations were speculative.
The one explanation that Lincoff highlighted in particular was the different placebos used in the two trials. REDUCE-IT used a placebo of mineral oil, which Lincoff noted increases LDL, apolipoprotein B, and high-sensitivity C-reactive protein, whereas the corn oil placebo used in STRENGTH “is truly neutral on a broad range lipid and cardiovascular biomarkers,” he said.
“It must therefore be considered that at least part of the benefit in REDUCE-IT is due to an increase in adverse cardiovascular event rate in the control arm, and our results from STRENGTH cast uncertainly on the net benefit or harm of any omega-3 fatty acid preparation,” Lincoff said.
Asked whether he used omega-3 fatty acids in his practice, Lincoff replied, “Aside from patients with triglycerides greater than 500 — for which there is other evidence of benefit — I do not routinely prescribe omega-3 fatty acids. For the reasons discussed, I think there are questions about whether the risks and benefits have a favorable ratio.”
Asked at an AHA press conference what advice he would give to other physicians on the use of Vascepa, Lincoff said, “On the one hand, we could take the REDUCE-IT study results at face value, but there are potential concerns on the construct of that trial and whether the effects were exaggerated. That having been said, the FDA has approved that initial indication, so this is not a straightforward issue of whether or not that trial result is valid,” he said.
“What I would like to see is a trial in future with a clearly neutral comparator. It’s hard to recommend taking your patients off Vascepa now, but I have a high threshold at this point to start patients on it because of these concerns,” he added.
A “Manufactured Controversy”
Commenting for theheart.org | Medscape Cardiology, lead investigator of the REDUCE-IT trial, Deepak L. Bhatt, MD, professor of medicine, Harvard Medical School, Boston, Massachusetts, described Lincoff’s comments as “absurd.”
He said the Japanese JELIS trial, while having some limitations, also showed a benefit of icosapent ethyl, which “in the context of this manufactured controversy about the mineral oil placebo in REDUCE-IT, completely rebuts concerns about the placebo in REDUCE-IT being toxic.”
Bhatt also suggested that DHA may counter some of the benefits of EPA. “It appears that the STRENGTH trial leadership is trying to stir up controversy, rather than just reporting objectively that they have a negative trial,” he added.
Lincoff outlined other possible explanations for the difference between the two trials.
He noted that icosapent ethyl increased levels of EPA by 45% in REDUCE-IT more than did the combined product used in STRENGTH. “But this moderate difference seems insufficient to account for the markedly different results of the two trials,” Lincoff added, “and both trials showed a 19% reduction in triglycerides, suggesting they have similar biochemical effects.”
There is also the possibility of an adverse effect of DHA, he noted, “but this has never been seen in previous studies.”
Another explanation could be differences in trial populations, with REDUCE-IT including more patients with established cardiovascular disease. “But the results were no different in this group compared to the patients without established cardiovascular disease, so this explanation is unlikely,” Lincoff suggested.
They were randomly assigned to a 4 g per day of carboxylic acid formulation of EPA and DHA or to corn oil as an inert comparator.
The trial was halted when 1384 patients had experienced a primary endpoint event (of a planned 1600 events), based on an interim analysis that indicated a low probability of clinical benefit of the active treatment.
At this point, the primary efficacy endpoint — a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization — occurred in 12.0% of patients treated with the omega-3 product vs 12.2% of those who received corn oil (hazard ratio, 0.99; P = .84).
A greater rate of gastrointestinal adverse events was observed in the omega-3 group (24.7%) than in corn oil–treated patients (14.7%). An increased rate of new-onset atrial fibrillation was also observed in the omega-3 group (2.2% vs 1.3%; hazard ratio, 1.69).
Moderator of an AHA press conference at which the STRENGTH trial was discussed, Amit Khera, MD, professor of medicine and director of preventive cardiology at UT Southwestern Medical Center, Dallas, Texas, commented to theheart.org | Medscape Cardiology that questions about how Vascepa brought about the benefits shown in REDUCE-IT have been ongoing since that trial was published.
“I think for now, we have to accept the REDUCE-IT results as a positive finding. However, the STRENGTH trial did amplify these questions a bit since there was no signal at all for benefit, and this heightens the call for additional trials of high-dose EPA formulations, including icosapent ethyl, versus corn oil or another neutral comparator,” he said.
Discussant of the STRENGTH trial at the AHA late-breaker session, Alberico Catapano, MD, PhD, University of Milan, Italy, noted that DHA may have less biological activity than EPA.
“We don’t know for certain, but there are studies suggesting that EPA may have more effect on stabilizing plaque membranes,” Catapano said. “Certainly, the dose of EPA was different in the two studies, and in my view this could be part of the explanation. But we are still in place where we need more evidence.”
In an editorial accompanying the JAMA publication of STRENGTH, Garima Sharma, MD, Seth S. Martin, MD, and Roger S. Blumenthal, MD, Johns Hopkins University School of Medicine, Baltimore, Maryland, say the trial’s findings “may invigorate further investigation regarding IPE [icosapent ethyl], generate additional constructive debate around the optimal placebo control, and should prompt reconsideration of over-the-counter mixed omega-3 fatty acid products for ASCVD [atherosclerotic cardiovascular disease] prevention.”
“This latter point is especially important given the lack of evidence for benefit, and the potential for harm due to increased AF [atrial fibrillation],” they note.
“The reasons the findings from the REDUCE-IT trial were positive and the STRENGTH trial were not, and that EPA levels correlated with outcomes in REDUCE-IT but did not in STRENGTH, remain uncertain,” they conclude. “The importance of the specific omega-3 formulation in achieving ASCVD risk reduction and the degree to which the placebo (ie, mineral oil vs corn oil) may have affected outcomes remain unresolved.”
The STRENGTH trial was sponsored by Astra Zeneca. Lincoff reported receiving grants from AstraZeneca during the conduct of the study. Catapano has received honoraria, lecture fees, or research grants from Sigma-Tau, Manarini, Kowa Pharmaceuticals, Recordati, Eli Lilly, Astra Zeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron Daiichi Sankyo, and Amarin. Martin reports receiving consulting fees from AstraZeneca, Amgen, Esperion, and REGENXBIO and has a patent pending for a system of LDL-C estimation filed by Johns Hopkins University. Bhatt reports serving as principal investigator for REDUCE-IT and that Brigham and Women’s Hospital has received research funding from Amarin.
American Heart Association (AHA) Scientific Sessions 2020. LBS.04. Presented November 15, 2020.