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 Nov. 15 at the virtual American Heart Association scientific sessions 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, of the Cleveland Clinic, said at 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.
Dr. 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 Dr. Lincoff highlighted in particular was the different placebos used in the two trials. REDUCE-IT used a placebo of mineral oil , which Dr. 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,” Dr. Lincoff said.
Asked whether he used omega-3 fatty acids in his practice, Dr. 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, Dr. 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 [Food and Drug Administration] has approved that initial indication, so this is not a straightforward issue of whether or not that trial result is valid.