In addition to the lack of benefit observed at 2 years, there was a nonsignificant increase in new-onset atrial fibrillation in those taking 1.8 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) daily compared with a corn oil placebo.
“Our findings do not support omega-3 fatty acid preparations for secondary prevention in elderly patients,” principal investigator Are A. Kalstad, MD, said at the virtual American Heart Association (AHA) 2020 Scientific Sessions.
The findings, which were published simultaneously in Circulation, echo those from the STRENGTH trial reported in the same late-breaking science session showing no benefit on cardiovascular event rates of a high dose combination of EPA and DHA in a new branded product (Epanova, AstraZeneca).
The OMEMI results, though, are particularly impactful for the elderly, who are often shut out of clinical trials and whose cardiovascular risk remains particularly high, even with contemporary secondary prevention.
Alberico L. Catapano, PhD, MD(HC), the discussant during the session tasked with interpreting both trials, said dose may have played a role in today’s neutral results compared with the REDUCE-IT trial, in which 4 g daily of EPA alone (icosapent ethyl, Vascepa, Amarin) cut the relative risk for major cardiovascular events by 25% in patients at elevated cardiovascular risk.
The new data are consistent with a meta-analysis showing a greater effect with higher vs lower doses of omega-3 fatty acids, he said. Recent studies also indicate EPA may behave differently in stabilizing cell membranes and in adding anti-inflammatory effects than DHA.
Although both the STRENGTH and OMEMI trials used a corn oil placebo, much has been made about a potential negative effect of a mineral oil placebo like that used by the REDUCE-IT investigators. However, “all the information we have is circumstantial to say that the placebo made a difference for REDUCE-IT,” said Catapano, from the University of Milano, Italy.
He also discarded the argument that REDUCE-IT may have enrolled patients with more established coronary artery disease (CAD), as all of the OMEMI patients had CAD.
Robust evidence is still needed to explain why the results are discordant, Catapano said. “Certainly the dose has been different and that may be, in my view, one of the likely explanations. There is certainly, though, one common result — an increasing incidence of atrial fibrillation, albeit insignificant in OMEMI.”
The Omega-3 fatty acids in Elderly with Myocardial Infarction (OMEMI) trial included 1027 patients, age 70 to 82 years, who experienced an acute MI 2 to 8 weeks prior to being assigned to receive either 1.8 g of omega-3 polyunsaturated fatty acids (930 mg EPA and 660 mg DHA; Pikasol, Orkla Health) or matching corn oil placebo (56% linoleic acid, 32% oleic acid, 10% palmitic acid). The total dose was divided into three capsules taken once daily.
At baseline, the median age was 74 years, 29% of patients were female, and all but two patients were White. Roughly half had known previous cardiovascular disease at the time of the index MI. Nearly all were taking statins (96%) and 86% were also receiving antihypertensive medications and dual antiplatelet therapy.
Kalstad pointed out that omega-3 supplements or cod liver oil was used by 40% of patients and triglyceride levels were relatively low, at 115.4 mg/dL in the omega-3 group and 107.4 mg/dL in the placebo group.
The investigators hypothesized that omega-3 fatty acids on top of standard care would reduce the primary endpoint — a composite of nonfatal MI, unscheduled revascularization, stroke, heart failure hospitalization, and all-cause death — by 30% at 2 years.
Among the 1014 patients with 2-year follow-up, however, the primary outcome did not differ between the omega-3 and placebo groups (108 vs 102 events; hazard ratio [HR], 1.07; 95% CI, 0.82 – 1.40; P = .62).
Similarly, there was no significant effect on any of the individual components, including death (28 events in each group), or across 12 subgroups, including age, triglyceride levels, and prior omega-3 supplementation. The results also remained neutral in per-protocol analyses.
For the prespecified secondary endpoint of new-onset atrial fibrillation, the investigators excluded 255 patients who experienced atrial fibrillation before randomization, leaving 759 available for analysis.
Among these, there were 28 new cases of atrial fibrillation in the omega-3 group and 15 in the control group (7.2% vs 4.0%; HR, 1.84; 95% CI, 0.98 – 3.44; P = .06).
Although the difference was not statistically significant and the patient numbers were small, “we cannot rule out potential harm in increasing the risk of atrial fibrillation,” Kalstad said.
The primary safety endpoint of major bleeding was not significantly different between the omega-3 and control groups (10.7% vs 11.0%; P =.87), and no patient discontinued the study drug because of bleeding.
The most common reasons for stopping the study drug were hospitalization or intercurrent disease, difficulty swallowing the capsules, and nonspecific gastrointestinal symptoms.
Overall, self-reported adherence was generally good at 88% in both groups, Kalstad said. This was supported by a nearly 100% increase from baseline in serum EPA levels in the omega-3 group — albeit well short of the 386% increase in EPA at 1 year in REDUCE-IT.
Specifically, the omega-3 group showed a median +87% change in the concentration of EPA and a +16% change in DHA, whereas the placebo group changes were –13% and –8%, respectively, expressed as relative changes from baseline, according to the paper.
Asked about the potential for biological differences in the effects of icosapent ethyl vs combination omega-3 formulations and whether the achieved EPA levels influenced clinical outcomes, Kalstad said the way they measured serum fatty acids generated set points that may not be directly comparable with other studies. OMEMI participants also appeared to start out at higher baseline levels than those in other studies.
Nevertheless, “it’s tempting to speculate on whether there is sort of ‘sweet spot’ for both cardiovascular effects, benefits, and the potential harm for atrial fibrillation,” Kalstad said.
The work was supported by unrestricted grants from the Stein Erik Hagen Foundation for Clinical Heart Research, the Olav Thons Foundation, and the Tom Wilhelmsen Foundation. Study medication and placebo were supplied by Orkla Health. Catapano has received honoraria, lecture fees, or research grants from Sigma-Tau, Manarini, Kowa, Recordati, Eli Lilly, AstraZeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron Daiichi-Sankyo, and Amarin.
American Heart Association (AHA) 2020 Scientific Sessions. LBS4. Presented November 15, 2020.
Circulation. Published online November 15, 2020. Abstract