Observational studies have demonstrated an inverse association between dietary consumption of either fatty fish or omega-3 fatty acids and incident cardiovascular events and that circulating concentrations of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) inversely correlate with cardiovascular risk.
Recent trials reported a cardiovascular benefit in 2 trials of purified EPA.1,2 However, other recent trials studying lower doses of omega-3 fatty acids in a broader range of patients failed to demonstrate significant reductions of total cardiovascular events.3,4
Omega-3 CA (Epanova; AstraZeneca) is a carboxylic acid formulation of omega-3 fatty acids (EPA and DHA) that does not require hydrolysis by pancreatic lipase during intestinal absorption, eliminating the need for consumption with a high-fat meal, resulting in greater bioavailability compared with standard omega-3 ethyl ester formulations.
This trial, the Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH), evaluated the effects of omega-3 CA on clinical outcomes in patients at high cardiovascular risk.
A sample of 13 078 patients were enrolled at 675 sites in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa between October 30, 2014, and June 14, 2017.
The patients were randomised to receive 4 g/d of a Omega-3 CA or corn oil as a comparator. After a median follow-up of 42 months, there was no significant difference between the omega-3 fatty acid group (6539 patients) and the corn oil group (6539 patients) in the primary end point, a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and hospitalization for unstable angina. This end point was observed in 12% of the omega-3 patients vs 12.2% of the corn oil patients
On January 8, 2020, when 1384 primary end points had been recorded in 13 078 randomised patients, the trial was stopped prematurely when it became apparent that the probability of clinical benefit was likely to be low and there was evidence of risk, including a higher, albeit small, incidence of investigator-reported atrial fibrillation in the omega-3 CA treatment group.
Does omega-3 benefit heart health?
Gregory Curfman, MD, Deputy Editor for JAMA, provides an editor's note alongside this study, pointing out that the null result is similar to another recent, large (25 871 participants) omega-3 clinical trial, VITAL (Vitamin D and Omega-3 Trial), that also reported no significant benefit of an omega-3 preparation, compared with placebo, on cardiovascular events in a primary prevention population. However, in that trial, the daily dose of the omega-3 preparation (1 g/d of a combination of EPA and DHA) was much lower than in the STRENGTH trial.
Curfman writes: "By contrast, the results of STRENGTH directly contradict the results of the REDUCE-IT trial (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial). In this clinical trial, 8179 participants were randomized to a high dose (4 g/d) of an omega-3 fatty acid preparation consisting of purified EPA (icosapent ethyl) or mineral oil as a comparator. After a median follow-up of 4.9 years, icosapent ethyl resulted in a 25% reduction in the primary end point, a composite of cardiovascular events, compared with mineral oil."
Discussing how these trials could possibly come to opposite conclusions, Curfman suggests one possibility is if a beneficial effect of EPA was offset by a detrimental effect of DHA, but he says that would be extremely unlikely.
A second possibility he suggests is that in REDUCE-IT, icosapent ethyl did not reduce the risk of cardiovascular events, but instead, the comparator, mineral oil, increased the risk of cardiovascular events. However, in a review by the US Food and Drug Administration (FDA) of the results, the reviewers concluded that only a small fraction of the difference in outcomes between icosapent ethyl and mineral oil could be explained by a harmful effect of mineral oil.
Whatever the answer, Curfman says cardiovascular health is a huge and growing health concern and the discrepancy in these results needs to be further investigated.
"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.
"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."
Garcia. M., et al
"Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular RiskThe STRENGTH Randomized Clinical Trial"