Second look at big omega-3s trial finds no cardio benefits even for subjects with most EPA in blood

By Hank Schultz contact

- Last updated on GMT

©Getty Images - santoelia
©Getty Images - santoelia

Related tags: EPA and DHA, Cardiovascular disease, cardiovascular health

A secondary analysis of a large scale trial whose result has flummoxed experts found that higher blood levels of EPA had no protective effect on cardiovascular health.

A secondary analysis of the data published this week found that higher achieved levels of EPA in the blood were not associated with better cardiovascular outcomes.  The study also found no negative effects associated with higher DHA levels.

The data arose from The Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia​ (STRENGTH) trial. ​That trial, which enrolled more than 10,000 subjects, tested four grams of a carboxylated omega-3s formulation (AstraZeneca’s Epanova) against a corn oil placebo for the treatment of patients with elevated cardiovascular disease risk and who were being treated with statins. The trial came up with a null result.

Secondary analysis looks at results in upper tertile of blood levels

In order to look further into the issue, the secondary analysis used a primary prespecified end point of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The primary outcome measure was the hazard ratio, adjusted for baseline characteristics, for patients in the omega-3s group versus placebo for the top tertile of achieved EPA and DHA plasma levels 12 months after randomization.

These authors found no benefit for patients with the highest achieved blood levels of EPA. The authors also did not find any evidence for a detrimental, or ‘blunting’ effect for high levels of DHA. 

The latter had been postulated for the almost diametrically opposed outcomes of the STRENGTH trial and the so-called REDUCE-IT trial, which used an EPA-only pharmaceutical in terms of lessening the risk of cardiovascular disease.  There is as yet not plausible explanation for these divergent results.

Experts puzzled by results

Harry Rice, PhD, chief science officer of the Global Organization for EPA and DHA Omega-3s said while this remains unresolved, science is often a bumpy road.  And the road for omega-3s has been pointing upward overall.

“In line with the initial results reported last November, an EPA/DHA carboxylic acid formulation provided no cardiovascular benefits. GOED, like many others, remains perplexed, but there remains clear evidence that other omega-3 formulations provide a range of health benefits. Also, results from this secondary analysis do not support the notion that DHA in the STRENGTH trial counteracted potential beneficial effects of EPA,”​ Rice told NutraIngredients-USA.

William S. Harris, PhD, director of the Fatty Acid Research Institute (FARI) was also perplexed.  Harris, who is also a professor at the Sanford School of Medicine at the University of South Dakota, has long been an advocate for determining the blood levels of omega-3s in such studies.  He is the founder of OmegaQuant, an omega-3s testing firm that provides such testing services for researchers and consumers.  So here, researchers had done just what the doctor ordered, so to speak, but still didn’t find the benefit that might have been expected.

“The STRENGTH study tested the effects of 4 g of Epanova (EPA+DHA as free fatty acids, as ‘carboxylic acids’) vs corn oil placebo for 5 years in high risk CV patients on statins. They found no effect in the original report. This followup report asked if higher omega-3 LEVELS were associated with better outcomes. They found that they were not. So the mystery of why STRENGTH was such an abject failure remains, and nobody really knows – myself included – what happened. The possibility exists that the chronic use of free fatty acids could be​ chronically inflammatory but we don’t have data to back that up,” Harris said.

Source:JAMA Cardiology
Published online May 16, 2021. doi:10.1001/jamacardio.2021.1157
Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular Risk;  A Secondary Analysis of the STRENGTH Trial
Authors: Nissen SE, et al

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