Cleveland Clinic-Led Trial Shows That High Levels of Prescription Fish Oil Showed No Effect on Cardiac Outcomes

Evidence from a secondary analysis of Cleveland Clinic’s STRENGTH trial shows that high levels of eicosapentaenoic acid (EPA), an omega-3 fatty acid, offered no benefit to patients at high risk for cardiovascular events.

Findings from the secondary analysis were presented today during a Late Breaking Science Session at the American College of Cardiology’s 70th Annual Scientific Session and simultaneously published online in JAMA Cardiology.

In the study, patients who achieved the highest levels of EPA had similar rates of major adverse cardiovascular events as patients taking a corn oil placebo. EPA was measured 12 months after patients began taking 4 grams daily of a prescription-grade omega-3 product.

“Our analysis shows no evidence that a high EPA level produces cardiovascular benefit,” said Steven Nissen, M.D., Chief Academic Officer of the Heart, Vascular and Thoracic Institute at Cleveland Clinic, and the study’s lead author. “Previous studies have found that for those with very high triglycerides, fish oil supplements or icosapent ethyl help in lowering them. However, based on the current evidence there is no reduction in overall cardiovascular risk for patients.”

In the STRENGTH trial, 13,078 patients were randomized to receive daily supplementation with high dose omega-3 fatty acids or placebo (corn oil). The high dose omega-3 fatty acid drug used in the study – not available over the counter – did not result in a significant reduction in major adverse cardiovascular events compared to corn oil. The trial was stopped early since there was no significant difference between groups in the primary outcome.

A prior clinical trial published in 2018 found that use of icosapent ethyl, a highly purified formulation of EPA, significantly reduced cardiovascular events and cardiovascular death among high-risk patients compared to a mineral oil placebo. However, according to STRENGTH’s authors, the study was controversial because mineral oil had unfavorable effects on cholesterol and markers of inflammation, which may have exaggerated the apparent benefit of icosapent ethyl.

The secondary analysis of the STRENGTH trial examined a subset of 10,382 patients with available omega-3 fatty acid levels, with 5,175 receiving omega-3 carboxylic acid and 5,207 receiving the corn oil placebo. Major adverse cardiovascular events occurred in 11.1% of patients treated with fish oil and 11% of patients in the placebo group. Overall, this group of patients was 62.5 years old, on average, one-third were women and another third had diabetes.

Researchers grouped patients into thirds based on how much EPA and DHA was in their blood at baseline and again a year later. They found no difference in major adverse events among patients in the top third of EPA and DHA levels at one year, compared with those treated with corn oil. Sensitivity analyses were also performed on changes in EPA and DHA plasma levels, red blood cell EPA and DHA levels, and primary and secondary prevention subgroups. Again, no treatment effects were found.

The study’s authors add that both the original trial and the secondary analysis found that administration of omega-3 fatty acids have risks.

“There was an increase in new onset atrial fibrillation which occurred in 2.2% of patients in the fish oil group compared with 1.3% of those taking corn oil,” said Michael Lincoff, M.D., vice chair in the department of cardiovascular medicine and director of C5Research at Cleveland Clinic, and STRENGTH’s second author.

The original STRENGTH trial was funded by AstraZeneca. Dr. Nissen has served as a consultant for many pharmaceutical companies and has overseen clinical trials for Amgen, AstraZeneca, Cerenis, Eli Lilly, Novartis, Novo Nordisk, The Medicines Company, Orexigen, Takeda and Pfizer. However, he does not accept honoraria, consulting fees or other compensation from commercial entities. Dr. Lincoff has received research funding from Amgen, Astra Zeneca, CSL Behring, Esperion, Eli Lilly, and Novartis and has served as a consultant for Novo Nordisk and Eli Lilly.

The trial was coordinated by the Cleveland Clinic Coordinating Center for Clinical Research (C5Research). The protocol was developed by members of the independent academic executive steering committee in conjunction with AstraZeneca, the sponsor of the study.