Higher achieved EPA and DHA levels not associated with changes in CV outcomes

Relationship Between Omega-3 Fatty Acid Levels And Major Adverse Cardiovascular Outcomes In Patients With High Cardiovascular Risk

News - May 18, 2021

A Secondary Analysis of the STRENGTH Trial

Presented at ACC.21 by Steven E. Nissen, MD (Cleveland, OH, USA)

Introduction and methods

Two recent large RCTs, the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention) and STRENGTH (the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) trials, reported different results for CV outcomes with treatment of omega-3 fatty acids in patients with high CV risk. The REDUCE-IT trial showed a 25% risk reduction for MACE, while the STRENGTH trial reported a neutral result. Several hypotheses have been proposed to explain the discrepancy in findings between the two trials. These include higher achieved eicosapentaenoic acid (EPA) plasma levels in patients who received purified EPA in the REDUCE-IT trial compared to those using a mixed supplement of EPA plus docosahexaenoic acid (DHA) in the STRENGTH trial. Or the possibility that DHA counteracted the CV benefits of EPA.

This post hoc analysis of the STRENGTH trial assessed the association between achieved omega-3 fatty acid levels and CV outcomes by dividing patients in tertiles of achieved levels of EPA or DHA in patients treated with 4 g of omega-3 carboxylic acid (CA) daily and using patients in the corn oil placebo group as reference.


  • Patients within the highest tertile of achieved EPA plasma levels (>116.4 µg/mL) had a similar risk for MACE compared to those who received placebo (HR 0.98, 95% CI: 0.83-1.16, P=0.81).
  • There was also no difference in MACE outcome between patients in the top tertile of plasma DHA levels (>105.2 µg/mL) and patients on placebo (HR 1.02, 95% CI: 0.86-1.20, P=0.85)


In patients within the top tertile of achieved EPA levels with omega-3 CA, EPA level was not associated with improved CV outcomes. Also, patients within the highest tertile of DHA levels had a similar MACE outcome compared to those with placebo. Considering the increased risk of AF that has been observed in omega-3FAs trials, there is uncertainty whether omega-3FA formulation provide net benefit or harm, Nissen concluded. In order to understand the discrepancy more research is needed, on the comparison of mineral oil with corn oil and on the comparison of purified EPA with other formulations of omega-3FAs.


The findings presented here are very important, said Eileen Handberg, PhD (Gainesville, FL, USA). Clinical research should not only focus on a primary outcome paper, but investigators should fully explore the trial data to learn as much as possible. The exploratory analyses are important because they might potentially show why these outcomes were different. The next step, she said, should either be a head-to-head study between the two omega-3 substances or looking into the different oils to see whether they result in differences in outcome.

– Our coverage of ACC.21 is based on the information provided during the congress –

This study was simultaneously published in JAMA Cardiology Watch a video by Eileen Handberg on this analysis

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