Meta-analysis: Effect of EPA vs. EPA+DHA Omega-3 Fatty Acids on Cardiovascular Outcomes

Discordant results from randomized, controlled trials have led to a debate about the value of omega-3 fatty acids for preventing adverse cardiovascular events. Most recently, the STRENGTH and OMEMI trials, published in 2020, showed null results for the combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

However, EPA and DHA differ in their effects on membrane structure and lipid metabolism, so combining DHA with EPA might partially offset the cardiovascular benefits of EPA.

Deepak L. Bhatt, MD, MPH, executive director of the Interventional Cardiovascular Program at Brigham and Women’s Hospital, and colleagues, recently performed a systematic review and meta-analysis that teased out the effects of EPA versus those of EPA+DHA. They report in EClinical Medicine that EPA supplementation, and not EPA+DHA, is associated with reductions in cardiovascular mortality and related outcomes.


The team searched EMBASE, PubMed,, the Cochrane Library and websites of major cardiovascular and medicine journals through June 7, 2021. They identified 38 relevant randomized, controlled trials encompassing 149,051 patients who had at least 12 months of follow-up.

Four trials compared EPA with control and 28 compared EPA+DHA with control. The median follow-up was 2 years.

Two experienced researchers rated the certainty for each outcome based on the risk of bias, inconsistency, dose-response effects and other considerations.

Key Outcomes

Cardiovascular mortality

  • Omega-3 fatty acid supplementation overall—RR, 0.93 (P=0.01) (Moderate certainty)
  • EPA monotherapy—RR, 0.82 (P=0.04)
  • EPA+DHA combination—RR, 0.94 (P=0.02; P for interaction, 0.19)

Nonfatal myocardial infarction

  • Overall—RR, 0.87 (P=0.0001) (Moderate certainty)
  • EPA—RR, 0.72 (P=0.00002)
  • EPA+DHA—RR, 0.92 (P=0.05; P for interaction, 0.01)

Coronary heart disease

  • Overall—RR, 0.91 (P=0.0002) (Moderate certainty)
  • EPA—RR, 0.73 (P=0.00004)
  • EPA+DHA—RR, 0.94 (P=0.01; P for interaction, 0.01)

Major adverse coronary events

  • Overall—RR, 0.95 (P=0.002) (Moderate certainty)
  • EPA—RR, 0.78 (P=0.00000001)
  • EPA+DHA—RR, 0.99 (P=0.48; P for interaction, 0.000005)

Nonfatal stroke

  • Overall—RR, 1.04 (P=0.55) (Very low certainty)
  • EPA—RR, 0.71 (P=0.01)

Other Results

Overall, omega-3 fatty acids did not prevent sudden cardiac death, all-cause mortality or atrial fibrillation. They did not increase gastrointestinal adverse events, total bleeding, major bleeding or minor bleeding, but there was a higher risk of total bleeding with EPA monotherapy than control (RR, 1.49; P=0.006).

Guidance for Clinicians

These results are reassuring evidence about the role of EPA in reducing the risk of adverse cardiovascular outcomes. The benefit of EPA was modest in terms of cardiovascular mortality, but it was obtained in a population with overall low baseline cardiovascular risk: 22 of the trials studied primary prevention.

Moreover, only 11% of the studies investigated doses ≥4 g/day. Patients who have higher baseline cardiovascular risk and those receiving adequate doses may demonstrate greater absolute benefits.

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