Systematic review supports risk reductions, especially with EPA monotherapy

Omega-3 fatty acids (FAs)—including eicosapentaenoic (EPA) and docosahexanoic (DHA) acids—not only improved cardiovascular outcomes but reduced cardiovascular mortality, according to a recent systematic review and meta-analysis published in EClinicalMedicine.

Further, monotherapy with EPA led to greater cardiovascular risk reductions than treatment with a combination of EPA and DHA.

Deepak Bhatt, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, and colleagues detailed the reason for their systematic review and meta-analysis.

“EPA and DHA differ in their biological effects on membrane structure and lipid metabolism. Therefore, combining DHA with the EPA may modify the clinical effects of EPA treatment. Previous meta-analyses have combined the EPA with EPA+DHA trials, which might have masked the effects of individual formulations of omega-3 fatty acids (FAs),” they wrote.

FAs are thought to reduce the risk of atherosclerotic cardiovascular disease through lowering triglycerides and stabilizing membranes, as well as via their antithrombotic, anti-inflammatory, and antiarrhythmic properties. But study results have varied greatly, and no consensus has been reached.

In 2018, researchers of the ASCEND and VITAL studies found that the combination of EPA+DHA did not significantly reduce primary cardiovascular outcomes. In the REDUCE-IT study, however, treatment with icosapent ethyl—a highly purified ethyl ester of EPA—led to significant reductions (25%) in the primary composite endpoint, which included cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularization, and unstable angina. In addition, this treatment effected a 26% reduction in the secondary endpoint (cardiovascular death, MI, or stroke) and a 20% reduction in cardiovascular mortality.

But in the 2020 STRENGTH and OMEMI studies, researchers found no evidence of reductions in cardiovascular primary endpoints after treatment with EPA+DHA.

“These discordant trial results have led to considerable uncertainty and debate about the potential role of omega-3 FAs in reducing ASCVD residual risk. Moreover, since EPA and DHA differ in their biological effects on membrane structure and lipid metabolism, this variability led to the hypothesis that combining DHA with the EPA might partially offset the beneficial clinical effects of EPA treatment alone,” wrote Bhatt and colleagues.

Thus, to assess the efficacy of omega-3 FAs on fatal and non-fatal cardiovascular outcomes, as well as the differences between monotherapy with EPA and combination therapy with EPA and DHA, Bhatt and colleagues searched EMBASE, PubMed,, and Cochrane library databases through June 7, 2021, and identified 38 randomized controlled studies of omega-3 FAs.

In all, these studies included 149,051 participants and showed that there was an association between omega-3 FAs and the following:

  • Reduced CV mortality: RR: 0.93; 95% CI: 0.88-0.98; P=0.01.
  • Non-fatal myocardial infarction (MI): RR: 0.87; 95% CI: 0.81-0.93; P=0.0001.
  • Coronary heart disease events (CHD): RR: 0.91; 95% CI: 0.87-0.96; P=0.0002.
  • Major adverse cardiovascular events (MACE): RR; 0.95; 95% CI: 0.92-0.98; P=0.002.
  • Revascularization: RR: 0.91; 95% CI: 0.87-0.95; P=0.0001.

Upon meta-analysis, Bhatt et al found that EPA monotherapy brought about higher reductions in relative risk compared with EPA+DHA for MACE, revascularization, along with all of the following:

  • Cardiovascular mortality: 0.82 versus 0.94, respectively.
  • Non-fatal MI: 0.72 versus 0.92.
  • CHD events: 0.73 versus 0.9.

Finally, monotherapy with EPAs was associated with a higher risk of total bleeding compared with control (RR: 1.49 vs 1.35, respectively).

Limitations include that none of the included trials studied the effects of DHA monotherapy on cardiovascular outcomes, failure to evaluate the association of EPA or DHA levels with clinical outcomes, much of the benefit seen in the pooled omega-3 FA clinical trial dataset is driven by the EPA preparation used in REDUCE-IT, failure to assess non-adherence to treatment, high risk of bias in 50% of trials included, heterogeneity in clinical settings, and the low certainty of evidence for some critical endpoints.

“This meta-analysis provides reassurance about the role of omega-3 FAs, specifically EPA, in the current treatment framework of ASCVD residual cardiovascular risk reduction and encourages investigators to explore further the cardiovascular effects of EPA across different clinical settings,” Bhatt and colleagues concluded.

  1. Omega-3 FAs—including eicosapentaenoic (EPA) and docosahexanoic (DHA) acids—reduced cardiovascular (CV) mortality and improved cardiovascular outcomes.

  2. CV risk reduction was more significant with EPA monotherapy compared with EPA plus DHA.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Bhatt reports grants from Amarin, grants from AstraZeneca, grants from Bristol-Myers Squibb, grants from Eisai, grants from Ethicon, grants from Medtronic, grants from Sanofi Aventis, grants from The Medicines Company, unfunded research collaborations with FlowCo, grants and other from PLx Pharma, unfunded research collaborations with Takeda, personal fees from Duke Clinical Research Institute, personal fees from Mayo Clinic, personal fees from Population Health Research Institute, personal fees, non-financial support and other from American College of Cardiology, personal fees from Belvoir Publications, personal fees from Slack Publications, personal fees from WebMD, personal fees from Elsevier. Bhatt is on the advisory board of Medscape Cardiology and Regado Biosciences, and on the board of directors of Boston VA Research Institute, reports personal fees and non-financial support from Society of Cardiovascular Patient Care, non-financial support from American Heart Association, personal fees from HMP Global, grants from Roche, personal fees from Harvard Clinical Research Institute (now Baim Institute for Clinical Research), other from Clinical Cardiology, personal fees from Journal of the American College of Cardiology, other from VA, grants from Pfizer, grants from Forest Laboratories/AstraZeneca, grants from Ischemix, other from St. Jude Medical (now Abbott), other from Biotronik, grants and other from Cardax, other from Bos[1]ton Scientific, grants from Amgen, grants from Lilly, grants from Chiesi, grants from Ironwood, personal fees from Cleveland Clinic, personal fees from Mount Sinai School of Medicine, other from Merck, grants from Abbott, grants from Regeneron, other from Svelte, grants and other from PhaseBio, grants from Idorsia, grants from Synaptic, personal fees from TobeSoft, grants, personal fees and other from Boehringer Ingelheim, personal fees from Bayer, grants and other from Novo Nordisk, grants from Fractyl, personal fees from Medtelligence/ReachMD, personal fees from CSL Behring, grants and other from Cereno Scientific, grants from Afimmune, grants from Ferring Pharmaceuticals, other from CSI, grants from Lexicon, personal fees from MJH Life Sciences, personal fees from Level Ex, grants from Contego Medical, grants and other from CellProthera, personal fees from K2P, personal fees from Canadian Medical and Surgical Knowledge Translation Research Group, grants and other from MyoKardia/ BMS, grants from Owkin, grants from HLS Therapeutics, grants and other from Janssen, grants from 89Bio, grants and other from Novo Nordisk, grants from Garmin, grants and collaborations from Novar[1]tis, outside the submitted work.

Cat ID: 102

Topic ID: 74,102,730,102,914,142,925