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Omega-3 Benefits Remain Strong Post-STRENGTH

      To The Editor:
      Eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, the 2 main omega-3 long-chain polyunsaturated fatty acids of marine origin, have shown promise for the prevention of cardiovascular disease (CVD) outcomes in animal studies and epidemiologic studies.
      • Mozaffarian D.
      • Wu J.H.
      Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events.
      Although several recent trials have shown benefits, as summarized in Mayo Clinic Proceedings in 2019,
      • O'Keefe E.L.
      • Harris W.S.
      • DiNicolantonio J.J.
      • et al.
      Sea change for marine omega-3s: randomized trials show fish oil reduces cardiovascular events.
      2 randomized control trials published in late 2020 showed neutral results. The situation is summarized thoughtfully in a recent editorial by Farukhi et al, published in Mayo Clinic Proceedings,
      • Farukhi Z.M.
      • Mora S.
      • Manson J.E.
      Marine omega-3 fatty acids and cardiovascular disease prevention: seeking clearer water.
      which cited our recent meta-analysis
      • Bernasconi A.A.
      • Wiest M.M.
      • Lavie C.J.
      • Milani R.V.
      • Laukkanen J.A.
      Effect of omega-3 dosage on cardiovascular outcomes: an updated meta-analysis and meta-regression of interventional trials.
      on the subject. The authors observe that the results of these new trials (Outcomes Study to Assess Statin Residual Risk Reduction With EpaNova in High CV Risk Patients With Hypertriglyceridemia [STRENGTH]
      • Nicholls S.J.
      • Lincoff A.M.
      • Garcia M.
      • et al.
      Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial.
      and Omega-3 Fatty Acids in Elderly With Myocardial Infarction [OMEMI]
      • Kalstad A.A.
      • Myhre P.L.
      • Laake K.
      • et al.
      Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized controlled trial.
      ) need to be examined in the context of existing research. In particular, they suggest that it is necessary to update the results and review the conclusions of our meta-analysis.
      Following their suggestion, with the addition of these new trials (both of which meet our inclusion criteria), our analysis now covers 42 studies with a combined 149,359 participants. As only results for CVD and coronary heart disease (CHD) outcomes were made available in the 2 new trials, our original results
      • Bernasconi A.A.
      • Wiest M.M.
      • Lavie C.J.
      • Milani R.V.
      • Laukkanen J.A.
      Effect of omega-3 dosage on cardiovascular outcomes: an updated meta-analysis and meta-regression of interventional trials.
      for myocardial infarction (MI) relative risk (RR), 0.87; 95% confidence interval [CI], 0.80 to 0.96, high GRADE certainty, fatal MI RR, 0.65; 95% CI, 0.46 to 0.91, moderate certainty and CHD mortality RR, 0.91; 95% CI, 0.85 to 0.98, low certainty remain unchanged.
      The newly published results change slightly the meta-analysis estimates, but not the conclusions, for CVD events and CHD events. For CVD events, the pooled estimate is now RR, 0.96; 95% CI, 0.91 to 1.00 (changed from RR, 0.95; 95% CI, 0.90 to 1.00). For CHD events: RR, 0.91; 95% CI, 0.85 to 0.97 (changed from RR, 0.90; 95% CI, 0.84 to 0.97). These results are summarized in the Figure.
      Figure thumbnail gr1
      FigurePooled results from meta-analysis. The figure shows the pooled estimate of relative risk and 95% confidence interval, as well as the number of studies and combined number of participants. CHD, coronary heart disease; CVD, cardiovascular disease; MI, myocardial infarction.
      The effect remains dose dependent for MI; an additional 1 g/d in EPA and DHA is associated with a 9% reduction in MI but no longer for CVD events. None of the other conclusions is changed; the effect remains independent of the year of publication, the population baseline risk, or whether the long-chain polyunsaturated fatty acids agent consisted of only EPA or a combination of EPA and DHA.
      Although we believe that understanding why a high-dosage trial, such as STRENGTH, failed to find an effect will require more research, the totality of the evidence, including now 42 studies involving almost 150,000 participants, shows statistically significant reductions in fatal MI (–35%), MI (–13%), CHD events, and CHD mortality (both –9%). This is still consistent with the conclusion that EPA and DHA intake is an effective lifestyle intervention for protection against CVD.

      References

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        • Wu J.H.
        Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events.
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        • O'Keefe E.L.
        • Harris W.S.
        • DiNicolantonio J.J.
        • et al.
        Sea change for marine omega-3s: randomized trials show fish oil reduces cardiovascular events.
        Mayo Clin Proc. 2019; 94: 2524-2533
        • Farukhi Z.M.
        • Mora S.
        • Manson J.E.
        Marine omega-3 fatty acids and cardiovascular disease prevention: seeking clearer water.
        Mayo Clin Proc. 2021; 96: 277-279
        • Nicholls S.J.
        • Lincoff A.M.
        • Garcia M.
        • et al.
        Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial.
        JAMA. 2020; 324: 2268-2280
        • Kalstad A.A.
        • Myhre P.L.
        • Laake K.
        • et al.
        Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized controlled trial.
        Circulation. 2021; 143: 528-539
        • Bernasconi A.A.
        • Wiest M.M.
        • Lavie C.J.
        • Milani R.V.
        • Laukkanen J.A.
        Effect of omega-3 dosage on cardiovascular outcomes: an updated meta-analysis and meta-regression of interventional trials.
        Mayo Clin Proc. 2021; 96: 304-313