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In Reply II—Prescribing More Stringent Design of Randomized Clinical Trials of Omega-3 Polyunsaturated Fatty Acids

      The concerns articulated by Drs McLennan and Pepe about the high intake of omega-3 fatty acids in the control groups of randomized controlled trials (RCTs) are critically important when evaluating this body of scientific data, and we thank these colleagues for their insightful comments. Indeed, RCTs of omega-3 supplementation performed 2 to 3 decades ago reported highly significant reductions in major adverse cardiovascular (CV) events,
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART).
      • Singh R.B.
      • Niaz M.A.
      • Sharma J.P.
      • Kumar R.
      • Rastogi V.
      • Moshiri M.
      Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian Experiment of Infarct Survival–4.
      GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)
      Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.
      similar to the 18% reduction noted in the recent comprehensive meta-analysis of prospective cohort studies by Alexander et al
      • Alexander D.D.
      • Miller P.E.
      • Van Elswyk M.E.
      • Kuratko C.N.
      • Bylsma L.C.
      A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk.
      that included 732,000 individuals. However, during the past 10 to 15 years, mass media outlets have widely publicized the potential benefits of fish and fish oil supplements, and thus, not surprisingly, the individuals who agreed to participate in trials testing omega-3 in recent years tended to have higher baseline consumption of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared with decades earlier, which may account for the muted to absent cardioprotective effects noted with omega-3 supplementation in many of the more recent RCTs.
      • DiNicolantonio J.J.
      • Niazi A.K.
      • McCarty M.F.
      • O'Keefe J.H.
      • Meier P.
      • Lavie C.J.
      Omega-3s and cardiovascular health.
      As a general rule, nutrients are best obtained from the diet rather than supplements. However, supplementation can be important for individuals with deficiencies of essential nutrients and who are unable or unwilling to obtain them from dietary sources. From the 13th through 18th centuries, scurvy was a common and often fatal affliction among sailors during long sea voyages. In 1753, James Lind, a Scottish physician in the British Royal Navy, published his study describing how all of the lethal signs and symptoms of scurvy quickly resolved after fresh oranges and lemons (which are high in vitamin C) were added to the sailors' food rations. In stark contrast, several large RCTs over the past 20 years have documented no benefit to vitamin C supplementation among modern Western populations, in whom scurvy is very rare.
      • Sesso H.D.
      • Buring J.E.
      • Christen W.G.
      • et al.
      Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial.
      Despite the broadcasting of information about potential benefits of fish and fish oil, the typical American (unlike the people who tend to volunteer for omega-3 studies) still consumes insufficient quantities of omega-3. Accordingly, the mean omega-3 levels in the cell membranes of US adults remain approximately half the levels noted among the citizens of Japan,
      • Stark K.D.
      • Van Elswyk M.E.
      • Higgins M.R.
      • Weatherford C.A.
      • Salem Jr., N.
      Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults.
      and this difference has been postulated to be a central reason for the superior CV health and longevity of the Japanese.
      • Miyagawa N.
      • Miura K.
      • Okuda N.
      • et al.
      Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80.
      Among individuals who consume inadequate quantities of omega-3, a supplement providing 250 to 1000 mg of EPA and DHA will increase the tissue levels of omega-3 fatty acids and will likely improve CV prognosis.

      References

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        Cardiovasc Drugs Ther. 1997; 11: 485-491
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        Mayo Clin Proc. 2017; 92: 15-29
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        Prog Lipid Res. 2016; 63: 132-152
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      Linked Article

      • Prescribing More Stringent Design of Randomized Clinical Trials of Omega-3 Polyunsaturated Fatty Acids
        Mayo Clinic ProceedingsVol. 92Issue 6
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          We read with interest the carefully designed and executed comprehensive meta-analysis of the effects of omega-3 polyunsaturated fatty acids (PUFA) on coronary heart disease in randomized controlled trials (RCTs) and prospective cohort studies by Alexander et al1 recently published in Mayo Clinic Proceedings. Together with the accompanying editorial by O'Keefe et al,2 these authors make an important contribution to the discourse on the use of omega-3 PUFA and fish oil supplement therapy in patients with cardiovascular disease, which is currently confounded by the results of several previous underwhelming RCTs and meta-analyses.
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