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Prescribing More Stringent Design of Randomized Clinical Trials of Omega-3 Polyunsaturated Fatty Acids

      To the Editor:
      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 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.
      recently published in Mayo Clinic Proceedings. Together with the accompanying editorial by O'Keefe et al,
      • O'Keefe J.H.
      • Jacob D.
      • Lavie C.J.
      Omega-3 fatty acid therapy: the tide turns for a fish story.
      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.
      In 2015, a review of only new evidence arising since 2008 was commissioned by the National Heart Foundation of Australia (NHFA).
      • Nestel P.
      • Clifton P.
      • Colquhoun D.
      • et al.
      Indications for omega-3 long chain polyunsaturated fatty acid in the prevention and treatment of cardiovascular disease.
      That analysis confirmed the benefits of eating fish on the basis of evidence from cohort studies, but it could not confirm any benefit for fish oil from RCTs (except for triglyceride lowering and in heart failure). As a consequence, the NHFA has removed their recommendation to consume omega-3 fish oil supplements for cardiovascular health (not withstanding that fish consumption in Australia and in other countries such as the United States remains very low).
      One major shortcoming of the NHFA review,
      • Nestel P.
      • Clifton P.
      • Colquhoun D.
      • et al.
      Indications for omega-3 long chain polyunsaturated fatty acid in the prevention and treatment of cardiovascular disease.
      which also occurs in the current meta-analysis,
      • 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.
      is the absence of discussion regarding the failure of most RCTs to recruit control groups with low baseline levels of the omega-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for example as reported by red blood cell membrane EPA + DHA analysis (ie, the omega-3 index). Some control groups exhibited quite high omega-3 PUFA levels, likely due to large variations in fish diet or other undocumented dietary sources. In our reexamination of the post-2008 RCTs considered in the NHFA review, we found that none of those studies excluded individuals who ate fish (at any level of intake), and only one measured omega-3 PUFA status before assignment to treatment group.
      • McLennan P.L.
      • Pepe S.
      Weighing up fish and omega-3 PUFA advice with accurate, balanced scales: stringent controls and measures required for clinical trials.
      As we and others
      • James M.J.
      • Sullivan T.R.
      • Metcalf R.G.
      • Cleland L.G.
      Pitfalls in the use of randomised controlled trials for fish oil studies with cardiac patients.
      have reported previously, the failure to prevent overlap between treatment and control group omega-3 PUFA level at baseline is a major confounder that flaws these RCTs and prevents valid assessments of outcomes and conclusions.
      When you consider that cohort studies consistently reveal differences between those eating little or no fish on a regular basis and those eating fish regularly
      • 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.
      • Nestel P.
      • Clifton P.
      • Colquhoun D.
      • et al.
      Indications for omega-3 long chain polyunsaturated fatty acid in the prevention and treatment of cardiovascular disease.
      and attribute the effects to omega-3 PUFA content of fish,
      • McLennan P.L.
      Cardiac physiology and clinical efficacy of dietary fish oil clarified through cellular mechanisms of omega-3 polyunsaturated fatty acids.
      it is not surprising that RCTs, in which the control group is not equivalent to the lowest quintile or grouping according to fish intake, do not reproduce these very strong findings. Does an RCT of a new β-receptor blocker, or indeed any novel active agent, allow the active drug to be present randomly in the control group? Absolutely not!
      There are other shortcomings in the design of RCTs that we have previously outlined
      • McLennan P.L.
      • Pepe S.
      Weighing up fish and omega-3 PUFA advice with accurate, balanced scales: stringent controls and measures required for clinical trials.
      ; however, we assert that if background omega-3 PUFA dietary intake and baseline red blood cell membrane PUFA measures were accounted for in each RCT recruitment, the outcome of the recent meta-analysis 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.
      would likely be considerably more than the reported 6% reduction in risk. We therefore advocate that prospective randomized clinical trials include only patients who can be stratified and allocated to treatment groups on the basis of baseline-verified membrane PUFA content in red blood cells or other relevant tissues, in conjunction with documented dietary intake of preceding and continuing oral omega-3 PUFA sources. At the conclusion of treatments, each recruited group can be contrasted to respective baselines by molecular validation of potential cell membrane changes in omega-3 PUFA content.
      We posit that systematic reviews that ostensibly pay strict attention to quality of recruitment and randomization within included RCTs should properly and systematically account for and discuss the quality of control groups in those trials and their adequate differentiation from treatment groups.

      References

        • 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.
        Mayo Clin Proc. 2017; 92: 15-29
        • O'Keefe J.H.
        • Jacob D.
        • Lavie C.J.
        Omega-3 fatty acid therapy: the tide turns for a fish story.
        Mayo Clin Proc. 2017; 92 ([editorial]): 1-3
        • Nestel P.
        • Clifton P.
        • Colquhoun D.
        • et al.
        Indications for omega-3 long chain polyunsaturated fatty acid in the prevention and treatment of cardiovascular disease.
        Heart Lung Circ. 2015; 24: 769-779
        • McLennan P.L.
        • Pepe S.
        Weighing up fish and omega-3 PUFA advice with accurate, balanced scales: stringent controls and measures required for clinical trials.
        Heart Lung Circ. 2015; 24: 740-743
        • James M.J.
        • Sullivan T.R.
        • Metcalf R.G.
        • Cleland L.G.
        Pitfalls in the use of randomised controlled trials for fish oil studies with cardiac patients.
        Br J Nutr. 2014; 112: 812-820
        • McLennan P.L.
        Cardiac physiology and clinical efficacy of dietary fish oil clarified through cellular mechanisms of omega-3 polyunsaturated fatty acids.
        Eur J Appl Physiol. 2014; 114: 1333-1356

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