The Effect of Omega-3 Dosage on Cardiovascular Outcomes

Abstract

Objectives: To quantify the effect of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on cardiovascular disease (CVD) prevention and the effect of dosage. Methods: This study is designed as a random effects meta-analysis and meta-regression of randomized control trials with EPA/DHA supplementation. This is an update and expanded analysis of a previously published meta-analysis which covers all randomized control trials with EPA/DHA interventions and cardiovascular outcomes published before August 2019. The outcomes included are myocardial infarction (MI), coronary heart disease (CHD) events, CVD events (a composite of MI, angina, stroke, heart failure, peripheral arterial disease, sudden death, and non-scheduled cardiovascular surgical interventions), CHD mortality and fatal MI. The strength of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework. Results: A total of 40 studies with a combined 135,267 participants were included. Supplementation was associated with reduced risk of MI (relative risk [RR], 0.87; 95% CI, 0.80 to 0.96), high certainty number needed to treat (NNT) of 272; CHD events (RR, 0.90; 95% CI, 0.84 to 0.97), high certainty NNT of 192; fatal MI (RR, 0.65; 95% CI, 0.46 to 0.91]), moderate certainty NNT 1⁄4 128; and CHD mortality (RR, 0.91; 95% CI, 0.85 to 0.98), low certainty NNT 1⁄4 431, but not CVD events (RR, 0.95; 95% CI, 0.90 to 1.00). The effect is dose dependent for CVD events and MI. Conclusion: Cardiovascular disease remains the leading cause of death worldwide. Supplementation with EPA and DHA is an effective lifestyle strategy for CVD prevention, and the protective effect probably increases with dosage. a 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) n Mayo Clin Proc. 2020;nn(n):1-10 From the Global Organization for EPA and DHA Omega-3s (GOED), Salt Lake City, UT (A.A.B.); the Department of Statistical Science, University of Idaho, Moscow, ID (M.M.W.); the Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Affiliations continued at the end of this article. D espite significant advances in the prevention and treatment of cardiovascular diseases (CVDs), they remain the leading cause of mortality in the United States andmost of theworld.According to the Centers for Disease Control and Prevention, diseases of the heart accounted for 23.1% and cerebrovascular diseases for 5.2%of all deaths in theUnited States in 2017. Eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, the two main omega-3 long-chain polyunsaturated fatty acids of marine origin, have shown promise for the prevention of CVD outcomes in animal Mayo Clin Proc. n XXX 2020;nn(n):1-10 n https://doi.org/10.1016/j. www.mayoclinicproceedings.org n a 2020 Mayo Foundation for Me under the CC BY-NC-ND license (http://creativecommons.org/licens studies and epidemiologic studies as previously reviewed in detail. However, randomized control trials (RCTs) have found inconsistent results. Whether a study finds a significant protective effect is not purely a function of study size or quality. Three large studies whose primary outcome was the occurrence of CVD events were published in 2018, and they reached diverging conclusions. A Study of Cardiovascular Events in Diabetes (ASCEND) (n1⁄415,480), a study on primary prevention in diabetics, found no reduction in CVD risk. Vitamin D and Omega-3 Trial (VITAL) (n1⁄425,871), the mayocp.2020.08.034 dical Education and Research. Published by Elsevier Inc. This is an open access article es/by-nc-nd/4.0/). 1 MAYO CLINIC PROCEEDINGS 2 first primary prevention study on healthy adults, found a non-statistically significant 7% reduction in the risk of CVD events, and an unexpectedly high 28% reduction in the risk of myocardial infarction (MI), a prespecified secondary outcome. Finally, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) (n1⁄48179), a trial that studied the effect of Vascepa (icosapent ethyl), a highly concentrated ethyl ester form of EPA on patients with mostly borderline and mildly high triglycerides who were taking statins, found a statistically significant 25% reduction in the risk of the primary endpoint, as well as risk reductions of similar magnitudes in multiple secondary endpoints. The results of meta-analyses are equally inconsistent. Three recent analyses of the effect of EPA and DHA on multiple CVD outcomes reached entirely different conclusions. For example, for coronary heart disease (CHD) mortality, Abdelhamid et al finds low certainty of a possible protective effect; Rizos et al finds a protective effect when using the usual P value cutoff of .05, but dismisses it as uncertain after using a very conservative multiple hypothesis correction; and Maki et al finds a statistically significant 8.0% risk reduction. The limitations of these analyses form the basis and rationale for ourmore extensive evaluation of the evidence. The reasons for this variability among the results of RCTs are not well understood, and although a number of possible explanations have been proposed, there is a dearth of data to support them. The explanations proposed range from differences in results depending on the year of publication (earlier trials, presumably being more likely to find positive results), the natural variability to be expected in insufficientlypowered trials, potential interference in the omega-3 mechanisms of action bymodern CVD prevention and treatment (especially use of statins and statin doses), differences in omega-3 baseline status and treatment compliance, baseline risk and dosage (11), and whether the study intervention included EPA alone or both EPA and DHA. A recent meta-analysis used metaregression to study the effect of dosage on Mayo Clin Proc. n XXX CVD outcomes and suggested significant protective effects of omega-3 against CVD events, but they restricted the analysis to only the 13 largest RCTs to date. Previous meta-analyses have compared the effect of dosages greater than or less than 1000 mg/ day, but reducing the existing dosage information in this manner using what is an arbitrary cutoff is not an efficient use of existing information, and does not allow for a proper quantification of the doseeffect relationship. In 2006, Mozaffarian and Rimm observed that for multiple CVD outcomes, a higher dosage was associated with increased protection, and quantified this effect, but their estimates were based on an unweighted combination of interventional and observational studies, and inclusion of the latter may have introduced confounders and biased the results. The current analysis builds on the work of Abdelhamid et al but differs in the choice of what trials to include, focusing only on studies for which the intervention is EPA/ DHA supplementation, and not dietary advice. This addresses more directly the question of what the effect is of long-chain omega-3 supplementation on CVD outcomes. Trials on dietary advice are important for designing efficient public health recommendations, but their results are confounded by problems in compliance and by the differences in EPA/DHA content of common foods. Unlike previous research, our work uses the totality of available evidence in measuring the effect of dosage. The larger study number and wider range of dosages allows for more precise and more robust estimates of the dose-effect relationship. Finally, the current study is the first to use meta-regression to examine other often cited potential sources of heterogeneity in the results from existing research. Given the prevalence of CVD, and their human and financial costs, it is important to determine which lifestyle modifications (and under what conditions) may provide some protection against these various CVD conditions. The use of fish oils and other products containing long-chain omega-3 fatty acids is a popular patient strategy to reduce CVD 2020;nn(n):1-10 n https://doi.org/10.1016/j.mayocp.2020.08.034 www.mayoclinicproceedings.org EFFECT OF OMEGA-3 DOSAGE ON CARDIOVASCULAR OUTCOMES risk, and a nuanced understanding of why some clinical trials yield positive results and others fail to do so is a fundamental step in the correct evaluation of the risks and benefits of this supplementation to adequately inform both clinicians and the public about the potential benefits or lack of efficacy. The current review focuses on determining whether supplementation with EPA and DHA results in reduced CVD risk, and in quantifying the relationship between dosage and other predictors and the risk of CVD outcomes.