| Summary: | BACKGROUND: Eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) intake may protect from cardiovascular or all-cause mortality. OBJECTIVE: To synthesize evidence from randomized controlled trials (RCTs) and large prospective cohorts on the effects of EPA and DHA on cardiac, cardiovascular, or all-cause mortality. DESIGN: We conducted a systematic review with random effects meta-analysis and mixed effects dose-response meta-regression. Included were RCTs of EPA and DHA supplementation (>4 weeks of intervention, <6 grams per day) and large prospective cohorts (>1000 people, >3 years of followup) quantifying DHA or EPA intake. RESULTS: In RCTs, the summary relative risks for all-cause mortality (17 trials, 51,264 patients) and cardiovascular mortality (14 trials, 48,500 patients) were 0.95 (95% confidence interval, CI: 0.89, 1.01) and 0.89 (95% CI, 0.83, 0.96), respectively, with no evidence for heterogeneity. The effect of DHA and EPA was not significantly associated with population or study characteristics or supplement dose. In dose-response meta-regressions, mean EPA and DHA intake up to 0.20 grams daily was associated with decreased risk of cardiac, cardiovascular, or sudden cardiac death (odds ratio 0.64 per 0.20 grams average daily intake, 95% CI: 0.46, 0.89--data from 7 cohorts, 123,122 participants), with no significant change in risk (positive or negative) at higher mean intakes. Dose-response analyses were not statistically significant for other intake thresholds or alternative mortality definitions. CONCLUSIONS: The maximal positive effect of EPA and DHA appears to plateau at a mean daily intake of 0.20 grams. There is no evidence that the effect of EPA and DHA on mortality phenotypes differs across populations and settings
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