Omega-3 polyunsaturated fatty acids supplementation and cardiovascular outcomes: do formulation, dosage, and baseline cardiovascular risk matter? An updated meta-analysis of randomized controlled trials

The recent publication of the REDUCE-IT study has reopened the debate about the efficacy of omega-3 fatty acids in reducing the risk of cardiovascular (CV) events. This meta-analysis aims at investigating the effect of omega-3 long-chain polyunsaturated fatty acids (n-3 PUFA) administration on CV outcomes in published randomized clinical trials (RCTs), with a focus on the role of dose, type of n-3 PUFA, and different CV risk at baseline. This meta-analysis was conducted according to the PRISMA reporting guidelines. PubMed, Cochrane and EMBASE were searched since inception to March 2020. Inclusion criteria were: (1) RCTs; (2) including subjects with previous CV events; (3) administration of n-3 PUFA ≥ 1 gram/day dosage for ≥1 year; (4) effects on all-cause mortality, cardiac death, major adverse cardiovascular events (MACE), fatal/nonfatal myocardial infarction (MI), or fatal/nonfatal stroke reported. Odds ratios (ORs) with 95% confident intervals (95%CI) were estimated. 16 RCTs were included in the meta-analysis accounting for 81,073 participants. Supplementation of n-3 PUFA was associated with a significant risk reduction of cardiac mortality (OR 0.91 [95% CI, 0.85-0.98]), MACE (OR 0.90 [95% CI, 0.82-0.99]), and MI (OR 0.83 [95% CI, 0.71-0.98]). In subgroup analyses, the risk reduction of cardiac mortality and MI was confirmed only in RCTs that enrolled patients in secondary prevention (-21% and -31%, respectively). Moreover, only the administration of more than 1 gram per day of n-3 PUFA was effective in reducing the risk of cardiac death (-35%), MACE (-24%), and MI (-33%). Finally, EPA + DHA supplementation was only associated with a significant risk reduction of cardiac death compared with EPA administered alone (-8%). Conversely, the efficacy of EPA administered alone seemed to be greater in terms of risk reduction of MACE (-25%) or MI (-30%) than the combined EPA + DHA supplementation. The pharmacological approach with n-3 PUFA significantly improves cardiovascular outcomes, with higher benefit achieved by patients in secondary CV prevention, using more than 1 gram/day, and taking EPA administered alone.