Seafood-Derived Omega-3 Fatty Acids and Cardiovascular Disease Prevention: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Cardiovascular disease (CVD) remains the leading cause of death globally, representing 32 % of all deaths and necessitating effective preventive strategies. Despite widespread interest in omega-3 fatty acids for cardiovascular protection, conflicting evidence from randomized trials has created uncertainty regarding optimal formulations (EPA vs. EPA+DHA), efficacy, and risk-benefit profiles. This systematic review addresses critical knowledge gaps by synthesizing randomized controlled trial (RCT) evidence through 2024, providing formulation-specific comparison between EPA monotherapy and EPA+DHA combinations, as well as integrating comprehensive atrial fibrillation risk assessment. We searched EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov through August 2024 using comprehensive Boolean search strategies, identifying 38 RCTs involving 149,051 participants. Two independent reviewers performed both study selection and data extraction work. The researchers used the Cochrane Risk of Bias 2 tool to determine the risk of bias assessment. The meta-analysis used random-effects models to measure statistical diversity through I² statistics. GRADE methodology evaluated certainty of evidence. Omega-3 supplementation significantly reduced cardiovascular mortality (RR 0.93, 95 % CI: 0.88-0.98; moderate certainty evidence), non-fatal myocardial infarction (RR 0.87, 95 % CI: 0.81-0.93; moderate certainty), coronary heart disease events (RR 0.91, 95 % CI: 0.87-0.96; moderate certainty), and major adverse cardiovascular events (RR 0.95, 95 % CI: 0.92-0.98; moderate certainty). EPA monotherapy demonstrated superior efficacy versus EPA+DHA (interaction p<0.01 for MACE). No benefit was observed for all-cause mortality (RR 0.97, 95 % CI: 0.93-1.02; low certainty) or stroke (RR 1.04, 95 % CI: 0.91-1.18; low certainty). Atrial fibrillation risk increased (RR 1.26, 95 % CI: 1.08-1.48; moderate certainty), particularly with high-dose EPA. This meta-analysis provides updated synthesis through 2024, first systematic formulation-specific comparison, and integrated benefit-harm assessment, addressing critical gaps in omega-3 therapy guidance. We recommend 2-3 weekly fish servings for primary prevention and purified EPA supplementation (4 g/day) for high-risk patients with established CVD, hypertriglyceridemia, and concurrent statin use, with atrial fibrillation monitoring. Future research should optimize patient selection criteria and clarify formulation-specific mechanisms.