Combined EPA and DHA supplementation showed no broad benefit for major adverse cardiovascular events in patients with established disease

Cardiovascular diseases (CVD) remain to impose a main global burden of morbidity and mortality despite advances in anticipation and treatment. Omega-3 fatty acids, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been extensively studied for potential cardioprotective effects, yet their impact on cardiovascular outcomes remains debated due to heterogeneity in formulation, dose, and patient subgroups. This meta-analysis evaluated the effects of EPA and DHA supplementation on major adverse cardiovascular events (MACE) and atrial fibrillation (AF), including postoperative AF (POAF), in patients with established CVD. A systematic search of Embase, PubMed/MEDLINE, Scopus, and Web of Science (January 2010-December 2021) identified randomized controlled trials (RCTs) of combined EPA + DHA supplementation in secondary prevention or perioperative settings. Data were synthesized using RevMan v5.3 with a random-effects model, and study quality was assessed via the Cochrane RoB 2 tool. From 3682 records, 25 RCTs (n = 25 578 patients) were included. Pooled analysis showed no significant reduction in MACE (effect estimate 0.042 ± 0.0499, Z = 0.850, 95% CI [-0.055, 0.140], p = 0.396; low heterogeneity) or AF/POAF incidence (trend toward reduction: -0.198 ± 0.1498, Z = -1.319, 95% CI [-0.491, 0.096], p = 0.187; modest heterogeneity). Neutral findings likely reflect moderate-dose combined EPA + DHA use, limited subgroup reporting on metabolic comorbidities (e.g., diabetes, hypertriglyceridemia) or concomitant therapies (e.g., statins), and high background guideline-directed medical therapy reducing residual risk. Although omega-3 fatty acids exert anti-inflammatory, antithrombotic, and lipid-modulating effects, this analysis indicates no broad benefit in reducing MACE or AF risk with combined moderate-dose EPA + DHA in heterogeneous post-event populations. Recent evidence highlights more MACE reductions with high-dose purified EPA monotherapy in high-metabolic-risk subgroups, balanced against dose-dependent AF increases at high doses (> 1.5 g/day). Future large-scale RCTs should prioritize biomarker-verified compliance, metabolic/concomitant therapy stratification, and formulation-specific comparisons to define targeted therapeutic roles. Trial Registration: This study has been registered in PROSPERO, and the registration code is 642795.