Effect of Long-Term Marine ɷ-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 34612056 · doi:10.1161/CIRCULATIONAHA.121.055654
What was done
A systematic review and meta-analysis of MEDLINE and Embase (2012–2020) and a previous 2019 meta-analysis to evaluate the effect of marine omega-3 fatty acids on atrial fibrillation (AF) risk in cardiovascular outcome randomized controlled trials (RCTs). Included trials had ≥500 patients, median follow-up ≥1 year, and reported AF as a prespecified outcome, adverse event, or hospitalization reason. Hazard ratios (HR) were pooled using random-effects models with Knapp-Hartung adjustment, and dose-response was evaluated with meta-regression.
What was found
Seven RCTs with 81,210 patients (58,939 at ≤1 g/d, 22,271 at >1 g/d; mean age 65 years; 39% female; weighted average follow-up 4.9 years) were analyzed. Marine omega-3 supplementation significantly increased AF risk overall (2,905 events; HR, 1.25 [95% CI, 1.07–1.46]; P = 0.013). AF risk was greater in trials testing >1 g/d (HR, 1.49 [95% CI, 1.04–2.15]; P = 0.042) than ≤1 g/d (HR, 1.12 [95% CI, 1.03–1.22]; P = 0.024; P for interaction <0.001). Meta-regression showed AF risk increased per 1 g higher daily dose (HR, 1.11 [95% CI, 1.06–1.15]; P = 0.001).
Why it matters
This meta-analysis demonstrates that long-term marine omega-3 fatty acid supplementation carries a dose-dependent risk of atrial fibrillation, indicating that cardiovascular benefits must be balanced against arrhythmia risk at higher doses.
Limits
AF was defined variably across trials (prespecified outcome, adverse event, or hospitalization) rather than through standardized systematic rhythm monitoring. The review included only seven trials and excluded short-term studies, postoperative AF, and patients with pre-existing AF.
Cited by
- context The increased risk of atrial fibrillation associated with omega-3 fatty acid supplementation is primarily observed at high doses around 4 grams per day of ethyl ester formulations.