Association Between Omega-3 Fatty Acid Treatment and Atrial Fibrillation in Cardiovascular Outcome Trials: A Systematic Review and Meta-Analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 34057665 · doi:10.1007/s10557-021-07204-z
What was done
Authors conducted a systematic review and meta-analysis of PubMed and Embase databases for randomized controlled trials (RCTs) evaluating omega-3 fatty acid (n-3 FA) therapy with atrial fibrillation (AF) as an outcome. Inclusion was limited to large RCTs (≥1,000 participants) with at least 1 year of follow-up. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using a Mantel-Haenszel random-effects model, and meta-regression evaluated the effect of n-3 FA dose on AF risk.
What was found
Across 8 RCTs totaling 83,112 participants (5 low-dose trials [≤1 g daily, n = 61,096] and 3 high-dose trials [>1 g daily, n = 22,016]), n-3 FA treatment was significantly associated with an increased risk of AF compared to control (4.0% vs. 3.3%; RR 1.24, 95% CI 1.11–1.38, p = 0.0002). The risk increase was modest in low-dose trials (RR 1.12, 95% CI 1.04–1.21, p = 0.004) and stronger in high-dose trials (RR 1.51, 95% CI 1.26–1.80, p < 0.001; p-interaction = 0.003). Meta-regression demonstrated a significant dose-dependent association with AF events (log RR 0.103, 95% CI 0.048–0.159, p < 0.001). No significant increase in stroke risk was observed (RR 1.04, 95% CI 0.90–1.20).
Why it matters
This meta-analysis demonstrates that omega-3 fatty acid therapy increases atrial fibrillation risk in a dose-dependent manner, requiring clinicians to weigh this adverse effect against cardiovascular benefits, particularly at doses exceeding 1 g daily.
Limits
The analysis was limited to large cardiovascular outcome trials and does not report whether risk varied by specific formulation (e.g., purified EPA vs. EPA/DHA mixtures). Overall AF event rates were relatively low across trials.
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.