Gencer B, Djousse L, Al-Ramady OT, et al. Effect of Long-Term Marine -3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Circulation. 2021 Dec 21;144(25):1981-1990. doi: 10.1161/CIRCULATIONAHA.121.055654. Epub 2021 Oct 6. (Systematic review)

BACKGROUND: Some, but not all, large-scale randomized controlled trials (RCTs) investigating the effects of marine ?-3 fatty acids supplementation on cardiovascular outcomes have reported increased risks of atrial fibrillation (AF). The potential reasons for disparate findings may be dose-related.

METHODS: The MEDLINE and Embase databases were searched for articles and abstracts published between January 1, 2012, and December 31, 2020, in addition to a meta-analysis of large cardiovascular RCTs published in 2019. RCTs of cardiovascular outcomes of marine ?-3 fatty acids that reported results for AF, either as a prespecified outcome, an adverse event, or a cause for hospitalization, with a minimum sample size of 500 patients and a median follow-up of at least 1 year were included. RCTs specifically examining shorter-term effects of ?-3 fatty acids on recurrent AF in patients with established AF or postoperative AF were not included. The hazard ratio (HR) for the reported AF outcomes within each trial was meta-analyzed using random effects model with Knapp-Hartung adjustment and evaluated a dose-response relationship with a meta-regression model.

RESULTS: Of 4049 screened records, 7 studies were included in the meta-analysis. Of those, 5 were already detected in a previous meta-analysis of cardiovascular RCTs. Among the 81 210 patients from 7 trials, 58 939 (72.6%) were enrolled in trials testing =1 g/d and 22 271 (27.4%) in trials testing >1 g/d of ?-3 fatty acids. The mean age was 65 years, and 31 842 (39%) were female. The weighted average follow-up was 4.9 years. In meta-analysis, the use of marine ?-3 fatty acid supplements was associated with an increased risk of AF (n=2905; HR, 1.25 [95% CI, 1.07-1.46]; P=0.013). In analyses stratified by dose, the HR was greater in the trials testing >1 g/d (HR, 1.49 [95% CI, 1.04-2.15]; P=0.042) compared with those testing =1 g/d (HR, 1.12 [95% CI, 1.03-1.22]; P=0.024; P for interaction <0.001). In meta-regression, the HR for AF increased per 1 g higher dosage of ?-3 fatty acids dosage (HR, 1.11 [95% CI, 1.06-1.15]; P=0.001).

CONCLUSIONS: In RCTs examining cardiovascular outcomes, marine ?-3 supplementation was associated with an increased risk of AF. The risk appeared to be greater in trials testing >1 g/d.

Related DynaMed Topics

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Cardiology 6 / 7
Internal Medicine 5 / 7
Public Health 4 / 7
Comments from MORE raters

Cardiology rater

Definitely a very important study given the interest in 3-fatty acid supplementation for ASCVD among the population and clinicians.

Family Medicine (FM)/General Practice (GP) rater

A strong case for dietary measures rather than pharmacologic supplementation.

Internal Medicine rater

A meta-analysis drawn from RCTs with pertinent and new information that seek to balance the risks vs benefits from EPA DHA supplementation.

Public Health rater

This is a comprehensive meta-analysis of RCTs showing an increased risk of atrial fibrillation with marine 2-3 supplementation, and this effect seems to be driven by higher doses.
Comments from EvidenceAlerts subscribers

Mr. Eduard Bokan (12/30/2021 3:42 PM)

What about the known heart benefits of a Mediterranean Diet with high content of Omega-3/fish?