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High-Dose Marine Omega-3s Raise Risk for Atrial Fibrillation
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JoAnn E. Manson, MD, DrPH
November 17, 2021
Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women's Hospital.
I'd like to talk with you about a recent report in Circulation: a meta-analysis of randomized clinical trials of the marine omega-3 fatty acids and risk for atrial fibrillation (AF). The report was led by Dr Baris Spencer from Geneva, Switzerland, and by Dr Christine Albert at Cedars-Sinai Medical Center. I'd like to acknowledge that I was also a co-author of this report and that it included the vitamin D and omega-3 trial VITAL, of which I am a principal investigator, and Dr Christine Albert is the principal investigator of the ancillary study, Vital Rhythm, which included AF endpoints. This meta-analysis included seven large-scale randomized clinical trials of the marine omega-3s and where they had ascertained AF endpoints. Four of the trials were testing relatively low doses of the marine omega-3s (< 1 g/day), and three of the trials tested high-dose omega-3s (> 1 g/day). In the lower-dose category were the VITAL trial, the GISSI heart failure trial, and the ASCEND trials. The higher-dose category included the REDUCE-IT and STRENGTH trials.
These seven trials, which included more than 81,000 participants, found that the risk for AF was elevated with the omega-3s, with a hazard ratio of 1.25. That was strongly statistically significant, but there was also evidence of a dose response. The trials had tested lower doses (< 1 g/day) and, individually, they did not show a significant increase in AF. In aggregate, however, there was a 12% increase in AF risk. In the high-dose (> 1 g/day) trials, there was a 49%-50% risk. In a dose-response gradient analysis, for each 1 g increase in the dose of the omega-3s, there was an 11% increase in the risk for AF - a strongly significant interaction.
Overall, there was evidence that higher doses of omega-3s were associated with an increased risk for AF and that the omega-3s conferred elevated risk for AF. It's also true that meta-analyses suggest that the higher doses of omega-3s are associated with a lower risk for total cardiovascular events, and that there is a dose response there as well. A recent meta-analysis suggested that there is about a 9% reduction in risk for major cardiovascular events with every 1 g increase in the dose of omega-3s.
However, it's interesting that the meta-analysis of the omega-3s have generally not suggested a benefit for stroke, except for the REDUCE-IT trial, which did show a substantial reduction in stroke. And the question arises as to whether this increased risk for AF with omega-3s may be contributing to the absence of stroke benefit because of the link between AF and stroke; this might be a particularly relevant issue for women who have a higher risk for stroke and stroke mortality related to AF.
These findings suggest that when patients are prescribed omega-3s, especially higher doses, there should be a discussion with the patient about the potential risk for AF, and it should be factored into the benefit-risk equation. Many patients will continue to be very good candidates for treatment, nonetheless. About 8% of the general US population who are taking over-the-counter omega-3 fish oilsupplements, and they should be informed about the potential relationship between high-dose omega-3s and risk for AF. We need much more research on the association between the omega-3s --and AF, how it might vary by formulation of omega-3s or dose, and how it fits into the overall benefit-risk ratio of omega-3supplementation.
Effect of Long-Term Marine Omega-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis
Some, but not all, large-scale randomized controlled trials (RCTs) investigating the effects of marine omega-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 omega-3 fatty acids that reported results for AF, either as pre-specified outcome, adverse event, or a cause for hospitalization, with a minimum sample size of 500 patients and a median followup of at least one year were included. RCTs specifically examining shorter term effects of omega-3 fatty acids on recurrent AF in patients with established AF or post-operative AF were not included. The hazard ratio (HR) for the reported AF outcomes within each trial was metaanalyzed using random-effects model with Knapp-Hartung adjustment and evaluated a doseresponse relationship with a meta-regression model.
Results: Of 4049 screened records, seven studies were included in the meta-analysis. Of those, five 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 ≤1gram per day (g/d) and 22,271 (27.4%) in trials testing >1g/d of omega-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 omega-3 fatty acid supplements was associated with an increased risk of AF (n=2,905; 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 >1g/d (HR 1.49, 95%CI 1.04-2.15, P=0.042) as 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 metaregression, the HR for AF increased per 1 gr increase of omega-3 fatty acids dosage (HR 1.11, 95%CI 1.06-1.15, P=0.001).
Conclusions: In RCTs examining cardiovascular outcomes, marine omega-3 supplementation was associated with an increased risk of AF. The risk appeared to be greater in trials testing >1g/d.

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