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High-Dose Marine Omega-3s Raise Risk for Atrial Fibrillation
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Download the PDF here
JoAnn E. Manson, MD, DrPH
November 17, 2021
https://www.medscape.com/viewarticle/961473?uac=27194HK&faf=1&sso=true&impID=3807648&src=wnl_edit_tpal
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.
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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
Abstract
Background: 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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