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Original Investigation
March 16, 2021

Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California
  • 2Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 4Division of Cardiovascular Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
  • 5Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA. 2021;325(11):1061-1073. doi:10.1001/jama.2021.1489
Key Points

Question  Does supplementation with marine omega-3 fatty acids and/or vitamin D3 affect the risk of developing atrial fibrillation (AF)?

Findings  In this ancillary primary prevention AF trial that was embedded within a 2 × 2 factorial randomized clinical trial and included 25 119 participants without AF at study entry, there was no significant difference in AF incidence with marine omega-3 fatty acids vs placebo (hazard ratio, 1.09) or with vitamin D3 supplementation vs placebo (hazard ratio, 1.09) over a median 5.3 years of treatment and follow-up.

Meaning  These findings do not support the use of marine omega-3 fatty acids or vitamin D3 in adults to prevent AF.

Abstract

Importance  Atrial fibrillation (AF) is the most common heart rhythm disturbance, continues to increase in incidence, and results in significant morbidity and mortality. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D have been reported to have both benefits and risks with respect to incident AF, but large-scale, long-term randomized trial data are lacking.

Objective  To test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF.

Design, Setting, and Participants  An ancillary study of a 2 × 2 factorial randomized clinical trial involving 25 119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017.

Interventions  Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D3 (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D3 and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed).

Main Outcomes and Measures  The primary outcome was incident AF confirmed by medical record review.

Results  Among the 25 119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24 127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D3 vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39).

Conclusions and Relevance  Among adults aged 50 years or older, treatment with EPA-DHA or vitamin D3, compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF.

Trial Registration  ClinicalTrials.gov Identifiers: NCT02178410; NCT01169259

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