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

Educational Objective
To learn about the prevention of atrial fibrillation.
1 Credit CME
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.


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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Article Information

Corresponding Author: Christine M. Albert, MD, MPH, Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S San Vincente Blvd, AHSP 3100, Los Angeles, CA 90048 (christine.albert@cshs.org).

Accepted for Publication: January 30, 2021.

Author Contributions: Dr Albert had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Albert, Danik, Mora, Manson.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Albert, Danik.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Cook, Moorthy.

Obtained funding: Albert, Manson.

Administrative, technical, or material support: Albert, Pester, Ridge, Ng, Mora, Manson.

Supervision: Albert, Danik, Manson.

Conflict of Interest Disclosures: Dr Albert reported receipt of grants from St Jude Medical, Abbott, and Roche Diagnostics. Dr Mora reported serving as a consultant to Quest Diagnostics and Pfizer and receipt of grants from Atherotech Diagnostics. Dr Buring reported that her spouse is on the scientific advisory board of Pharmavite LLC, which provided the vitamin D/placebo for this trial. Dr Manson reported receiving grants from Mars Symbioscience. No other disclosures were reported.

Funding/Support: The VITAL Rhythm Study was supported by grant R01HL116690 from the National Heart, Lung, and Blood Institute and the VITAL trial was supported by grants U01 CA138962 and R01 CA138962, which included support from the National Cancer Institute, National Heart, Lung and Blood Institute, Office of Dietary Supplements, National Institute of Neurological Disorders and Stroke, and National Center for Complementary and Integrative Health. Pharmavite LLC (vitamin D3) and Pronova BioPharma/BASF (omega-3 fatty acids) donated the study agents, matching placebos, and packaging. Quest Diagnostics performed the serum 25-hydroxyvitamin D and plasma phospholipid omega-3 measurements at no additional cost. Dr Siddiqi was supported by grant HL007575 from the National Heart, Lung, and Blood Institute. Dr Mora was supported by grant DK112940 from the National Institute of Diabetes and Digestive and Kidney Diseases and grants R01HL134811 and K24 HL136852 from the National Heart, Lung, and Blood Institute.

Role of the Funder/Sponsor: The NIH, the sponsors of the VITAL trial, participated in discussions in the design and conduct of the parent VITAL trial but not in the VITAL Rhythm Study. The NIH did not participate in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The other funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Group Information: A list of the members of the VITAL Research Group is included in Supplement 3.

Disclaimer: The opinions expressed in the article are those of the study authors.

Meeting Presentation: Portions of this study were presented at the American Heart Association 2020 Annual Scientific Sessions Meeting; November 13, 2020; Dallas, Texas (virtual).

Data Sharing Statement: See Supplement 4.

Additional Contributions: We acknowledge the invaluable contributions and dedication of the 25 871 participants in VITAL and the entire staff of the VITAL trial and the VITAL Rhythm Study. In particular, we acknowledge Jennie Lytel-Sternberg, BA, Ashley Lawrence, BSN, RN, and Lindsay Ventura, BS, of the Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, who collected data for the AF end point, and Min Wu, MPH, and Matthew Driver, MPH, of the Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, for editorial assistance with the tables and figures, all of whom were compensated for their efforts.

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Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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