Effect Of Marine Omega-3 Fatty Acid And Vitamin D Supplementation On Incident Atrial Fibrillation: A Randomized Clinical Trial

Key PointsQuestionDoes supplementation with marine omega-3 fatty acids and/or vitamin D-3 affect the risk of developing atrial fibrillation (AF)? FindingsIn this ancillary primary prevention AF trial that was embedded within a 2x2 factorial randomized clinical trial and included 25119 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 D-3 supplementation vs placebo (hazard ratio, 1.09) over a median 5.3 years of treatment and follow-up. MeaningThese findings do not support the use of marine omega-3 fatty acids or vitamin D-3 in adults to prevent AF.ImportanceAtrial 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. ObjectiveTo test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF. Design, Setting, and ParticipantsAn ancillary study of a 2 x 2 factorial randomized clinical trial involving 25119 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. InterventionsParticipants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D-3 (2000 IU/d) (n=6272 analyzed); EPA-DHA and placebo (n=6270 analyzed); vitamin D-3 and placebo (n=6281 analyzed); or 2 placebos (n=6296 analyzed). Main Outcomes and MeasuresThe primary outcome was incident AF confirmed by medical record review. ResultsAmong the 25119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24127 (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 D-3 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 RelevanceAmong adults aged 50 years or older, treatment with EPA-DHA or vitamin D-3, 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 RegistrationClinicalTrials.gov Identifiers: NCT02178410; NCT01169259This 2 x 2 factorial trial compares the effects of omega-3 fatty acids (460 mg/d of EPA and 380 mg/d of DHA) vs placebo, vitamin D3 vs placebo, both, or neither on risk of incident atrial fibrillation (AF) among adults aged 50 years or older over a median of more than 5 years of treatment.