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

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.

Figure 1.. Flow of Participants in the VITAL Rhythm Study

Participants were randomized to receive vitamin D₃, marine omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]), both active agents, or both placebos between November 2011 and March 2014. Randomization was computer generated in block sizes of 8 within sex, race, and 5-year age groups, with an equal representation of sex and an oversampling of Black/African American participants. ^aWilling/ineligible category included 76 190 individuals with history of cardiovascular disease, cancer, and/or safety exclusion criteria; 32 647 individuals unwilling to forgo supplemental vitamin D₃ intake greater than 800 IU/d, supplemental calcium intake greater than 1200 mg/d, or fish oil supplementation during the trial; 13 521 men younger than 50 years and women younger than 55 years; and 4465 individuals who reported another exclusion criterion (eg, participation in another trial).

Figure 2.. Cumulative Incidence of Atrial Fibrillation According to Randomized Treatment Groups

A, Cumulative incidence of the primary end point according to randomized treatment group of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) vs placebo derived from Cox regression models controlling for age, sex, and vitamin D₃ randomization group. Median observation time was 5.3 (interquartile range, 5.0-5.7) person-years. B, Cumulative incidence of the primary end point according to randomized treatment group of vitamin D₃ vs placebo derived from Cox regression models controlling for age, sex, and EPA-DHA randomization group. Median observation time was 5.3 (interquartile range, 5.0-5.7) person-years.

Figure 3.. Effect of Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) on the Primary End Point in Prespecified Subgroups

^aCox regression models controlled for age, sex, and randomization group; interactions tested using multiplicative interaction terms. ^bIncludes Hispanic, Asian/Pacific Islander, Native American/Alaska Native, and other, multiple, or unspecified race/ethnicity. ^cCHA₂DS₂-VASc score estimates stroke risk in patients with atrial fibrillation (see Table 1 footnote "d" for details). Risk factors were self-reported at baseline. Scores ranged from 0 to 8 in this study. ^dRestricted to ≤800 IU/d from all sources combined.

Figure 4.. Effect of Vitamin D₃ on the Primary End Point in Prespecified Subgroups

^aCox regression models controlled for age, sex, and randomization group; interactions tested using multiplicative interaction terms. ^bIncludes Hispanic, Asian/Pacific Islander, Native American/Alaska Native, and other, multiple, or unspecified race/ethnicity. ^cCHA₂DS₂-VASc score estimates stroke risk in patients with atrial fibrillation (see Table 1 footnote "d" for details). Risk factors were self-reported at baseline. Scores ranged from 0 to 8 in this study. ^dRestricted to ≤800 IU/d from all sources combined.