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

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.

Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease.

BACKGROUND: It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited. METHODS: We conducted a nationwide, randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (cholecalciferol) at a dose of 2000 IU per day and marine n-3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of vitamin D with placebo. RESULTS: A total of 25,871 participants, including 5106 black participants, underwent randomization. Supplementation with vitamin D was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). No excess risks of hypercalcemia or other adverse events were identified. CONCLUSIONS: Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .).

Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer.

BACKGROUND: Higher intake of marine n-3 (also called omega-3) fatty acids has been associated with reduced risks of cardiovascular disease and cancer in several observational studies. Whether supplementation with n-3 fatty acids has such effects in general populations at usual risk for these end points is unclear. METHODS: We conducted a randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (at a dose of 2000 IU per day) and marine n-3 fatty acids (at a dose of 1 g per day) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of the composite cardiovascular end point, the composite end point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from cancer. Safety was also assessed. This article reports the results of the comparison of n-3 fatty acids with placebo. RESULTS: A total of 25,871 participants, including 5106 black participants, underwent randomization. During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n-3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.24). Invasive cancer was diagnosed in 820 participants in the n-3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56). In the analyses of key secondary end points, the hazard ratios were as follows: for the expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); for total stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascular causes, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths from cancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any cause (978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). No excess risks of bleeding or other serious adverse events were observed. CONCLUSIONS: Supplementation with n-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .).

Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL).

Evidence for a role of supplemental vitamin D and marine omega-3 fatty acids in preventing cancer and cardiovascular disease (CVD) remains inconclusive and insufficient to inform nutritional recommendations for primary prevention. The VITamin D and Omega-A 3 TriaL (VITAL) is an ongoing nationwide, randomized, double-blind, placebo-controlled clinical trial designed to fill this knowledge gap. The study population consists of 25,874 U.S. adults without cancer or CVD at baseline, who were selected only on age (men aged ≥50 and women aged ≥55), with an oversampling of African Americans (n=5,107). In a 2 × 2 factorial design, participants were randomized to one of four supplement groups: [1] active vitamin D3 (cholecalciferol; 2000 IU/d) and active marine omega-3 fatty acids (Omacor® fish oil, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA], 1g/d); [2] active vitamin D and omega-3 placebo; [3] vitamin D placebo and active marine omega-3 fatty acids; or [4] vitamin D placebo and omega-3 placebo. The mean length of the randomized treatment period will be 5 years. The randomization was successful, as evidenced by similar distributions of baseline demographic, health, and behavioral characteristics across treatment groups. The similar distribution of known potential confounders across treatment groups strongly suggests that unmeasured or unknown potential confounders are also equally distributed. VITAL is expected to provide important information on the benefit-risk balance of vitamin D and omega-3 fatty acid supplementation when taken for the primary prevention of cancer and CVD.