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Neither mega-3 nor vitamin D supplementation prevent atrial fibrillation

Among adults aged 50 years or older, treatment with neither marine omega-3 fatty acids nor vitamin D3, resulted in significant difference in the risk of incident atrial fibrillation (Afib) over more than five years, found a US study in JAMA.

Adults showed no reduction in incident atrial fibrillation (Afib) over a median 5.3 years of daily treatment with omega-3 fatty acids (3.7% vs 3.4% with olive oil placebo, HR 1.09, 95% CI 0.96-1.24) or vitamin D3 supplementation (3.7% vs 3.4% with soybean oil placebo, HR 1.09, 95% CI 0.96-1.25), reported Dr Christine Albert, of Cedars-Sinai Medical Centre in Los Angeles, and colleagues.

MedPage Today reports that there was no interaction between the two treatments in the 2×2 factorial randomised trial. Results remained nonsignificant when individuals were censored for nonadherence, they stated.

Hypothesis-generating subgroup findings included Afib risk being modestly increased in taller individuals taking fish oil, as well as younger people and those who drank less alcohol on vitamin D3 supplementation.

VITAL Rhythm was an ancillary study embedded in the VITAL trial that randomised people to daily supplementation with omega-3 fatty acids – an 840-mg mix of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) – and/or vitamin D3 (2,000 IU) or matching placebos. Included were 25,119 people without prior cardiovascular disease, cancer, or Afib who were ages 50 or older.

"Overall, these findings do not support the use of supplemental EPA-DHA or vitamin D3 for the primary prevention of Afib and provide reassurance regarding lack of a major risk of Afib incidence associated with these commonly used supplements at these doses," Albert's group said.

It had been suggested that omega-3 fatty acids and vitamin D might prevent Afib due to their electrophysiologic effects on atrial structural and electrical remodeling. "Although it is feasible that benefits might have accrued if treatment and follow-up were continued beyond 5 years, the observed cumulative incidence curves and HRs suggest that this would be unlikely," the authors noted.

Yet several other trials have shown higher doses of omega-3 fatty acids to increase a person's risk of developing Afib.

REDUCE-IT participants on icosapent ethyl (Vascepa) 4 g/day had a 48% higher risk of hospitalisation for Afib over placebo, and the STRENGTH trial showed a 69% increase in new-onset Afib with a mix of EPA and DHA 4 g/day. The intermediate dose of EPA 1.8 g/day in the OMEMI trial was associated with a nonsignificant increase in incident Afib.

"Considered together, the data from the four trials suggest, but do not prove, that there may be a dose-related risk of Afib with omega-3 fatty acid intake," according to an accompanying note by Dr Gregory Curfman.

"Patients who choose to take omega-3 fatty acids, especially in high doses, should be informed of the risk of Afib and followed up for the possible development of this common and potentially hazardous arrhythmia," Curfman urged.

VITAL Rhythm participants averaged age 66.7 and were roughly split between the sexes. About one in five individuals were Black.

Treatment groups shared similar 80%-82% rates of adherence to study drug and taking at least two-thirds of trial capsules. Outside supplement use remained below 3.5% for fish oil and ranged from 3.8% to 10.8% for vitamin D at 5 years.

Investigators tracked incident Afib through annual patient questionnaires and linked CMS claims data. Afib was categorized as paroxysmal at the time of diagnosis in 58% of cases and persistent in 38.4%.

Asymptomatic and paroxysmal cases of Afib were likely under-detected in the study, Albert and colleagues acknowledged. Their findings also may not be generalisable to younger populations or to patients with established cardiovascular disease.

"To our knowledge, this study is the first randomised, placebo-controlled trial to prospectively test the effect of any intervention on incident Afib and is the only trial to test alternative upstream preventive agents for Afib in a large enough population over a long enough time period to provide an assessment of the plausible benefits and risks," the authors maintained.


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

Christine M Albert; Nancy R Cook; Julie Pester; M Vinayaga Moorthy; Claire Ridge; Jacqueline S Danik; Baris Gencer; Hasan K Siddiqi; Chee Ng; Heike Gibson; Samia Mora; Julie E Buring; JoAnn E Manson

Published in JAMA on 16 March 2021

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.
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.
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.
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.


[link url=""]Full MedPage Today report (Restricted access)[/link]


[link url=""]JAMA study (Restricted access)[/link]


[link url=""]JAMA editor’s note (Open access)[/link]

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