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Neither fish oil nor vitamin D supplementation worked in the long-term primary prevention of atrial fibrillation (Afib), according to the VITAL Rhythm study.

Adults showed no reduction in incident 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 Christine Albert, MD, MPH, of Cedars-Sinai Medical Center in Los Angeles, and colleagues.

There was no interaction between the two treatments in the 2×2 factorial randomized trial. Results remained nonsignificant when individuals were censored for nonadherence, they stated in . Top-line results of the study were reported at the 2020 American Heart Association virtual meeting.

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 randomized 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.

participants on icosapent ethyl (Vascepa) 4 g/day had a 48% higher risk of hospitalization 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 by Gregory Curfman, MD, JAMA deputy editor.

"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 underdetected in the study, Albert and colleagues acknowledged. Their findings also may not be generalizable to younger populations or to patients with established cardiovascular disease.

"To our knowledge, this study is the first randomized, 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.

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