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Fish oil supplements and vitamin D didn't reduce incidence of atrial fibrillation (Afib, AF) in a primary prevention setting in the .

In fact, the hazard ratio for new-onset arrhythmia went in the wrong direction for the low-dose mixed and fatty acid pills used, with a point estimate favoring placebo (HR 1.09, 95% CI 0.96-1.24), Christine M. Albert, MD, MPH, of Cedars-Sinai Medical Center in Los Angeles, reported at the .

The same was true for vitamin D3 (HR 1.09, 95% CI 0.96-1.25) given in this two-by-two factorial design study ancillary to the landmark VITAL trial.

These findings add to VITAL's negative primary results, reported at the AHA meeting in 2018, with neither fish oil capsules nor vitamin D reducing major cardiovascular events or cancer.

A sensitivity analysis looking at only on-treatment incidence showed a trend for more Afib events in the fish oil group (HR 1.13, P=0.09).

In the large REDUCE-IT outcomes trial with the prescription fish-oil product icosapent ethyl (Vascepa), hospital admissions for Afib or atrial flutter were more common with the agent than with placebo (3.1% vs 2.1%, P=0.004).

However, Albert dismissed the possibility of a substantial risk.

"Our findings do not support the use of EPA or DHA or vitamin D3 for primary prevention of incident AF," she said at a press conference for the late-breaking clinical trial. "Fortunately, they also do not show any increased risk in atrial fibrillation for patients who are using these supplements for other indications."

The trial was powered to rule out a 20% impact on risk, positive or negative, so a smaller difference remains possible, she told 麻豆传媒. But while the curves appeared to be separating later in the 5.3-year study period, the test for interaction of treatment effect by time was not significant, she said. "I don't think if we followed people longer we would have found something. Had we had more people, it's possible."

"Prevention is the hardest thing to study and prove," commented Marc Pfeffer, MD, PhD, of Brigham and Women's Hospital in Boston. With this "definitive answer," he said at the press conference, "we can save our nutritional dollars."

AHA session discussant Renate Schnabel, MD, MSc, of University Heart Center in Hamburg, Germany, noted how popular such over-the-counter supplements are.

"Having a definitive negative study that informs us about what we should not pursue is very important," agreed Clyde Yancy, MD, past president of the AHA and press conference moderator. "It also prompts these very important conversations about how we can prevent atrial fibrillation."

Other strategies for primary prevention are still worth trying, such as weight loss, blood pressure reduction, lifestyle changes, Albert said. "I hope this trial can provide a roadmap for how these primary prevention trials can be performed."

Prior studies had suggested higher rates of Afib in people with low omega-3 fatty acid and vitamin D levels, but observational findings have gone in all directions for cardiovascular event prevention, Albert noted. There hadn't been any large prevention trials in Afib for any agents.

Other fish oil supplement trials are slated for presentation later at the AHA meeting, including the in an elderly population with acute myocardial infarction and the STRENGTH trial, from which suggested lack of efficacy in mixed dyslipidemia patients at high cardiovascular risk.

The VITAL-Rhythm trial included 25,119 men age 50 and older and women 55 and older with no history of cardiovascular disease, cancer, or Afib.

Participants were randomized double-blind to take placebo or 2,000 IU vitamin D3 as well as placebo or 840 mg of omega-3 fatty acids (Omacor, 1 g/day), which includes 460 mg EPA. The only positive fish oil trial to date -- REDUCE-IT -- provided 4,000 mg per day of EPA.

VITAL-Rhythm's placebos were olive oil for the omega-3 fatty acid comparison and soybean oil for the vitamin D comparison. REDUCE-IT has been criticized for its use of mineral oil as a placebo.

VITAL-Rhythm looked for clinical diagnoses of Afib (recorded on annual follow-up questionnaires or confirmed by medical record review of events that turned up in Medicare or Medicaid claims), so brief and asymptomatic Afib could have been under-ascertained. But, Albert noted, the prognostic significance of those cases are less clear.

"Everybody wants to show that something simple you can take every day will benefit you, because the risks seem to be low," Albert told 麻豆传媒. "That's why it's important to study all these different endpoints to make sure that there isn't any risk."

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