Clinical trials of omega-3 fatty acid or vitamin D supplements have followed a long and winding road in search of benefits in cardiovascular (CV) disease, with wildly mixed results. But the journey may be in vain in one of cardiology’s frontier research areas, primary prevention of atrial fibrillation (AF), suggest primary results of the VITAL-Rhythm trial, presented November 13 during the American Heart Association (AHA) Scientific Sessions 2020 virtual meeting.

Neither marine-oil caps nor the vitamin D3 supplements made a difference to risk for incident AF, whether paroxysmal or persistent, over more than 5 years in the study, with more than 25,000 adults in the community. Nor did they seem to cause harm.

“To our knowledge, this is the first large-scale, long-term, randomized placebo-controlled trial to test the effect of any intervention on incident AF,” Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center in Los Angeles, California, said at a media briefing on VITAL-Rhythm before her formal presentation of the trial during the conference.

Its findings, she said, don’t support the use of marine-oil caps or vitamin D3 for primary prevention of incident AF. “Fortunately, they also do not show any increased risk in atrial fibrillation for patients who are using these supplements for other indications.”

Both agents are widely taken without physician supervision for their perceived benefits, and marine-oil caps in particular — often in special prescription formulations — may be used for reducing elevated triglyceride levels and, based on the results of REDUCE-IT, cutting cardiovascular risk.

“It’s pretty clear that there’s no evidence to suggest that either of these supplements is helpful for preventing atrial fibrillation. And I think that’s clear from the evidence these investigators presented,” said Jonathan P. Piccini, MD, MHS, Duke University, Durham, North Carolina, who wasn’t part of the study.

“It’s also a little disappointing because atrial fibrillation is such a huge problem, and the inability to identify preventative strategies is a repeated theme,” he told | Medscape Cardiology.

VITAL-Rhythm is an ancillary study within the VITAL trial, which showed no benefit from either supplement regarding risk for incident cancer or CV events, as reported at the AHA sessions 2 years ago. In fact, their effects seem sweepingly negative throughout the trial; in another ancillary study, VITAL-DKD, neither supplement helped preserve renal function over 5 years in patients with type 2 diabetes.

The participants started VITAL without a history of AF, CV disease, or cancer; they were randomly assigned to take about a gram of omega-3 fatty acids, 2000 IU vitamin D3 daily, or their placebos, in a double randomization.

VITAL and its ancillary studies collectively undercut mechanistic theories about how omega-3 fatty acid and vitamin D supplements may affect AF risk, ideas derived from epidemiologic and dietary studies. They were thought perhaps “to have direct antiarrhythmic effects on myocytes through effects on ion channels, electrical remodeling, electrical stabilizing effects, and fluidity of the cell membranes,” observed Renate B. Schnabel, MD, MSc, University Heart Center, Hamburg, Germany, at the briefing. Or such effects might be related to beneficial effects on atherosclerosis, inflammation, or ischemic heart disease, she noted.