Fish Oil, Vitamin D Don’t Prevent A-fib: VITAL Rhythm
“Having a definitive negative study that informs us about what we should not pursue is very important,” Clyde Yancy says.
Supplements containing omega-3 fatty acids or vitamin D3 are not the answer for the primary prevention of A-fib in middle-age men and women with no history of CV or cancer, results from the placebo-controlled VITAL Rhythm trial show.
Over a median follow-up of about 5 years, the risk of incident A-fib was not significantly lower—or higher—when participants took fish oil or vitamin D3 (HR 1.09; P = 0.19 for both), Christine Albert, MD (Smidt Heart Institute at Cedars-Sinai, Los Angeles, CA), reported during the virtual American Heart Association (AHA) 2020 Scientific Sessions.
“Our findings do not support the use or the practice of using marine omega-3 fatty acids or vitamin D to prevent atrial fibrillation,” she said. “However, we do need future primary prevention AF trials to test other promising agents, and I hope that this trial can serve as a road map for those.”
Former AHA President Clyde Yancy, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), who chaired a press briefing where the results were discussed, said the study provides valuable information. “Having a definitive negative study that informs us about what we should not pursue is very important and it also promises very, very important conversations about how we can prevent atrial fibrillation,” he commented.
Despite the need for effective primary preventive strategies for A-fib, no trials have been performed, mostly because of concerns about feasibility, Albert said. Dietary supplementation would be an ideal approach for primary prevention, she added, because it would be relatively easy to implement across broad populations.
Marine omega-3 fatty acids and vitamin D both touch on biologic processes related to the electrical and structural remodeling of the atria that can occur years before the development of A-fib, Albert said, noting that prior research has shown that low levels of both are associated with increased risks of incident A-fib. That suggests that supplementation would be beneficial for primary prevention, but large-scale randomized trials have been lacking.
VITAL Rhythm is an ancillary study of the main VITAL trial, which showed that vitamin D and marine omega-3 fatty acid supplements do not reduce risks of major CVD events or cancer. In the 2x2 factorial trial, participants received vitamin D3 at a dose of 2000 IU/day, omega-3 fatty acids—a mix of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—at a dose of 1 g/day, or both. Men had to be at least 50 years old and women at least 55 years old; all had to be free of a history of CVD or cancer.
VITAL Rhythm included almost all of the larger trial’s participants, with 25,119 contributing to the final analysis. Mean age was 67 years, 51% of the participants were women, and 20.1% were Black.
In the pragmatic trial design, participants received study pills by mail and completed baseline and annual questionnaires to provide information on health status. When new diagnoses of A-fib were reported, the investigators obtained permission to review Centers for Medicare & Medicaid Services claims data, and they confirmed A-fib by reviewing medical records.
During follow-up, 3.6% of participants had a confirmed A-fib event, confirmed by ECG in 72.9% and medical record review in the rest. A-fib was paroxysmal in 58.4% and permanent in 38.4%; it could not be classified in 3.1%. Most patients (61.9%) were symptomatic at diagnosis.
The risk of incident A-fib was no different compared with placebo for either omega-3 fatty acids (HR 1.09; 95% CI 0.96-1.24) or vitamin D3 (HR 1.09; 95% CI 0.96-1.25). The findings were consistent in various sensitivity analyses and an on-treatment analysis.
Albert acknowledged that the trial was limited by the lack of monitoring for A-fib and some episodes may have been missed. That issue, however, should be balanced between the trial arms, she said.
Leading the Way for Future Trials
Serving as a discussant for the study, Renate Schnabel, MD, PhD (University Heart & Vascular Center Hamburg, Germany), said much can be learned from VITAL Rhythm in spite of its neutral results, noting that “the field is moving towards more pragmatic trials.”
Though traditional randomized controlled trials remain the gold standard, they are often very expensive and inefficient, she said. Pragmatic trials, on the other hand, can be run at comparatively lower costs, enroll large sample sizes, and capture representative populations. They can also be embedded in routine clinical care processes and, as in this trial, use remote and mail-based interventions. Trial designs are usually similar compared with RCTs. “They may require an infrastructure that facilitates easy and quick enrollment, and they can leverage electronic health data,” Schnabel said, noting that in the field of A-fib, such studies will be supported by novel technologies for rhythm monitoring.
There are upcoming substudies of VITAL Rhythm delving into phenotypes based on echocardiography and ECG that will provide further insights, Schnabel said.
VITAL Rhythm “sets the stage for primary prevention trials in atrial fibrillation,” she concluded. “In the future, the detection of atrial fibrillation will be enhanced by wearables, but for now it paves the way for pragmatic trial designs in primary prevention, in particular in atrial fibrillation.”
Albert C. The VITAL Rhythm trial: omega-3 fatty acid and vitamin D supplementation in the primary prevention of atrial fibrillation. Presented at: AHA 2020. November 14, 2020.
- VITAL Rhythm was supported by a grant from the National Heart, Lung and Blood Institute (NHLBI), and VITAL was supported by the National Cancer Institute, NHLBI, the Office of Dietary Supplements, the National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health. Pharmavite LLC (vitamin D3) and Pronova BioPharma/BASF (Omacor fish oil) donated the study agents, matching placebos, and packaging in the form of calendar packs.
- Albert reports grant support from St. Jude Medical, Abbott, and Roche Diagnostics.
- Schnabel reports no relevant conflicts of interest.