Clinical Context

Omega-3 fatty acid supplements are used by millions of people around the world, although many clinical trials of eicosapentaenoic acid/docosahexaenoic acid (EPA/DHA) supplements have failed to demonstrate a benefit in terms of cardiovascular health. An exception to this trend for omega-3 fatty acid supplements was the REDUCE-IT trial, which featured a purified form of icosapent ethyl. The results of this major study were published in the January 3, 2019, issue of the New England Journal of Medicine.

A total of 8179 adults, 71 of whom had a prior history of cardiovascular disease and all of whom had received statin therapy, were randomly assigned to receive icosapent ethyl 2 g twice daily, or placebo. During a mean follow-up period of nearly 5 years, the icosapent ethyl cohort experienced a 25% relative reduction in the primary combined outcome of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, cardiac revascularization, and unstable angina. Limiting these combined outcomes to cardiovascular death, MI, and stroke resulted in a similar benefit associated with icosapent ethyl. Icosapent ethyl was associated with a 20% reduction in the risk for cardiovascular death versus placebo.

However, eicosapent ethyl was also associated with a nonsignificant trend toward a higher rate of bleeding events, and the rates of incident atrial fibrillation (AF) in the icosapent ethyl and placebo groups were 3.1% and 2.1%, respectively (P=.004). The current study puts EPA-DHA as well as vitamin D supplements to the test in the prevention of AF.

Study Synopsis and Perspective

There may be a dose-related risk for AF with omega-3 fatty acid intake, data from 4 randomized clinical trials suggest.

The latest trial to evaluate the association, the VITAL-RHYTHM study, showed that using a low dose of omega-3 fatty acids or a vitamin D supplement had no significant effect on the risks of developing incident AF.

The trial, first reported at last year's American Heart Association meeting, was published in JAMA.^[2,3]

Together with 3 other randomized clinical trials, however, these results suggest a possible dose-related effect of omega-3 fatty acids on the risk for AF, an accompanying Editor's Note suggests.^[4]

The note, by JAMA deputy editor Gregory Curfman, MD, points out that in the past 2 years, 4 randomized clinical trials have provided data on the risk for AF with omega-3 fatty acid intake.

In the STRENGTH and REDUCE-IT trials, both of which evaluated high doses (4 g/day) of omega-3 fatty acids in patients with heart disease (or at high risk for it), there was a highly statistically significant increase in risk for AF in the omega-3 groups vs control in both trials.^[5,6]

In the OMEMI trial in elderly patients with a recent MI, an intermediate dose of (1.8 g/day) of omega-3 fatty acids also showed an increase in AF risk (hazard ratio, 1.84), but this was not significant.^[7] And now, the VITAL-RHYTHM trial shows no significant effect of a low dose (840 mg/day) of omega-3 fatty acids on the risk of developing AF in a primary prevention population.

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

The authors of the VITAL-RHYTHM trial, led by Christine M. Albert, MD, MPH, from Cedars-Sinai Medical Center, Los Angeles, California, explain that the trial was conducted after observational studies had shown that individuals with low blood levels of omega-3 fatty acids, EPA and DHA, and vitamin D3 have higher risks for incident AF, but data on dietary or supplemental intake of these nutrients on AF risk were mixed.

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

The VITAL-RHYTHM study was an ancillary trial embedded within the Vitamin D and Omega-3 (VITAL) trial, which used a 2x2 factorial design to evaluate daily supplementation with 2000 IU vitamin D3 and/or 840 mg marine omega-3 fatty acids (460 mg EPA and 380 mg DHA) in the primary prevention of cardiovascular disease and cancer in 25,871 men and women aged 50 years and older in the United States.

Results showed that during a median 5.3 years of treatment and follow-up, the primary endpoint of incident AF occurred in 3.6% of the study population. For the omega-3 part of the trial, incident AF events occurred in 3.7% of patients taking EPA/DHA vs 3.4% of the placebo group, giving a hazard ratio of 1.09, which was not significant (P=.19).

For the vitamin D3 vs placebo comparison, results were very similar, with incident AF events occurring in 3.7% vs 3.4% of participants, respectively, giving a hazard ratio of 1.09, which was again not significant (P=.19). "There was no evidence for interaction between the 2 study agents," the authors note.

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

Noting that significant increases in AF have been seen with much higher doses of omega-3 fatty acids in the REDUCE-IT and STRENGTH trials, they add: "Potentially, the adverse effect on AF risk may be dose related, and the higher dosages of EPA used in these other studies might account for the significant adverse effect on AF."

The researchers add that, to their knowledge, this is the only randomized trial to assess the effect of vitamin D3 supplementation on AF risk, and the results suggest a null effect. They add that subgroup analyses in patients with vitamin D levels considered deficient (<20 ng/mL) did not suggest a benefit; however, the power to detect a benefit in this much smaller subset of the population was limited.

They point out that although there were no significant differences in incident AF for either omega-3 fatty acid or vitamin D in the overall study population, an increased risk for incident AF associated with randomized treatment was observed in selected subgroups.

For omega-3 fatty acids, AF risk was modestly increased in taller individuals, and for vitamin D3, elevations in AF risk were observed in younger individuals and participants who drank less alcohol.

"Although the [hazard ratios] and tests for interaction were significant, the P values associated with these subgroup analyses have not been adjusted for multiple comparisons. Thus, these findings should be interpreted with caution and considered hypothesis generating," they warn.

The VITAL Rhythm Study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr Albert reported receipt of grants from St Jude Medical, Abbott, and Roche Diagnostics. Dr Curfman reports no relevant disclosures.

JAMA. Published online March 16, 2021.

Clinical Implications

• In REDUCE-IT, icosapent ethyl was superior to placebo in reducing a composite of cardiovascular events and cardiovascular death, but it was also associated with a mild increase in the risk for AF.
• The current study fails to find any benefit of EPA-DHA, vitamin D, or both supplements in the prevention of incident AF.
• Implications for the healthcare team: The healthcare team should not recommend vitamin D or EPA-DHA for the prevention of AF.

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