Fish oil and atrial fibrillation: the AF signal in omega-3 trials

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For years, omega-3 fish oil was marketed to cardiac patients partly on the idea that it stabilized heart rhythm. The large cardiovascular outcome trials of the late 2010s and early 2020s delivered a surprise in the opposite direction: several reported a small but consistent excess of new-onset atrial fibrillation (AF) in the omega-3 arm. The signal is now reproducible across multiple major randomized trials and has been quantified in a pooled meta-analysis. It is dose-dependent, clinically relevant at pharmacologic doses, and almost never mentioned on supplement labels.

What the major trials reported

REDUCE-IT randomized 8,179 statin-treated patients with high cardiovascular risk and elevated triglycerides to 4 g/day of icosapent ethyl (a purified EPA ester) or placebo. The trial met its primary endpoint with a 25% reduction in ischemic events — but more patients in the icosapent group were hospitalized for atrial fibrillation or flutter (3.1% vs 2.1%, P=0.004) [1]. STRENGTH tested a different 4 g/day formulation — a mixed EPA/DHA carboxylic acid — against a corn-oil comparator in 13,078 similar patients. It was halted early for futility (no cardiovascular benefit; hazard ratio 0.99), and a prespecified safety analysis again found a higher rate of new-onset AF in the omega-3 arm [2]. The OMEMI trial took a more modest dose — 1.8 g/day of EPA+DHA — in elderly patients after a recent myocardial infarction. New-onset AF occurred in 7.2% on omega-3 versus 4.0% on corn-oil placebo (hazard ratio 1.84; 95% CI 0.98–3.45, P=0.06), a point estimate consistent with the other trials even though it did not reach statistical significance in this smaller study [3].

The pooled picture

A 2021 systematic review and meta-analysis in Circulation pooled seven cardiovascular outcome trials totaling 81,210 patients and found that marine omega-3 supplementation was associated with a 25% relative increase in AF (hazard ratio 1.25; 95% CI 1.07–1.46) [4]. Critically, the effect was dose-dependent: in trials testing more than 1 g/day the hazard ratio was 1.49 (95% CI 1.04–2.15), versus 1.12 (95% CI 1.03–1.22) in trials at 1 g/day or less, and a meta-regression estimated the risk rose by roughly 11% per additional gram per day. The absolute increase is modest in individual terms, but it is real and scales with dose.

Why omega-3 might promote AF

The mechanisms are not fully established. EPA and DHA incorporate into cardiomyocyte membranes and modulate ion-channel behavior and membrane properties; at high tissue concentrations these electrophysiologic effects appear capable of facilitating atrial arrhythmia in susceptible hearts. Notably, in secondary analyses of OMEMI the rise in AF risk tracked with the on-treatment increase in serum EPA specifically [3]. This dose-and-exposure relationship — neutral-to-protective at dietary intakes, increased risk at pharmacologic doses — is the throughline that makes the signal biologically plausible rather than a chance finding, though the precise pathway remains under study. (We have linked calcium here only as one of the cardiac ion systems discussed; the mechanism is not calcium-specific.)

Who is actually affected

The risk is concentrated in exactly the populations these trials enrolled: older adults, often with established cardiovascular disease, diabetes, hypertension, or prior MI, taking 1.8–4 g/day under prescription. A 70-year-old post-infarct patient on 4 g/day has a measurably higher AF risk; the trial evidence does not demonstrate a comparable risk for a healthy younger adult taking a typical 1 g/day supplement. Most over-the-counter fish oil capsules deliver only a few hundred milligrams of EPA+DHA each, and ordinary daily totals sit at or below the dose band where the meta-analysis still showed an effect — so even routine users are not entirely outside the dose-response curve, just much further down it.

The clinical takeaway

The AF signal does not erase the established triglyceride-lowering and (for icosapent ethyl specifically) ischemic-event benefits in the right patients — it changes the risk-benefit conversation, particularly for high-dose, self-directed use. The reasonable posture, reflected in how many cardiologists now practice, is to weigh baseline AF risk before starting high-dose omega-3, to ask about palpitations on follow-up, and to reconsider therapy if AF develops. Patients should not stop a prescribed omega-3 medication on their own; they should discuss it with the prescriber.

What this means for supplement users

At ordinary supplement doses (around 1 g/day or less of combined EPA+DHA), the absolute AF risk is low and most users can continue with reasonable reassurance. The caution applies to high-dose use — 3–4 g/day taken for triglyceride lowering or anti-inflammatory effect, and especially stacking a supplement on top of a prescription-strength formulation. Anyone with known paroxysmal AF, a prior cardioversion, or a history of palpitations should be particularly careful with high-dose products and should raise it with their clinician.

Sources

1. Bhatt DL, Steg PG, Miller M, et al. "Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia." N Engl J Med, 2019;380(1):11-22. PMID 30415628.
2. Nicholls SJ, Lincoff AM, Garcia M, et al. "Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial." JAMA, 2020;324(22):2268-2280. PMID 33190147.
3. Kalstad AA, Myhre PL, Laake K, et al. "Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction: A Randomized, Controlled Trial (OMEMI)." Circulation, 2021;143(6):528-539. PMID 33191772.
4. Gencer B, Djousse L, Al-Ramady OT, et al. "Effect of Long-Term Marine ω-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis." Circulation, 2021;144(25):1981-1990. PMID 34612056.
5. Myhre PL, Berge T, Kalstad AA, et al. "Omega-3 fatty acid supplements and risk of atrial fibrillation and 'micro-atrial fibrillation': A secondary analysis from the OMEMI trial." Clin Nutr, 2023;42(9):1657-1660. PMID 37515843.