Large trials of fish oil for cardiovascular disease prevention have yielded conflicting results. The 2018 REDUCE-IT trial randomized 8,179 high-risk patients on statins with elevated triglycerides to icosapent ethyl (a purified ethyl ester formulation of EPA) or mineral oil placebo. After a median of 4.9 years, icosapent ethyl reduced the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, and unstable angina by 25% (hazard ratio, 0.75; 95% CI, 0.68 to 0.83; P<0.001). In contrast, the 2020 STRENGTH trial randomized 13,078 similar patients to an omega-3 carboxylic acid formulation (EPA plus DHA) or corn oil placebo and was stopped early for futility, showing no cardiovascular benefit. The divergent findings have left clinicians uncertain about the role of fish oil in cardiovascular prevention.

Patients receiving maintenance hemodialysis are at substantially greater risk of cardiovascular events, with a cardiovascular mortality that is approximately 20 times higher than that of the general population. To determine whether fish oil could reduce this risk, researchers conducted the PISCES (Protection against Incidences of Serious Cardiovascular Events Study) trial. In this double-blind, randomized, placebo-controlled trial, 1,228 adults receiving maintenance hemodialysis at 26 sites in Canada and Australia were assigned to daily fish oil (4 g containing 1.6 g EPA and 0.8 g DHA) or corn-oil placebo. The primary endpoint was a composite of serious cardiovascular events (cardiac death, fatal and nonfatal myocardial infarction, peripheral vascular disease leading to amputation, and fatal and nonfatal stroke). During 3.5 years of follow-up, the rate of serious cardiovascular events was significantly lower in the fish-oil group (0.31 vs. 0.61 per 1000 patient-days; hazard ratio, 0.57; 95% CI, 0.47 to 0.70; P<0.001). Hazard ratios for cardiac death, fatal and nonfatal myocardial infarction, and fatal and nonfatal stroke were 0.55, 0.56, and 0.37, respectively. Adherence and adverse events did not differ meaningfully between groups.

The PISCES investigators offered several explanations for why their trial showed benefit when STRENGTH did not:

• Antiarrhythmic effects: Fish oil may reduce arrhythmias by inhibiting cardiomyocyte sodium and calcium currents and prolonging the refractory period. Hemodialysis creates a proarrhythmic milieu due to rapid shifts in fluid, electrolytes, and calcium. This rationale is ironic, given that other fish oil trials have shown an increased risk of atrial fibrillation with omega-3 supplementation.
• Low baseline omega-3 levels: Patients receiving hemodialysis have markedly lower levels of EPA and DHA in serum phospholipids than the general population. Supplementation may be especially beneficial when baseline levels are deficient.
• Formulation differences: PISCES used the ethyl ester formulation (as in REDUCE-IT), which is absorbed more slowly than the carboxylic acid form used in STRENGTH. The rapid absorption of the free fatty acid formulation in STRENGTH may have contributed to greater gastrointestinal adverse effects (24.7% vs. 14.7% in the placebo group) and potentially reduced adherence.
• Placebo choice: PISCES used corn oil as placebo rather than mineral oil. REDUCE-IT’s use of mineral oil as placebo has been criticized because mineral oil may have adverse effects (e.g., reduced absorption of statins and fat-soluble vitamins) that could have inflated the apparent benefit of icosapent ethyl. Corn oil is believed to have a more neutral effect.

PISCES contradicts STRENGTH but is consistent with REDUCE-IT. Whether fish oil reduces cardiovascular events may depend on formulation, dose, baseline omega-3 levels, patient population, and placebo choice. Until these factors are clarified, the overall effects of fish oil on cardiovascular disease remain inconclusive.

• Fish-Oil Supplementation and Cardiovascular Events in Patients Receiving Hemodialysis, NEJM (2025) [PubMed abstract]
• Fish oil review