The cardiovascular evidence for omega-3 fatty acids has evolved considerably. Early observational studies of fish-eating populations (notably Greenland Inuit) suggested dramatic cardioprotection, but the interventional trial landscape is more nuanced.
The REDUCE-IT trial (Bhatt et al., 2019) randomized 8,179 patients with established cardiovascular disease or diabetes plus additional risk factors, all on statin therapy with residual hypertriglyceridemia (135-499 mg/dL), to icosapent ethyl 4 g/day or mineral oil placebo. The primary composite endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina) was reduced by 25% (HR 0.75; 95% CI 0.68-0.83; p<0.001). Key secondary endpoints including cardiovascular death were also significantly reduced [1]. The magnitude of benefit exceeded what triglyceride lowering alone would predict, suggesting pleiotropic mechanisms including anti-inflammatory, antithrombotic, and membrane-stabilizing effects.
The VITAL trial (Manson et al., 2019) took a different approach, studying primary prevention in 25,871 generally healthy adults randomized to 1 g/day of combined EPA+DHA or placebo using a 2x2 factorial design with vitamin D. While the primary composite endpoint of major cardiovascular events was not significantly reduced (HR 0.92; 95% CI 0.80-1.06), the prespecified secondary endpoint of total MI was reduced by 28% (HR 0.72; 95% CI 0.59-0.90). Subgroup analyses showed greater benefit among African Americans and those with low baseline fish intake [2].
The AHA Science Advisory (Siscovick et al., 2017, updated 2019) affirmed that prescription omega-3 therapy is reasonable for reducing triglycerides at doses of 4 g/day, and that 1 g/day EPA+DHA is reasonable for secondary prevention of coronary heart disease and sudden cardiac death [4]. The Advisory notes the distinction between prescription-grade concentrated formulations and over-the-counter supplements, which vary in EPA/DHA content and purity.
Hu et al. (2019) conducted an updated meta-analysis of 13 randomized trials encompassing 127,477 participants and found a significant 8% reduction in CHD risk (RR 0.92; 95% CI 0.86-0.99) with marine omega-3 supplementation. Critically, marine omega-3 dosage was linearly associated with CHD risk reduction, with each 1 g/day increment associated with a 5.8% reduction (p=0.0063) [5]. This dose-response relationship helps reconcile earlier null trials that used lower doses.
The American Heart Association continues to recommend at least two servings of fatty fish per week for the general population, and to consider omega-3 supplementation for patients with prevalent CHD or heart failure [3].