Observational and clinical trial evidence suggests an inverse association of omega-3 polyunsaturated fatty acids with coronary artery disease (CAD) mortality, although relationships with non-fatal CAD and stroke are less clear. We investigated whether omega-3 fatty acid supplement use and fish intake were associated with incident non-fatal CAD and ischemic stroke among US Veterans.The Million Veteran Program (MVP) is an ongoing nation-wide longitudinal cohort study of US Veterans with self-reported survey, biospecimen, and electronic health record data. Regular use of omega-3 supplements (yes/no) and frequency of fish intake within the past year were assessed using a food frequency questionnaire. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations of omega-3 supplement use and fish intake with incident non-fatal CAD and ischemic stroke, defined from electronic health records using validated algorithms. Multivariable models included demographics, body mass index, education, smoking status, alcohol intake, and exercise frequency.Among 197,761 participants with food frequency data (mean age: 66 ± 12 years, 92% men), 21% regularly took omega-3 supplements and median fish intake was 1 (3-5 ounce) serving/week. Over a median follow-up of 2.9 years for non-fatal CAD and 3.3 years for non-fatal ischemic stroke, we observed 6265 and 4042 incident cases of non-fatal CAD and non-fatal ischemic stroke, respectively. Omega-3 fatty acid supplement use was independently associated with a lower risk of non-fatal ischemic stroke [HR (95% CI): 0.88 (0.81, 0.95)] but not non-fatal CAD [0.99 (0.93, 1.06)]. Fish intake was not independently associated with non-fatal CAD [1.01 (0.94, 1.09) for 1-3 servings/month, 1.03 (0.98, 1.11) for 1 serving/week, 1.02 (0.93, 1.11) for 2-4 servings/week, and 1.15 (0.98, 1.35) for ≥5 servings/week, reference = <1 serving/month, linear p-trend = 0.09] or non-fatal ischemic stroke [0.92 (0.84, 1.00) for 1-3 servings/month, 0.93 (0.85, 1.02) for 1 serving/week, 0.96 (0.86, 1.07) for 2-4 servings/week, and 1.13 (0.93-1.38) for ≥5 servings/week, linear p-trend = 0.16].Neither omega-3 supplement use, nor fish intake, was associated with non-fatal CAD among US Veterans. While omega-3 supplement use was associated with lower risk of non-fatal ischemic stroke, fish intake was not. Randomized controlled trials are needed to confirm whether omega-3 supplementation is protective against ischemic stroke in a US population.
