A Randomized trial of aspirin at clinically relevant doses and nitric oxide formation in humans

Background: We performed the first test in humans of whether aspirin at clinically relevant doses increases nitric oxide (NO) formation. Methods: Seventy primary prevention patients with metabolic syndrome were randomly assigned to 81 mg, 162.5 mg, 325 mg, 650 mg, or 1300 mg aspirin daily for 12 weeks to test changes in heme oxygenase (HO-1), a downstream target of NO formation and asymmetrical dimethylarginine (ADMA), a competitive inhibitor of NO synthase. Findings: For HO-1, the mean was 29.37 nanograms per milliliter at baseline and 57.45 at 12 weeks giving a mean ratio (MR) of 1.96 (P <.001) and 95% confidence interval (CI) from 1.91 to 2.00. There was no effect modification by dose or gender (P =.341). For ADMA, the mean was 1.70 micromoles per liter at baseline and 0.81 at 12 weeks, giving an MR of 0.48 (P <.001) and CI from 0.46 to 0.49. There was no effect modification by dose but a possible difference by gender (P =.055). Interpretation: In high-risk primary prevention patients, aspirin significantly increases markers of NO formation. All doses produce similar increases in HO-1 and decreases in ADMA. The antiplatelet properties of aspirin to irreversibly inhibit platelet dependent cyclooxygenase are sufficient to explain benefits in patients with occlusive vascular diseases. Nonetheless, these data contribute to the formulation of the hypothesis that aspirin has additional beneficial effects mediated through NO formation. Further research, including direct randomized comparisons on atherosclerosis using noninvasive techniques as well as on occlusive vascular disease events, is necessary to test whether this hypothesis has clinical or public health relevance.