Aspirin Dosing Frequency and Dose Influence Thromboxane Suppression Despite Uniform Inhibition of Arachidonic Acid-induced Platelet Aggregation

Abstract Incomplete thromboxane suppression with 81 mg aspirin daily is common and predicts higher vascular risk. We compared the effects of aspirin in controls and patients with cardiovascular disease and tested strategies to improve thromboxane suppression. Two-phase randomized, open-label pharmacodynamic study. In Phase 1, controls and patients received enteric-coated (EC) aspirin 81 mg daily for 3 weeks. In Phase 2, the best responders within each cohort were randomized to EC aspirin 81 mg daily, EC aspirin 81 mg alternate daily, or soluble aspirin 81 mg daily, and the poorest responders to EC aspirin 81 mg daily, 325 mg daily, or 162 mg twice daily. Where results with EC and soluble aspirin 81 mg daily were similar, these arms were pooled for comparisons of daily versus alternate daily dosing. Outcome measures were light transmission aggregation in response to arachidonic acid, adenosine diphosphate, and collagen; serum thromboxane B2 (sTXB2); and urinary 11-dehydro-thromboxane B2 (uTXB2; creatinine-normalized). We enrolled 136 controls and 115 patients. Among controls, EC aspirin 81 mg daily suppressed platelet aggregation and reduced sTXB2 from 238.4 to 2.7 ng/mL and uTXB2 from 112.0 to 39.0 ng/mmol creatinine (all p < 0.0001). After 3 weeks, aggregation and serum thromboxane were similar in controls and patients but uTXB2 remained higher in patients (46.5 vs. 39.0, p = 0.004). In Phase 2, different aspirin formulations, doses, and dose frequencies did not materially affect platelet aggregation. In the best responders, EC and soluble aspirin had similar effects on thromboxane, but sTXB2 levels were higher with alternate daily versus daily dosing (pooled EC and soluble) in both controls (8.1 vs. 2.2 ng/mL, p = 0.005) and patients (5.2 vs. 1.7 ng/mL, p = 0.048). In the poorest responders, EC aspirin 162 mg twice daily produced the greatest suppression of both sTXB2 and uTXB2, with intermediate suppression with EC aspirin 325 mg daily and the least with EC aspirin 81 mg daily (all trend P values <0.05). Daily low-dose aspirin suppresses aggregation and serum thromboxane, but urinary thromboxane metabolites are less completely suppressed in patients with established cardiovascular disease. Alternate daily dosing attenuates thromboxane suppression, whereas divided dosing improves suppression in the poorest responders.