Aspirin dose, urinary thromboxane and prostacyclin metabolites, and clinical outcome in acute coronary syndrome: A nested case-control study from CURRENT-OASIS 7.

BACKGROUND

Aspirin reduces urinary thromboxane, which predicts major adverse cardiovascular events (MACE) during aspirin therapy. However, in CURRENT-OASIS 7, higher-dose aspirin did not improve outcomes compared with lower-dose aspirin.

OBJECTIVES

To assess relationships between aspirin dose, urinary thromboxane and prostacyclin metabolites, and ischemic and bleeding outcomes, and to determine whether greater prostacyclin suppression with higher-dose aspirin explains the absence of clinical benefit.

METHODS

In a nested case-control study within CURRENT-OASIS 7, urinary 11-dehydro thromboxane B2 (11-dTXB2) and 2,3-dinor-6-keto-prostaglandin F1α, corrected for creatinine and expressed as ng/mmol creatinine, were measured in patients not taking nonsteroidal anti-inflammatory drugs. Cases had myocardial infarction, ischemic stroke, or non-hemorrhagic cardiovascular death (n = 275), or major bleeding (n = 137); controls had neither ischemic nor bleeding events (n = 1014). Associations were assessed with multivariable logistic regression by quartiles and restricted cubic splines.

RESULTS

Compared with aspirin 75-100 mg/day, aspirin 300-325 mg/day modestly lowered 11-dTXB2 (153.0 vs 164.3 ng/mmol creatinine; p = 0.03) and the 11-dTXB2/prostacyclin metabolite ratio (0.09 vs 0.10; p = 0.02) but not the prostacyclin metabolite (1767.1 vs 1694.5 ng/mmol creatinine; p = 0.25). Higher 11-dTXB2 quartiles predicted MACE, with adjusted odds ratios of 1.01, 2.38, and 3.44 for quartiles 2-4 versus quartile 1, whereas prostacyclin-metabolite quartiles did not. In spline analyses, 11-dTXB2 remained associated with MACE (p < 0.0001), whereas the prostacyclin metabolite did not (p = 0.67).

CONCLUSIONS

In acute coronary syndrome, higher-dose aspirin modestly reduced urinary thromboxane without lowering the urinary prostacyclin metabolite. These findings do not support the hypothesis that systemic prostacyclin suppression by higher dose aspirin offsets any benefits of greater thromboxane suppression.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT00335452.