Letter by cattaneo regarding article, "incomplete inhibition of thromboxane biosynthesis by acetylsalicylic Acid: determinants and effect on cardiovascular risk".

Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid: Determinants and Effect on Cardiovascular Risk” To the Editor: In their article about 3261 aspirin-treated patients enrolled in the Clopidogrel for the High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial,1 Eikelboom et al suggest that incomplete inhibition of platelet thromboxane biosynthesis by aspirin is associated with heightened cardiovascular risk on the basis of the finding that high urinary concentrations of the thromboxane A2 metabolite, 11-dehydrothromboxane B2, were associated with increased risk for cardiovascular events. Among the limitations of this study that have been acknowledged by the authors, the choice of urinary 11-dehydrothromboxane B2 concentrations as a measure of aspirin’s antiplatelet effects is the most relevant and potentially misleading. The urinary levels of 11-dehydrothromboxane B2 represent a time-integrated index of thromboxane A2 biosynthesis in vivo.2 Detection of this metabolite in the urine reflects systemic thromboxane A2 formation, which does not exclusively occur in the platelets. Calculations show that 30% of the urinary metabolite derives from extraplatelet sources3 and that this fraction increases in inflammatory conditions. Inflammatory cells produce thromboxane A2 via the cyclooxygenase (COX) isoform COX-2, which is minimally affected by the low doses of aspirin used in the clinical setting to completely inhibit the COX-1–dependent platelet function. Therefore, measurement of urinary levels of 11-dehydrothromboxane B2 is not specific for monitoring the effects of aspirin on platelets. Considering that atherothrombosis is an inflammatory disease, a possible alternative interpretation of the results published by Eikelboom et al is that high urinary levels of 11-dehydrothromboxane B2 reflect an increased generation of COX-2–dependent prostaglandins and thromboxanes by monocytes/macrophages in severely inflamed atherosclerotic plaques, which are at high risk of thrombotic complication. Perhaps the association between the urinary concentration of 11-dehydrothromboxane B2 and cardiovascular events in the study would disappear after adjustment for other markers of inflammation, such as C-reactive protein, which is associated with heightened cardiovascular risk.4 Several findings are compatible with the hypothesis that high urinary levels of 11-dehydrothromboxane B2 are not caused by insufficient inhibition of the platelet COX-1 by aspirin: (1) aspirin at higher doses ( 150 mg/d) than those required to inhibit platelet COX-1 completely ( 75 mg) was associated with lower urinary concentration of 11-dehydrothromboxane B2 (presumably because at high doses aspirin partially inhibits COX-2); (2) no association was found between urinary levels of 11-dehydrothromboxane B2 and the risk of bleeding (which increases with the degree of inhibition of platelet function); (3) an association was found between low levels of 11-dehydrothromboxane B2 and treatment with nonsteroidal antiinflammatory drugs (which inhibit COX-2) and statins, which have antiinflammatory effects4; and (4) an association was found between high levels of urinary 11-dehydrothromboxane B2 and female sex, which is not consistent with the report that women display similar or even greater inhibition of COX-1–dependent platelet activation pathways compared with men.5