Simvastatin administration reduces thromboxane production in subjects taking aspirin: links between aspirin resistance and thrombin generation

Background

Growing evidence indicates that statins may reduce thromboxane A₂ synthesis and thrombin generation. We investigated the relationships between thromboxane production, thrombin generation, and oxidative stress in patients receiving aspirin before and after statin administration.

Methods

An open-label study was conducted in 112 men, aged 54.4 ± 7.3 years, at an increased cardiovascular risk receiving aspirin (75 mg/d). Prior to and following a 3-month simvastatin treatment (40 mg/d), we evaluated circulating thromboxane B₂ (TXB₂), inflammatory markers, 8-isoprostane, and prothrombin fragment 1.2 (F1.2), a marker of thrombin generation, which was also measured in blood collected every 60 s at the site of standardized skin incisions.

Results

Subjects (n = 28) with pretreatment TXB₂ concentrations in the highest quartile (“aspirin-resistant patients”) were more frequently current smokers and had elevated C-reactive protein (CRP), interleukin-6, 8-isoprostane, shorter bleeding time, and increased F1.2 production in a model of microvascular injury, when compared with the 3 remaining quartiles (all, p < 0.001). Simvastatin decreased serum TXB₂ in the whole group (by 20%, p = 0.0008). Patients in the highest quartile of the baseline TXB₂ had still higher posttreatment TXB₂, CRP, interleukin-6, and F1.2 formation following injury (all, p < 0.001). Simvastatin-induced change in TXB₂ correlated with the magnitude of changes in maximum levels and the velocity of F1.2 formation (all p < 0.001) but not with changes in inflammatory markers or lipid profile.

Conclusions

The study shows that statins significantly reduce platelet TXA₂ formation in patients taking low-dose aspirin and this effect is associated with attenuated thrombin formation in response to vascular injury.