Combined effects of aspirin and the novel antiplatelet agent clopidogrel on platelet function in vivo and in vitro

Abstract Background The platelet adenosine 5′-diphosphate (ADP) receptor antagonist clopidogrel has proved an effective antiplatelet agent in the prevention of arterial thrombosis. In the vast majority of studies clopidogrel has been used as an alternative to aspirin, but the widespread use of aspirin, and the different modes of actions of the two drugs, makes it important to determine the safety and efficacy of using both drugs in combination. This study reports the effect of this drug combination on bleeding times and platelet function in humans. Methods The study was conducted in normal, healthy subjects to evaluate the effects of different doses of clopidogrel on bleeding time, platelet aggregation and activation, above a baseline of standard aspirin therapy. Seven normal men (mean age 30 years) were given aspirin (150 mg) for 3 days. Subjects received clopidogrel (75 mg) at 24 and 48 h, followed by a third dose of clopidogrel (300 mg) on day 3. Results The combination of aspirin plus clopidogrel leads to a significant reduction in platelet function relative to aspirin alone (P < 0·05), and is associated with a significant increase in the bleeding time (P < 0·05). The response to collagen was similarly affected. Platelet fibrinogen binding in response to both ADP and thrombospondin-related adhesive protein was reduced only partially by aspirin, but significantly reduced by both doses of clopidogrel (P < 0·05 for all). P-selectin expression in response to both agonists was also reduced, but not significantly. Basal levels of fibrinogen binding, P-selectin, glycoprotein (GP) IIb–IIIa and GPIb expression were not affected by treatment. Conclusion Blocking both the cyclo-oxygenase and ADP pathways of platelet activation has a profound effect on platelet response to agonists, which may offer significant potential benefit in preventing thrombotic events relative to aspirin alone. Achieving the correct balance between haemostasis and thrombosis with these useful agents will require further study.