Antiplatelet effect of clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions – Limited inhibition of the P2Y 12 receptor

Abstract

Introduction Large individual variability in clopidogrel responses has been reported. However, mechanisms of the non-responsiveness are unclear. Our aim was to study the extent of platelet inhibition at the receptor level by in vitro receptor antagonists of P2Y 12 (AR-C69931MX, cangrelor) and P2Y 1 (adenosine 3’,5’diphosphate) in aspirin treated patients with coronary artery disease (CAD) prior to and after in vivo clopidogrel. Materials and Methods 51 aspirin-treated (100 mg/day) patients participated. Blood was collected before and after administration of clopidogrel at 300 mg loading dose on day one, followed by 75 mg/d for four days. Aggregation in platelet-rich plasma was assessed. Results In 20% of patients clopidogrel failed to inhibit platelet responses to ADP. These non-responders had also decreased sensitivity to an in vitro P2Y 12-receptor antagonist compared with the responders (mean inhibition of aggregation 25 vs. 32%, difference of means 7% (95% CI 2-12%), P < 0.02). Moreover, the P2Y 12-receptor inhibition by in vivo clopidogrel correlated with the inhibition by in vitro ARMX measured prior to administration of clopidogrel. Neither P2Y 1-receptor activity, thrombin generation while on aspirin nor basal platelet activity associated with clopidogrel responses. Conclusions Concomitant aspirin and clopidogrel treatment failed to suppress platelet activity in 20% of patients. Non-responders to clopidogrel had decreased responses also to another ADP receptor antagonist, which suggests that the impaired response occurs at the level of P2Y 12-receptor.