Antiplatelet effect of clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions--limited inhibition of the P2Y12 receptor.
BACKGROUND
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.


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.
Lepäntalo
Aino
A
Department of Medicine, Division of Hematology, Helsinki University Central Hospital, Helsinki, Finland. aino.lepantalo@uta.fi
Virtanen
Kari S
KS
Reséndiz
Julio C
JC
Mikkelsson
Jussi
J
Viiri
Leena E
LE
Karhunen
Pekka J
PJ
Lassila
Riitta
R
D000249:Adenosine Monophosphate / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015906:Angioplasty, Balloon, Coronary; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D058919:Purinergic P2 Receptor Antagonists; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D000249:Adenosine Monophosphate; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin