The objective of this study was to determine if orally-administered
PD0348292, a direct specific
factor Xa inhibitor, inhibits
thrombosis following porcine carotid arterial injury comparably to
aspirin or
clopidogrel alone or in combination. We further sought to determine whether the antithrombotic efficacy in vivo could be predicted using an ex-vivo perfusion chamber. Oral treatments included:
PD0348292 (0.4, 0.9, or 4.3 mg/kg);
PD0348292 (0.4 mg/kg) plus
aspirin (325 mg);
aspirin;
clopidogrel (75 mg);
aspirin plus
clopidogrel; or vehicle (n = 6-10/group).
Aspirin and
clopidogrel were administered 27 and four hours pre-injury and
PD0348292 or vehicle was administered four hours pre-injury. Both carotid arteries were crush-injured, and
thrombus was measured by detection of (111)In-platelets over 30 minutes. Prior to injury, the antithrombotic efficacy was assessed by ex-vivo perfusion chamber platelet deposition.
PD0348292 produced dose-dependent prothrombin time (0.9- to 2.9-fold) and aPTT (1.4- to 2.5-fold) prolongations. Bleeding times were significantly prolonged in each active
drug group compared to vehicle, but were not significantly different between
drug groups.
PD0348292 significantly inhibited arterial platelet deposition (x10(6)/cm(2)) at 4.3(549 +/- 1,066), 0.9 (399 +/- 162) and 0.4 mg/kg (531 +/- 470) compared to vehicle (2,242 +/- 1,443).
Aspirin (992 +/- 973),
clopidogrel (537 +/- 483),
clopidogrel plus
aspirin (228 +/- 66) or
PD0348292 plus
aspirin (558 +/- 317) also significantly inhibited platelet deposition, although these values were not significantly different than with any dose of PD348292. Perfusion chamber platelet deposition correlated significantly with in-vivo anti-thrombotic response. In conclusion,
PD0348292 inhibited arterial
thrombosis comparable to
aspirin plus
clopidogrel. Perfusion chamber methodology may be useful in predicting in-vivo antithrombotic efficacy.