Clopidogrel inhibition of stent, graft, and vascular thrombogenesis with antithrombotic enhancement by aspirin in nonhuman primates.
BACKGROUND
A recent study showed that clopidogrel reduces thrombo-occlusive complications in patients with symptomatic atherosclerosis more effectively than aspirin.


RESULTS
The effects of clopidogrel and aspirin have been compared, singly and in combination, for measurements of 111In-labeled platelets and 125I-labeled fibrin deposition in baboon models of arterial thrombosis and related to platelet aggregation and expression of activation epitopes induced by ADP, collagen, and thrombin receptor agonist peptide (TRAP) and to template bleeding times (BTs). Low-dose oral clopidogrel (0.2 mg. kg-1. d-1) produced cumulative (1) intermediate decreases in 111In-platelet and 125I-fibrin deposition for segments of prosthetic vascular graft, deployed endovascular metallic stents, and endarterectomized aorta (P<0.009 in all cases); (2) elimination of ADP-induced platelet aggregation (P<0.001); (3) modest inhibition of collagen-induced platelet aggregation (P<0.01); (4) no reduction in TRAP-induced platelet aggregation; and (5) minimal prolongation of BTs (P=0.03). High-dose oral clopidogrel (>/=2 mg/kg) produced the same effects within 3 hours. The effects of clopidogrel dissipated over 5 to 6 days. Aspirin 10 mg. kg-1. d-1 alone did not decrease 111In-platelet and 125I-fibrin deposition on segments of vascular graft but detectably decreased 111In-platelet and 125I-fibrin accumulation on stents (P<0.01), minimally inhibited ADP- and collagen-induced platelet aggregation (P<0.05 in both cases), and minimally prolonged BTs (P=0.004). Within 3 hours of aspirin administration, the antithrombotic effects of acute high-dose or chronic low-dose clopidogrel were substantially enhanced, and BTs were modestly prolonged without inhibiting platelet aggregation induced by TRAP (P<0.001 in all cases compared with clopidogrel alone).


CONCLUSIONS
Clopidogrel produces irreversible, dose-dependent, intermediate reduction in thrombosis that is substantially enhanced by the addition of aspirin. The effects of combining aspirin and clopidogrel need to be evaluated in patients at risk of vascular thrombosis.
Harker
L A
LA
Division of Hematology and Oncology, Department of Medicine, and Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, GA, USA. 1harker@emory.edu
Marzec
U M
UM
Kelly
A B
AB
Chronos
N R
NR
Sundell
I B
IB
Hanson
S R
SR
Herbert
J M
JM
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001760:Bleeding Time; D000077144:Clopidogrel; D004347:Drug Interactions; D004691:Endarterectomy / Q000009:adverse effects*; D006487:Hemostasis / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D008297:Male; D010215:Papio; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011093:Polyethylene Terephthalates / Q000009:adverse effects*; D015607:Stents / Q000009:adverse effects*; D013927:Thrombosis / Q000209:etiology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D011093:Polyethylene Terephthalates; D006493:Heparin; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin