(Circulation. 1998;98:2461-2469.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Clopidogrel Inhibition of Stent, Graft, and Vascular Thrombogenesis With Antithrombotic Enhancement by Aspirin in Nonhuman Primates
From the Division of Hematology and Oncology, Department of Medicine, and Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, Ga, and Sanofi Recherche, Toulouse, France (J.-M.H.).
Correspondence to Laurence A. Harker, MD, Blomeyer Professor and Director, Division of Hematology and Oncology, Emory University School of Medicine, 1639 Pierce Dr, WMB Room 1003, Atlanta, GA 30322. E-mail lharker{at}emory.edu
Background—A recent study showed that clopidogrel reduces thrombo-occlusive complications in patients with symptomatic atherosclerosis more effectively than aspirin.
Methods and 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.
Key Words: clopidogrel • thrombus • stents • aspirin
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