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European Heart Journal 2002 23(22):1771-1779; doi:10.1053/euhj.2000.3234
Copyright © 2002 by the European Society of Cardiology.
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Clopidogrel does not suppress blood markers of coagulation activation in aspirin-treated patients with non-ST-elevation acute coronary syndromes

J.W. Eikelbooma,f1, J.I. Weitzb,c, A. Budajd, F. Zhaoe, I. Coplande, P. Maciejewskid, M. Johnstonb,f and S. Yusufc,e

a Thrombosis and Haemophilia Unit, Royal Perth Hospital, Perth, Australia
b Hamilton Civic Hospitals Research Centre, Hamilton, Canada
c Department of Medicine, McMaster University, Hamilton, Canada
d Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland
e Population Health Institute, McMaster University, Hamilton, Canada
f Hemostasis Reference Laboratory, Hamilton Civic Hospitals, Hamilton, Canada

revised February 11, 2002; accepted February 13, 2002

Abstract

Aims The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study demonstrated that clopidogrel plus aspirin was superior to aspirin alone for prevention of recurrent vascular events in patients with acute coronary syndromes. The aim of this study was to compare the effect of these two regimens on biochemical markers of platelet and coagulation activation.

Methods and Results We studied 485 patients with non-ST-elevation acute coronary syndrome who were randomized to clopidogrel (300mg loading dose followed by 75mg daily) or placebo for a period of 3–12 months. All patients also received aspirin (recommended dose 75–325mg daily). Blood levels of P-selectin, prothrombin fragment F1.2, D-dimer, and von Willebrand factor were measured at baseline, day 7 (or hospital discharge), and at day 30 after randomization. Patients receiving clopidogrel plus aspirin compared with aspirin alone had similar baseline geometric mean plasma levels of P-selectin (50·2 vs 51·7ng.ml–1, P=0·45), prothrombin fragment F1.2 (1·13 vs 1·12nmol.l–1, P=0·94), D-dimer (467 vs 460ng.ml–1, P=0·85), and von Willebrand factor levels (1·89 vs 1·85U.ml–1, P=0·59) and there also were no significant differences at day 7, or day 30. However, compared with baseline, there was a significant rise in prothrombin fragment F1.2 at day 7 (from 1·12 to 1·39nmol.l–1, P<0·0001) and day 30 (from 1·12 to 1·44nmol.l–1, P<0·0001), and D-dimer at day 7 (from 464 to 539nmol.l–1, P<0·0001) and day 30 (from 464 to 576nmol.l–1, P<0·0001). The magnitude of this rise appeared to be greatest in patients who experienced the primary outcome, a composite of cardiovascular death, myocardial infarction, stroke, or refractory ischaemia by the end of the study. P-selectin levels were not elevated at any time point but von Willebrand factor values were elevated at baseline and remained elevated at days 7 and 30.

Conclusions Our results indicate that the clinical benefits of clopidogrel are not associated with a parallel reduction in markers of coagulation activation. Early suppression of coagulation markers most likely reflects the effects of heparin. The persistence of thrombin generation despite long-term clopidogrel and aspirin therapy suggests that even more intensive antithrombotic therapy may be required in these patients.

Key Words: Aspirin, clopidogrel, unstable angina, myocardial infarction, platelets, coagulation.

f1 Correspondence: John Eikelboom, Department of Medicine, University of Western Australia, Department of Haematology, Royal Perth Hospital, Wellington Street, Perth, Box X2213 GPO, Perth WA 6897, Australia.

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