Clopidogrel does not suppress blood markers of coagulation activation in aspirin-treated patients with non-ST-elevation acute coronary syndromes.
OBJECTIVE
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.


RESULTS
We studied 485 patients with non-ST-elevation acute coronary syndrome who were randomized to clopidogrel (300 mg loading dose followed by 75 mg daily) or placebo for a period of 3-12 months. All patients also received aspirin (recommended dose 75-325 mg 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 51.7 ng.ml(-1), P=0.45), prothrombin fragment F1.2 (1.13 vs 1.12 nmol.l(-1), P=0.94), D-dimer (467 vs 460 ng.ml(-1), P=0.85), and von Willebrand factor levels (1.89 vs 1.85 U.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 1.39 nmol.l(-1), P<0.0001) and day 30 (from 1.12 to 1.44 nmol.l(-1), P<0.0001), and D-dimer at day 7 (from 464 to 539 nmol.l(-1), P<0.0001) and day 30 (from 464 to 576 nmol.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.
Eikelboom
J W
JW
Thrombosis and Haemophilia Unit, Royal Perth Hospital, Perth, Australia.
Weitz
J I
JI
Budaj
A
A
Zhao
F
F
Copland
I
I
Maciejewski
P
P
Johnston
M
M
Yusuf
S
S
D000941:Antigens / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000378:metabolism; D000077144:Clopidogrel; D015331:Cohort Studies; D003327:Coronary Disease / Q000097:blood / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000097:blood; D010972:Platelet Activating Factor / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D016896:Treatment Outcome; D014841:von Willebrand Factor / Q000276:immunology
D000941:Antigens; D015415:Biomarkers; D001779:Blood Coagulation Factors; D005338:Fibrin Fibrinogen Degradation Products; D019007:P-Selectin; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; C029417:Von Willebrand antigen; C036309:fibrin fragment D; D014841:von Willebrand Factor; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin