Prolonged heparin administration during clopidogrel treatment in healthy subjects.
The potential pharmacological interaction between clopidogrel and heparin was assessed in a randomized, placebo-controlled study carried out in 12 healthy male subjects. Clopidogrel 75 mg once daily or placebo was given in a randomized fashion for 12 days during two periods separated by a 21-day washout period. Sodium heparin was administered as a prolonged intravenous infusion at a starting dose of 300 IU/kg/24 hours then adjusted so as to maintain the activated partial thromboplastin time (APTT) ratio for subject versus control within the therapeutic range of 1.7 to 2.3 for 4 days from day 9 through day 13 of each period. For each period, the following main parameters were measured: total heparin consumption; APTT on days 1 and 8 to 12 before drug intake and on days 13, 14 and 26; bleeding time and platelet aggregation induced by 5 microM ADP on days 1, 8 to 10 and 12 before drug intake, and on days 14 and 26; APTT measured 3 times on day 9, i.e., before the start of heparin infusion, then 3 and 6 hours later. During day 9 to 13 period, the subject/control APTT ratio remained within the specified 1.7 to 2.3 range with no statistically significant difference between the clopidogrel and placebo treatments. The mean (+/-s.e.m.) volumes of heparin infused in each group were 81384+/-2793 IU and 79867+/-2788 IU in the clopidogrel and placebo groups, respectively. The 90% confidence interval of the mean heparin volume difference fell within the+/-10% interval of the placebo mean centered on zero. Bleeding time in the placebo group remained practically unchanged throughout the study. In the clopidogrel group, bleeding time prolongation factor was significantly increased from baseline to day 9, with clopidogrel alone then remained stable at 1.2 following co-administration of heparin until the end of treatment; hence, it was not modified by the coadministration of heparin. ADP (5 microM)-induced platelet aggregation was inhibited by 27+/-12% after 7 days of clopidogrel administration alone, and no significant further change was observed when heparin was coadministered. There were no adverse events that could be related to clopidogrel. In conclusion, under the study conditions, no interactions between clopidogrel and heparin were observed.
Caplain
H
H
Institut Aster, Hôpital Cognacq-Jay, Paris, France.
D'Honneur
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G
Cariou
R
R
D000244:Adenosine Diphosphate / Q000097:blood; D000284:Administration, Oral; D000328:Adult; D000077144:Clopidogrel; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D006493:Heparin / Q000008:administration & dosage*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010314:Partial Thromboplastin Time; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D004338:Drug Combinations; D000244:Adenosine Diphosphate; D006493:Heparin; D000077144:Clopidogrel; D013988:Ticlopidine