Combined therapy with clopidogrel and aspirin significantly increases the bleeding time through a synergistic antiplatelet action

Objective: Many thromboembolic events occur in patients taking aspirin. Dual therapy with aspirin and clopidogrel may prove effective at reduction of thromboembolic complications. However, the extent to which these two drugs interact may significantly increase the risk of bleeding in open surgery. Because of the increased use of combination antiplatelet therapy in populations with significant atherosclerotic disease, this risk needs to be evaluated by the assessment of the combined effect in vivo of clopidogrel and aspirin on bleeding time and platelet function. Outcomes: In seven healthy subjects, addition of low dose clopidogrel (2 x 75 mg) to aspirin (150 mg) therapy significantly increased bleeding time (from 7.6 +/- 3.4 minutes to 17.5 +/- 8.6 minutes; P < .05), with concomitant falls in adenosine diphosphate (ADP)-induced platelet fibrinogen binding and aggregation (P < .05). Increasing the dose of clopidogrel to 300 mg increased bleeding time (to 24.9 +/- 8.5 minutes; P < .05) without significant additional platelet inhibition. There was considerable variability in the individual subject platelet response to the lower dose of clopidogrel. Those patients with the highest ADP response at baseline had the least response, and subjects with a weak response to ADP at baseline achieved maximal platelet inhibition with the low dose of clopidogrel. Conclusion: The increases in bleeding times should be considered in combination antiplatelet therapy in patients who undergo open vascular surgery.