Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin

There is a need for a rapid antithrombotic effect after the administration of antiplatelet drugs in the setting of acute coronary syndromes and percut aneous interventions. Clopidogrel, a new thienopyridine derivative, is an e fficient antiplatelet agent. However, the standard regimen of clopidogrel ( 75 mg/d) requires 2 to 3 days before significant antithrombotic effects. Pa tients with stable arterial disease on chronic aspirin therapy (n=20) were treated with clopidogrel either with a front-loaded regimen, 300 mg the fir st day and 75 mg/d the next 7 days, or with a standard regimen, 75 mg/d for 8 days. Blood thrombogenicity was assessed by quantification of platelet-t hrombus formation in an ex vivo perfusion chamber, by ADP-induced platelet aggregation, and by ADP-induced fibrinogen binding. At 2 hours, mean total thrombus area with the standard regimen was not significantly reduced. In c ontrast, at 2 hours, the mean total thrombus area with the front-loaded reg imen was significantly decreased by 23.1+/-8.5% versus baseline (P<0.05). A DP-induced platelet aggregation (with 5 and 10 <mu>mol/L) was also signific antly (P<0.05) reduced with the front-loaded regimen at 2 hours, with the m ean platelet aggregation being 82.2+/-4.4% and 81.8+/-4.5%, respectively, v ersus baseline. Similarly, flow cytometry demonstrated a significant decrea se (P<0.05) in the ADP-induced fibrinogen binding (with 0.12 and 0.6 mu mol /L) at 2 hours in this front-loaded regimen group (36.1+/-2.0% and 53.2+/-9 .3%). With the standard regimen, platelet activity was not significantly re duced at 2 hours. Our data suggest that a front-loaded regimen of clopidogr el added to aspirin achieves a significant antithrombotic effect at 2 hours in patients with known atherosclerotic disease on chronic aspirin therapy. This provides a rationale for using front-loaded clopidogrel in combinatio n with aspirin in percutaneous coronary interventions.