title: Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin.
abstract: There is a need for a rapid antithrombotic effect after the administration of antiplatelet drugs in the setting of acute coronary syndromes and percutaneous interventions. Clopidogrel, a new thienopyridine derivative, is an efficient antiplatelet agent. However, the standard regimen of clopidogrel (75 mg/d) requires 2 to 3 days before significant antithrombotic effects. Patients with stable arterial disease on chronic aspirin therapy (n=20) were treated with clopidogrel either with a front-loaded regimen, 300 mg the first 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-thrombus 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 contrast, at 2 hours, the mean total thrombus area with the front-loaded regimen was significantly decreased by 23.1+/-8.5% versus baseline (P<0.05). ADP-induced platelet aggregation (with 5 and 10 micromol/L) was also significantly (P<0.05) reduced with the front-loaded regimen at 2 hours, with the mean platelet aggregation being 82.2+/-4.4% and 81.8+/-4.5%, respectively, versus baseline. Similarly, flow cytometry demonstrated a significant decrease (P<0. 05) in the ADP-induced fibrinogen binding (with 0.12 and 0.6 micromol/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 reduced at 2 hours. Our data suggest that a front-loaded regimen of clopidogrel 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 combination with aspirin in percutaneous coronary interventions.
authors.affiliation: Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Helft
authors.forename: J I
authors.initials: JI
authors.lastname: Osende
authors.forename: S G
authors.initials: SG
authors.lastname: Worthley
authors.forename: A G
authors.initials: AG
authors.lastname: Zaman
authors.forename: O J
authors.initials: OJ
authors.lastname: Rodriguez
authors.forename: E I
authors.initials: EI
authors.lastname: Lev
authors.forename: M E
authors.initials: ME
authors.lastname: Farkouh
authors.forename: V
authors.initials: V
authors.lastname: Fuster
authors.forename: J J
authors.initials: JJ
authors.lastname: Badimon
authors.forename: J H
authors.initials: JH
authors.lastname: Chesebro
mesh_terms: D000244:Adenosine Diphosphate; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use; D001792:Blood Platelets / Q000378:metabolism; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000473:pathology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D010477:Perfusion / Q000379:methods; D015539:Platelet Activation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin