L. Millet, A. Bernat, P. Schaeffer, J.M. Herbert, P. Savi Sanofi Synthélabo, Cardiovascular/Thrombosis Research Department, Toulouse, France Abstract: P1635 Citation: Supplement to the journal Thrombosis and Haemostasis, July 2001 (ISSN 0340-6245) Antiaggregant therapy has demonstrated its efficacy in preventing arterial thrombosis in a number of pathologies. Today, three different classes of compounds are available to prevent platelet aggregation: inhibitors of cycloxygenase (aspirin), P2t antagonists (ticlopidine and clopidogrel) and Gp IIb-IIIa antagonists (abciximab, integrelin, tirofiban...). However, oral anti Gp IIb-IIIa compounds failed to demonstrate a clear benefit in clinical trials, due either to a poor antithrombotic activity or to an increased risk of major bleeding. Recently, several studies have reported the effects of antithrombotic drug associations in animal models of thrombosis (aspirin + ticlopidine or clopidogrel, ticlopidine + abciximab or tirofiban...), and have suggested that the association of compounds with different mechanisms of action may result in a potent antithrombotic effect. The aim of our study was to determine whether the association of the new oral anti Gp IIb-IIIa SR121787 with the P2t antagonist clopidogrel would result in a significantly greater benefit in vivo. Clopidogrel is a potent antiaggregating compound preventing thrombosis in several animal species. In the rabbit, clopidogrel (20 mg/kg, po) decreased thrombus weight in an arterio-venous shunt model by 49 ± 6% without significantly affecting bleeding time. In the same model, SR121787 (20 mg/kg, po) was able to reduce the thrombus weight by 64 ± 10%. However, under these conditions the compound also dramatically increased blood loss in a model of haemorrhage (25 fold increase as compared to control animals). The co-administration of lower doses of both compounds was therefore tested in order to determine if the same pharmacological effect would be reached with a lower bleeding side effect. Interestingly, the association of 5 mg/kg of clopidogrel with 10 mg/kg of SR121787 resulted in a decrease in thrombus weight which was identical to that observed with 20 mg/kg of SR121787 (65 ± 3% inhibition). Under these conditions, bleeding was only increased 1.8 fold, an effect which was barely significant. Further statistical analysis using several doses of these compounds clearly showed a positive synergy as determined by the method of Berenbaum. Our results demonstrate that an antithrombotic efficacy equivalent to the maximal antithrombotic efficacy of the GpIIb/IIIa antagonist SR121787 can be reached with the association of a moderate dose of SR121787 and a low dose of clopidogrel. This association does not result in a significant increase in bleeding suggesting that the association of these two orally active compounds allows a strong protection against thrombosis, while inducing a limited risk of haemorrhage.