EFFECTS OF NAPSAGATRAN (RO-46-6240), A NEW SYNTHETIC THROMBIN INHIBITOR AND OF HEPARIN IN A CANINE MODEL OF CORONARY-ARTERY THROMBOSIS - COMPARISON WITH AN EX-VIVO ANNULAR PERFUSION CHAMBER MODEL

Napsagatran, a new synthetic direct thrombin inhibitor, was compared w ith heparin in a canine model of coronary thrombosis and concomitantly in an ex vivo perfusion chamber model. Occlusive thrombosis of the le ft circumflex coronary artery was induced by electrical injury. In par allel, arterial subendothelium was exposed to native blood using an an nular perfusion chamber for 5, 10 and 20 min at a wall shear rate of 6 50/s. Dogs received saline, heparin (40 and 70 U/kg/h) or napsagatran (3 and 10 mu g/kg/min). Heparin (40 U/kg/h) and napsagatran (3 mu g/kg /min) delayed or prevented in vivo thrombotic occlusion, but only naps agatran (10 mu g/kg/min) significantly decreased the intracoronary thr ombus when compared with saline. High-dose heparin (70 U/kg/h) or naps agatran (10 mu g/kg/min) decreased the platelet-rich thrombus after a 20-min chamber perfusion. Neither heparin nor napsagatran decreased th e thrombus volume after a 5-min perfusion. Heparin (70 U/kg/h) and nap sagatran (10 mu g/kg/min) prolonged the activated partial thromboplast in time differently (> x6 and x1.4, respectively, P < 0.01), whereas t he activated clotting time was prolonged equally (x2.5). Thus napsagat ran in this model shows arterial antithrombotic effects similar to tho se of heparin. The chamber experiments suggest that neither compound a ffects the initiation of platelet thrombus formation. In arterial thro mbosis, the activated clotting time has a higher predictive value than the activated partial thromboplastin time when a direct thrombin inhi bitor is compared with heparin.