Abstract
Open-heart surgery performed with cardiopulmonary extracorporeal bypass (CPB) of anticoagulated blood often is complicated by excessive postoperative hemorrhage due to an acquired platelet function defect and thrombocytopenia inherent to the procedure. One strategy for reducing excessive blood loss is to protect the platelets pharmacologically from activation and damage during the surgical procedure and the CPB, but most inhibitors of platelet activation used in this way would exacerbate bleeding because of the duration of their effect. INS50589 is a competitive and selective P2Y12 receptor antagonist in development by Inspire Pharmaceuticals Inc. Previous studies in normal dogs indicate that 20μM ADP induced ex vivo whole blood platelet aggregation is completely inhibited by the administration of INS50589 and that the effect is quickly reversed upon discontinuation of the administration. This drug is now being tested for efficacy and safety in a canine model of CPB established at East Carolina University. Subjects in the range of 20–30 kg are prepared by sternotomy for extracorporeal recirculation of blood after systemic heparinization. CPB occurs for ninety minutes, followed by weaning from the pump and maintenance for a four hour postoperative period. INS50589 was administered by continuous infusion at a rate of 17 mg/kg/min at initiation of sternotomy and throughout CPB until weaned. Special testing in all subjects includes ex vivo whole blood aggregometry with two doses of ADP, thromboelastography with the TEG® ADP Mapping kit, bleeding times using a 23 gauge puncture of the exposed jugular vein, and measurements of blood loss from the surgical fields. In the placebo treated group, there was a significant loss of platelet response to ADP during CPB that remained in the post-op period at approx 50% of initial values; in contrast, the drug-treated subjects show post-op recovery of ADP response to within 90% of initial values (p<0.01). The vessel bleeding time (VBT) within both groups was greatly prolonged during CPB. Preliminary analysis suggests that in the post-operative period the VBT returned to baseline values after the infusion was discontinued; however, the return was faster in the INS50589-treated animals when compared with the placebo group. The volume of post-operative blood loss was variable but appears to be less in the drug-treatment group versus placebo controls. When adjusted on the basis of red cell mass in the shed blood per body weight the difference was significant (4.78±1.99e10 vs. 10.1±2.91e10 red blood cells/kg), p <0.05. Other preliminary findings in the treatment group included a lesser CPB-related decrease in platelet count, a higher average hematocrit, higher post-op fibrinogen concentration, and a more stable post-op course. These preliminary findings suggest that INS50589 should be effective in protecting platelet function and reducing blood loss in human patients undergoing open-heart surgery.
