MELAGATRAN, AND HIRUDIN AND HEPARIN AS ADJUNCTS TO TISSUE-TYPE PLASMINOGEN-ACTIVATOR IN A CANINE MODEL OF CORONARY-ARTERY THROMBOLYSIS

The objective of this study was to characterize the modulation of reco mbinant tissue-type plasminogen activator (rt-PA)-induced thrombolysis by three thrombin inhibitors with a different mode of action in a can ine model of copper-coil-induced coronary artery thrombosis. Thirty-si x dogs were assigned to one of the following groups: (1) rt-PA, (2) rt -PA + melagatran, 0.1 mg/kg per h. (3) rt-PA + melagatran, 0.3 mg/kg p er h. (4) rt-PA + hirudin, 1.2 mg/kg per h. (5) rt-PA + hirudin, 3.6 m g/kg per h. (6) rt-PA + heparin, 50 IU/kg per h. A flow probe was appl ied to LAD to monitor time to reperfusion and coronary reocclusions. A ll three thrombin inhibitors in combination with rt-PA caused a signif icant increase in LAD coronary artery blood flow compared to mono-trea tment with rt-PA (average flow 150 ml/h, n = 6). The best results were obtained with high-dose melagatran (average flow 922 ml/h, n = 6) and high-dose hirudin (average flow 740 ml/h, n = 4 as two dogs died due to ventricular fibrillation). Low-dose melagatran (average flow 449 ml /h, n = 6) and hirudin (average flow 440 ml/h, n = 6) were equipotent to heparin (average flow 462 ml/h, n = 6). The increase in coronary ar tery blood flow was a combined effect of faster recanalization and a l onger time to reocclusion in dogs receiving thrombin inhibitors togeth er with rt-PA. The plasma concentration of hirudin and melagatran at s teady state was 0.4-0.5 mu mol/L and 1.3-1.4 mu mol/L, after the low a nd high dose, respectively. However, the effect on activated partial t hromboplastin time (APTT) was more pronounced for hirudin. A prolongat ion of APTT to about twice the baseline levels was obtained with hepar in, low-dose hirudin and high-dose melagatran while high-dose hirudin prolonged APTT > 600 seconds. The two direct thrombin inhibitors, hiru din and melagatran, were found to be equipotent when they were compare d at doses that resulted in similar molar plasma concentrations. Howev er, their anticoagulant effect, measured as prolongation of APTT, was different. At a dose that resulted in a two-fold prolongation of APTT, melagatran caused a significantly higher blood flow through LAD than both hirudin and heparin.