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 recombinant tissue-type plasminogen activator (rt-PA)-induced thrombolysis by three thrombin inhibitors with a different mode of action in a canine model of copper-coil-induced coronary artery thrombosis. Thirty-six 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 per h. (4) rt-PA + hirudin, 1.2 mg/kg per h. (5) rt-PA + hirudin, 3.6 mg/kg per h. (6) rt-PA + heparin, 50 IU/kg per h. A flow probe was applied to LAD to monitor time to reperfusion and coronary reocclusions. All three thrombin inhibitors in combination with rt-PA caused a significant increase in LAD coronary artery blood flow compared to mono-treatment 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 artery blood flow was a combined effect of faster recanalization and a longer time to reocclusion in dogs receiving thrombin inhibitors together with rt-PA. The plasma concentration of hirudin and melagatran at steady state was 0.4-0.5 mu mol/L and 1.3-1.4 mu mol/L, after the low and high dose, respectively. However, the effect on activated partial thromboplastin time (APTT) was more pronounced for hirudin. A prolongation of APTT to about twice the baseline levels was obtained with heparin, low-dose hirudin and high-dose melagatran while high-dose hirudin prolonged APTT > 600 seconds. The two direct thrombin inhibitors, hirudin and melagatran, were found to be equipotent when they were compared at doses that resulted in similar molar plasma concentrations. However, 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.