The effect of a low molecular mass thrombin inhibitor, inogatran, and heparin on thrombin generation and fibrin turnover in patients with unstable coronary artery disease

Aim This study evaluated a novel specific thrombin inhibitor, inogatran, in comparison with unfractionated heparin, with regard to markers for coagula tion activity in patients with unstable coronary artery disease. Methods and Results In the Thrombin Inhibition In Myocardial ischaemia (TRI M) study patients were randomized to one of three different doses of inogat ran or to unfractionated heparin, given intravenously over 72 h. In a subpo pulation of 320 patients, markers for coagulation activity were measured at baseline, during and after the study infusion. Prothrombin fragment 1 + 2, indicating thrombin generation, decreased in th e low, medium and high dose inogatran groups and in the heparin group durin g the first 6 h of treatment by 12%, 15%, 21% and 26%, respectively. From 6 h to 72 h after the start of infusion the levels changed by -7%, -6%, -4% and +34%, respectively. The increase in the heparin group continued after t he infusion was stopped. Thrombin-antithrombin complex, also indicating thr ombin generation, decreased by 0%, 2%, 18% and 22%, respectively, during th e first 6 h of treatment. During the same period soluble fibrin, an interme diate in fibrin formation, increased both in the low and medium inogatran g roup by 9%, while a decrease by 4% and 18%, respectively, was seen in the h igh dose inogatran group and in the heparin group. Fibrin dissolution, as m easured by fibrin D-dimer, decreased during the first 24 h of treatment by 20%, 18%, 18% and 20%, respectively. The first 24 h after discontinuation o f infusion, fibrin D-dimer increased by 6%, 23%, 25% and 44%, respectively. After 72 h, at the end of infusion, patients treated with inogatran, to a l arger extent than those given heparin, had suffered from death, myocardial infarction or refractory angina pectoris. After 7 days this trend was less marked. Conclusion The more pronounced decrease in thrombin generation and fibrin t urnover during the first 6 h of infusion, and the later increase in thrombi n generation and fibrin turnover, in the heparin group, as compared to the inogatran groups, may be related to the lower clinical event rate during in fusion with heparin compared with inogatran and the recurrence of ischaemic events, early after cessation of heparin infusion.