Copyright © 1999 by the European Society of Cardiology.
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
a Department of Cardiology, Karolinska Hospital, Stockholm, Sweden
b Department of Laboratory Medicine, Karolinska Hospital, Stockholm, Sweden
c Department of Cardiology, Uppsala University Hospital, Uppsala, Sweden
d Department of Laboratory Medicine, Uppsala University Hospital, Uppsala, Sweden
e Department of Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden
f Department of Laboratory Medicine, Sahlgrenska University Hospital, Göteborg, Sweden
revised September 22, 1998; accepted September 30, 1998
Abstract
Aim This study evaluated a novel specific thrombin inhibitor, inogatran, in comparison with unfractionated heparin, with regard to markers for coagulation activity in patients with unstable coronary artery disease.
Methods and Results In the Thrombin Inhibition In Myocardial ischaemia (TRIM) study patients were randomized to one of three different doses of inogatran or to unfractionated heparin, given intravenously over 72h. In a subpopulation 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 the low, medium and high dose inogatran groups and in the heparin group during the first 6h of treatment by 12%, 15%, 21% and 26%, respectively. From 6h to 72h after the start of infusion the levels changed by –7%, –6%, –4% and +34%, respectively. The increase in the heparin group continued after the infusion was stopped. Thrombin–antithrombin complex, also indicating thrombin generation, decreased by 0%, 2%, 18% and 22%, respectively, during the first 6h of treatment. During the same period soluble fibrin, an intermediate in fibrin formation, increased both in the low and medium inogatran group by 9%, while a decrease by 4% and 18%, respectively, was seen in the high dose inogatran group and in the heparin group. Fibrin dissolution, as measured by fibrin D-dimer, decreased during the first 24h of treatment by 20%, 18%, 18% and 20%, respectively. The first 24h after discontinuation of infusion, fibrin D-dimer increased by 6%, 23%, 25% and 44%, respectively.After 72h, at the end of infusion, patients treated with inogatran, to a larger 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 turnover during the first 6h of infusion, and the later increase in thrombin generation and fibrin turnover, in the heparin group, as compared to the inogatran groups, may be related to the lower clinical event rate during infusion with heparin compared with inogatran and the recurrence of ischaemic events, early after cessation of heparin infusion.
Key Words: Unstable coronary artery disease, heparin, direct thrombin inhibition, biochemical markers, thrombin generation, fibrin
f1 Correspondence : Rikard Linder, MD, Department of Cardiology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
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