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

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 ResultsIn 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 72 h. 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 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 the infusion was stopped. Thrombin-antithrombin complex, also indicating thrombin generation, decreased by 0%, 2%, 18% and 22%, respectively, during the first 6 h 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 24 h of treatment by 20%, 18%, 18% and 20%, respectively. The first 24 h after discontinuation of 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 larger extent than those given heparin, had suffered from death, myocardial infarction or refractory angina pectoris. After 7 days this trend was less marked. ConclusionThe more pronounced decrease in thrombin generation and fibrin turnover during the first 6 h 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. (Eur Heart J 1999; 20: 506-518)

Coagulation Activity and Clinical Outcome in Unstable Coronary Artery Disease

“…10 Furthermore, none of these 4 markers of coagulation activity were independent predictors of long-term risk for adverse ischemic events in this study.…”

“…During heparin infusion, after this early decrease there was an increase in the F1ϩ2 value to a level slightly above baseline at the cessation of treatment. 10 However, this late increase was not related to an increase in cardiac events during or after heparin infusion.…”

“…7 The effects of different doses of inogatran and heparin on molecular markers of coagulation activity in this substudy population have previously been presented. 10 …”

“…We previously reported changes in the markers of coagulation activity during and after treatment with either unfractionated heparin or inogatran in a substudy comprising 320 patients. 10 The prespecified aim of the present study was to assess the influence of antithrombin therapy on coagulation activity and its relation to manifestations of myocardial ischemia during and after such treatment.…”

Recurrent cardiac ischemic events early after discontinuation of short-term heparin treatment in acute coronary syndromes

“…Other mechanisms that could lead to a transient hypercoagulable state include depletion of natural anticoagulants such as tissue-factor pathway inhibitor and antithrombin (12)(13)(14)(15)(16)(17). This is supported by the highly increased thrombin generation and activation markers observed 3 to 24 h after both UFH and LMWH treatment cessation, with prothrombin fragments 1 ϩ 2 levels exceeding pretreatment prothrombin fragments 1 ϩ 2 levels (18).…”