Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischaemic events: observations from the ESTEEM Trial.
OBJECTIVE
Patients with a recent myocardial infarction have an increased risk of recurrent ischaemic events. In the ESTEEM trial, the oral direct thrombin inhibitor ximelagatran reduced the risk of new ischaemic events when compared with placebo in aspirin treated post myocardial infarction patients. Ximelagatran persistently reduced markers of coagulation activity, i.e. prothrombin fragment 1 + 2 (F1 + 2) and D-dimer levels. The aim of this substudy was to evaluate the levels of these markers and activated thromboplastin time (APTT) in relation to new ischaemic events or bleeding.


RESULTS
In the substudy, 518 out of 1883 patients were included and within 14 days after a myocardial infarction randomized to ximelagatran or placebo for 6 months. The clinical endpoints death, myocardial infarction, severe recurrent ischaemia, ischaemic stroke, and bleeding were evaluated. The levels of F1 + 2, D-dimer, and APTT were analysed at randomization and in serial samples during the study. Ximelagatran treatment appeared to have a larger treatment effect in patients with F1 + 2 and D-dimer levels above the median at randomization with a reduction of ischaemic events from 18 to 9% (P = 0.03) for F1 + 2 and from 20 to 9% for D-dimer (P = 0.009). A reduction of D-dimer levels was found in 60% of the patients 1 week after randomization and these patients had less ischaemic events when compared with patients with unchanged or increased levels (P = 0.03) regardless of treatment. F1 + 2 and D-dimer levels were unrelated to bleeding risk. In the ximelagatran group, increased APTT was not related to ischaemic events but associated with a raised risk of bleeding.


CONCLUSIONS
A reduction of initially high coagulation activity, as measured by the D-dimer level, in patients with recent myocardial infarction identifies patients with a decreased risk of new ischaemic events, regardless whether the reduction occurs spontaneously or is induced by pharmacological means. Patients with higher initial coagulation activity seemed to benefit most from long-term treatment with ximelagatran.
Christersson
Christina
C
Department of Cardiology and Medical Sciences, Uppsala University Hospital, Uppsala, Sweden. christina.christersson@akademiska.se
Oldgren
Jonas
J
Bylock
Anders
A
Siegbahn
Agneta
A
Wallentin
Lars
L
D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use; D001384:Azetidines / Q000627:therapeutic use; D001596:Benzylamines / Q000627:therapeutic use; D001778:Blood Coagulation Disorders / Q000097:blood*; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism*; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy; D017202:Myocardial Ischemia / Q000097:blood*; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D011516:Prothrombin / Q000378:metabolism*; D012307:Risk Factors; D013917:Thrombin / Q000378:metabolism
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D005338:Fibrin Fibrinogen Degradation Products; D010446:Peptide Fragments; D011498:Protein Precursors; C036309:fibrin fragment D; C426686:ximelagatran; C029733:prothrombin fragment 1; C044183:prothrombin fragment 2; D011516:Prothrombin; D005337:Fibrin; D013917:Thrombin