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Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischemic events: Observations from the ESTEEM trial
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
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2007 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 28, no 6, 692-698 p.Article in journal (Refereed) Published
Abstract [en]

AIM: 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. METHODS AND 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. CONCLUSION: 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.

Place, publisher, year, edition, pages
2007. Vol. 28, no 6, 692-698 p.
Keyword [en]
Myocardial infarction, Ischaemic event, Coaguulation activity, Direct thrombin inhibitor
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97121DOI: 10.1093/eurheartj/ehl564ISI: 000244960400014PubMedID: 17314111OAI: oai:DiVA.org:uu-97121DiVA: diva2:171920
Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Regulation of Tissue Factor and Coagulation Activity: Translation Studies with Focus on Platelet-Monocyte Aggregates and Patients with Acute Coronary Syndrome
Open this publication in new window or tab >>Regulation of Tissue Factor and Coagulation Activity: Translation Studies with Focus on Platelet-Monocyte Aggregates and Patients with Acute Coronary Syndrome
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Myocardial infarction (MI) is often caused by a disruption of an atherosclerotic plaque with activation of coagulation, platelets and inflammation. The aims were; to investigate whether the oral direct thrombin inhibitor, ximelagatran affected markers for coagulation, platelet and inflammation in a patient cohort with recent MI and if the coagulation markers could identify patients with increased risk of new ischemic events; to evaluate some of the mechanisms involved in formation of platelet-monocyte aggregates (PMAs).

In a biomarker substudy patients with recent MI were randomized to 24-60 mg of ximelagatran or placebo for six months. There was a persistent dose-independent reduction of coagulation markers (F1+2, D-dimer) by ximelagatran treatment. 60 % reduced their D-dimer levels after one week and that group had less ischemic events during treatment. There was an early increase of the platelet activation marker and ximelagatran in higher doses attenuated these increased levels. Both in vivo and in vitro the direct thrombin inhibitor diminished procoagulant activity and tissue factor (TF) presenting microparticles. In contrast, the inflammatory markers increased after six months of ximelagatran treatment. The PMA-levels were elevated for long-term after MI. In vitro thrombin inhibition diminished formation of PMAs. Formation of PMAs in stimulated whole blood was P-selectin dependent and induced TF expression through phosphorylation of the Src-family member Lyn in monocytes.

Addition of an oral direct thrombin inhibitor reduces coagulation and platelet activation markers for long-term after a MI together with reduced procoagulant activity which may contribute to the clinical benefit of the drug. Early reduction of D-dimer levels seems to be suitable to identify patients with reduced risk of new ischemic events independent of antithrombotic treatment. Circulating PMAs persist after a MI connecting coagulation to inflammation. Within these aggregates P-selectin induces TF, the main initiator of coagulation, partly through phosphorylation of Lyn.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 87 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 341
Keyword
Internal medicine, Myocardial infarction, Coagulation, Platelet-monocyte aggregates, Tissue factor, Thrombin inhibition, Invärtesmedicin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-8669 (URN)978-91-554-7177-4 (ISBN)
Public defence
2008-05-17, Enghoffsalen, Ingång 50 bv, Uppsala Universitets Sjukhus, Uppsala, 10:00
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Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2012-03-06Bibliographically approved

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Christersson, ChristinaOldgren, JonasSiegbahn, AgnetaWallentin, Lars

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