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Inflammation and Coagulation Activity in Unstable Coronary Artery Disease and the Influences of Thrombin Inhibition

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Inflammation and Coagulation Activity in Unstable Coronary Artery Disease and the Influences of Thrombin Inhibition ! " # " $ # # %& '()" (*+,-) "$" ) .-, $"$ /"* -) //"*" 0 Dissertation for the Degree of Doctor of Philosophy (Faculty of Medicine) in Cardiology presented at Uppsala University in 2001 ABSTRACT Oldgren, J. 2001. Inflammation and coagulation activity in unstable coronary artery disease and the influences of thrombin inhibition. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1103. 68 pp. Uppsala. ISBN 91-554-5182-9. In patients with unstable coronary artery disease, this study evaluated the degree of inflammation and coagulation activity, relations to myocardial cell damage, prognosis, and influences of randomisation to 72 h infusion with three different doses of inogatran, a direct thrombin inhibitor (n=904), or unfractionated heparin (n=305). Anticoagulant treatment effects were evaluated with aPT time. In inogatran treated patients with aPT times ³ 44 s (median), the 7-days event rate - death, myocardial infarction or refractory angina – was 11.6%, compared to 6.6% with aPT times < 44 s (p=0.01). Higher aPT times was related to improved outcome during heparin treatment. Markers of inflammation, i.e. fibrinogen and C-reactive protein (CRP), and coagulation, i.e. prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), soluble fibrin (SF) and D-dimer were analysed in serial samples (n=320). High fibrinogen, F1+2 and D-dimer levels persisted at 30 days. Patients with myocardial damage, detected by elevated troponin, had higher levels of all markers except TAT. Ischemic events occurred at 30 days in 17% of patients with high (pre-treatment top tertile) and 8.5% of patients with lower fibrinogen levels (p=0.03), while high CRP levels only were related to increased mortality. At 30 days, patients with high compared to low pre-treatment levels of TAT or SF had 40% lower event rate. Patients with early decreased compared to raised F1+2 or TAT levels during treatment had 50% lower 30-days event rate (p<0.05). Conclusions: The aPT time is an inappropriate indicator of antithrombotic efficacy. The raise in fibrinogen in the acute phase is sustained, and indicates risk of thrombosis and new ischemic events. The pronounced CRP elevation is transient, but associated with increased mortality. Higher coagulation activity may identify patients with a thrombotic condition as the major cause of instability, who are best responders to anticoagulant therapy. However, reactivation of coagulation activity with raised risk of ischemic events is a concern at cessation of treatment. Key words: Unstable coronary artery disease, inflammation, coagulation, thrombin inhibition. Jonas Oldgren, Department of Medical Sciences, Cardiology, University Hospital, SE-751 85 Uppsala, Sweden © Jonas Oldgren 2001 ISSN 0282-7476 ISBN 91-554-5182-9 Printed in Sweden by Uppsala University, Tryck & Medier, Uppsala 2001 2 Man lives with arteriosclerosis, and dies of the complicating thrombosis Jens Dedichen, 1956 3 Papers This thesis is based on the following original papers which will be referred to by their Roman numerals: I. Activated Partial Thromboplastin Time and Clinical Outcome after Thrombin Inhibition in Unstable Coronary Artery Disease Oldgren J, Linder R, Grip L, Siegbahn A, Wallentin L Eur Heart J 1999;20(22):1657-66. II. Myocardial Damage, Inflammation and Thrombin Inhibition in Unstable Coronary Artery Disease Oldgren J, Wallentin L, Grip L, Linder R, Nørgaard B, Siegbahn A In progress III. 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 Linder R, Oldgren J, Egberg N, Grip L, Larson G, Siegbahn A, Wallentin L Eur Heart J 1999;20(7):506-18 IV. Coagulation Activity and Clinical Outcome in Unstable Coronary Artery Disease Oldgren J, Linder R, Grip L, Siegbahn A, Wallentin L Arterioscler Thromb Vasc Biol 2001;21(6):1059-64. V. Myocardial Damage, Coagulation Activity and the Response to Thrombin Inhibition in Unstable Coronary Artery Disease Oldgren J, Siegbahn A, Grip L, Linder R, Thygesen K, Wallentin L Submitted Reprints were made with permission from the publishers. 4 Contents Abbreviations........................................................................................................ 6 Introduction and background.............................................................................7 Definition and clinical manifestations of unstable coronary artery disease ...................7 Atherosclerosis and plaque disruption...........................................................................7 Inflammation and markers of inflammation ..................................................................8 Haemostasis and molecular markers of coagulation activity .........................................9 Myocardial infarction and biochemical markers of myocardial cell injury ................. 13 Prognosis and risk stratification in unstable coronary artery disease ........................... 13 Treatment of unstable coronary artery disease ............................................................ 14 Aims of the study ................................................................................................ 17 Material and methods ........................................................................................ 19 Patients and design ...................................................................................................... 19 aPT time and dose adjustments ................................................................................... 19 Inogatran plasma concentrations and thrombin time ................................................... 20 Substudy blood samples .............................................................................................. 20 Markers of inflammation............................................................................................. 20 Molecular markers of coagulation activity .................................................................. 20 Marker of myocardial cell injury................................................................................. 21 End-points ................................................................................................................... 21 Statistics ...................................................................................................................... 22 Results.................................................................................................................. 24 The TRIM study.......................................................................................................... 24 aPT time and the influence of inogatran or UF heparin ............................................... 25 Clinical outcome in relation to aPT times ................................................................... 27 Baseline characteristics and the degree of inflammation and coagulation activity ...... 29 The influences of thrombin inhibition on inflammation and coagulation activity ....... 30 Signs of myocardial cell injury and inflammation and coagulation activity ................ 33 Clinical outcome in relation to the degree of inflammation and coagulation activity.. 37 Discussion ............................................................................................................ 44 Activated partial thromboplastin time ......................................................................... 44 The influences of thrombin inhibition on inflammation and coagulation activity ....... 46 Inflammation and coagulation activity in relation to myocardial cell injury ............... 48 The degree of inflammation and clinical outcome ...................................................... 49 The degree of coagulation activity and clinical outcome ............................................ 51 Limitations .................................................................................................................. 53 Summary and implications ............................................................................... 54 Acknowledgements............................................................................................. 56 References ........................................................................................................... 58 5 Abbreviations aPT activated partial thromboplastin ASA acetylsalicylic acid CK-MB MB isoenzyme of creatine kinase ECG electrocardiogram ELISA enzyme-linked immunoassay F1+2 prothrombin fragment 1+2 LMW low molecular weight TAT thrombin-antithrombin complex TRIM thrombin inhibition in myocardial ischemia UF unfractionated 6 Introduction and background Definition and clinical manifestations of Unstable angina and non-ST-elevation unstable coronary artery disease myocardial infarction (previously called Coronary artery disease is the major cause non-q-wave myocardial infarction) are of mortality and morbidity in developed closely related conditions and - because countries. The predominant underlying of the similarities in pathogenesis, clinical cause of coronary artery disease is presentation and initial treatment – they atherosclerosis, a process that starts early are often merged together into one entity, in life and progresses slowly and silently unstable coronary artery disease. The for decades (1). The clinical clinical presentation includes new onset manifestations of coronary artery disease of severe angina (within the
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