Treatment with an oral direct thrombin inhibitor decreases platelet activity but increases markers of inflammation in patients with myocardial infarction.
BACKGROUND
Thrombin has a role not only in the coagulation process but also in inflammatory responses. Oral direct thrombin inhibitors (DTIs) are currently being evaluated in patients with thromboembolic diseases.


OBJECTIVE
To investigate whether an oral DTI affects markers for platelet and inflammatory activity after myocardial infarction (MI).


METHODS
A total of 518 patients with MI were randomly assigned to ximelagatran treatment (four different dose groups) in combination with aspirin, or aspirin alone for 6 months. The levels of soluble (s) P-selectin, soluble tissue factor, C-reactive protein (CRP), interleukin (IL)-10 and IL-18 were analysed in serial blood samples.


RESULTS
sP-selectin concentration increased after 1 week and persisted at an elevated level for 6 months in all study groups (P < 0.001). In the two highest ximelagatran dose groups, there was a reduced increase in sP-selectin compared to treatment with lower doses of ximelagatran and aspirin alone (P = 0.01 and P = 0.002, respectively). IL-18 levels did not change in the aspirin alone treatment group. By contrast, there was an elevation in IL-18 level in the lower and higher ximelagatran dose groups after 6 months (P = 0.006 and P < 0.001, respectively). Ximelagatran increased IL-10 levels (P = 0.002) and reduced the decrease in CRP levels after 6 months compared to treatment with aspirin alone (P = 0.002).


CONCLUSIONS
A persistent elevation of platelet activity is found in patients with a recent MI after the cessation of acute antithrombotic treatment, and the addition of an oral DTI at higher doses decreases the activity. By contrast, long-term treatment with a DTI increases the levels of several markers of inflammation. Further studies with prolonged exposure of oral DTIs are needed for evaluation of the effect on inflammatory processes and to determine whether these agents influence clinical outcomes.
Department of Medical Sciences, Uppsala University, Uppsala, Sweden. christina.christersson@akademiska.se
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Christersson
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Oldgren
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Wallentin
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Siegbahn
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins / Q000008:administration & dosage / Q000627:therapeutic use*; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use*; D001384:Azetidines / Q000008:administration & dosage / Q000627:therapeutic use*; D001596:Benzylamines / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood*; D001792:Blood Platelets / Q000187:drug effects*; D002097:C-Reactive Protein / Q000378:metabolism; D015897:Comorbidity; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood*; D016753:Interleukin-10 / Q000097:blood; D020382:Interleukin-18 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood* / Q000188:drug therapy*; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects; D012307:Risk Factors; D013925:Thromboplastin / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
D000991:Antithrombins; D001384:Azetidines; D001596:Benzylamines; D015415:Biomarkers; D020382:Interleukin-18; D019007:P-Selectin; D016753:Interleukin-10; C426686:ximelagatran; D002097:C-Reactive Protein; D013925:Thromboplastin; D001241:Aspirin