Ximelagatran: Oral direct thrombin inhibition as anticoagulant therapy in atrial fibrillation
Jonathan L. Halperin, MD, FACC*
Mount Sinai School of Medicine, New York, New York
View larger version (17K):
[in a new window]
|
Figure 1 Antithrombotic effect versus dose, for four different anticoagulant agents, in a rat model of arterial thrombosis. The direct thrombin inhibitors melagatran (triangles) and inogatran (squares) were administered by continuous infusion throughout the experiment; warfarin was administered once daily for four consecutive days (circles); and heparin was administered by infusion (broken line). Warfarin (µmol/kg per day); melagatran and inogatran (µmol/kg per h); heparin (kU/kg per h). The slope of the dose-response curve (the Hill coefficient) for each agent is given in parentheses.
|
|
View larger version (17K):
[in a new window]
|
Figure 2 Hypothetical schema of ximelagatran metabolism in humans. Melagatran is formed via two intermediate compounds, ethyl-melagatran and OH-melagatran, by reduction of the OH group and hydrolysis of the ethyl ester group, respectively (19).
|
|
View larger version (134K):
[in a new window]
|
Figure 3 Model illustrating the close fit of melagatran (a small molecule represented by the stick model at the center of the image) to the active catalytic site of thrombin (a globular protein represented by the space-filling model that dominates the image) (18).
|
|
View larger version (23K):
[in a new window]
|
Figure 4 Stroke Prevention with an ORal Thrombin Inhibitor in Atrial Fibrillation (SPORTIF)-III trial: event-rate comparisons for various composite end points and sensitivity analyses. Comparisons are presented first for the primary objective, then the two secondary objectives, two prespecified sensitivity analyses for the primary end point, and an exploratory, post-hoc analysis (47). ITT = intention-to-treat analysis; MI = myocardial infarction; OT = on-treatment analysis; SEE = systemic embolic event; TIA = transient ischemic attack.
|
|
View larger version (14K):
[in a new window]
|
Figure 5 Cumulative rate of primary events (all strokes and systemic embolic events) according to assigned treatment and intention-to-treat in the Stroke Prevention with an ORal Thrombin Inhibitor in Atrial Fibrillation (SPORTIF)-III trial (47).
|
|
|
