TY - JOUR
T1 - First experience with direct factor Xa inhibition in patients with stable coronary disease
T2 - A pharmacokinetic and pharmacodynamic evaluation
AU - Dyke, Christopher K.
AU - Becker, Richard C.
AU - Kleiman, Neal S.
AU - Hochman, Judith S.
AU - Bovill, Edwin G.
AU - Lincoff, A. Michael
AU - Gerstenblith, Gary
AU - Dzavik, Vladimir
AU - Gardner, Laura H.
AU - Hasselblad, Vic
AU - Zillman, Linda A.
AU - Shimoto, Yoshimasa
AU - Robertson, Thomas L.
AU - Kunitada, Satoshi
AU - Armstrong, Paul W.
AU - Harrington, Robert A.
PY - 2002/5/21
Y1 - 2002/5/21
N2 - Background - Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa. Methods and Results - In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti-factor Xa activity (r=0.97), prothrombin time (r=0.77), and international normalized ratio (r=0.72) but less so with activated partial thromboplastin time (r=0.56; all P<0.001). Conclusions - This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.
AB - Background - Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa. Methods and Results - In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti-factor Xa activity (r=0.97), prothrombin time (r=0.77), and international normalized ratio (r=0.72) but less so with activated partial thromboplastin time (r=0.56; all P<0.001). Conclusions - This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.
KW - Anticoagulants
KW - Coronary disease
KW - Pharmacokinetics
KW - Thrombin
KW - Thrombosis
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U2 - 10.1161/01.CIR.0000016351.12759.52
DO - 10.1161/01.CIR.0000016351.12759.52
M3 - Article
C2 - 12021225
AN - SCOPUS:0037150191
SN - 0009-7322
VL - 105
SP - 2385
EP - 2391
JO - Circulation
JF - Circulation
IS - 20
ER -