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(Circulation. 2002;105:2385.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

First Experience With Direct Factor Xa Inhibition in Patients With Stable Coronary Disease

A Pharmacokinetic and Pharmacodynamic Evaluation

Christopher K. Dyke, MD; Richard C. Becker, MD; Neal S. Kleiman, MD; Judith S. Hochman, MD; Edwin G. Bovill, MD; A. Michael Lincoff, MD; Gary Gerstenblith, MD; Vladimir Dzavik, MD; Laura H. Gardner, BSPH; Vic Hasselblad, PhD; Linda A. Zillman, RN; Yoshimasa Shimoto, PhD; Thomas L. Robertson, MD; Satoshi Kunitada, PhD; Paul W. Armstrong, MD; Robert A. Harrington, MD

From the Duke Clinical Research Institute, Durham, NC (C.K.D., L.H.G., V.H., L.A.Z., R.A.H.); University of Massachusetts Memorial Medical Center, Worcester (R.C.B.); Methodist Hospital, Houston, Tex (N.S.K.); St Luke’s–Roosevelt Medical Center, New York, NY (J.S.H.); University of Vermont Medical Center, Burlington (E.G.B.); The Cleveland Clinic Foundation, Cleveland, Ohio (A.M.L.); The Johns Hopkins Hospital, Baltimore, Md (G.G.); University of Alberta, Edmonton, Canada (V.D., P.W.A.); and Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan (T.L.R., S.K.), and Montvale, NJ (Y.S.).

Correspondence to Robert A. Harrington, MD, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. E-mail harri019{at}mc.duke.edu

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.

Key Words: anticoagulants • coronary disease • pharmacokinetics • thrombin • thrombosis

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