Published Online
on April 29, 2002

A more recent version of this article appeared on May 21, 2002

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Submitted on January 11, 2002
Revised on March 11, 2002
Accepted on March 12, 2002

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, and 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.).

^* To whom correspondence should be addressed. 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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