First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation.
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.


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.
Dyke
Christopher K
CK
Duke Clinical Research Institute, Durham, NC 27715, USA.
Becker
Richard C
RC
Kleiman
Neal S
NS
Hochman
Judith S
JS
Bovill
Edwin G
EG
Lincoff
A Michael
AM
Gerstenblith
Gary
G
Dzavik
Vladimir
V
Gardner
Laura H
LH
Hasselblad
Vic
V
Zillman
Linda A
LA
Shimoto
Yoshimasa
Y
Robertson
Thomas L
TL
Kunitada
Satoshi
S
Armstrong
Paul W
PW
Harrington
Robert A
RA
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001241:Aspirin / Q000627:therapeutic use; D015331:Cohort Studies; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015951:Factor Xa / Q000032:analysis; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007262:Infusions, Intravenous; D019934:International Normalized Ratio; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010314:Partial Thromboplastin Time; D011422:Propionates / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011517:Prothrombin Time; D013997:Time Factors
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D000960:Hypolipidemic Agents; D009281:Naphthalenes; D011422:Propionates; D015951:Factor Xa; D001241:Aspirin