BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.
BACKGROUND
BAY 59-7939, a novel, oral, direct factor Xa inhibitor, is in clinical development for the prevention of venous thromboembolism (VTE), a frequent complication following orthopaedic surgery.


METHODS
In a multicenter, parallel-group, double-blind, double-dummy study, 621 patients undergoing elective total knee replacement were randomly assigned to oral BAY 59-7939 (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6-8 h postsurgery), or subcutaneous enoxaparin (30 mg b.i.d., initiated 12-24 h postsurgery). Treatment was continued until mandatory bilateral venography 5-9 days after surgery. The primary efficacy endpoint was a composite of any deep vein thrombosis (proximal and/or distal), confirmed non-fatal pulmonary embolism and all-cause mortality during treatment. The primary safety endpoint was major, postoperative bleeding during treatment.


RESULTS
Of the 613 patients treated, 366 (59.7%) were evaluable for the primary efficacy analysis. The primary efficacy endpoint occurred in 31.7%, 40.4%, 23.3%, 35.1%, and 25.4% of patients receiving 2.5, 5, 10, 20 and 30 mg b.i.d. doses of BAY 59-7939, respectively (test for trend, P = 0.29), compared with 44.3% in the enoxaparin group. The frequency of major, postoperative bleeding increased with increasing doses of BAY 59-7939 (test for trend, P = 0.0007), with no significant difference between any dose group compared with enoxaparin. Bleeding endpoints were lower for the 2.5-10 mg b.i.d. doses compared with higher doses of BAY 59-7939.


CONCLUSIONS
Oral administration of 2.5-10 mg b.i.d. of BAY 59-7939, early in the postoperative period, showed potential efficacy and an acceptable safety profile, similar to enoxaparin, for the prevention of VTE in patients undergoing elective total knee replacement.
Turpie
A G G
AG
HHS-General Hospital, Hamilton, Canada. turpiea@mcmaster.ca
Fisher
W D
WD
Bauer
K A
KA
Kwong
L M
LM
Irwin
M W
MW
Kälebo
P
P
Misselwitz
F
F
Gent
M
M
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000990:Antithrombin III / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019645:Arthroplasty, Replacement, Knee / Q000009:adverse effects*; D004311:Double-Blind Method; D017984:Enoxaparin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006470:Hemorrhage / Q000453:epidemiology* / Q000209:etiology; D006801:Humans; D015994:Incidence; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069552:Rivaroxaban; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013923:Thromboembolism / Q000453:epidemiology / Q000209:etiology* / Q000517:prevention & control*; D020246:Venous Thrombosis / Q000453:epidemiology / Q000209:etiology* / Q000517:prevention & control*
D000925:Anticoagulants; D017984:Enoxaparin; D009025:Morpholines; D013876:Thiophenes; D000990:Antithrombin III; D000069552:Rivaroxaban