A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery.
BACKGROUND
YM150, a new oral direct factor Xa inhibitor is used as prophylaxis for venous thromboembolism (VTE), a well-known risk after orthopaedic surgery.


OBJECTIVE
To assess the safety and efficacy of thromboprophylaxis with YM150 in a dose escalation study.


METHODS
Patients (174) undergoing hip replacement surgery were randomized per cohort to oral once daily YM150 or subcutaneous enoxaparin (40 mg daily) in a 4:1 ratio for 7-10 days treatment. The YM150 doses were 3, 10, 30 and 60 mg by sequential four-dose escalation cohorts. The primary endpoint was major and/or clinically relevant non-major bleeding. The incidence of VTE was defined as a composite of verified symptomatic events and/or positive findings at bilateral venography on the last treatment day. An independent adjudication committee evaluated blindly the outcomes of the open-label study.


RESULTS
No major and three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI, 0.1-15.1) in the 3 mg and 2 (5.7%; 95% CI, 1.0-18.8) in the 10 mg YM150 dose groups. Of 147 patients (84%) with an evaluable venogram, VTE was observed in 51.9% (95% CI, 31.9-71.4), 38.7% (95% CI, 22.6-57.0), 22.6% (95% CI, 9.7-39.4), and 18.5% (95% CI, 7.5-36.5) in the YM150 dose groups 3, 10, 30 and 60 mg, respectively. A significant YM150 dose-related trend in VTE incidence was found (P=0.006). VTE with enoxaparin was 38.7% (95% CI, 22.6-57.0).


CONCLUSIONS
YM150, 10-60 mg daily, starting 6-10 h after primary hip replacement, was shown to be safe, well tolerated and effective.
Eriksson
B I
BI
Department of Orthopaedics, Sahlgrenska University/Ostra Hospital, Gothenburg, Sweden. b.eriksson@orthop.gu.se
Turpie
A G G
AG
Lassen
M R
MR
Prins
M H
MH
Agnelli
G
G
Kälebo
P
P
Gaillard
M L
ML
Meems
L
L
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000990:Antithrombin III / Q000008:administration & dosage* / Q000494:pharmacology*; D019644:Arthroplasty, Replacement, Hip / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D017984:Enoxaparin / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000517:prevention & control*
D017984:Enoxaparin; D000990:Antithrombin III