Dose-escalation study of rivaroxaban (BAY 59-7939)--an oral, direct Factor Xa inhibitor--for the prevention of venous thromboembolism in patients undergoing total hip replacement.
BACKGROUND
Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention of thromboembolic disorders. The aim of this study was to demonstrate proof-of-principle for rivaroxaban.


METHODS
This was an open-label, dose-escalation study to assess the efficacy and safety of rivaroxaban, relative to enoxaparin, for the prevention of venous thromboembolism (VTE) after total hip replacement surgery. Patients were randomized in a 3:1 ratio to rivaroxaban (2.5, 5, 10, 20 and 30 mg twice daily [bid] or 30 mg once daily [od] starting 6-8 h after surgery) or enoxaparin (40 mg od starting the evening before surgery). Therapy continued until mandatory bilateral venography was performed 5-9 days after surgery.


RESULTS
A total of 625 patients received therapy, of whom 466 patients were eligible for the per-protocol efficacy analysis. The primary efficacy endpoint - deep vein thrombosis (DVT), pulmonary embolism (PE) or all-cause mortality - occurred in 22.2%, 23.8%, 20.0%, 10.2%, 17.4%, 15.1% and 16.8% of patients receiving rivaroxaban 2.5, 5, 10, 20, 30 mg bid, 30 mg od and enoxaparin, respectively. The dose-response relationship with rivaroxaban for the primary efficacy endpoint was not statistically significant (p=0.0504), although major VTE (proximal DVT, PE and VTE-related death) decreased dose dependently with rivaroxaban (p=0.0108). Major, post-operative bleeding increased dose dependently with rivaroxaban (p=0.0008), occurring in 0-10.8% of patients, compared with 0% in patients receiving enoxaparin.


CONCLUSIONS
This study demonstrated proof-of-principle for rivaroxaban for the prevention of VTE after total hip replacement surgery.
Eriksson
Bengt I
BI
Department of Orthopaedics, Sahlgrenska University Hospital/Ostra, SU/Ostra sjukhuset, SE-41685 Goteborg, Sweden. b.eriksson@orthop.gu.se
Borris
Lars C
LC
Dahl
Ola E
OE
Haas
Sylvia
S
Huisman
Menno V
MV
Kakkar
Ajay K
AK
Misselwitz
Frank
F
Muehlhofer
Eva
E
Kälebo
Peter
P
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019644:Arthroplasty, Replacement, Hip / Q000379:methods*; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000627:therapeutic use*; D010690:Phlebography; D011183:Postoperative Complications / Q000517:prevention & control; D000069552:Rivaroxaban; D013876:Thiophenes / Q000627:therapeutic use*; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000150:complications* / Q000517:prevention & control*
D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban