Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthroplasty. A dose finding study (ONYX-2).
BACKGROUND
Anticoagulant prophylaxis substantially reduces the risk of venous thromboembolism (VTE) after major orthopedic surgery. The direct factor Xa inhibitor YM150 is currently under investigation for the prevention of VTE, stroke and ischemic vascular events in patients after orthopedic surgery, with atrial fibrillation and with acute coronary syndrome, respectively.


OBJECTIVE
To investigate the efficacy and safety of YM150 for the prevention of VTE following elective total hip arthroplasty.


METHODS
Patients were randomized to postoperative, once-daily, oral YM150 (5, 10, 30, 60 or 120 mg) (double-blind) or preoperative subcutaneous (open label) enoxaparin (40 mg) for 5 weeks. The primary efficacy endpoint comprised VTE diagnosed by mandatory bilateral venography or verified symptomatic deep vein thrombosis (DVT) plus all deaths up to 9 days after surgery. The primary safety outcome was major bleeding up to 9 days after surgery.


RESULTS
Primary efficacy endpoint: of 1017 patients randomized, 960 patients were evaluable for safety and 729 patients for efficacy. A dose-related decrease in VTE incidence from YM150 5 to 60 mg (P = 0.0005) and from 5 to 120 mg (P = 0.0002) was found. The VTE incidence was 27.4%, 31.7%, 19.3%, 13.3% and 14.5% for 5, 10, 30, 60 and 120 mg YM150, respectively, and 18.9% for enoxaparin. Primary safety endpoint: there was one major bleed with YM150 (60 mg) and one with enoxaparin.


CONCLUSIONS
The oral direct FXa inhibitor YM150 demonstrated a significant dose response regarding efficacy. Doses from 30 to 120 mg had comparable efficacy to enoxaparin, without compromising safety regarding major bleeding events.
Eriksson
B I
BI
Department of Orthopaedics, Sahlgrenska University 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
Wetherill
G
G
Wilpshaar
J W
JW
Meems
L
L
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D017558:Elective Surgical Procedures; D017984:Enoxaparin / Q000008:administration & dosage* / Q000009:adverse effects; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D015994:Incidence; D016015:Logistic Models; D008875:Middle Aged; D010690:Phlebography; D019106:Postoperative Hemorrhage / Q000139:chemically induced; D018570:Risk Assessment; D013997:Time Factors; D016896:Treatment Outcome; D054556:Venous Thromboembolism / Q000000981:diagnostic imaging / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D055815:Young Adult
D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents