The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.
BACKGROUND
Heparins and warfarin are currently used as venous thromboembolism (VTE) prophylaxis in surgery. Inhibition of factor (F) Xa provides a specific mechanism of anticoagulation and the potential for an improved benefit-risk profile.


OBJECTIVE
To evaluate the safety and efficacy of apixaban, a potent, direct, oral inhibitor of FXa, in patients following total knee replacement (TKR), and to investigate dose-response relationships.


METHODS
A total of 1238 patients were randomized to one of six double-blind apixaban doses [5, 10 or 20 mg day(-1) administered as a single (q.d.) or a twice-daily divided dose (b.i.d.)], enoxaparin (30 mg b.i.d.) or open-label warfarin (titrated to an International Normalized Ratio of 1.8-3.0). Treatment lasted 10-14 days, commencing 12-24 h after surgery with apixaban or enoxaparin, and on the evening of surgery with warfarin. The primary efficacy outcome was a composite of VTE (mandatory venography) and all-cause mortality during treatment. The primary safety outcome was major bleeding.


RESULTS
A total of 1217 patients were eligible for safety and 856 patients for efficacy analysis. All apixaban groups had lower primary efficacy event rates than either comparator. The primary outcome rate decreased with increasing apixaban dose (P = 0.09 with q.d./b.i.d. regimens combined, P = 0.19 for q.d. and P = 0.13 for b.i.d. dosing).A significant dose-related increase in the incidence of total adjudicated bleeding events was noted in the q.d. (P = 0.01) and b.i.d. (P = 0.02) apixaban groups; there was no difference between q.d. and b.i.d. regimens.


CONCLUSIONS
Apixaban in doses of 2.5 mg b.i.d. or 5 mg q.d. has a promising benefit-risk profile compared with the current standards of care following TKR.
Lassen
M R
MR
Department of Orthopaedics and Clinical Trial Unit, Nordsjaellands Hospital Hoersholm, University of Copenhagen, Usseroed Kongevej 102, Hoersholm, Denmark. mirula@noh.regionh.dk
Davidson
B L
BL
Gallus
A
A
Pineo
G
G
Ansell
J
J
Deitchman
D
D
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001118:Argentina; D019645:Arthroplasty, Replacement, Knee / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D017984:Enoxaparin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005060:Europe; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007557:Israel; D008297:Male; D008875:Middle Aged; D009656:North America; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018570:Risk Assessment; D013021:South Australia; D016896:Treatment Outcome; D054556:Venous Thromboembolism / Q000097:blood / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin; D015951:Factor Xa