Oral, Direct Factor Xa Inhibition with Rivaroxaban for the Prevention of Venous Thromboembolism After Total Hip Replacement Eriksson BI, Borris L, Dahl OE, Haas S, Huisman MV, Kakkar AK, Misselwitz F, Kalebo P ODIXa-HIP Study Investigators J Thromb Haemost. 2006;4(1):121-8.

Oral, Direct Factor Xa Inhibition with Rivaroxaban for the Prevention of VTE After Total Hip Replacement Joint replacement surgery is an appropriate model for dose-ranging studies investigating new anticoagulants Background: Eriksson B.I., et al. J Thromb Haemost. 2006;4(1): To assess the efficacy and safety of a novel, oral, direct Factor Xa (FXa) inhibitor, rivaroxaban, relative to enoxaparin in patients undergoing elective total hip replacement Objective:

Oral, Direct Factor Xa Inhibition with Rivaroxaban for the Prevention of VTE After Total Hip Replacement In this double-blind, double-dummy, dose-ranging study, patients were randomized to the following treatments: –Oral rivaroxaban (2.5, 5, 10, 20, or 30 mg b.i.d.), starting 6-8 h after surgery –Subcutaneous enoxaparin 40 mg once daily, starting on the evening before surgery Treatment was continued until mandatory bilateral venography was performed 5-9 days after surgery Methods: Eriksson B.I., et al. J Thromb Haemost. 2006;4(1):121-8.

Study Design Eriksson B.I., et al. J Thromb Haemost. 2006;4(1): days treatment post-op Bilateral Venography BAY mg bid BAY mg bid BAY mg bid BAY mg bid BAY mg bid Enoxaparin 40 mg qd Start oral dose 6-8hr post-op Daily s.c. injections starting the evening before surgery

Oral, Direct Factor Xa Inhibition with Rivaroxaban for the Prevention of VTE After Total Hip Replacement Of 706 patients treated, 548 were eligible for the primary efficacy analysis Primary efficacy endpoint was incidence of any: –Deep vein thrombosis –Non-fatal pulmonary embolism –All-cause mortality The primary efficacy analysis did not demonstrate any significant trend in dose-response relationship for rivaroxaban Results: Eriksson B.I., et al. J Thromb Haemost. 2006;4(1):121-8.

Efficacy Analysis TreatmentPrimary Efficacy Rivaroxaban 2.5mg bid 15% Rivaroxaban 5mg bid 14% Rivaroxaban 10mg bid 12% Rivaroxaban 20mg bid 18% Rivaroxaban 2.5mg bid 7% Enoxaparin17% Eriksson B.I., et al. J Thromb Haemost. 2006;4(1):121-8.

Oral, Direct Factor Xa Inhibition with Rivaroxaban for the Prevention of VTE After Total Hip Replacement The primary safety endpoint: –Major, postoperative bleeding There was a significant increase in the frequency of events with increasing doses of rivaroxaban (P=0.045) –But no significant differences between individual rivaroxaban doses and enoxaparin Results: Eriksson B.I., et al. J Thromb Haemost. 2006;4(1):121-8.

Safety Analysis Eriksson B.I., et al. J Thromb Haemost. 2006;4(1): TreatmentSafety Rivaroxaban 2.5mg bid 0.8% Rivaroxaban 5mg bid 2.2% Rivaroxaban 10mg bid 2.3% Rivaroxaban 20mg bid 4.5% Rivaroxaban 2.5mg bid 5.4% Enoxaparin1.5%

Oral, Direct Factor Xa Inhibition with Rivaroxaban for the Prevention of VTE After Total Hip Replacement There was a significant dose trend for major, postoperative bleeding (P = 0.045), as shown by logistic regression Results: Eriksson B.I., et al. J Thromb Haemost. 2006;4(1):121-8.

Dose-Response Relationship Between Rivaroxaban and the Primary Efficacy Endpoint Eriksson B.I., et al. J Thromb Haemost. 2006;4(1): Enoxaparin Bay (mg twice daily) Incidence (%) Total VTE and all-cause mortality Major, postoperative bleeding Dose-response curves 95% confidence intervals

Oral, Direct Factor Xa Inhibition with Rivaroxaban for the Prevention of VTE After Total Hip Replacement There were no significant differences in the incidence of major, postoperative bleeding between any rivaroxaban dose and enoxaparin Results: Eriksson B.I., et al. J Thromb Haemost. 2006;4(1):121-8.

Post-Operative Bleeding Bleeding Classification Bay b.i.d.Enoxaparin q.d. 2.5 mg (n=132) 5 mg (n=136) 10 mg (n=133) 20 mg (n=134) 30 mg (n=37) 40 mg (n= 132) Major, post-operative bleeding, n (%)1 (0.8)3 (2.2)3 (2.3)6 (4.5)2 (5.4)2 (1.5) Confidence interval (%)0.0, , , , , , 5.4 Components of primary safety endpoint Fatal/critical bleeding, n (%) Bleeding leading to reoperation, n (%)02 (1.5) 000 Clinically overt bleeding leading to treatment cessastion 0001 (0.7)1 (2.7)1 (0.8) Clinically overt bleeding with a fall in hemoglobin, n (%) 01 (0.7)1 (0.8)3 (2.2)1 (2.7)2 (1.5) Clinically overt bleeding leading to blood transfusion, n (%) 1 (0.8)1 (0.7)1 (0.8)4 (3.0)2 (5.4)2 (1.5) Bleeding site Surgical-site bleeds, n (%)1 (0.8)3 (2.2)3 (2.3)5 (3.7)2 (5.4)1 (0.8) Extrasurgical-site bleeds, n (%)0002 (1.5)01 (0.8) Clinically relevant non-major bleeding, n (%)2 (1.5)8 (5.9)3 (2.3)6 (4.5)1 (2.7)0 Minor bleeding, n (%)4 (3.0)6 (4.4)11 (8.3)14 (10.4)1 (2.7)6 (4.5) Eriksson B.I., et al. J Thromb Haemost. 2006;4(1):121-8.

Oral, Direct Factor Xa Inhibition with Rivaroxaban for the Prevention of VTE After Total Hip Replacement For patients at high risk of developing thrombosis and bleeding, direct FXa inhibition with rivaroxaban –Was effective across the dose range studied –Compared favorably with enoxaparin Safety was similar between rivaroxaban 2.5–10 mg b.i.d. and enoxaparin Conclusions: Eriksson B.I., et al. J Thromb Haemost. 2006;4(1):121-8.