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):121-8.

• 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):121-8.

5-9 days treatment post-op

Bilateral Venography

BAY 59-7939

2.5 mg bid

BAY 59-7939 5 mg bid

BAY 59-7939

10 mg bid

BAY 59-7939

20 mg bid

BAY 59-7939

30 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

Treatment Primary EfficacyRivaroxaban2.5mg bid

15%

Rivaroxaban5mg bid

14%

Rivaroxaban10mg bid

12%

Rivaroxaban20mg bid

18%

Rivaroxaban2.5mg bid

7%

Enoxaparin 17%

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):121-8.

Treatment SafetyRivaroxaban2.5mg bid

0.8%

Rivaroxaban5mg bid

2.2%

Rivaroxaban10mg bid

2.3%

Rivaroxaban20mg bid

4.5%

Rivaroxaban2.5mg bid

5.4%

Enoxaparin 1.5%

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):121-8.

30

25

20

15

10

5

00 5 10 15 20 25 20 Enoxaparin

Bay 59-7939 (mg twice daily)

Inci

denc

e (%

)Total VTE and all-cause mortalityMajor, postoperative bleedingDose-response curves95% 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 59-7939 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, 4.1 0.5, 6.3 0.5, 6.5 1.7, 9.5 0.7, 18.2

0.2, 5.4

Components of primary safety endpoint

Fatal/critical bleeding, n (%) 0 0 0 0 0 0

Bleeding leading to reoperation, n (%) 0 2 (1.5) 2 (1.5) 0 0 0

Clinically overt bleeding leading to treatment cessastion

0 0 0 1 (0.7) 1 (2.7) 1 (0.8)

Clinically overt bleeding with a fall in hemoglobin, n (%)

0 1 (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 (%) 0 0 0 2 (1.5) 0 1 (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.