Randomized, Double-Blind, Multi-Dose Efficacy, Safety and Biomarker Study of the Oral Factor Xa Inhibitor DU-176b Compared with Placebo for Prevention of Venous Thromboembolism in Patients after Total Knee Arthroplasty

Abstract

Introduction: The objectives of this study were to assess the safety, efficacy and dose-response relationship of DU-176b for the prevention of venous thromboembolism (VTE) in Japanese patients after elective total knee arthroplasty (TKA). Changes in biomarkers in relation to VTE and bleeding were also evaluated.Methods: This was a randomized, parallel-group, placebo-controlled, double-blind, doubledummy, multicenter study. DU-176b (5–60 mg QD) or placebo was administered for 11–14 days after TKA. A placebo control was used because at the time no other anticoagulants had been approved for thromboprophylaxis after TKA in Japan. The primary efficacy endpoint included the adjudicated incidence of VTE, including asymptomatic and symptomatic deep vein thrombosis, as evaluated by venograms, and symptomatic pulmonary embolism. The primary safety endpoint included major and clinically relevant bleeding. Secondary efficacy endpoints included the pharmacodynamic (PD) indices prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), anti-FXa activity and key coagulation biomarkers including prothrombin fragment F1+2, plasmin-α2-plasmin inhibitor complex (PIC), D-dimer, thrombin-antithrombin III complex and soluble fibrin. Secondary safety endpoints included incidence of adverse events (AEs).Results: There were no clinically relevant differences in baseline demographics of the 523 patients randomized. Mean age was 71.1 ± 7.6 years, mean weight was 60.3 ± 9.9 kg and ~78% of patients were female. All DU-176b doses had significantly less VTE than placebo when each DU-176b dose group was compared with placebo (Table), and there was a dose-related response (P <0.001 across DU-176b dose). Paired comparisons showed no significant differences in VTE incidence between the 5 & 15 mg groups or between the 30 & 60 mg groups but significant differences between other paired groups (χ2 test; P<0.001 to P=0.021). PD indices were dose-related (Table, P <0.001 across DU-176b dose). After surgery, coagulation biomarkers increased with a trend for DU-176b to affect these markers more than placebo (Table, P <0.001 across DU-176b dose). The incidence of major and clinically relevant bleeding was comparable across all groups without any significant differences among groups or between DU-176b doses and placebo (Table). There were no trends in other AEs, including liver enzymes, across DU-176b dose.Conclusions: DU-176b demonstrated significant, dose-dependent reductions in VTE after TKA without increases in major or clinically relevant bleeding. There were also consistent dose-dependent changes in PD indices and coagulation biomarkers. The observed dose-dependent decreases in VTE without concomitant increases in bleeding should be further evaluated.PlaceboDU-176b 5 mgDU-176b 15 mgDU-176b 30 mgDU-176b 60 mgPrimary Efficacy Endpoint: VTEn/N (%) (95% CI)43/89 (48.3) (37.9–58.7)26/88 (29.5)* (20.0–39.1)24/92 (26.1)** (17.1–35.1)11/88 (12.5)** 5.6–19.4)8/88 (9.1)** (3.1–15.1)Primary Safety Endpoint: % Major + Clinically Relevant bleedingn/N (%)4/102 (3.9)3/103 (2.9)†5/106 (4.7)‡4/103 (3.9)‡5/106 (4.7)‡PD and Coagulation Biomarkers, all data mean ± SD post-operation/pre-treatment initiation 1–3 h post-dose Day 7N87869187878686898787PT (sec)13.5±0.913.3±0.813.3±0.713.4±0.913.1±0.612.7±0.613.3±0.8**14.9±1.5**17.8±2.7**22.1±5.9**anti-FXa activity (IU/mL)0.10±0.00.10±0.00.10±0.00.13±0.230.10±0.00.10±0.00.44±0.80**1.18±0.68**2.40±1.17**4.38±2.56**Prothrombin fragment F1+2, pM479.6±229.7431.4±257.5468.7±249.0428.9±269.0417.9±223.6588.9±228.9484.6±184.9*450.8±158.2**414.0±172.8**398.8±147.4**D-dimer μg/mL12.4±10.513.6±10.514.3±11.212.2±10.311.4±10.19.4±5.77.5±3.76.7±2.7**6.5±3.3**5.8±2.4***P<0.01, **P<0.001, †P=0.445, ‡P=1.00 vs placebo.