Elective Primary Hip Replacement Surgery Research Articles

YM150, an Oral Direct Factor Xa Inhibitor, as Prophylaxis for Venous Thromboembolism in Patients with Elective Primary Hip Replacement Surgery. A Dose Escalation Study.

Activated factor X (FXa) is a pivotal blood coagulation factor positioned at the crossroads of the extrinsic and intrinsic coagulation cascade. Inhibitors of FXa are anticoagulants that could be used in the prevention and treatment of thrombosis and venous thromboembolism (VTE). YM150 is a once daily, orally active FXa inhibitor. A randomized, enoxaparin-controlled, dose escalation study was performed in 174 patients undergoing elective primary hip replacement surgery to assess safety and efficacy of 7–10 days treatment with oral doses of YM150 (3, 10, 30 or 60 mg once daily starting 6–10 h after surgery) or s.c. enoxaparin (40 mg once daily starting 12 h before surgery). Safety is defined as major and/or clinically relevant non-major bleeding, and efficacy as venous thromboembolism detected by mandatory bilateral venography on the last treatment day and/or symptomatic VTE. The study was open-label with blinded evaluation of all outcomes by an independent Adjudication Committee. There were no major bleeds. Three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI: 0–16%) in the 3 mg and 2 (5.7%; 1–19%) in the 10 mg YM150 dose groups. No trend was observed in the incidence of minor bleeds with dose of YM150 in the range 10 mg to 60 mg daily. The proportion of patients with minor bleeding events in the enoxaparin group (22%; 95% CI: 10–39%) was similar to that in the YM150, 60 mg daily group (24%; 11–41%). 147 patients (84%) were considered to have an evaluable venogram. The incidences of VTE were 52% (95% CI: 31–72%), 39% (22–57%), 23% (9–40%), and 19% (7–37%) for the respective 3, 10, 30 and 60 mg YM150 once daily dose groups in comparison with 39% (22–57%) for enoxaparin. Logistic regression analysis revealed a statistically significant dose-related trend (p=0.006) for patients reaching the VTE endpoint during YM150 treatment. No trend in any of the measured safety parameters was observed with study treatment (YM150 or enoxaparin) or dose of YM150. Oral, once daily doses of YM150, 10 mg to 60 mg administered 6 to 10 h after primary hip replacement, were shown to be safe, well tolerated and effective in this study.

Once Daily YM150, an Oral Direct Factor Xa Inhibitor, for Prevention of Venous Thromboembolism in Patients Undergoing Elective Primary Hip Replacement.

YM150 is an orally active direct FXa inhibitor in clinical development. Proof of concept of YM150 was previously obtained in a dose escalation study, demonstrating a statistically significant dose-related trend in VTE prevention in patients undergoing total hip replacement (ONYX; J Thromb Haemost 2007; 5:1660–5). The present study with YM150 is a double blind, parallel, multi-center dose finding study in patients undergoing elective primary hip replacement surgery, with open label enoxaparin as control. Patients were randomly treated with 5, 10, 30, 60 or 120 mg YM150 once daily orally or 40 mg enoxaparin once daily subcutaneously. Patients were treated in hospital for approximately 1–2 weeks followed by home treatment for another 4 weeks, for in total 33–38 treatment days (prolonged treatment for hip replacements according to guidelines of Am. College of Chest Physicians (Geerts et al. Chest 2004: 126;338–400)). The administration of YM150 started 6–10 h after surgery, while treatment with enoxaparin started 12 ± 2 h before surgery. Mandatory bilateral venography was performed after 7–10 days of treatment. Follow up visits were performed at 2 and 4 weeks during home treatment, and 2, 4, and 8 weeks after end of study treatment. The sample size was estimated to be 960 randomized patients in order to yield 110 patients per treatment group with an evaluable venogram. The primary efficacy endpoint was defined as deep vein thrombosis, and/or symptomatic VTE and/or death, and primary safety endpoint as the incidence of major bleeding during the first 7–10 days of study treatment. Secondary efficacy endpoints were proximal and distal DVT (during the first 7–10 days) and symptomatic VTE during home treatment, and follow up. Secondary safety endpoints were the incidences of major, clinically relevant non-major (CRNM) and minor bleeding during the three study periods. Independent Adjudication Committees reviewed all venograms, bleeding reports, symptomatic VTEs, and deaths unaware of treatment allocation. An independent DSMB monitored the data to ensure the safety of the patients. 1017 patients were randomized from 81 sites in 17 European countries. Preliminary data showed that DVT was detected in 149 out of 727 evaluable venograms, one patient had symptomatic VTE, and one patient died (myocardial infarction) during the hospital treatment period. This results in a total primary efficacy outcome rate of 20.7% (151/729) in the evaluable study population, with a corresponding rate of major bleeding of 0.6% (6/1017). The breakdown of the results according to treatment group will be presented.

A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery.

YM150, a new oral direct factor Xa inhibitor is used as prophylaxis for venous thromboembolism (VTE), a well-known risk after orthopaedic surgery. To assess the safety and efficacy of thromboprophylaxis with YM150 in a dose escalation study. Patients (174) undergoing hip replacement surgery were randomized per cohort to oral once daily YM150 or subcutaneous enoxaparin (40 mg daily) in a 4:1 ratio for 7-10 days treatment. The YM150 doses were 3, 10, 30 and 60 mg by sequential four-dose escalation cohorts. The primary endpoint was major and/or clinically relevant non-major bleeding. The incidence of VTE was defined as a composite of verified symptomatic events and/or positive findings at bilateral venography on the last treatment day. An independent adjudication committee evaluated blindly the outcomes of the open-label study. No major and three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI, 0.1-15.1) in the 3 mg and 2 (5.7%; 95% CI, 1.0-18.8) in the 10 mg YM150 dose groups. Of 147 patients (84%) with an evaluable venogram, VTE was observed in 51.9% (95% CI, 31.9-71.4), 38.7% (95% CI, 22.6-57.0), 22.6% (95% CI, 9.7-39.4), and 18.5% (95% CI, 7.5-36.5) in the YM150 dose groups 3, 10, 30 and 60 mg, respectively. A significant YM150 dose-related trend in VTE incidence was found (P=0.006). VTE with enoxaparin was 38.7% (95% CI, 22.6-57.0). YM150, 10-60 mg daily, starting 6-10 h after primary hip replacement, was shown to be safe, well tolerated and effective.

Biochemical and Pharmacological Profiles of YM150, an Oral Direct Factor Xa Inhibitor.

YM150 is an oral direct FXa inhibitor used as prophylaxis for venous thromboembolism in patients undergoing elective primary hip replacement surgery (Blood 106: 530a(abstract#1865), 2005). No preclinical data has been reported for this compound so far. The biochemical and pharmacological properties of YM150 were evaluated in this study. In addition, the anticoagulation activity of orally administered YM150 was compared with that of YM466, a 1st generation FXa inhibitor, in fed cynomolgus monkeys and in bile duct-cannulated rats. The Ki values for YM150 and YM-222714, its major metabolite, against human FXa were 0.031 and 0.020 μM, respectively (n=4). Those for other serine proteases, such as trypsin, plasmin, and thrombin, were greater than 10 μM. YM150 and YM-222714 doubled the FXa clotting time and PT at 2.0 and 1.8 μM, and 1.2 and 0.95 μM, respectively (n=4). They also strongly inhibited prothrombin activation induced by free Xa, prothrombinase, and whole-blood clots with similar IC50 values (0.025–0.082 μM, n=5). In contrast, enoxaparin was much less effective at inhibiting prothrombin activation induced by prothrombinase or clots than prothrombin activation induced by free Xa (IC50 values: 330, 120, and 3.5 mU/mL, respectively, n=5). In the thromboplastin-induced venous thrombosis model in rats, YM150 (0.3–10 mg/kg i.d.) exerted its antithrombotic effects dose-dependently, with significance at 1 mg/kg (ED50: 0.97 mg/kg, n=6). YM150 prolonged the PT slightly at 10 and 30 mg/kg (1.2 and 1.4 times that of the control group), but the template bleeding time was not affected at 30 mg/kg. Although warfarin also exerted antithrombotic effects dose-dependently and with significance at 0.2 mg/kg (ED50: 0.12 mg/kg, n=6), this dose level markedly prolonged PT and bleeding time (4.4 and 2.2 times that of the control group). In an arterio-venous shunt thrombosis model in rabbits, YM150 (1–10 mg/kg p.o.) exerted antithrombotic effects dose-dependently and with significance at 10 mg/kg (ED50: 4.8 mg/kg, n=6), but did not prolong bleeding time at any dose level. Warfarin also exerted antithrombotic effects dose-dependently and with significance at 0.1 mg/kg/day (ED50: 0.29 mg/kg, n=6). Bleeding time was prolonged significantly at this dose level (control: 3.5 min warfarin: 5.8 min). The plasma concentrations of YM-222714 were 129+/−73.7, 396+/−224, and 3,641+/−902 ng/mL after dosing 1, 3, and 10 mg/kg, respectively, while those of YM150 was substantially lower (less than 125+/−265 ng/mL at 10 mg/kg). In fasted cynomolgus monkeys, oral administration of either YM150 (3–30 mg/kg) or YM466 (1–10 mg/kg) dose-dependently prolonged PT. The anticoagulation activity of YM466 was 3 times that of YM150, but this activity decreased significantly in the presence of food, while that of YM150 did not. The peak plasma anti-FXa activity after oral administration of 3 mg/kg YM150 to bile duct-cannulated rats and sham-operated rats were 67.7% and 68.5%, respectively. In contrast, those of 3 mg/kg YM466 were 57.4% and 26.2%, respectively. These data suggest that food or bile interferes with YM150 less than it does with YM466. In conclusion, YM150 is a promising oral FXa inhibitor that carries a bleeding risk that is less than that of warfarin. It also seems be well-absorbed without interference by food or bile. The in vivo antithrombotic activity of YM150 after oral administration was also determined to be produced by its active metabolite, YM-222714.