Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study

Summary. Background: Prophylaxis is recommended following total joint replacement because of the high risk of venous thromboembolism (VTE). Postoperative low‐molecular‐weight heparin (LMWH) reduces the incidence of venographically detected deep vein thrombosis (DVT) to about 10–15% in total hip replacement (THR) patients. Ximelagatran is a novel, oral direct thrombin inhibitor that selectively and competitively inhibits both free and clot‐bound thrombin. We compared the efficacy and safety of ximelagatran with those of enoxaparin for the prevention of VTE in patients undergoing THR. Methods: This was a prospective, randomized, multicenter, double‐blind study conducted principally in the USA and Canada. Patients received fixed‐dose oral ximelagatran 24 mg bid or subcutaneous enoxaparin 30 mg bid and matched placebo for 7–12 days; both regimens were initiated the morning after surgery. The incidence of VTE (by postoperative day 12) included thrombosis determined by mandatory venography of the leg on which surgery was performed and symptomatic, objectively proven DVT or pulmonary embolism (PE). VTE and bleeding events were interpreted by an independent central adjudication committee for primary analysis. Results: Of the 1838 patients randomized, 1557 had either adequate venography or symptomatic, proven VTE (efficacy population). Overall rate of venography acceptable for evaluation was 85.4%. Overall rates of total VTE were 7.9% (62 of 782 patients) in the ximelagatran group and 4.6% (36 of 775 patients) in the enoxaparin group, with an absolute difference of 3.3% and a 95% confidence interval for the difference of 0.9% to 5.7%. Proximal DVT and/or PE occurred in 3.6% (28 of 782 patients) in the ximelagatran group and 1.2% (nine of 774 patients) in the enoxaparin group. Major bleeding events were observed in 0.8% (seven of 906) of the ximelagatran‐treated patients and in 0.9% (eight of 910) of the enoxaparin‐treated patients (P > 0.95). Non‐inferiority of ximelagatran 24 mg bid based on a prespecified margin of 5% was not met, resulting in superiority of the enoxaparin regimen. Conclusions: Both ximelagatran and enoxaparin decreased the overall rate of VTE compared with that reported historically. However, in this study, enoxaparin 30 mg bid was more effective than ximelagatran 24 mg bid for prevention of VTE in THR. Oral ximelagatran was used without coagulation monitoring, was well tolerated, and had bleeding rates comparable to those of enoxaparin. Further refinement by testing a higher dose of ximelagatran in the patients undergoing THR is warranted.     

A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I

Summary.  This randomized, controlled, multicentre study evaluated the efficacy and tolerability of the oral direct thrombin inhibitor ximelagatran, compared with a low-molecular-weight heparin (dalteparin) followed by warfarin, in the treatment of deep vein thrombosis (DVT) of the lower extremity. Patients with acute DVT received oral ximelagatran (24, 36, 48 or 60 mg twice daily) or dalteparin and warfarin for 2 weeks. Evaluation of paired venograms from 295 of 350 patients showed regression of the thrombus in 69% of patients treated with ximelagatran and 69% of patients treated with dalteparin and warfarin. Progression was observed in 8% and 3% of patients, respectively. Changes in thrombus size according to the Marder score were similar in all groups. Treatment discontinuation due to bleeding occurred in two patients receiving ximelagatran (24- and 36-mg groups) and in two patients receiving dalteparin and warfarin. Reduction in pain, edema and circumference of the affected leg was similar in all groups. Oral ximelagatran appears to be a promising alternative to current anticoagulant therapy to limit the progression of acute DVT, and it seems to possess a wide therapeutic window.     

A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial

BACKGROUND: Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following orthopedic surgery. METHODS: In a multicenter, parallel-group, double-blind study, 1973 patients undergoing total hip or knee replacement were randomized to 6-10 days of oral dabigatran etexilate (50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily), starting 1-4 h after surgery, or subcutaneous enoxaparin (40 mg once daily) starting 12 h prior to surgery. The primary efficacy outcome was the incidence of VTE (detected by bilateral venography or symptomatic events) during treatment. RESULTS: Of the 1949 treated patients, 1464 (75%) patients were evaluable for the efficacy analysis. VTE occurred in 28.5%, 17.4%, 16.6%, 13.1% and 24% of patients assigned to dabigatran etexilate 50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily and enoxaparin, respectively. A significant dose-dependent decrease in VTE occurred with increasing doses of dabigatran etexilate (P < 0.0001). Compared with enoxaparin, VTE was significantly lower in patients receiving 150 mg twice daily [odds ratio (OR) 0.65, P = 0.04], 300 mg once daily (OR 0.61, P = 0.02) and 225 mg twice daily (OR 0.47, P = 0.0007). Compared with enoxaparin, major bleeding was significantly lower with 50 mg twice daily (0.3% vs. 2.0%, P = 0.047) but elevated with higher doses, nearly reaching statistical significance with the 300 mg once-daily dose (4.7%, P = 0.051). CONCLUSIONS: Oral administration of dabigatran etexilate, commenced early in the postoperative period, was effective and safe across a range of doses. Further optimization of the efficacy/safety balance will be addressed in future studies.     

Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I.

BACKGROUND: Dabigatran etexilate (BIBR 1048) is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following total hip replacement. Following oral administration, dabigatran etexilate is rapidly converted to its active form dabigatran (BIBR 953 ZW). OBJECTIVES: To determine the safe therapeutic range of dabigatran etexilate following total hip replacement. METHODS: In a multicenter, open-label, dose-escalating study, 314 patients received oral doses of dabigatran etexilate (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4-8 h after surgery, for 6-10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. RESULTS: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose-response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. CONCLUSIONS: Dabigatran etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.     

A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement

BACKGROUND: LY517717 is an oral direct inhibitor of activated factor X that is currently under clinical development. OBJECTIVES: The aims of this proof-of-concept study in patients undergoing total knee replacement (TKR) or total hip replacement (THR) were to determine whether LY517717 can safely reduce the risk of venous thromboembolism (VTE) and to identify at least one dose of LY517717 that is non-inferior to enoxaparin. METHODS: In a double-blind, parallel-arm, dose-ranging study, patients undergoing TKR or THR were randomly allocated to receive once-daily oral LY517717 (25, 50, 75, 100, 125 or 150 mg), started 6-8 h after wound closure, or s.c. enoxaparin, 40 mg, started in the evening before surgery. The primary efficacy endpoint was the composite of deep venous thrombosis (DVT), detected by mandatory bilateral venography performed at the end of the study treatment (between days 5 and 9), and objectively confirmed symptomatic DVT and/or pulmonary embolism (PE), occurring during the treatment period. The combination of major and minor bleeding was the primary safety endpoint. RESULTS: Five hundred and seven patients received at least one dose of LY517717 or enoxaparin (safety population). Three hundred and ninety-one patients had evaluable bilateral venography or experienced a clinical DVT and/or PE (primary efficacy population). LY517717 treatment resulted in a dose-dependent decrease in the incidence of thromboembolic events (P = 0.0001). The incidences of VTE with 100, 125, and 150 mg of LY517717 were 19%, 19% and 16%, respectively, compared to 21% with enoxaparin. The efficacies of 100-mg, 125-mg and 150-mg doses of LY517717 were non-inferior to that of enoxaparin according to prespecified criteria. Bleeding events were uncommon in both LY517717 and enoxaparin patients. CONCLUSIONS: Doses of 100, 125 and 150 mg of LY517717 are non-inferior to enoxaparin for the prevention of VTE after TKR or THR, and are associated with similar low rates of bleeding.     

Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial

BACKGROUND: Oral anticoagulants, such as dabigatran etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism (VTE) after total knee replacement surgery. METHODS: In this randomized, double-blind study, 2076 patients undergoing total knee replacement received dabigatran etexilate, 150 mg or 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery, for 6-10 days. Patients were followed-up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. RESULTS: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group versus 36.4% (183 of 503) of the dabigatran etexilate 220 mg group (absolute difference, -1.3%; 95% CI, -7.3 to 4.6) and 40.5% (213 of 526) of the 150 mg group (2.8%; 95% CI, -3.1 to 8.7). Both doses were noninferior to enoxaparin based on the pre-specified noninferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% versus 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow-up. CONCLUSIONS: Dabigatran etexilate (220 mg or 150 mg) was at least as effective and with a similar safety profile as enoxaparin for prevention of VTE after total knee-replacement surgery.     

BAY 59-7939: an oral, direct Factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study

BACKGROUND: BAY 59-7939, a novel, oral, direct factor Xa inhibitor, is in clinical development for the prevention of venous thromboembolism (VTE), a frequent complication following orthopaedic surgery. METHODS: In a multicenter, parallel-group, double-blind, double-dummy study, 621 patients undergoing elective total knee replacement were randomly assigned to oral BAY 59-7939 (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6-8 h postsurgery), or subcutaneous enoxaparin (30 mg b.i.d., initiated 12-24 h postsurgery). Treatment was continued until mandatory bilateral venography 5-9 days after surgery. The primary efficacy endpoint was a composite of any deep vein thrombosis (proximal and/or distal), confirmed non-fatal pulmonary embolism and all-cause mortality during treatment. The primary safety endpoint was major, postoperative bleeding during treatment. RESULTS: Of the 613 patients treated, 366 (59.7%) were evaluable for the primary efficacy analysis. The primary efficacy endpoint occurred in 31.7%, 40.4%, 23.3%, 35.1%, and 25.4% of patients receiving 2.5, 5, 10, 20 and 30 mg b.i.d. doses of BAY 59-7939, respectively (test for trend, P = 0.29), compared with 44.3% in the enoxaparin group. The frequency of major, postoperative bleeding increased with increasing doses of BAY 59-7939 (test for trend, P = 0.0007), with no significant difference between any dose group compared with enoxaparin. Bleeding endpoints were lower for the 2.5-10 mg b.i.d. doses compared with higher doses of BAY 59-7939. CONCLUSIONS: Oral administration of 2.5-10 mg b.i.d. of BAY 59-7939, early in the postoperative period, showed potential efficacy and an acceptable safety profile, similar to enoxaparin, for the prevention of VTE in patients undergoing elective total knee replacement.     

Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement

BACKGROUND: Joint replacement surgery is an appropriate model for dose-ranging studies investigating new anticoagulants. OBJECTIVES: To assess the efficacy and safety of a novel, oral, direct factor Xa (FXa) inhibitor--BAY 59-7939--relative to enoxaparin in patients undergoing elective total hip replacement. METHODS: In this double-blind, double-dummy, dose-ranging study, patients were randomized to oral BAY 59-7939 (2.5, 5, 10, 20, or 30 mg b.i.d.), starting 6-8 h after surgery, or s.c. 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. RESULTS: Of 706 patients treated, 548 were eligible for the primary efficacy analysis. The primary efficacy endpoint was the incidence of any deep vein thrombosis, non-fatal pulmonary embolism, and all-cause mortality; rates were 15%, 14%, 12%, 18%, and 7% for BAY 59-7939 2.5, 5, 10, 20, and 30 mg b.i.d., respectively, compared with 17% for enoxaparin. The primary efficacy analysis did not demonstrate any significant trend in dose-response relationship for BAY 59-7939. The primary safety endpoint was major, postoperative bleeding; there was a significant increase in the frequency of events with increasing doses of BAY 59-7939 (P = 0.045), but no significant differences between individual BAY 59-7939 doses and enoxaparin. CONCLUSIONS: When efficacy and safety were considered together, the oral, direct FXa inhibitor BAY 59-7939, at 2.5-10 mg b.i.d., compared favorably with enoxaparin for the prevention of venous thromboembolism in patients undergoing elective total hip replacement.     

Long-term treatment with ximelagatran, an oral direct thrombin inhibitor, persistently reduces the coagulation activity after a myocardial infarction

BACKGROUND: In the ESTEEM study, patients with a recent myocardial infarction were treated with aspirin and randomized to one of four doses (24-60 mg b.i.d) of the oral direct thrombin inhibitor ximelagatran or placebo for 6 months. Ximelagatran and aspirin reduced the risk of recurrent ischemic events compared with aspirin alone. In the present substudy we evaluated the different doses of ximelagatran on pharmacokinetics as measured by plasma concentration of the active compound melagatran and activated partial thromboplastin time (APTT) and pharmacodynamics as related by markers for coagulation activity, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer. METHODS AND RESULTS: Plasma samples from 518 patients were collected before, during and after the treatment period. There was a linear dose-concentration relation at peak and trough and a linear relation between concentration and APTT (P < 0.001). F1 + 2 and D-dimer were decreased by 25% and 52% at 1 week (P < 0.001) in the ximelagatran groups compared with the placebo group and the reductions were maintained during the 6 months treatment. There were no differences detected in F1 + 2 or D-dimer levels between the different ximelagatran dosages. There was no correlation between the melagatran concentration and the change in F1 + 2 and D-dimer levels. After cessation of ximelagatran F1 + 2 and D-dimer levels returned to the initial levels. CONCLUSION: The dose of ximelagatran and APTT are linearly related to the plasma concentration of melagatran. Ximelagatran induces a sustained and stable reduction of thrombin generation and fibrin turnover without any relation to dose above 24 mg b.i.d. These properties indicate that long-term treatment with a low dose of ximelagatran may provide valuable depression of coagulation activity in aspirin treated post myocardial infarction patients.     

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

BACKGROUND: YM150, a new oral direct factor Xa inhibitor is used as prophylaxis for venous thromboembolism (VTE), a well-known risk after orthopaedic surgery. OBJECTIVES: To assess the safety and efficacy of thromboprophylaxis with YM150 in a dose escalation study. PATIENTS/METHODS: 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. RESULTS: 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). CONCLUSIONS: YM150, 10-60 mg daily, starting 6-10 h after primary hip replacement, was shown to be safe, well tolerated and effective.     

利伐沙班、达比加群与肝素在全髋或全膝置换后的抗凝治疗

背景:目前临床上主要使用依诺肝素预防全髋或全膝置换后静脉血栓形成,但其并非百分之百的有效与安全. 目的:系统评价新型口服抗凝药利伐沙班和达比加群与依诺肝素在临床随机对照试验中预防全髋或全膝置换后静脉血栓形成的有效性和安全性. 方法:计算机检索 Pubed、ScienceDirect、Cochrane Library、CBM、CNKI,收集有关利伐沙班、达比加群与依诺肝素在全髋或全膝置换后抗凝治疗有效性和安全性的临床随机对照试验,并评价纳入研究的方法学质量,统计软件用 RevMan5.1.0. 结果与结论:共纳入14个临床随机对照试验,共17212例患者.Meta 分析显示,利伐沙班组总静脉血栓发生率、大静脉血栓及有症状静脉血栓发生率均低于依诺肝素组;利伐沙班和达比加群组深静脉血栓发生率低于依诺肝素组;利伐沙班和达比加群与依诺肝素在出血率方面差异无显著性意义.提示新型口服抗凝药对全髋或全膝置换后深静脉血栓的预防效果优于依诺肝素,且利伐沙班优于达比加群.     

Dose-response study of recombinant human soluble thrombomodulin (ART-123) in the prevention of venous thromboembolism after total hip replacement.

BACKGROUND: Recombinant human soluble thrombomodulin (ART-123) is composed of the active, extracellular, domain of thrombomodulin. ART-123 binds to thrombin and this complex converts protein C into the natural anticoagulant activated protein C. This study was performed to identify an effective and safe dose of ART-123 for prevention of venous thromboembolism after elective, unilateral total hip replacement. METHODS AND RESULTS: An open-label, sequential, dose-ranging study was performed in which 312 patients received either 0.3 mg kg(-1) or 0.45 mg kg(-1) of ART-123, subcutaneously, 2-4 h after surgery (day 1). Those who received 0.3 mg kg(-1) were given a second dose of 0.3 mg kg(-1) on day 6, and the first 29 of these patients also used intermittent pneumatic compression devices. Those who received 0.45 mg kg(-1) were not given a second dose. Primary efficacy outcome was all deep vein thrombosis on mandatory bilateral venography performed on day 9 +/- 2 and symptomatic venous thromboembolism up to day 11. Primary safety outcome was major bleeding up to day 11. Among patients who did not use intermittent pneumatic compression, venous thromboembolism occurred in 3.4% of 116 evaluable patients in the 0.3 mg kg(-1) group and 0.9% of 111 patients in the 0.45 mg kg(-1) group. Major bleeding occurred in 1.4% of 139 patients in the 0.3 mg kg(-1) group and 6.3% of 144 patients in the 0.45 mg kg(-1) group. CONCLUSION: ART-123 is a highly effective antithrombotic agent that should be directly compared with current methods of prophylaxis in patients who have major orthopedic surgery.     

早期训练联合利伐沙班预防髋关节置换术后深静脉血栓的效果

目的探讨早期训练联合利伐沙班预防髋关节置换术后深静脉血栓的效果。方法选取110例髋关节置换术患者,将其随机分为2组。对照组采取利伐沙班治疗,观察组则给予早期肢体功能锻炼联合利伐沙班治疗。比较2组患者治疗前后的凝血指标、D-D水平、围术期并发症情况、术后引流量、皮下瘀斑面积及血红蛋白水平。结果干预后2组患者TT、FIB、APTT、PT等指标及D-D水平均较干预前显著改善(P0.05),且观察组显著优于对照组(P0.05)。观察组术后并发症发生率显著高于对照组(P0.05)。结论早期训练联合利伐沙班能显著改善髋关节置换术患者的血液黏滞度,促进血液循环,有效预防DVT的发生,值得临床推广应用。     

Incidence of cancer after a first episode of idiopathic venous thromboembolism treated with 3 months or 1 year of oral anticoagulation

Summary.  Background : A prolonged treatment with oral anticoagulants has been claimed to reduce the incidence of newly diagnosed cancer in the long-term follow-up of patients with venous thromboembolism. Objectives : In a multicenter prospective study we assessed the incidence of newly diagnosed clinically overt cancer in patients with a first episode of idiopathic venous thromboembolism (VTE) treated with oral anticoagulants for 3 months or 1 year. Patients and methods : Consecutive patients with an idiopathic venous thromboembolism who had completed 3 months of oral anticoagulant therapy without having a recurrence, bleeding or newly diagnosed cancer were randomized to discontinue oral anticoagulant therapy or to continue it for nine additional months. Idiopathic venous thromboembolism was defined as thrombosis occurring in the absence of known cancer, known thrombophilia, or temporary risk factors for venous thromboembolism. All patients were followed up for at least 1 year after randomization. Results : A total of 429 patients, 265 patients with DVT and 164 with PE, were followed up for an average of 43.7 months after randomization. A newly diagnosed cancer occurred in 32 patients (7.5%), 13 (6.2%) of the 210 patients treated for 3 months and 19 (8.7%) of the 219 patients treated for 1 year (RR = 0.71, 95% confidence interval 0.36–1.41). Conclusions : The incidence of newly diagnosed clinically overt cancer is not reduced in patients with idiopathic venous thromboembolism treated with 1-year anticoagulant treatment compared with patients treated for 3 months.     

Efficacy and safety of bemiparin compared with enoxaparin in the prevention of venous thromboembolism after total knee arthroplasty: a randomized, double-blind clinical trial

Summary.  In this randomized, multicenter, controlled, double-blind, sequential trial, 381 patients undergoing primary total knee replacement were randomly assigned to receive subcutaneous injections of either 3500 IU anti-factor Xa of bemiparin sodium, first dose 6 h after surgery, or 40 mg of enoxaparin, first dose 12 h before surgery, followed by daily doses for 10 ± 2 days, for the prophylaxis of venous thromboembolism. The primary efficacy endpoint was venous thromboembolism up to postoperative day 10 ± 2, defined as deep vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep vein thrombosis and/or documented symptomatic pulmonary embolism. The primary safety endpoint was major bleeding. Eighty-seven percent of all randomized patients (333 of 381 patients) were evaluable for efficacy. The incidence of venous thromboembolism was 32.1% (53 of 165 patients) in the bemiparin group and 36.9% (62 of 168 patients) in the enoxaparin group. The absolute risk difference was 4.8% in favor of bemiparin [95% confidence interval (CI), −15.1% to 5.6%; non-inferiority P -value: 0.02; superiority P -value: 0.36]. The incidence of proximal deep vein thrombosis was 1.8% (three of 165 patients) in the bemiparin group and 4.2% (seven of 168 patients) in the enoxaparin group. Major bleeding occurred in six patients (three in each group). There were no deaths during the study. This trial shows that bemiparin started postoperatively is as effective and safe as enoxaparin started preoperatively in the prevention of venous thromboembolism in patients undergoing total knee replacement.     

Prevention of venous thromboembolism with an oral factor Xa inhibitor,YM150, after total hip arthroplasty. A dose finding study (ONYX‐2)

Background: Anticoagulant prophylaxis substantially reduces the risk of venous thromboembolism (VTE) after major orthopedic surgery. The direct factor Xa inhibitor YM150 is currently under investigation for the prevention of VTE, stroke and ischemic vascular events in patients after orthopedic surgery, with atrial fibrillation and with acute coronary syndrome, respectively. Objectives: To investigate the efficacy and safety of YM150 for the prevention of VTE following elective total hip arthroplasty. Patients/methods: Patients were randomized to postoperative, once‐daily, oral YM150 (5, 10, 30, 60 or 120 mg) (double‐blind) or preoperative subcutaneous (open label) enoxaparin (40 mg) for 5 weeks. The primary efficacy endpoint comprised VTE diagnosed by mandatory bilateral venography or verified symptomatic deep vein thrombosis (DVT) plus all deaths up to 9 days after surgery. The primary safety outcome was major bleeding up to 9 days after surgery. Results: Primary efficacy endpoint: of 1017 patients randomized, 960 patients were evaluable for safety and 729 patients for efficacy. A dose‐related decrease in VTE incidence from YM150 5 to 60 mg (P = 0.0005) and from 5 to120 mg (P = 0.0002) was found. The VTE incidence was 27.4%, 31.7%, 19.3%, 13.3% and 14.5% for 5, 10, 30, 60 and 120 mg YM150, respectively, and 18.9% for enoxaparin. Primary safety endpoint: there was one major bleed with YM150 (60 mg) and one with enoxaparin. Conclusions: The oral direct FXa inhibitor YM150 demonstrated a significant dose response regarding efficacy. Doses from 30 to 120 mg had comparable efficacy to enoxaparin, without compromising safety regarding major bleeding events.     

Sustained prothrombotic profile after hip replacement surgery: the influence of prolonged prophylaxis with dalteparin

Summary.  In a randomized trial on the effect of dalteparin for 5 weeks after HRS we evaluated hemostatic variables in plasma sampled before and 1, 6 and 35 days postoperatively. In 218 patients we found that prothrombin fragment 1 + 2 (F1 + 2), thrombin–antithrombin complexes (TAT), d -dimer and fibrinogen were significantly higher on day 35 as compared with baseline values in the placebo group ( P  < 0.001 for all). The same pattern was found in the dalteparin group, but with significantly lower values for F1 + 2, TAT and d -dimer. In patients in the placebo group with venographically proven deep vein thrombosis (DVT) on day 35 (33%), significantly higher values were found for F1 + 2, TAT and d -dimer than in patients without DVT. Patients in the highest quartile of d -dimer (>2850 ng mL⁻¹) had an odds ratio for the presence of DVT of 24.0 when compared with patients in the lowest quartile (<1625 ng mL⁻¹). It is concluded that a substantial hypercoagulability is sustained until day 35 after HRS, significantly reduced with prolonged administration of dalteparin.     

Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits

Summary.  Background: Apixaban is an oral, direct factor Xa (FXa) inhibitor in late-stage clinical development. This study assessed effects of the direct FXa inhibitors, apixaban and rivaroxaban, vs. the direct thrombin inhibitor, dabigatran, on venous thrombosis (VT), bleeding time (BT) and clotting times in rabbits. Methods: We induced the formation of non-occlusive thrombus in VT models by placing threads in the vena cava, and induced bleeding by the incision of cuticles in anesthetized rabbits. Apixaban, rivaroxaban and dabigatran were infused IV to achieve a stable plasma level. Clotting times, including the activated partial thromboplastin time (aPTT), prothrombin time (PT), modified PT (mPT) and thrombin time (TT), were measured. Results: Apixaban, rivaroxaban and dabigatran exhibited dose-related efficacy in preventing VT with EC₅₀ of 65, 33 and 194 n m , respectively. At doses for 80% reduction of control thrombus, apixaban, rivaroxaban and dabigatran prolonged BT by 1.13 ± 0.02-, 1.9 ± 0.1-* and 4.4 ± 0.4-fold*, respectively (* P  <   0.05, vs. apixaban). In the treatment model, these inhibitors equally prevented growth of a preformed thrombus. Antithrombotic doses of apixaban and rivaroxaban prolonged aPTT and PT by <3-fold with no effect on TT. Dabigatran was ≥50-fold more potent in prolonging TT than aPTT and PT. Of the clotting assays studied, apixaban, rivaroxaban and dabigatran responded the best to mPT. Conclusion: Comparable antithrombotic efficacy was observed between apixaban, rivaroxaban and dabigatran in the prevention and treatment of VT in rabbits. Apixaban and rivaroxaban exhibited lower BT compared with dabigatran at equivalent antithrombotic doses. The clinical significance of these findings remains to be determined.