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.     

Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism after total knee and hip replacement surgery

Objective: This was an evaluation of the cost-effectiveness of oral dabigatran etexilate compared with subcutaneous low-molecular-weight heparin (enoxaparin) for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR) and total hip replacement (THR) surgery from the perspective of the UK National Health Service.Methods: Dabigatran etexilate (220 mg once daily) was compared with enoxaparin (40 mg once daily) in patients undergoing TKR (duration of prophylaxis, 6–10 days) and THR (duration of prophylaxis, 28–35 days). The 10-week acute postsurgical phase was modeled using a decision tree. A Markov process (1-year cycle length) was used to model long-term events (recurrent VTE, postthrombotic syndrome, and consequences of intracranial hemorrhage) for patients' remaining lifetimes. Relative risks for VTE and bleeding events were derived from 2 Phase III studies that compared dabigatran etexilate with enoxaparin 40 mg once daily. The probabilities of long-term events were estimated using data from published longitudinal studies.Results: Rates of VTE and bleeding events did not differ significantly between dabigatran etexilate and enoxaparin. Dabigatran etexilate was less costly than enoxaparin in TKR and substantially less costly in THR, primarily due to differences in administration costs. The cost of prophylaxis for THR patients, including drugs and administration costs, was estimated at £137 for dabigatran etexilate and £237 for enoxaparin (£7 for nursing time during the hospital stay, £91 for nurse home visits for administration after hospital discharge, and an additional £2 in drug costs). At a willingness-to-pay threshold of £20,000 per quality-adjusted life-year, the probability of cost-effectiveness for dabigatran etexilate was 75% in TKR and 97% in THR. These results were robust across a range of sensitivity analyses.Conclusion: From the perspective of the UK National Health Service, thromboprophylaxis with dabigatran etexilate was cost-saving compared with enoxaparin 40 mg once daily, with comparable efficacy and safety profiles.     

Type of anaesthesia and the safety and efficacy of thromboprophylaxis with enoxaparin or dabigatran etexilate in major orthopaedic surgery: pooled analysis of three randomized controlled trials

Background

There has been a shift towards greater use of neuraxial over general anaesthesia for patients undergoing total hip or knee arthroplasty. Furthermore, suggestions that peripheral nerve block may reduce adverse effects have recently been put forward. Although older studies showed a reduction in venous thromboembolism (VTE) with neuraxial compared with general anaesthesia, this difference has not been confirmed in studies using effective current thromboprophylaxis. We used a large data set to investigate the pattern of anaesthesia usage, and whether anaesthesia type affects efficacy and bleeding outcomes of thromboprophylaxis overall, within each treatment group, or for the novel oral anticoagulant dabigatran etexilate versus enoxaparin.

Methods

Three previously reported trials compared 220?mg and 150?mg dabigatran etexilate once daily with enoxaparin after knee or hip arthroplasty. A pooled analysis was performed in patients receiving general or neuraxial anaesthesia, or the combination of either with peripheral nerve block (n?=?8062). Outcome measures were major VTE plus VTE-related mortality, major bleeding and major plus clinically relevant bleeding events.

Results

General, neuraxial and combination anaesthesia were used in 29%, 52% and 19% of patients, respectively. Differences in efficacy and safety between anaesthesia subgroups were small and not significant, except for a slightly higher rate of major VTE and VTE-related mortality with general versus neuraxial anaesthesia (odds ratio: 1.40; 95% confidence interval: 1.03?C1.90; p?=?0.035) in the overall population. There were no significant effects of anaesthesia type on efficacy or safety of dabigatran etexilate versus enoxaparin.

Conclusions

Anaesthesia type did not greatly affect efficacy and safety outcomes in the pooled population of all three treatment groups. The efficacy and safety of dabigatran etexilate was comparable with enoxaparin, regardless of type of anaesthesia.

Trial registration

ClinicalTrials.gov identifiers: NCT00168805, NCT00168818, NCT00152971.     

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.     

AVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery – TREK: a dose-ranging study

Summary.  Background: AVE5026 is a new hemisynthetic ultra-low-molecular-weight heparin, with a novel anti-thrombotic profile resulting from high anti-factor (F)Xa activity and residual anti-FIIa activity. AVE5026 is in clinical development for venous thromboembolism (VTE) prevention, a frequent complication after total knee replacement (TKR) surgery. Objectives: This study evaluated the dose-response of AVE5026 for the prevention of VTE in patients undergoing TKR surgery. Patients/methods: In this parallel-group, double-blind, double-dummy study, 690 patients were randomized, and 678 treated with once-daily doses of AVE5026 (5, 10, 20, 40, or 60 mg) or enoxaparin 40 mg in the calibrator arm. The primary efficacy end point was VTE until post-operative day 11, defined as deep vein thrombosis (DVT) detected by bilateral venography, symptomatic DVT, non-fatal pulmonary embolism (PE) and VTE-related death. The primary safety outcome was the incidence of major bleeding. Results: The primary efficacy outcome was assessed in 464 patients. There was a significant dose-response across the five AVE5026 groups for VTE prevention ( P  <   0.0001), with the incidence of VTE ranging from 5.3% to 44.1% compared with 35.8% in the enoxaparin group and for proximal DVT ( P  =   0.0002). Also, a significant dose-response for AVE5026 was seen for major bleeding ( P  =   0.0231) and any bleeding ( P  =   0.0003). Six patients in the AVE5026 groups, four in the 60 mg group, experienced major bleeding; none did in the enoxaparin group. Conclusions: The safety and efficacy results of this study suggest that a AVE5026 dose of between 20 and 40 mg presents an adequate benefit-to-risk ratio.     

The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study

Summary.  Background : Ximelagatran and its subcutaneous (s.c.) form melagatran are novel direct thrombin inhibitors for the prevention and treatment of thromboembolic disease. Methods : In a double-blind study, 2835 consecutive patients undergoing total hip or knee replacement were randomized to either melagatran/ximelagatran or enoxaparin. Melagatran 2 mg was started immediately before surgery; 3 mg was then administered postoperatively, followed by 24 mg of oral ximelagatran b.i.d. beginning the next day. Enoxaparin 40 mg, administered subcutaneously o.d., was started 12 h before surgery. Both treatments were continued for 8–11 days. The main efficacy outcome measures were major venous thromboembolism (VTE); [proximal deep vein thrombosis (DVT), non-fatal and/or fatal pulmonary embolism (PE), death where PE could not be ruled out], and total VTE (proximal and distal DVT; PE; death from all causes). DVT was detected by mandatory bilateral ascending venography at the end of the treatment period or earlier if clinically suspected. The main safety outcome was bleeding. Results : The rates of major and total VTE were significantly lower in the melagatran/ximelagatran group compared with the enoxaparin group (2.3% vs. 6.3%, P  = 0.0000018; and 20.3% vs. 26.6%, P  < 0.0004, respectively). Fatal bleeding, critical site bleeding and bleeding requiring reoperation did not differ between the two groups. 'Excessive bleeding as judged by the investigator' was more frequent with melagatran/ximelagatran than with enoxaparin. Conclusions : In patients undergoing total hip or knee replacement, preoperatively initiated s.c. melagatran followed by oral ximelagatran was significantly more effective in preventing VTE than preoperatively initiated s.c. enoxaparin.     

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.     

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.     

Epidemiology of venous thromboembolism after lower limb arthroplasty: the FOTO study

BACKGROUND: In view of recent substantial changes in the management of orthopedic surgery patients, a study was performed in order to update data on the epidemiology of venous thromboembolism (VTE) in patients undergoing lower limb arthroplasty according to contemporary practise. METHODS: We performed a prospective observational study of a cohort of consecutive patients hospitalized for total hip or knee replacement in June 2003. The primary study outcome was the incidence of symptomatic VTE at 3 months. All events were adjudicated by an independent critical event committee. RESULTS: Data from 1080 patients (mean age 68.0 years) were available; 63.2% were undergoing total hip replacement and 36.8% total knee replacement. Pharmacological thromboprophylaxis was administered for a mean time of 36 days. Injectable antithrombotics were used in more than 99% of patients, irrespective of the type of surgery. The incidence of the primary study outcome was 1.8% (20 events; 95% CI: 1.0-2.6%). The incidences were 1.3% and 2.8% in hip and knee surgery patients, respectively. There were two pulmonary embolisms, both in knee surgery patients; neither was fatal. Thirty-five per cent of VTEs occurred after hospital discharge. An age of at least 75 years and the absence of ambulation before hospital discharge were the only significant (P < 0.05) predictors of VTE. The rate of clinically significant bleeding was 1.0% and the rate of death was 0.9%. CONCLUSIONS: The incidence of symptomatic VTE after lower limb arthroplasty is low, even if there is still a need to improve thromboprophylaxis, notably in patients undergoing knee arthroplasty.     

Single intravenous administration of TB‐402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose‐escalating,randomized, controlled trial

Summary. Background: TB‐402 is a novel anticoagulant monoclonal antibody with a prolonged antithrombotic effect resulting from its partial factor (F)VIII inhibition and long half‐life. We evaluated the efficacy and safety of a single administration of TB‐402 for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR). Patients and methods: This was a phase II, dose‐escalating, randomized, enoxaparin‐controlled, open‐label study. Patients were post‐operatively assigned to a single dose of TB‐402 (0.3, 0.6 or 1.2 mg kg^?1) or enoxaparin 40 mg for at least 10 days (n = 75 per group; 3:1 TB‐402 to enoxaparin). The primary efficacy outcome was total VTE defined as asymptomatic deep vein thrombosis (DVT) detected by bilateral venography and symptomatic VTE by day 7 to 11. The principal safety outcome was the incidence of major bleeding and clinically relevant non‐major bleeding. Results: Total VTE was lower in all TB‐402 groups compared with enoxaparin: 16.7%(95% CI 9.8–26.9), 23.9%(95% CI 15.3–35.3), 24.1%(95% CI 16.0–34.5) and 39.0%(95% CI 28.8–50.1) for TB‐402 0.3, 0.6, 1.2 mg kg^?1 and enoxaparin, respectively (P = 0.003 for TB‐402 0.3 mg kg^?1 vs. enoxaparin). The incidence of total VTE in the pooled TB‐402 groups was 21.6% (95%CI 16.6–27.5), an absolute risk reduction vs. enoxaparin of 17.4% (95% CI 5.2–29.6). Major or clinically relevant non‐major bleeding was observed in 3/75(4.0%), 4/74(5.4%), 7/87(8.0%) and 3/79(3.8%) patients for TB‐402 0.3, 0.6, 1.2 mg kg^?1 and enoxaparin, respectively. Conclusions: TB‐402, as a single post‐operative administration, was associated with a lower rate of VTE in all doses tested, compared with enoxaparin. The incidence of major and clinically relevant non‐major bleeding was similar to enoxaparin 40 mg for TB‐402 0.3 and 0.6 mg kg^?1.     

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.     

Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials,SAVE‐HIP1, SAVE‐HIP2 and SAVE‐KNEE

Background:  Semuloparin is a novel ultra‐low‐molecular‐weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. Objectives:  Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE‐KNEE), elective hip replacement (SAVE‐HIP1) and hip fracture surgery (SAVE‐HIP2). Patients/Methods:  All studies were multinational, randomized and double‐blind. Semuloparin and enoxaparin were administered for 7–10 days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non‐fatal pulmonary embolism or all‐cause death. Safety outcomes included major bleeding, clinically relevant non‐major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). Results:  In total, 1150, 2326 and 1003 patients were randomized in SAVE‐KNEE, SAVE‐HIP1 and SAVE‐HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE‐HIP1. In SAVE‐HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE‐KNEE and SAVE‐HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. Conclusions:  Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles.     

The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.

BACKGROUND: Heparins and warfarin are currently used as venous thromboembolism (VTE) prophylaxis in surgery. Inhibition of factor (F) Xa provides a specific mechanism of anticoagulation and the potential for an improved benefit-risk profile. OBJECTIVES: To evaluate the safety and efficacy of apixaban, a potent, direct, oral inhibitor of FXa, in patients following total knee replacement (TKR), and to investigate dose-response relationships. PATIENTS/METHODS: A total of 1238 patients were randomized to one of six double-blind apixaban doses [5, 10 or 20 mg day(-1) administered as a single (q.d.) or a twice-daily divided dose (b.i.d.)], enoxaparin (30 mg b.i.d.) or open-label warfarin (titrated to an International Normalized Ratio of 1.8-3.0). Treatment lasted 10-14 days, commencing 12-24 h after surgery with apixaban or enoxaparin, and on the evening of surgery with warfarin. The primary efficacy outcome was a composite of VTE (mandatory venography) and all-cause mortality during treatment. The primary safety outcome was major bleeding. RESULTS: A total of 1217 patients were eligible for safety and 856 patients for efficacy analysis. All apixaban groups had lower primary efficacy event rates than either comparator. The primary outcome rate decreased with increasing apixaban dose (P = 0.09 with q.d./b.i.d. regimens combined, P = 0.19 for q.d. and P = 0.13 for b.i.d. dosing).A significant dose-related increase in the incidence of total adjudicated bleeding events was noted in the q.d. (P = 0.01) and b.i.d. (P = 0.02) apixaban groups; there was no difference between q.d. and b.i.d. regimens. CONCLUSIONS: Apixaban in doses of 2.5 mg b.i.d. or 5 mg q.d. has a promising benefit-risk profile compared with the current standards of care following TKR.     

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.     

Dabigatran and rivaroxaban for prevention of venous thromboembolism--systematic review and adjusted indirect comparison

What is known and objective: Dabigatran and rivaroxaban are new oral anticoagulants for thromboprophylaxis after elective orthopaedic surgery. We aimed to systematically compare their relative benefits and harms through meta‐analysis, and adjusted indirect comparison. Methods: We searched PubMed, EMBASE, trial registries and regulatory documents through May 2009 for randomized controlled trials (RCTs) of dabigatran (150 and 220 mg daily) and rivaroxaban (10 mg daily) compared with enoxaparin (40–60 mg daily) in elective orthopaedic surgery. We used random effects meta‐analysis to calculate pooled relative risks (RRs) and 95% confidence intervals (95% CI) for the outcomes of total venous thromboembolism, VTE (deep venous thrombosis, non‐fatal pulmonary embolism and all‐cause mortality), and haemorrhagic adverse events (major and clinically relevant non‐major bleeds). Adjusted indirect comparison was used for the pooled RRs of dabigatran and rivaroxaban with enoxaparin as the common control. Results: Rivaroxaban was superior to enoxaparin for the prevention of venous thromoboembolism (RR 0·56, 95% CI 0·43–0·73, P < 0·0001), with a trend for increased haemorrhage (RR 1·26, 95% CI 0·94–1·69, P = 0·13). Dabigatran was not superior to enoxaparin for prevention of VTE (RR 1·12, 95% 0·97–1·29, P = 0·12), and did not reduce haemorrhage risk (RR 1·10, 95% 0·90–1·35, P = 0·32). Adjusted indirect comparison showed that rivaroxaban was superior to dabigatran in preventing VTE, RR 0·50 (95% CI 0·37–0·68), but with a slight trend towards increased haemorrhage RR 1·14 (95% CI 0·80–1·64). What is new and conclusion: Rivaroxaban may be more effective than dabigatran for prevention of VTE after elective orthopaedic surgery but might also slightly increase the risk of haemorrhage.     

Fondaparinux for prevention of venous thromboembolism in major orthopedic surgery

OBJECTIVE: To review clinical information related to fondaparinux, a synthetic pentasaccharide recently approved for the prevention of deep-vein thrombosis (DVT) in patients undergoing major orthopedic surgeries and for extended DVT prophylaxis after hip fracture surgery. DATA SOURCES: Primary and review articles were identified by MEDLINE (1983-June 2003) using the key words pentasaccharide, Org31540, SR90107A, DVT prophylaxis, and fondaparinux. Additional sources were found listed in articles, abstracts, and unpublished data on file from the manufacturer. Articles selected were based on their coverage of the pharmacology, pharmacokinetics, safety, and efficacy of fondaparinux. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified were evaluated and all information deemed relevant was included. DATA SYNTHESIS: Fondaparinux is a selective antithrombin-dependent, indirect inhibitor of activated factor Xa. It has a favorable and predictable pharmacokinetic profile when administered subcutaneously, and has a long half-life, allowing once-daily dosing. Fondaparinux lacks in vitro cross-reactivity with heparin-induced antibodies. Major Phase III studies have demonstrated that subcutaneous fondaparinux sodium 2.5 mg given at least 6 hours postoperatively resulted in a 55% reduction in the risk of venous thromboembolism (VTE) in patients undergoing hip fracture surgery, total hip replacement surgery, or knee replacement surgery compared with standard enoxaparin therapy. It has a safety profile similar to that of enoxaparin with respect to clinically relevant major bleeding, including fatal bleeding, nonfatal bleeding, and bleeding requiring repeat surgery. The use of fondaparinux for prolonged prophylaxis after hip fracture has demonstrated further reduction in VTE events without increasing the risk of bleeding.CONCLUSIONS: Fondaparinux is the first of a new class of synthetic factor Xa inhibitors that demonstrated greater efficacy compared with enoxaparin for the prevention of VTE in major orthopedic surgery without an increase in clinically relevant bleeding. Given the favorable cost-effectiveness analysis and improved efficacy profile, fondaparinux should be considered for formulary addition for DVT prophylaxis in patients undergoing hip and knee replacement surgery. In patients undergoing hip fracture surgery, fondaparinux should be considered the DVT prophylaxis of choice. Extended thromboprophylaxis up to 28 days resulted in additional reduction in VTE (both symptomatic and venography-proven DVT) in patients with hip fracture surgery.     

A randomized study comparing the efficacy and safety of nadroparin 2850 IU (0.3 mL) vs. enoxaparin 4000 IU (40 mg) in the prevention of venous thromboembolism after colorectal surgery for cancer

BACKGROUND: The optimal thromboprophylactic dosage regimen of low-molecular-weight heparins in high-risk general surgery remains debatable. OBJECTIVES: We performed a randomized, double-blind study to compare the efficacy and safety of nadroparin 2850 IU (0.3 mL) and enoxaparin 4000 IU (40 mg) in the prevention of venous thromboembolism (VTE) after colorectal surgery for cancer. Patients and methods: Patients undergoing resection of colorectal adenocarcinoma were randomized to receive once daily either 2850 IU nadroparin or 4000 IU enoxaparin s.c. for 9 +/- 2 days. The primary efficacy outcome was the composite of deep vein thrombosis (DVT) detected by bilateral venography or documented symptomatic DVT or pulmonary embolism up to day 12. The main safety outcome was major bleeding. A blinded independent committee adjudicated all outcomes. RESULTS: Out of 1288 patients analyzed, efficacy was evaluable in 950 (73.8%) patients. The VTE rate was 15.9% (74/464) in nadroparin-treated patients and 12.6% (61/486) in enoxaparin-treated patients, a relative risk of 1.27 (95% confidence interval; CI: 0.93-1.74) that did not met the criterion for non-inferiority of nadroparin. The rate of proximal DVT was comparable in the two groups (3.2% vs. 2.9%, respectively), but that of symptomatic VTE was lower in nadroparin-treated patients (0.2% vs. 1.4%). There was significantly (P = 0.012) less major bleeding in nadroparin- than in enoxaparin-treated patients (7.3% vs. 11.5%, respectively). CONCLUSION: Compared with those receiving enoxaparin 4000 IU, patients treated with nadroparin 2850 IU showed a higher incidence of asymptomatic distal DVT, but a lower incidence of symptomatic VTE. Nadroparin treatment was safer in terms of bleeding risk.     

Low-dose warfarin for prevention of symptomatic thromboembolism after orthopedic surgery

BACKGROUND: Warfarin dosing with a target international normalized ratio (INR) range of 1.5-2.5 has not been reported as adequate for venous thromboembolism (VTE) prophylaxis after total knee (TKR) and total hip replacement (THR) surgery. OBJECTIVE: To evaluate the rate of symptomatic VTE after TKR and THR surgery using a low-dose (INR 1.5-2.5) warfarin protocol started the evening before surgery compared with a literature cohort treated with enoxaparin. METHODS: TKR/THR patients treated with a 21-day low-dose warfarin protocol were followed via a consecutive observational design. Main outcome measures were symptomatic VTE and pulmonary embolism (PE), with major bleeds and death as secondary outcomes. Low-dose warfarin was compared with a literature cohort of patients treated with enoxaparin who received enoxaparin for a similar length of time and was evaluated for the same outcomes. Cohort event rates were derived as a weighted average using the DerSimonian model. RESULTS: VTE, PE, bleeds, and deaths in the low-dose warfarin group were 8 (1.04%), 4 (0.52%), 8 (1.04%), and 4 (0.52%), respectively. The cohort weighted average values were 35 (1.33%), 19 (0.72%), 65 (2.46%), and 18 (0.67%), respectively. Odds ratios for low-dose warfarin for VTE, PE, and VTE plus PE were 0.778 (95% CI 0.36 to 1.68), 0.717 (0.24 to 2.11), and 0.754 (0.41 to 1.42), respectively, all nonsignificant. Odds ratios for bleeds and death were 0.420 (0.20 to 0.87; p = 0.02) and 0.756 (0.26 to 2.24; NS), respectively. CONCLUSIONS: For this evaluation, low-dose warfarin was comparable to the enoxaparin cohort for development of VTE, PE, and VTE+PE. Incidences of bleeds in the enoxaparin cohort were significantly higher than in patients receiving low-dose warfarin.     

Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data

For many years, warfarin was the only effective oral anticoagulant to prevent and treat thromboembolism. Nevertheless, its clinical use is limited by a narrow therapeutic window, extensive drug interactions, need of strict dietary control and frequent monitoring. The pharmacological response is also unpredictable and highly variable among patients. Suboptimal anticoagulation can lead to detrimental thromboembolic events or life-threatening bleeding. Direct thrombin inhibitor (DTI) activity represents a new class of anticoagulant activity that was intended to replace warfarin. Ximelagatran was the first DTI shown to have similar efficacy to warfarin, but failed to replace it because of a high incidence of liver toxicity. Dabigatran etexilate is another novel DTI with a more predictable pharmacokinetic profile and fewer drug interactions compared with warfarin. Recent large-scaled, randomized studies have shown that it does not share ximelagatran's hepatotoxicity, and is as effective as conventional anticoagulants for venous thromboembolism (VTE) and prophylaxis in atrial fibrillation (AF). These findings led to the approval of dabigatran etexilate for thromboprophylaxis following hip or knee replacement surgery in Europe, Canada and the United Kingdom. Here we summarize the latest evidence concerning the use of dabigatran etexilate in VTE (BISTRO, RE-MODEL, RE-NOVATE, RE-MOBILIZE and RECOVER) and AF (PETRO and RELY). Potential problems related to dabigatran use are also discussed to examine whether it can truly replace warfarin as the gold standard.