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• W2016234199 abstract "SummaryBackground: 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. 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. Evidence-based guidelines recommend the use of a low-molecular-weight heparin (LMWH) or adjusted-dose warfarin as thromboprophylaxis in patients undergoing total hip replacement (THR) [1Geerts W.H. Heit J.A. Clagett G.P. Pineo G.F. Colwell C.W. Anderson Jr, F.A. Wheeler H.B. Prevention of venous thromboembolism.Chest. 2001; 0: 132S-75SAbstract Full Text Full Text PDF Scopus (1623) Google Scholar]. While approximately 50–60% of THR patients who receive no prophylaxis develop deep vein thrombosis (DVT) detectable by venography, the pooled incidences from clinical trials in which LMWH or warfarin regimens were used are 16% and 22%, respectively [1Geerts W.H. Heit J.A. Clagett G.P. Pineo G.F. Colwell C.W. Anderson Jr, F.A. Wheeler H.B. Prevention of venous thromboembolism.Chest. 2001; 0: 132S-75SAbstract Full Text Full Text PDF Scopus (1623) Google Scholar]. Currently, LMWHs and warfarin are commonly used in North America [2Gross M. Anderson D.R. Nagpal S. O'Brien B. Venous thromboembolism prophylaxis after total hip or knee arthroplasty: a survey of Canadian orthopaedic surgeons.Can J Surg. 1999; 42: 457-61PubMed Google Scholar, 3Freedman K.B. Brookenthal K.R. Fitzgerald Jr, R.H. Williams S. Lonner J.H. A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty.J Bone Joint Surg Am. 2000; 82: 929-38Crossref PubMed Google Scholar]. LMWHs have demonstrated efficacy superior to that of warfarin in a meta-analysis of large, head-to-head trials, although the associated risk of bleeding and wound hematoma are slightly higher with LMWHs than with warfarin [1Geerts W.H. Heit J.A. Clagett G.P. Pineo G.F. Colwell C.W. Anderson Jr, F.A. Wheeler H.B. Prevention of venous thromboembolism.Chest. 2001; 0: 132S-75SAbstract Full Text Full Text PDF Scopus (1623) Google Scholar, 4Hull R. Raskob G. Pineo G. Rosenbloom D. Evans W. Mallory T. Anquist K. Smith F. Hughes G. Green D. et al.A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation.N Engl J Med. 1993; 329: 1370-6Crossref PubMed Google Scholar, 5RD Heparin Arthroplasty Group.RD heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty.J Bone Joint Surg Am. 1994; 76: 1174-85Crossref PubMed Google Scholar, 6Hamulyak K. Lensing A.W. Van Der Meer J. Smid W.M. Van Ooy A. Hoek J.A. Subcutaneous low-molecular weight heparin or oral anticoagulants for the prevention of deep-vein thrombosis in elective hip and knee replacement? Fraxiparine Oral Anticoagulant Study Group.Thromb Haemost. 1995; 74: 1428-31Crossref PubMed Scopus (124) Google Scholar, 7Francis C.W. Pellegrini Jr, V.D. Totterman S. Boyd Jr, A.D. Marder V.J. Liebert K.M. Stulberg B.N. Ayers D.C. Rosenberg A. Kessler C. Johanson N.A. Prevention of deep-vein thrombosis after total hip arthroplasty. Comparison of warfarin and dalteparin.J Bone Joint Surg Am. 1997; 79: 1365-72Crossref PubMed Google Scholar, 8Hull R.D. Pineo G.F. Francis C. Bergqvist D. Fellenius C. Soderberg K. Holmqvist A. Mant M. Dear R. Baylis B. Mah A. Brant R. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison. The North American Fragmin Trial Investigators.Arch Intern Med. 2000; 160: 2199-207Crossref PubMed Google Scholar]. LMWH does not require routine coagulation monitoring but must be administered parenterally; therefore, continuing this therapy after hospital discharge can be problematic. Warfarin is administered orally but is inconvenient because it requires frequent coagulation monitoring and dose adjustment to maintain target drug levels within its narrow therapeutic window [9Hirsh J. Dalen J.E. Anderson D.R. Poller L. Bussey H. Ansell J. Deykin D. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.Chest. 2001; 119: 8S-21SAbstract Full Text Full Text PDF PubMed Google Scholar]. Ximelagatran is an oral direct thrombin inhibitor that provides competitive, direct inhibition of both free and clot-bound thrombin. It is rapidly absorbed and transformed to its active form, melagatran [10Eriksson U.G. Johansson L. Frison L. Bredberg U. Gustafsson D. Single and repeated oral dosing of H 376/95, a prodrug of the direct thrombin inhibitor melagatran, to young healthy male subjects.Blood. 1999; 94: 26aGoogle Scholar], resulting in predictable plasma concentrations of melagatran that increase linearly in relation to dose in healthy volunteers [10Eriksson U.G. Johansson L. Frison L. Bredberg U. Gustafsson D. Single and repeated oral dosing of H 376/95, a prodrug of the direct thrombin inhibitor melagatran, to young healthy male subjects.Blood. 1999; 94: 26aGoogle Scholar] and orthopedic surgery patients [11Eriksson U.G. Frison L. Gustafsson D. Mandema J. Karlsson M.O. Eriksson B.I. The pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor, ximelagatran (pINN, formerly H 376/95), in orthopaedic surgery patients treated to prevent deep vein thrombosis and pulmonary embolism.Thromb Haemost. 2001; : P3092Google Scholar, 12Peters G. Whipple J. Eriksson U.G. Pharmacokinetics of H 376/95, a novel oral direct thrombin inhibitor, in patients undergoing total knee arthroplasty.Clin Pharmacol Ther. 2001; 69: 35Google Scholar]. Ximelagatran has a rapid onset of anticoagulant effect [10Eriksson U.G. Johansson L. Frison L. Bredberg U. Gustafsson D. Single and repeated oral dosing of H 376/95, a prodrug of the direct thrombin inhibitor melagatran, to young healthy male subjects.Blood. 1999; 94: 26aGoogle Scholar], predictable, dose-dependent pharmacokinetics and pharmacodynamics [10Eriksson U.G. Johansson L. Frison L. Bredberg U. Gustafsson D. Single and repeated oral dosing of H 376/95, a prodrug of the direct thrombin inhibitor melagatran, to young healthy male subjects.Blood. 1999; 94: 26aGoogle Scholar, 12Peters G. Whipple J. Eriksson U.G. Pharmacokinetics of H 376/95, a novel oral direct thrombin inhibitor, in patients undergoing total knee arthroplasty.Clin Pharmacol Ther. 2001; 69: 35Google Scholar], and no known clinically relevant interactions with food [13Gustafsson D. Nyström J.-.E. Carlsson S. Bredberg U. Eriksson U. Gyzander E. Elg M. Antonsson T. Hoffmann K. Ungell A. Sorensen H. Nagard S. Abrahamsson A. Bylund R. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects.Thomb Res. 2001; 101: 171-81Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] or CYP-450-metabolized drugs [14Johansson S. Bylock A. Eriksson-Lepkowska M. Thuresson A. Frison L. Eriksson U.G. The effect of the oral direct thrombin inhibitor, ximelagatran (pINN, formerly H 376/95), on the pharmacokinetics of nifedipine, in healthy male volunteers.Thromb Haemost. 2001; : P784PubMed Google Scholar, 15Eriksson U.G. Fager G. Eriksson-Lepkowska M. Cullberg M. Frison L. Bylock A. Ahnoff M. Effect of acetyl salicylic acid (ASA) on the pharmacodynamics and pharmacokinetics of melagatran, active form of the oral direct thrombin inhibitor, H 376/95.Clin Pharmacol Ther. 2001; 69: 24PubMed Google Scholar, 16Eriksson-Lepkowska M. Thuresson A. Bylock A. Frison L. Eriksson U.G. The effect of the oral direct thrombin inhibitor, ximelagatran (pINN, formerly H 376/95), on the pharmacokinetics of diazepam in healthy male volunteers.Thromb Haemost. 2001; : P785Google Scholar, 17Eriksson-Lepkowska M. Thuresson A. Bylock A. Frison L. Eriksson U.G. The effect of the oral direct thrombin inhibitor, ximelagatran (pINN, formerly H 376/95), on the pharmacokinetics and pharmacodynamics of diclofenac in healthy male volunteers.Thromb Haemost. 2001; : P786Google Scholar]. Studies in animals have also demonstrated a wide therapeutic window, whereby dose increases in the therapeutic range for the antithrombotic effect of ximelagatran produce only small increases in bleeding [18Elg M. Gustafsson D. Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat.Thromb Res. 1999; 94: 187-97Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 19Elg M. Gustafsson D. Deinum J. The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis.Thromb Haemost. 1997; 78: 1286-92Crossref PubMed Scopus (122) Google Scholar, 20Eriksson B.I. Carlsson S. Halvarsson M. Risberg B. Mattsson C. Antithrombotic effect of two low molecular weight thrombin inhibitors and a low-molecular weight heparin in a caval vein thrombosis model in the rat.Thromb Haemost. 1997; 78: 1404-7Crossref PubMed Scopus (82) Google Scholar]. These characteristics have allowed ximelagatran to be studied using fixed oral doses without routine coagulation monitoring. In studies to date, ximelagatran has shown good efficacy and safety in the prevention of venous thromboembolism [(VTE), defined as the occurrence of DVT and/or pulmonary embolism (PE)] following elective THR or total knee replacement (TKR) in comparisons with warfarin [21Francis C.W. Davidson B.L. Berkowitz S.D. Lotke P.A. Ginsberg J.S. Lieberman J.R. Webster A.K. Whipple J.P. Peters G.R. Colwell Jr, C.W. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty.Ann Intern Med. 2002; 137: 648-55Crossref PubMed Google Scholar], enoxaparin [22Heit J.A. Colwell C.W. Francis C.W. Ginsberg J.S. Berkowitz S.D. Whipple J.P. Peters G.R. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a Phase II dose-finding study.Arch Intern Med. 2001; 161: 2215-21Crossref PubMed Google Scholar, 23Eriksson B.I. Agnelli G. Cohen A.T. Dahl O.E. Mouret P. Rosencher N. Eskilson C. Nylander I. Frison L. Ogren M. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement.Thromb Haemost. 2003; 89: 288-96Crossref PubMed Google Scholar], and dalteparin [24Eriksson B.I. Bergqvist D. Kalebo P. Dahl O.E. Lindbratt S. Bylock A. Frison L. Eriksson U.G. Welin L. Gustafsson D. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial.Lancet. 2002; 360: 1441-7Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar]. The present study was the first in a Phase III program to determine the efficacy and safety of oral ximelagatran for the prophylaxis of VTE after THR. The primary objective was to compare the efficacy of ximelagatran 24 mg bid with that of enoxaparin 30 mg bid for prevention of total venous thromboembolic events in patients who have undergone THR. Secondary objectives were to compare the incidence of proximal DVT and/or PE, as well as the incidence of bleeding events, between the two treatment groups during the treatment period. Prophylaxis was started postoperatively for both regimens, consistent with usual clinical practice in the USA and Canada. This was a prospective, randomized, double-blind, double-dummy controlled study comparing ximelagatran with enoxaparin for the prevention of VTE after unilateral primary THR. It was conducted at 126 centers: 89 in the USA, 24 in Canada, five in Israel, four in Mexico, three in Argentina, and one in South Africa. Patients were prescreened for eligibility 1–30 days before and on the day of their surgery. Their treatment was assigned according to a computer-generated randomization schedule after THR. Each patient received 26 tablets and 26 prefilled syringes (one active treatment and the other placebo). Treatment was given for 7–12 days; venography was performed on the last day of treatment. Patients were to return for a follow-up visit 6 ± 2 weeks after surgery. The Institutional Review Board at each center approved the protocol. The study was conducted in accordance with the principles stated in the Declaration of Helsinki and in compliance with Good Clinical Practice. Patients were eligible if they were scheduled for elective THR and were at least 18 years old, weighed 40–125 kg, and provided written informed consent. Women had to be sterile by surgical means, postmenopausal for at least 2 years, or using a reliable form of contraception. Criteria for exclusion were as follows: scheduled hemiarthroplasty, surface replacement, or revisionary surgery; planned external pneumatic compression prophylaxis; immobilization for ≥ 3 days within 30 days preoperatively; prior major surgery, ischemic stroke, myocardial infarction, or administration of any investigational drug within 30 days prior to surgery; a history of intracranial, retroperitoneal, or intraocular bleeding or other disorder associated with increased risk of bleeding; gastrointestinal bleeding within 90 days and/or endoscopically verified ulcer disease within 30 days before surgery; uncontrolled hypertension; malignancy currently under cytostatic treatment or being the reason for hip replacement; known significant liver disorder or alanine transaminase or aspartate transaminase more than three times the upper limit of the normal range; thrombocytopenia (platelets < 100 × 109 L−1); a history of drug or alcohol abuse in the past 6 months; known allergy to contrast media or iodine; contraindication to enoxaparin; significant renal impairment (defined as estimated creatinine clearance < 30 mL min−1 using the Cockcroft–Gault formula); and traumatic epidural/spinal puncture just prior to surgery. If use of an epidural or spinal catheter extended into the treatment period, the catheter had to be removed during expected trough levels of melagatran and at least 1 h before the next dose. Treatment with thrombolytic drugs and the following anticoagulants or antiplatelet agents was not allowed within 7 days prior to surgery or during study drug administration: heparins (except those used in connection with intraoperative salvage of red blood cells), warfarin, dipyridamole, sulfinpyrazone, ticlopidine, clopidogrel, non-selective cyclo-oxygenase non-steroidal anti-inflammatory drugs with a half-life > 20 h, aspirin (≥ 500 mg day−1), and dextran. Patients were prescreened for eligibility 1–30 days before and on the day of their surgery. Their treatment was assigned according to a computer-generated randomization schedule after THR. Each patient received 26 tablets and 26 prefilled syringes (one active treatment and the other placebo). A ximelagatran 24-mg tablet (Exanta™; AstraZeneca, Mölndal, Sweden) or enoxaparin 30-mg subcutaneous injection (Lovenox®; Aventis, Collegeville, PA, USA) was given, along with the corresponding placebo, in the morning and evening, starting on the morning after surgery (at least 12 h postoperatively) when adequate hemostasis had been achieved. The ximelagatran dose was chosen on the basis of a previous dose-finding study [22Heit J.A. Colwell C.W. Francis C.W. Ginsberg J.S. Berkowitz S.D. Whipple J.P. Peters G.R. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a Phase II dose-finding study.Arch Intern Med. 2001; 161: 2215-21Crossref PubMed Google Scholar]. Patients remained in the hospital according to local practice, usually 3–4 days, after which they self-administered their medication, having been instructed in subcutaneous injection technique prior to hospital discharge. Treatment was given for 7–12 days, and unilateral venography of the leg on which surgery was performed was done on the last day of treatment. Treatment compliance was assessed by counting tablets and syringes used in the hospital, dispensed at discharge, and returned by patients at the end of the study. Patients were asked to return for a follow-up visit 6 ± 2 weeks after surgery. The primary efficacy variable was the composite endpoint of DVT (symptomatic or detected by routine venography) and/or PE occurring during treatment. The secondary efficacy variable was the incidence of proximal DVT and/or PE. DVT was evaluated by ascending venography on the leg undergoing surgery using the method of Rabinov and Paulin [25Rabinov K. Paulin S. Roentgen diagnosis of venous thrombosis in the leg.Arch Surg. 1972; 104: 134-44Crossref PubMed Google Scholar] with minor modifications [26Kälebo P. Ekman S. Lindbratt S. Eriksson B.I. Pauli U. Zachrisson B.E. Close P. Percentage of inadequate phlebograms and observer agreement in thromboprophylactic multicenter trials using standardized methodology and central assessment.Thromb Haemost. 1996; 76: 893-6Crossref PubMed Google Scholar]. For the primary analysis, venograms were assessed by two independent central adjudicators without knowledge of study treatment. The criterion for DVT was a consistent intraluminal filling defect on at least two images. Venograms judged to be adequate for evaluation required visualization of all the deep veins except the muscular veins and the anterior tibial veins, although thrombi found in these veins were included in the assessment if they were visible. Venograms not adequate for evaluation were those that were not done, not available, or indeterminate (defined as a lack of intraluminal filling of a region of the deep vein system of the leg without the presence of an intraluminal filling defect elsewhere in the same region). Ultrasound diagnosis was sufficient for symptomatic proximal DVT but not for diagnosis of symptomatic distal DVT or as a substitute for end-of-study venography. The diagnosis of PE was made when a lung scan showed one or more segmental perfusion defects in at least two views with corresponding normal ventilation. Pulmonary angiography could also be used to diagnose PE when a persistent intraluminal defect or abrupt cutoff of a vessel >2.5 mm in diameter was observed. Finally, PE was diagnosed when patients with suspected PE had an abnormal ultrasound or venogram if a clear-cut abnormality was seen in a large vessel on a spiral computed tomography (CT) scan. All cases of suspected PE were adjudicated centrally. Patients diagnosed locally with thrombosis were treated according to local clinical practice. All bleeding events were recorded, including bleeding complications at the site of surgery, the volumes of blood loss and transfusion, and characteristics of the wound. A committee of independent experts performed a central classification of bleeding events as ‘major’ if they were clinically overt and showed one or more of the following: critical site involvement (intracranial, retroperitoneal, intraocular, intraspinal, or pericardial); bleeding index ≥2.0 [calculated as the prebleeding hemoglobin level (g dL−1) minus the postbleeding hemoglobin level plus the number of units of red blood cells transfused]; medical or surgical intervention at the operative site; or fatal bleeding. Clinically overt bleeding with none of the other characteristics was classified as ‘minor’. Also, the study investigators classified the overall appearance and characteristics of the surgical wound as being ‘as expected’, ‘better than expected’, or ‘worse than expected’. This was a non-inferiority study, with the margin prespecified at 5%. In trials in which the comparator is a known active drug, at least clinical equivalence is established through non-inferiority testing, which in statistical terms is actually rejecting the hypothesis of inferiority by at least the specified margin. International Conference on Harmonization (ICH) guidelines [27International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Statistical Principles for Clinical Trials. Federal Register of the Food and Drug Administration. Vol 63, No. 179, Section 3.3.2., September 16, 1998.Google Scholar] state that an equivalence margin should be the largest difference that is considered clinically acceptable and smaller than differences established for the control drug relative to placebo in superiority trials. The Executive Committee, a panel of independent experts external to the sponsor, considered an actual difference in total VTE rates of 5% to be acceptable and unlikely to be associated with differences in clinical outcomes; this interval has also been used in a study by Planes et al. [28Planès A. Samama M.M. Lensing A.W. Buller H.R. Barre J. Vochelle N. Beau B. Prevention of deep vein thrombosis after hip replacement—comparison between two low-molecular heparins, tinzaparin and enoxaparin.Thromb Haemost. 1999; 81: 22-5Crossref PubMed Google Scholar]. The data used to establish the enoxaparin 30 mg bid effect size were taken from the labeling for enoxaparin, which shows a 36% reduction [with 95% confidence interval (CI) of 20, 52] in total VTE compared with placebo (by bilateral venography) [29Physicians' Desk Reference. 55th edn. Medical Economics Co., 2001: 713-5Google Scholar]. Since only unilateral assessments were performed in this study, a correction (decreasing the DVT rates by 20% in each group) was applied, so that the unilateral effect size became 28% (95% CI 13, 43). Therefore, a 5% non-inferiority margin (between-group difference) is well below the minimum effect size for enoxaparin based on the lower limit of the 95% CI margin of 13%. Moreover, the proposed non-inferiority margin of 5% is consistent with ICH statistical recommendations. Assuming a total VTE incidence of 15% for enoxaparin [30Clagett G.P. Anderson F.A. Geerts W. Heit J.A. Knudson M. Lieberman J.R. Merli G.J. Wheeler H.B. Prevention of venous thromboembolism.Chest. 1998; 114: 531S-60SAbstract Full Text Full Text PDF PubMed Google Scholar] and 13.5% (a 10% relative reduction) for ximelagatran, approximately 1280 patients acceptable for evaluation were needed to provide > 90% power to demonstrate that the difference is no more than the 5% non-inferiority margin using a two-sided 95% CI. Approximately 1600 patients were to be enrolled in this study, anticipating that up to 20% of the randomized patients would not have a venogram adequate for evaluation. Efficacy analyses included all patients who had a venogram adequate for evaluation or symptomatic, objectively confirmed DVT and/or PE during the treatment period. The proportions of patients with VTE were recorded; the differences in proportions of patients with verified VTE (ximelagatran vs. enoxaparin) were assessed using a two-sided 95% CI. Non-inferiority was established if the upper border of the CI around the between-group difference in VTE frequency was <5%. Statistical superiority of ximelagatran was established if the upper border of the CI for VTE was <0%. Statistical superiority of enoxaparin was established if the lower border of the CI was >0%. The frequency of bleeding events in each treatment group was reported as a proportion with 95% CIs, and the difference between the groups was examined using Fisher's exact test. Differences in ratings of the overall wound appearance and in bleeding complications of the surgical wound between treatment groups were also examined using Fisher's exact test. Between-group differences in blood loss associated with surgery and transfusion requirements were tested using analysis of variance (anova). Of the 1838 patients randomized between March 2000 and April 2001, 1816 are included in the safety population (22 did not receive study medication). In the safety population, 51 patients assigned to ximelagatran and 56 assigned to enoxaparin discontinued study medication prematurely (Table 1). An additional 237 patients were screened, but not randomized. Consent was withdrawn by 82 patients, five experienced adverse events prior to randomization, 103 did not meet eligibility requirements, and 47 were withdrawn for other reasons, including six for medical reasons and 17 for postponement or cancellation of surgery. The efficacy population comprised 1557 patients (782 ximelagatran and 775 enoxaparin) who had venograms adequate for evaluation or confirmed symptomatic VTE (Table 1). Within the efficacy population, protocol deviations were similar in each group and occurred in 35 and 39 patients in the ximelagatran and enoxaparin groups, respectively. More than 95% of patients received more than 10 doses of study medication. All but one patient in each group had unilateral THR surgery (one ximelagatran patient had revision to a cemented right THR, and one enoxaparin patient had a bilateral replacement).Table 1Disposition of the patientsXimelagatranEnoxaparinRandomize" @default.
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• W2016234199 title "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" @default.
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