SR123781A: A New Once-Daily Synthetic Oligosaccharide Anticoagulant for Thromboprophylaxis After Total Hip Replacement Surgery

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1 Journal of the American College of Cardiology Vol. 51, No. 15, by the American College of Cardiology Foundation ISSN /08/$34.00 Published by Elsevier Inc. doi: /j.jacc EXPEDITED PUBLICATION ACC Rapid Track Abstract : A New Once-Daily Synthetic Oligosaccharide Anticoagulant for Thromboprophylaxis After Total Hip Replacement Surgery The DRIVE (Dose Ranging Study in Elective Total Hip Replacement Surgery) Study Michael R. Lassen, MD,* Ola Dahl, MD, PHD, Patrick Mismetti, MD, Dirk Zielske, MD, Alexander G. G. Turpie, MD, FACC Hørsholm, Denmark; London, England; Saint-Étienne, France; Frankfurt am Main, Germany; and Hamilton, Ontario, Canada Objectives Background Methods Results This study assessed the dose response of for the prevention of venous thromboembolism (VTE) in patients undergoing total hip replacement (THR) surgery. Despite VTE preventive measures, residual VTE complications still occur after THR., a synthetic oligosaccharide with a mixed profile of anti-factor Xa and IIa activities, could be an alternative to current treatments. In this double-blind study, 1,023 patients undergoing THR were randomly assigned to 1 of 5 daily doses of or to a calibrator arm of enoxaparin. Treatment was continued for 10 days or until bilateral venography was performed after a minimum of 5 days. A significant dose-response effect for VTE was observed for (p ). The VTE rates were 21.2%, 17.7%, 13.5%, 7.0%, and 4.4% in the 0.25-, 0.5-, 1.0-, 2.0-, and 4.0-mg dose groups of, respectively, and 8.7% in the enoxaparin group. Doses of 2.0 and 4.0 mg of reduced the risk of VTE by 67% and 79%, respectively, compared with the 0.25-mg dose group. Major bleeding was observed in 1.2%, 0.6%, 0.6%, 0.6%, and 5.8% of the patients in the 0.25-, 0.5-, 1.0-, 2.0-, and 4.0-mg dose groups of, respectively, and in 0.6% of patients in the enoxaparin group. The dose-response effect for major bleeding was significant (p ). Conclusions The model based on these dose-finding study results suggests that doses ranging from 1.5 to 2.5 mg show a reasonable risk-to-benefit ratio for VTE prevention after major orthopedic surgery. (Dose Ranging Study in Elective Total Hip Replacement Surgery [DRIVE]; NCT ) (J Am Coll Cardiol 2008;51: ) 2008 by the American College of Cardiology Foundation With an aging population, the number of people undergoing total hip replacement (THR) surgery is expected to increase over the coming decades. In the U.S., the annual number of primary THRs is expected to increase by 174% between 2005 and 2030, and the number of total hip revisions is projected to grow by 137% over this time period (1). Patients undergoing THR surgery are at high risk of venous thromboembolism (VTE). Historically, approximately 40% to 60% of such patients develop deep vein thrombosis (DVT) in the absence of prophylaxis (2,3) and 0.2% develop fatal pulmonary embolism (PE) (4 6). Current guidelines from the American College of Chest Physicians recommend that all patients undergoing THR sur- From *Hørsholm Hospital, Hørsholm, Denmark; Thrombosis Research Institute, London, England; University Hospital of Saint-Étienne, Saint-Étienne, France; sanofi-aventis, Frankfurt am Main, Germany; and McMaster University, Hamilton, Ontario, Canada. This study was funded by an unrestricted grant from sanofi-aventis (Paris, France). The authors received editorial support in the preparation of this manuscript funded by sanofi-aventis. Dr. Lassen has served as a consultant for Astellas Pharma Europe, Bayer Healthcare AG, Bristol-Myers Squibb, Glaxo- SmithKline, Merck Serono, Pfizer, and sanofi-aventis; Dr. Dahl has received economic compensation from sanofi-aventis for the work done in the scientific Steering Committee; Dr. Mismetti has served as a member of Steering Committees for sanofi-aventis; Dr. Zielske is an employee of sanofi-aventis; and Dr. Turpie has served as a consultant for Astellas Pharma Europe, Bayer Healthcare AG, Protola Pharma, and sanofi-aventis. Manuscript received January 18, 2008; revised manuscript received March 5, 2008, accepted March 10, 2008.

2 JACC Vol. 51, No. 15, 2008 April 15, 2008: Lassen et al. Prevention of VTE With 1499 gery receive thromboprophylaxis with a low-molecularweight heparin, vitamin K antagonist, or fondaparinux (2). Although heparins and vitamin K antagonists are widely used to prevent VTE in this setting, residual VTE complications can still occur. Recently, specific factor Xa inhibitors such as fondaparinux, and anticoagulants with pure anti-factor IIa properties, such as dabigatran, have been developed (7,8). is the first synthetic oligosaccharide developed that has a mixed profile of antithrombin-dependent antifactor Xa and IIa activities. This synthetic hexadecasaccharide has been shown to have marked antithrombotic activity in animal models of arterial and venous thrombosis (9 11). Human studies have shown that administered subcutaneously is completely absorbed, reaching a maximum concentration 4 h post-dosing, and that has a half-life of 11 to 16 h (data on file). shows dose-proportional and linear pharmacokinetics over the dose range studied (0.8 to 18 mg) (data on file). The objective of this study was to assess the dose response of for the prevention of VTE in patients undergoing THR surgery. Methods Study design. This was a multicenter, multinational, randomized, double-blind, double-dummy, dose-ranging study of (sanofi-aventis, Paris, France) for the prevention of VTE in patients undergoing elective THR surgery, with an enoxaparin (Clexane/Lovenox; sanofiaventis) calibrator arm. The calibrator arm was used to ensure that the study design reflects a representative standard; enoxaparin was not intended for use in statistical comparisons. The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. The research protocol was approved by an institutional review board at each participating center. After obtaining written informed consent, patients were randomized to receive at doses 0.25, 0.5, 1.0, 2.0, and 4.0 mg, or enoxaparin. (singleuse vials) was administered subcutaneously 8 1 h after surgery and once-daily thereafter in the morning (every 24 2 h). (0.4 ml pre-filled syringes) was initiated either 12 1 h before surgery or post-operatively (in the case of loco-regional anesthesia) according to local labeling and the usual practice of the participating center. Subcutaneous treatment with enoxaparin was continued once daily. Both treatments were administered for a minimum of 5 days and a maximum of 10 days after surgery. Mandatory bilateral venography was performed no later than 1 day after the administration of the last dose of study medication, and after a minimum of 5 days of study drug administration. The use of nonsteroidal anti-inflammatory drugs was discouraged, and intermittent pneumatic compression was not permitted during the treatment period. Prolonged thromboprophylaxis was recommended and was at the discretion of the investigator. Patients attended a clinical follow-up visit 30 3 days after surgery. Patients. Patients were enrolled into the study if they were age 18 years and were undergoing elective THR surgery or a revision of at least 1 component of a THR Abbreviations and Acronyms CI confidence interval DVT deep vein thrombosis PE pulmonary embolism THR total hip replacement VTE venous thromboembolism that had been performed at least 6 months before entry into the study. Exclusion criteria included major orthopedic surgery within the previous 3 months before the study; clinical signs or symptoms of VTE in the previous 12 months; myocardial infarction or stroke in the previous 3 months; past or present bleeding disorder; uncontrolled hypertension; contraindication to heparin therapy or sensitivity to iodinated contrast medium; treatment with anticoagulant or antiplatelet drugs in the week before surgery; recent trauma, major surgery, eye surgery, or parenchymal organ biopsy; a current addictive disorder; serum creatinine level 2 mg/dl; thrombocytopenia; significant anemia; history of hemorrhagic stroke; structural damage to the central nervous system; and progressive malignant disease. Women were excluded if they were pregnant or nursing or were not using effective contraception. Thromboembolic events. The primary efficacy end point was a composite of the following VTE events: any DVT identified on mandatory venography of the lower limbs, symptomatic DVT and/or nonfatal PE, and VTE-related death (fatal PE and unexplained death). The VTE events were evaluated 5 to 11 days after surgery, or earlier if the patient developed symptoms of VTE. Secondary efficacy end points included any DVT, proximal and isolated distal DVT, fatal and nonfatal PE, and any confirmed symptomatic VTE. Patients were screened for DVT with bilateral venography 5 to 11 days after surgery, or sooner if signs and symptoms were present. Venography was performed according to the technique of Rabinov and Paulin (12). The PE was confirmed by a perfusion/ventilation lung scan and/or pulmonary angiography or spiral computerized tomography. All VTE events were confirmed by an independent and blinded adjudication committee (Hamilton, Ontario, Canada). Safety. The primary safety criterion was the incidence of major bleeding, adjudicated by an independent committee, between the first dose of study drug and 3 days after the last injection. Major bleeding included fatal bleeding, surgical site bleeding leading to intervention, bleeding that was retroperitoneal or intracranial or that involved any other critical organ (eye, adrenal gland, pericardium, or spine), and non surgical site bleeding requiring surgical intervention or non surgical site overt bleeding with a bleeding

3 1500 Lassen et al. JACC Vol. 51, No. 15, 2008 Prevention of VTE With April 15, 2008: Figure 1 DRIVE Study Patients Flow Diagram DRIVE Dose Ranging Study in Elective Total Hip Replacement Surgery. index of 2. The bleeding index was calculated as the difference between pre-bleeding and post-bleeding hemoglobin plus the number of transfused blood units. Minor bleeding was defined as clinically overt bleeding that did not meet the criteria for major bleeding. Adverse events were also monitored during the study. The safety population was composed of all randomized patients who received at least 1 dose of study drug and underwent THR surgery. An independent Data Monitoring Committee continuously monitored safety and efficacy in this study; the committee did not recommend any changes to the protocol. Statistical analysis. All statistical analyses were carried out using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina). Assuming event rates for the primary efficacy end point of 5% to 15%, and also that 30% of randomized patients would not be evaluable for the primary efficacy analysis, 170 patients were calculated to be required in each of the dose groups to provide 80% power to detect a dose effect for the 5 doses of. The primary efficacy analysis to show a dose-response relationship for in the prevention of VTE was performed on the group of patients who received at least 1 dose of study drug, who underwent THR surgery, and who had an evaluable efficacy end point. The incidence of the primary end point was compared across the dose groups using a 2-sided Cochran-Armitage test trend at Reasons for Prematurely Discontinuing Study Drug in the Safety Population Table 1 Reasons for Prematurely Discontinuing Study Drug in the Safety Population the 0.05 significance level, using the values of the logarithm of the doses as score and a logistic regression model including logarithmic dose levels as covariates. Also, pairwise comparisons were made between the 4.0- and 0.25-mg dose of using the 2-sided Fisher exact test at the 0.05 significance level. Comparisons of the next highest dose level to the 0.25 mg dose were performed if the p value for the previous comparison was Safety end points were analyzed on the safety population. Results Study population. A total of 1,080 patients were enrolled between June 1, 2006, and April 3, 2007, at 53 centers in 12 countries, and a total of 1,023 were randomized to receive either or enoxaparin (Fig. 1). The main reasons for not being randomized to study treatment were lack of eligibility (n 11) and at the patient s request (n 23). Fourteen patients who were randomized did not receive any study drug, 11 in the dose groups and 3 in the enoxaparin group, because of adverse events (n 7), patients request (n 4), or other reasons (n 3). Of the remaining 1,009 patients who compose the safety population, 843 received and 166 received enoxaparin. Twenty-six patients from the safety population prematurely stopped the study drug, mostly (20 patients) because Reason, n (%) 0.25 mg 0.5 mg (n 163) 1.0 mg (n 170) 2.0 mg (n 168) 4.0 mg (n 166) Adverse event 2 (1.2) 0 (0) 2 (1.2) 1 (0.6) 12 (7.0) 3 (1.8) Patient s request 1 (0.6) 0 (0) 0 (0) 0 (0) 1 (0.6) 0 (0) Other 0 (0) 0 (0) 0 (0) 0 (0) 3 (1.8) 1 (0.6) Any reason 3 (1.8) 0 (0) 2 (1.2) 1 (0.6) 16 (9.4) 4 (2.4)

4 JACC Vol. 51, No. 15, 2008 April 15, 2008: Baseline Risk Factor Characteristics, Profiles of Patients Surgery indetails, the Safety andpopulation Venous Thromboembolism (N 1,009) Table 2 Baseline Characteristics, Surgery Details, and Venous Thromboembolism Risk Factor Profiles of Patients in the Safety Population (N 1,009) Lassen et al. Prevention of VTE With 1501 Characteristic, n (%) 0.25 mg 0.5 mg (n 163) 1.0 mg (n 170) 2.0 mg (n 168) 4.0 mg (n 166) Median age (range), yrs 59 (25 86) 60 (18 86) 60 (33 83) 60 (25 90) 58 (23 86) 59 (28 83) Female 100 (58.5) 96 (58.9) 100 (58.8) 98 (58.3) 99 (57.9) 102 (61.4) Caucasian 156 (91.2) 151 (92.6) 157 (92.4) 153 (91.1) 156 (91.2) 153 (92.2) Median weight (range), kg 78 (50 128) 75 (43 116) 76 (46 128) 76 (47 129) 78 (42 133) 75 (45 122) Body mass index 30 kg/m 2 57 (33.5) 36 (22.1) 58 (34.3) 45 (26.8) 50 (29.2) 48 (28.9) History of thromboembolism 0 (0) 2 (1.2) 1 (0.6) 0 (0) 2 (1.2) 1 (0.6) History of cancer 5 (2.9) 5 (3.1) 3 (1.8) 4 (2.4) 3 (1.8) 8 (4.8) Surgery details Primary surgery 168 (98.2) 158 (96.9) 161 (94.7) 159 (95.2) 165 (96.5) 160 (96.4) Cemented prosthesis 68 (39.8) 64 (39.3) 72 (42.4) 61 (36.5) 63 (36.8) 62 (37.3) Mean duration of surgery SD, min Type of anesthesia General only 34 (19.9) 28 (17.2) 27 (15.9) 23 (13.8) 27 (15.8) 26 (15.7) Regional only 133 (77.8) 133 (81.6) 140 (82.4) 140 (83.8) 139 (81.3) 137 (82.5) of an adverse event (Table 1). The primary efficacy population comprised 736 patients; 610 received and 126 received enoxaparin. Six patients from the primary efficacy population prematurely stopped the study drug treatment, mostly (5 patients) because of a serious adverse event. The 6 treatment groups were similar with respect to demographic variables, surgical characteristics, or VTE risk factor profiles (Table 2). Approximately 35% of the patients received a preoperative injection of study drug. The median duration of treatment was similar across all treatment groups (9 days for those in the 0.25-, 0.5-, 1.0-, and 2.0-mg dose groups and the enoxaparin group and 8 days for those in the 4.0-mg dose group). Efficacy outcomes. The incidence of confirmed VTE in patients in the primary efficacy population is shown in Table 3. The rates of confirmed VTE were 21.2%, 17.7%, 13.5%, 7.0%, and 4.4% in the 0.25-, 0.5-, 1.0-, 2.0-, and 4.0-mg dose groups, respectively. The incidence of VTE in the enoxaparin calibrator arm was 8.7%. A clear dose-response effect was observed for (p ). Using a logarithmic model, the incidence of patients with VTE was shown to decrease with increasing doses of (p ) (Fig. 2). The 2.0- and 4.0-mg doses were significantly more effective at preventing VTE compared with the 0.25-mg dose, reducing the risk of VTE by 67% (95% confidence interval [CI] 33% to 84%) and 79% (95% CI 50% to 92%), respectively (Table 3). No events of symptomatic VTE were confirmed during the study. Statistical analysis showed a significant doseresponse relationship between and proximal DVT (p ). The 1.0-, 2.0-, and 4.0-mg doses of were significantly more effective at preventing proximal DVT compared with the 0.25-mg dose. There were no events of proximal DVT in the 4.0-mg dose group, and the risk of proximal DVT was reduced by 80% and 90% in the 1.0- and 2.0-mg dose groups of, respectively (Table 3). Safety outcomes. The frequency of major bleeding and all bleeding in the different treatment groups is presented in Table 4. Major bleeding was observed in 1.2%, 0.6%, 0.6%, 0.6%, and 5.8% of the patients in the 0.25-, 0.5-, 1.0-, 2.0-, Incidence and Risk of Confirmed Venous Thromboembolism (VTE) and Proximal Deep Vein Thrombosis (DVT) Table 3 Incidence and Risk of Confirmed Venous Thromboembolism (VTE) and Proximal Deep Vein Thrombosis (DVT) Parameter 0.25 mg 0.5 mg 1.0 mg 2.0 mg 4.0 mg Confirmed VTE, n/n 25/118 22/124 17/126 9/128 5/114 11/126 Percent (95% CI) 21.2 ( ) 17.7 ( ) 13.5 ( ) 7.0 ( ) 4.4 ( ) 8.7 ( ) p value* Relative risk (95% CI)* 0.84 ( ) 0.64 ( ) 0.33 ( ) 0.21 ( ) Proximal DVT, n/n 9/135 9/143 2/147 1/149 0/130 2/136 Percent (95% CI) 6.7 ( ) 6.3 ( ) 1.4 ( ) 0.7 ( ) 0.0 ( ) 1.5 ( ) p value* Relative risk (95% CI)* 0.94 ( ) 0.20 ( ) 0.10 ( ) 0.00 ( ) *For comparison with 0.25 mg. CI confidence interval; DVT deep vein thrombosis; VTE venous thromboembolism.

5 1502 Lassen et al. JACC Vol. 51, No. 15, 2008 Prevention of VTE With April 15, 2008: Any VTE (%) Figure (mg) (mg) Dose-Response Curves for Incidence of confirmed adjudicated venous thromboembolism (VTE) (blue) from surgery up to 10 days post-surgery or day of mandatory venography (whichever came first), and incidence of confirmed adjudicated major bleeding (red) from first study drug injection up to last study drug injection plus 3 days. Point estimates for groups (dots) and enoxaparin group (circles), and logistic regression curve (solid lines) with 2-sided 95% confidence intervals (dotted lines). and 4.0-mg dose groups, respectively. There was a significant dose-response effect for major bleeding (p ) and any bleeding (p ) in the safety population. The incidence of major bleeding in the enoxaparin calibrator arm was 0.6%. Using a logarithmic model, the incidence of patients with major bleeding was shown to increase with increasing doses of (p ) (Fig. 2). The 4.0-mg dose of was associated with a significantly higher rate of major bleeding and any bleeding compared with the 0.25-mg dose (Table 4). There was a 5-fold increase in the risk of major bleeding (relative risk 5.00; 95% CI 1.25 to 27.0) and 6-fold increase in the risk of any bleeding (relative risk 6.00; 95% CI 2.85 to 12.7) in the 4.0-mg dose group, compared with the lowest dose group (0.25 mg) Major bleedings (%) No bleeding into a critical organ was reported, and no patient developed a stroke or a myocardial infarction. Approximately one-half of the major bleeding events were confined to the surgical site (Table 4). Two patients died during the study: 1 patient in the 0.25-mg dose group died 1 day post-surgery of a hypovolemia leading to a myocardial infarction and death (confirmed by the adjudication committee as fatal bleeding), and 1 patient in the 4.0-mg dose group died of an encephalopathic brain hypoxia (confirmed by the adjudication committee to be unrelated to bleeding or VTE) occurring 44 days post-surgery. No dose arm was stopped prematurely because of safety concerns. The proportion of patients experiencing adverse events in the 4.0-mg dose group (60.2%) was nearly double that in the other groups (33.9%, 41.7%, 31.8%, and 32.7% in the 0.25-, 0.5-, 1.0-, and 2.0-mg dose groups respectively, and 36.1% in the enoxaparin group). Similarly, more patients in the 4.0-mg dose group experienced drug-related or serious adverse events during treatment (most of those were bleeding events). Discussion The results of this study show a statistically significant dose-response effect for for both efficacy and safety outcomes. Therefore, the main objective of the study was accomplished. The incidence of VTE after THR surgery decreased with increasing doses of, and the highest dose of tested was associated with an increased rate of major bleeding compared with the lowest dose (0.25 mg). The doses of investigated in this study were based on previous experience with the compound (9,13) (data on file). was chosen as the calibrator arm in the current study because low-molecular-weight heparins are currently recommended by the American College of Chest Physicians for the prevention of VTE after THR surgery (2) and of the low-molecular-weight heparins, enoxaparin is the most commonly used around the world. A once-daily regimen of enoxaparin was chosen in Incidence of Bleeding End Points Table 4 Incidence of Bleeding End Points Bleeding Classification 0.25 mg 0.5 mg (n 163) 1.0 mg (n 170) 2.0 mg (n 168) 4.0 mg (n 166) Major bleeding, n * 1 Percent (95% CI) 1.2 ( ) 0.6 ( ) 0.6 ( ) 0.6 ( ) 5.8 ( ) 0.6 ( ) Fatal bleeding, n (%) 1 (0.6) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Surgical site bleeding leading to intervention, n (%) 1 (0.6) 1 (0.6) 1 (0.6) 0 (0) 5 (2.9) 0 (0) Non surgical site bleeding with bleeding index 2, n (%) 0 (0) 0 (0) 0 (0) 1 (0.6) 5 (2.9) 1 (0.6) Any bleeding, n Percent (95% CI) 4.1 ( ) 5.5 ( ) 2.9 ( ) 6.5 ( ) 24.6 ( ) 3.6 ( ) *p versus 0.25-mg ; p versus 0.25-mg. CI confidence interval.

6 JACC Vol. 51, No. 15, 2008 April 15, 2008: Lassen et al. Prevention of VTE With 1503 accordance with the product labeling in the participating countries. Recently conducted dose-ranging studies of specific factor Xa or IIa inhibitors have consistently shown a doseresponse relationship for major bleeding, although not all have shown a dose response for efficacy (14 17). A study of indirect factor Xa inhibition with the synthetic pentasaccharide fondaparinux 0.75 to 8.0 mg/day showed a doseresponse relationship for this anticoagulant for VTE prevention and major bleeding in patients undergoing THR surgery (14). Major bleeding rates of 17% were observed, with the 2 highest doses (6.0 and 8.0 mg) necessitating premature discontinuation of these doses from the study. Dose-ranging studies of the direct factor Xa inhibitor, rivaroxaban, either once daily or twice daily (5 to 80 mg), did not show a dose response for efficacy, but did reveal a dose response for major bleeding in patients undergoing THR surgery (15,16). Direct inhibition of thrombin with dabigatran has also been evaluated in patients undergoing major orthopedic surgery. A dose-response relationship was shown over a dose range from 100 to 450 mg/day for both efficacy and safety outcomes (17). The current study was not designed to compare the efficacy of to that of enoxaparin. was included as a calibrator arm and was associated with similar rates of VTE, although lower rates of major bleeding, compared with other studies that used a similar patient population, treatment duration, and primary end points (14,18,19). The results of this study suggest that a similar proportion of patients receiving 2.0 mg or 40 mg enoxaparin experienced confirmed events of VTE (7.0% and 8.7%, respectively). In addition, a similar proportion of patients receiving 0.5, 1.0, and 2.0 mg or 40 mg enoxaparin experienced major bleeding (0.6% for each of these groups). Study limitations. A potential limitation of our study is that only 72% of randomized patients were eligible for the primary efficacy analysis. However, this eligibility rate is similar to that seen in contemporary clinical studies of anticoagulants in patients undergoing major orthopedic surgery. For example, 71% to 76% of patients were eligible for the primary efficacy analysis in similar dose-ranging studies of rivaroxaban for VTE prevention after THR surgery (15,16), 64% were eligible in a similar study of fondaparinux (14), and 75% were eligible in a dose-ranging study of dabigatran in patients undergoing major orthopedic surgery (17). Conclusions In summary, there was a dose-related increase in VTE prevention with over a 16-fold dose range in patients at high risk of developing thrombosis in the present study. The highest dose of was associated with an increased rate of major bleeding. Based on the data obtained in this dose-ranging study, the resulting model suggests that doses ranging from 1.5 to 2.5 mg show a reasonable risk-to-benefit ratio for the prevention of VTE in patients undergoing major orthopedic surgery. Acknowledgments The authors thank the DRIVE Investigators, Luis Carreras, the Clinical Events Adjudication Committee, and the Data Monitoring Committee. Reprint requests and correspondence: Dr. Michael R. Lassen, Hørsholm Hospital, Spine Clinic, Clinical Trial Unit Usserød Kongevej 102, DK-2970 Hørsholm, Denmark. mirula@ noh.regionh.dk. REFERENCES 1. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to J Bone Joint Surg Am 2007;89: Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126 Suppl:338S 400S. 3. Salvati EA, Pellegrini VD Jr., Sharrock NE, et al. Recent advances in venous thromboembolic prophylaxis during and after total hip replacement. J Bone Joint Surg Am 2000;82: Fender D, Harper WM, Thompson JR, Gregg PJ. Mortality and fatal pulmonary embolism after primary total hip replacement. Results from a regional hip register. J Bone Joint Surg Br 1997;79: Gillespie W, Murray D, Gregg PJ, Warwick D. Risks and benefits of prophylaxis against venous thromboembolism in orthopaedic surgery. J Bone Joint Surg Br 2000;82: Warwick D, Williams MH, Bannister GC. Death and thromboembolic disease after total hip replacement: a series of 1162 cases with no routine chemical prophylaxis. J Bone Joint Surg Br 1995;77: Turpie AG, Eriksson BI, Lassen MR, Bauer KA. Fondaparinux, the first selective factor Xa inhibitor. Curr Opin Hematol 2003;10: Ieko M. Dabigatran etexilate, a thrombin inhibitor for the prevention of venous thromboembolism and stroke. 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A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 2001;344: Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY ), for thromboprophylaxis after total hip replacement. Circulation 2006;114: Eriksson BI, Borris L, Dahl OE, et al. Oral, direct factor Xa inhibition with BAY for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006;4: Eriksson BI, Dahl OE, Büller HR, et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for preven

7 1504 Lassen et al. JACC Vol. 51, No. 15, 2008 Prevention of VTE With April 15, 2008: tion of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005;3: Lassen MR, Bauer KA, Eriksson BI, Turpie AG, European Pentasaccharide Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002;359: Turpie AG, Bauer KA, Eriksson BI, Lassen MR, PENTATHALON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002;359: APPENDIX For a complete list of investigators, please see the online version of this article.