Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty

Sorrel E. Wolowacz; Neil S. Roskell; Jonathan M. Plumb; Joseph A. Caprini; Bengt I. Eriksson

doi:10.1160/TH08-07-0493

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2009; 101(01): 77-85
DOI: 10.1160/TH08-07-0493

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty

A meta-analysis

Sorrel E. Wolowacz

¹RTI Health Solutions, Williams House, Manchester University Science Park, Lloyd Street North, Manchester, UK

,

Neil S. Roskell

¹RTI Health Solutions, Williams House, Manchester University Science Park, Lloyd Street North, Manchester, UK

,

Jonathan M. Plumb

²Boehringer Ingelheim GmbH, Binger Strasse, Ingelheim am Rhein, Germany

,

Joseph A. Caprini

³Robert R. McCormick School of Engineering and Applied Sciences, Department of Surgery, Evanston Northwestern Healthcare, Evanston IL and Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

,

Bengt I. Eriksson

⁴Professor of Orthopaedics, Surgical Sciences Gothenburg University, Sahlgrenska University Hospital/ÖSTRA, Gothenburg, Sweden

› Institutsangaben

Abstract

Summary

Dabigatran etexilate has been investigated in three phase III trials for the prevention of venous thromboembolism (VTE). Health technology assessment agencies increasingly require meta-analyses of all relevant evidence for an intervention, if appropriate. The objective of this study was to perform a meta-analysis of efficacy and safety data for the recommended dose of dabigatran etexilate, 220 mg once daily (od), for VTE prophylaxis after total knee arthroplasty (TKA) and total hip arthroplasty (THA), and discuss the appropriateness of combining the data. Risk ratios (RR) for VTE and bleed end-points were estimated using fixed and random effects meta-analysis. Analyses were performed combining RE-MODEL and RE-NOVATE, which compared dabigatran etexilate with enoxaparin 40 mg od after TKA and THA, respectively, and also including RE-MOBILIZE, which compared dabigatran etexilate with enoxaparin 30 mg twice daily after TKA. Tests for statistical heterogeneity were performed using the Chi-squared statistic. No significant differences were detected between dabigatran etexilate and enoxaparin in any of the end-points analysed, either in the two trial analysis (all p>0.15), or when all three trials were combined ( all p>0.30). RRs (random effects) for the composite end-point total VTE and all-cause mortality were 0.95 [95% confidence intervals 0.82 – 1.10] and 1.05 [0.87 – 1.26] in the two and three trial analyses, respectively. Meta-analysis of RE-MODEL and RE-NOVATE supported the conclusions of the individual trials that dabigatran etexilate is non-inferior to enoxaparin 40 mg od, with a similar safety profile. Meta-analysis of all three trials found no significant differences between treatments in any of the end-points analysed. Heterogeneity between the trials cannot be ruled out.

Keywords

Embolism - thrombosis - prophylaxis - anticoagulants - meta-analysis

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Referenzen

References
1 Arcelus JI, Monreal M, Caprini JA. et al. RIETE investigators.. Clinical presentation and time-course of postoperative venous thromboembolism: Results from the RIETE Registry. Thromb Haemost 2008; 99: 546-551.
2 Tapson VF, Hyers TM, Waldo AL. et al. Antithrombotic therapy practices in US hospitals in an era of practice guidelines. Arch Intern Med 2005; 165: 1458-1464.
3 Anderson Jr FA, Hirsh J, White K. et al. Temporal trends in prevention of venous thromboembolism following primary total hip or knee arthroplasty 1996–2001: findings from the Hip and Knee Registry. Chest 2003; 124: 349S-356S.
4 UK National Joint Registry for England and Wales 3rd Annual Clinical Report. Available at: http://www.njrcentre.org.uk/documents/reports/annual/3rd/NJR_AR2_LR.pdf Accessed 10 July 2007.
5 The Canadian Joint Replacement Registry (CJRR) 2006 Annual Report on Hip and Knee Replacements in Canada. Available at: http://www.cihi.ca/cihiweb/disp/Page.jsp?cw_page=PG_387_E&cw_topic=387&cw_rel=AR_30_E. Accessed 20 March 2008.
6 Caprini JA. Anticoagulants for thrombosis prophylaxis following surgery: a continuing saga. Thromb Haemost 2008; 99: 993-994.
7 Amin AN, Stemkowski S, Lin J. et al. Preventing venous thromboembolism in US hospitals: are surgical patients receiving appropriate prophylaxis?. Thromb Haemost 2008; 99: 796-797.
8 Geerts WH, Bergqvist D, Pineo GF. et al. Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 381S-453S.
9 Venous Thromboembolism.. Reducing the risk of venous Thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. Published by: National Collaborating Centre for Acute Care at The Royal College of Surgeons of England, 35–43 Lincoln’s Inn Fields, London, WC2A 3PE. Available at: http://www.rcseng.ac.uk/surgical_research_units/nccac/guidelines/venous_thrombo_guideline.html
10 O’Donnell M, Linkins LA, Kearon C. et al. Reduction of out-of-hospital symptomatic venous thromboembolism by extended thromboprophylaxis with low-molecular-weight heparin following elective hip arthroplasty: a systematic review. Arch Intern Med 2003; 163: 1362-1366.
11 Cohen AT. et al. ENDORSE study. Lancet 2008; 371: 387-394.
12 Stassen JM, Hauel NH, Nar H. et al. Identification and in vitro characterization of BIBR 953 ZW, a novel synthetic low molecular weight direct thrombin inhibitor. 28^th Congress of the International Society on Thrombosis and Haemostasis; Paris; July 6–12, 2001.
13 Hauel NH, Nar H, Priepke H. et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002; 45: 1757-1766.
14 Eriksson BI, Dahl OE, Rosencher N. et al. REMODEL Study Group. Oral dabigatran etexilate vs.. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 05: 2178-2185.
15 Ginsberg JS, Davidson BL, Comp PC. et al. The RE-MOBILIZE Writing Committee.. The Oral Thrombin Inhibitor Dabigatran Etexilate vs the North American Enoxaparin Regimen for the Prevention of Venous Thromboembolism after Knee Arthroplasty Surgery. J Arthroplasty. 2008 prepub online.
16 Eriksson BI, Dahl OE, Rosencher N. et al. RE-NOVATE Study Group.. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370: 949-956.
17 NICE 2004; Guide to the Methods of Technology Appraisal (reference N0515). 7 May 2004. Available at: http://www.nice.org.uk/page.aspx?o=201973 Accessed 19 September 2007.
18 Summary of Product Characteristics, Pradaxa 110 mg hard capsules. Boehringer Ingelheim Limited, Ellesfield Avenue, Bracknell, Berkshire, RG12 8 YS UK Available at: http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=20760. Accessed April 16, 2008.
19 Eriksson BI, Dahl OE, Buller HR. et al. 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. J Thromb Haemost 2005; 03: 103-111.
20 Committee for Proprietary Medicinal Products.. Points to consider on clinical investigation of medicinal products for prophylaxis of intra- and post-operative venous thromboembolic risk. http://www.emea.europa.eu/pdfs/human/ewp/070798en.pdf. Accessed July 31, 2007.
21 Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106: 2710-2715.
22 Mismetti P, Laporte S, Zufferey P. et al. Prevention of venous thromboembolism in orthopedic surgery with vitamin K antagonists: a meta-analysis. J Thromb Haemost 2004; 02: 1058-1070.
23 Anderson DR, O’Brien B, Nagpal S. Economic evaluation comparing low molecular weight heparin with other modalities for the prevention of deep vein thrombosis and pulmonary embolism following total hip or knee arthroplasty. Ottawa: Canadian Coordinating Office of Health Technology Assessment; 1998
24 Koch A, Ziegler S, Breitschwerdt H. et al. Low molecular weight heparin and unfractionated heparin in thrombosis prophylaxis: meta-analysis based on original patient data. Thromb Res 2001; 102: 295-309.
25 Nurmohamed MT, Rosendaal FR, Buller HR. et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992; 340: 152-156.
26 Fisher WD, Eriksson BI, Bauer KA. et al. Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies. Thromb Haemost 2007; 97: 931-937.
27 Spiro TE, Johnson GJ, Christie MJ. et al. Efficacy and safety of enoxaparin to prevent deep venous thrombosis after hip replacement surgery. Enoxaparin Clinical Trial Group. Ann Internal Med 1994; 121: 81-89.
28 Colwell Jr CW, Spiro TE, Trowbridge AA. et al. Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. A clinical trial comparing efficacy and safety. Enoxaparin Clinical Trial Group. J Bone Joint Surg 1994; 76: 3-14.
29 Colwell CW, Spiro TE. Efficacy and safety of enoxaparin to prevent deep vein thrombosis after hip arthroplasty. Clin Orthop Rel Res 1995; 319: 215.