International Orthopaedics

, Volume 36, Issue 4, pp 741–748

Thromboprophylaxis with dabigatran etexilate in patients over seventy-five years of age with moderate renal impairment undergoing or knee replacement

  • Ola E. Dahl
  • Andreas A. Kurth
  • Nadia Rosencher
  • Herbert Noack
  • Andreas Clemens
  • Bengt I. Eriksson
Review Article



Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor dabigatran etexilate (hereafter referred to as dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation.


We extracted and analysed data from the elderly or from moderately renally impaired patients (n 632 of = 5,539) from the orthopaedic clinical development programme of dabigatran.


Dabigatran 150 mg once daily was as effective as the standard European enoxaparin regimen, with numerically fewer major bleeding events. Rates of major VTE were 4.3% vs 6.4% of patients, respectively. Major bleeding events occurred in four (1.3%) vs 11 (3.3%), which shows a trend towards lower bleeding with dabigatran 150 mg [odds ratio (OR) 0.40; 95% confidence interval (CI) 0.13–1.25; p = 0.110]. Mean volume of blood loss was 395 vs 417 ml, and transfused units were 2.4 vs 2.5, respectively. Other safety parameters, including the incidence of wound infections and complications, were similar for 150 mg once daily dabigatran and enoxaparin.


For patients at higher risk of bleeding, dabigatran 150 mg once daily is as effective as enoxaparin following major orthopaedic surgery and is associated with a favourable bleeding rate.


  1. 1.
    Dahl OE (2004) Orthopaedic surgery as a model for drug development in thrombosis. Drugs 64(Suppl 1):17–25PubMedCrossRefGoogle Scholar
  2. 2.
    Colwell CW Jr, Berkowitz SD, Lieberman JR, Comp PC, Ginsberg JS, Paiement G, McElhattan J, Roth AW, Francis CW; EXULT B Study Group (2005) Oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty. J Bone Joint Surg Am 87:2169–2177CrossRefGoogle Scholar
  3. 3.
    Eriksson BI, Kakkar AK, Turpie AG, Gent M, Bandel TJ, Homering M, Misselwitz F, Lassen MR (2009) Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement. J Bone Joint Surg Br 91:636–644PubMedCrossRefGoogle Scholar
  4. 4.
    Schulman S, Beyth RJ, Kearon C, Levine MN (2008) Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:257S–298SPubMedCrossRefGoogle Scholar
  5. 5.
    Pola E, Papaleo P, Santoliquido A, Gasparini G, Aulisa L, De Santis E (2004) Clinical factors associated with an increased risk of perioperative blood transfusion in nonanemic patients undergoing total hip arthroplasty. J Bone Joint Surg Am 86-A:57–61PubMedGoogle Scholar
  6. 6.
    McNally MA, Mollan RA (1993) Venous thromboembolism and orthopaedic surgery. J Bone Joint Surg Br 75:517–519PubMedGoogle Scholar
  7. 7.
    Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW (2008) Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:381S–453SPubMedCrossRefGoogle Scholar
  8. 8.
    Mantilla CB, Horlocker TT, Schroeder DR, Berry DJ, Brown DL (2002) Frequency of myocardial infarction, pulmonary embolism, deep venous thrombosis, and death following primary hip or knee arthroplasty. Anesthesiology 96:1140–1146PubMedCrossRefGoogle Scholar
  9. 9.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41PubMedCrossRefGoogle Scholar
  10. 10.
    Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Kälebo P, Christiansen AV, Hantel S, Hettiarachchi R, Schnee J, Büller HR, Study Group RE-MODEL (2007) Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 5:2178–2185PubMedCrossRefGoogle Scholar
  11. 11.
    Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Prins MH, Hettiarachchi R, Hantel S, Schnee J, Büller HR; RE-NOVATE Study Group (2007) Dabigatran etexilate vs enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 370:949–956CrossRefGoogle Scholar
  12. 12.
    Eriksson BI, Dahl OE, Huo MH, Kurth AA, Hantel S, Hermansson K, Schnee JM, Friedman RJ, Study Group RE-NOVATEII (2011) Oral dabigatran vs enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, non-inferiority trial. Thromb Haemost 105:721–729PubMedCrossRefGoogle Scholar
  13. 13.
    Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, Huo MH, Lieberman JR, Muntz JE, Raskob GE, Clements ML, Hantel S, Schnee JM, Caprini JA (2009) Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 24:1–9PubMedGoogle Scholar
  14. 14.
    European Medicines Agency (2011). Pradaxa – Summary of Product Characteristics. Accessed 16 September 2011
  15. 15.
    The European Agency for the Evaluation of Medicinal Products (2007) Accessed 16 March 2011
  16. 16.
    Dahl OE, Borris LC, Bergqvist D, Schnack RM, Eriksson BI, Kakkar AK, Colwell CW, Caprini JA, Fletcher J, Friedman RJ, Lassen MR, Frostick SP, Sakon M, Kwong LM, Kakkar VV; International Surgical Thrombosis Forum (2008) Major joint replacement. A model for antithrombotic drug development: from proof-of-concept to clinical use. Int Angiol 27:60–67Google Scholar
  17. 17.
    Hull RD, Yusen RD, Bergqvist D (2009) State-of-the-art review: Assessing the safety profiles of new anticoagulants for major orthopedic surgery thromboprophylaxis. Clin Appl Thromb Hemost 15:377–388PubMedCrossRefGoogle Scholar
  18. 18.
    Eriksson BI, Dahl OE, Buller HR, Hettiarachchi R, Rosencher N, Bravo ML, Ahnfelt L, Piovella F, Stangier J, Kälebo P, Reilly P; BISTRO II Study Group (2005) 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 3:103–111CrossRefGoogle Scholar
  19. 19.
    Ginzburg E, Dujardin F (2011) Physicians’ perceptions of the definition of major bleeding in major orthopaedic surgery; results of an international survey. J Thromb Thrombolysis 31:188–195PubMedCrossRefGoogle Scholar
  20. 20.
    Dahl OE, Bergqvist D (2002) Current controversies in deep vein thrombosis prophylaxis after orthopaedic surgery. Curr Opin Pulm Med 8:394–397PubMedCrossRefGoogle Scholar
  21. 21.
    Colwell CW Jr, Spiro TE (1995) Efficacy and safety of enoxaparin to prevent deep vein thrombosis after hip arthroplasty. Clin Orthop Relat Res 319:215–222PubMedGoogle Scholar
  22. 22.
    European Medicines Agency (2007) Fondaparinux summary of product characteristics. Accessed 16 March 2011
  23. 23.
    Turpie AG, Lensing AW, Fuji T, Boyle DA (2009) Pharmacokinetic and clinical data supporting the use of fondaparinux 1.5 mg once daily in the prevention of venous thromboembolism in renally impaired patients. Blood Coagul Fibrinolysis 20:114–121PubMedCrossRefGoogle Scholar
  24. 24.
    Douketis J, Cook D, Meade M, Guyatt G, Geerts W, Skrobik Y, Albert M, Granton J, Hébert P, Pagliarello G, Marshall J, Fowler R, Freitag A, Rabbat C, Anderson D, Zytaruk N, Heels-Ansdell D, Crowther M; Canadian Critical Care Trials Group (2008) Prophylaxis against deep vein thrombosis in critically ill patients with severe renal insufficiency with the low-molecular-weight heparin dalteparin: an assessment of safety and pharmacodynamics: the DIRECT study. Arch Intern Med 168:1805–1812CrossRefGoogle Scholar
  25. 25.
    Gouin-Thibault I, Pautas E, Siguret V (2005) Safety profile of different low-molecular weight heparins used at therapeutic dose. Drug Saf 28:333–349PubMedCrossRefGoogle Scholar
  26. 26.
    Gerlach AT, Pickworth KK, Seth SK, Tanna SB, Barnes JF (2000) Enoxaparin and bleeding complications: a review in patients with and without renal insufficiency. Pharmacotherapy 20:771–775PubMedCrossRefGoogle Scholar
  27. 27.
    sanofi-aventis US LLC (2009) Lovenox Prescribing Information. Accessed 16 March 2011
  28. 28.
    Van Thiel D, Kalodiki E, Wahi R, Litinas E, Haque W, Rao G (2009) Interpretation of benefit-risk of enoxaparin as comparator in the RECORD Program: rivaroxaban oral tablets (10 milligrams) for use in prophylaxis in deep vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery. Clin Appl Thromb Hemost 15:389–394PubMedCrossRefGoogle Scholar
  29. 29.
    Turpie AG, Levine MN, Hirsh J, Carter CJ, Jay RM, Powers PJ, Andrew M, Hull RD, Gent M (1986) A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 315:925–929PubMedCrossRefGoogle Scholar
  30. 30.
    Planes A, Vochelle N, Darmon JY, Fagola M, Bellaud M, Huet Y (1996) Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin vs placebo. Lancet 348:224–228PubMedCrossRefGoogle Scholar
  31. 31.
    Eriksson BI, Bauer KA, Lassen MR, Turpie AGG; Steering Committee of the Pentasaccharide in Hip-fracture Surgery Group (2001) Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 345:1298–1304CrossRefGoogle Scholar
  32. 32.
    Saleh K, Olson M, Resig S, Bershadsky B, Kuskowski M, Gioe T, Robinson H, Schmidt R, McElfresh E (2002) Predictors of wound infection in hip and knee joint replacement: results from a 20 year surveillance program. J Orthop Res 20:506–515PubMedCrossRefGoogle Scholar
  33. 33.
    Patel VP, Walsh M, Sehgal B, Preston C, DeWal H, Di Cesare PE (2007) Factors associated with prolonged wound drainage after primary total hip and knee arthroplasty. J Bone Joint Surg Am 89:33–38PubMedCrossRefGoogle Scholar
  34. 34.
    Bonneux IM, Bellemans J, Fabry G (2006) Evaluation of wound healing after total knee arthroplasty in a randomized prospective trial comparing fondaparinux with enoxaparin. Knee 13:118–121PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ola E. Dahl
    • 1
    • 2
  • Andreas A. Kurth
    • 3
  • Nadia Rosencher
    • 4
  • Herbert Noack
    • 5
  • Andreas Clemens
    • 6
  • Bengt I. Eriksson
    • 7
  1. 1.Department of OrthopaedicsElverum Central HospitalElverumNorway
  2. 2.Thrombosis Research InstituteLondonUK
  3. 3.Orthopaedic University Hospital MainzMainzGermany
  4. 4.Department of Anaesthesiology and Intensive CareParis Descartes University, Cochin Hospital (AP HP)ParisFrance
  5. 5.Medical Data ServicesBoehringer Ingelheim Pharma GmbH & Co. KGIngelheim am RheinGermany
  6. 6.Department of Medical AffairsBoehringer Ingelheim GmbHIngelheim am RheinGermany
  7. 7.Department of Orthopaedic SurgeryUniversity Hospital Sahlgrenska/ÖstraGothenburgSweden

Personalised recommendations