Quality Improvement Program: Advancement of Hospital Venous Thromboembolism - Free Zones

Supplements and Featured Publications, Venous Thromboembolism After Total Hip Arthroplasty and Total Knee Arthroplasty: Current and Future , Volume 17, Issue 1 Suppl

Abstract

Venous thromboembolism is a frequent complication of total hip or total knee arthroplasty, with serious clinical and economic consequences. It is largely preventable with adherence to evidence-based guidelines for thromboprophylaxis. Nevertheless, many clinicians are either unaware of the serious consequences of venous thromboembolism or skeptical of the value of the guidelines. Now, however, government and quality agencies are stepping in with new initiatives that affect reimbursement for preventable events and are designed to reduce the number of thromboembolic events that occur as the result of insufficient or no prophylactic therapy. The development of new oral anticoagulants will play an important role in increasing the effectiveness, safety, and convenience of thromboprophylactic therapy, which may improve adherence to guidelines for thromboprophylaxis.

(Am J Manag Care. 2011;17:S9-S14)

Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE),1 is a common medical problem in the general population.2 A first episode of VTE occurs in about 1 in 1000 persons who have not had surgery and there are >200,000 new cases annually in the United States.3,4 Unrecognized and untreated DVT may predispose patients to recurrent VTE and long-term complications.5 PE is one of the most common preventable causes of in-hospital death,6 and it can also lead to chronic thromboembolic pulmonary hypertension.7 In 20% to 50% of patients, DVT can develop into a chronic condition known as post-thrombotic syndrome.8 Post-thrombotic syndrome has serious long-term consequences and is a cause of substantial patient morbidity.8,9 The cost of healthcare related to VTE and its treatment in the United States has been estimated at $1.5 billion per year.10

Relationship of VTE With Surgery

VTE is a serious complication after total hip and total knee arthroplasty (THA and TKA),11 and it is the most common cause for readmission following THA.12 The rates of venographic DVT and proximal DVT 7 to 14 days after major orthopedic surgery in patients who receive no thromboprophylaxis are approximately 40% to 60% and 10% to 30%, respectively.11 A major challenge in the management of anticoagulants is to balance the benefits against the risks of treatment, including bleeding complications and their consequences.13 Many orthopedic surgeons appear concerned about post-operative bleeding and therefore tend to adopt an ineffective approach toward prescribing antithrombotics.14

Guidelines, Duration of Thromboprophylaxis, and Adherence

In its guidelines for prevention of VTE, the American College of Chest Physicians (ACCP) recommends thromboprophylaxis with either a low molecular weight heparin (LMWH), fondaparinux, or a vitamin K antagonist (VKA).11 The ACCP recommends that thromboprophylaxis be continued for at least 10 days after THA and TKA and up to 35 days after THA, and suggests that therapy for up to 35 days could also be beneficial after TKA.11 This is because there is solid evidence that the risk of VTE remains for some time after THA15,16 and, to a lesser extent, after TKA.17-19 The prospective cohort Million Women Study found that 1 in 45 women undergoing inpatient THA or TKA was admitted with VTE during the 12 weeks after surgery, compared with 1 in 6200 women during a 12-week period without surgery.20 There is also increasing evidence that extended prophylaxis after surgery significantly reduces the frequency of DVT.19,21-25 An early recommendation for patients undergoing THA was to extend the use of LMWHs beyond hospital discharge,23 particularly since patients are discharged earlier (average 3.7 days) than in the past.24 However, results from the Global Orthopedic Registry indicated that after THA and TKA, thromboprophylaxis was of insufficient duration and often not in accordance with guidelines in terms of type, duration, start time, and dose.25

Evidence suggests that thromboprophylaxis is still used suboptimally according to guideline recommendations.13,26-28 In fact, 1 study found that fewer than 1 in 5 elderly patients received post-discharge thromboprophylaxis after THA or TKA.29 Thus, patients may remain at risk of VTE after these procedures. According to Arnold et al,30 in patients for whom thromboprophylaxis was indicated, an estimated 2 of every 3 cases of VTE could have been prevented had the ACCP guidelines been followed. A study by Caprini et al indicated that hospitals should evaluate their prophylaxis of VTE and implement performance-improvement initiatives to align their practice with guidelines.31

Quality Improvement Initiatives for VTE Prevention: National

Several strategies have been developed to increase appropriate use of thromboprophylaxis whenever appropriate.32-35

Several national quality organizations are helping to guide VTE prevention:

  • The National Quality Forum (NQF)36
  • The Joint Commission (TJC)37
  • Centers for Medicare and Medicaid Services (CMS)38
  • Office of the Surgeon General of the United States (OSG)39

A study reviewing 18 types of medical events concluded that medical errors may account for 2.4 million extra hospital days, $9.3 billion in excess charges (for all payers), and 32,600 deaths per year.38 According to the NQF, "never events" are errors in medical care that are clearly identifiable and preventable, pose serious consequences for patients, and indicate a real problem in the safety and credibility of a healthcare facility. Accordingly, the CMS has developed a list of hospital-acquired conditions classified as "never events." DVT or PE after THA and TKA are now included among the "never events" and care for these events will not be reimbursed by CMS when they occur during the same hospitalization as the index surgical procedure. This means that hospitals now have a greater incentive to reduce the cost burden of VTE and adopt new quality initiatives. However, it is important to remember that even when adhering to all guidelines, VTE after THA and TKA can never be prevented 100% of the time.

These initiatives, in addition to affecting payers and hospitals, also impact providers. The CMS provides financial incentives to healthcare professionals who document a standing order/protocol for VTE prophylaxis under the physician quality reporting initiative.40 Providers who reported at least 3 applicable quality improvement measures in 2009 will receive an incentive of 2% of estimated allowable charges.

A CMS-sponsored pilot program promotes seamless transitions from hospital to skilled nursing facilities or home healthcare. Its goal is to reduce miscommunication, patient dissatisfaction, poor outcomes, fragmented care, and hospital readmission.38 Fifty-three quality improvement organizations are now contracted with the CMS to safeguard the care of Medicare beneficiaries and are assigned in each state. The Surgical Care Improvement Project (SCIP) is a national quality partnership of healthcare organizations committed to improving surgical care safety through the reduction of postoperative complications. They set themselves the goal of reducing complications by 25% by the end of 2010.37,41 SCIP has 2 VTE outcome measures: SCIP1-VTE prophylaxis ordered prior to surgery; and SCIP2-VTE prophylaxis given within 24 hours prior to, or 24 hours after, surgery.28

Quality Improvement Initiatives for VTE Prevention: Local

A simple intervention to improve quality is to introduce a paper-based system into hospitals. While this does tend to improve thromboprophylaxis and reduce the incidence of VTE, there are numerous drawbacks that limit the efficacy of such systems.42 Using a computerized data entry system will likely improve matters. In fact, my institution, the Thomas Jefferson University Hospital, uses an electronic system, which has a VTE risk-assessment model integrated into a prevention protocol and computer physician-order entry system. This enables physicians to assess a patient's VTE risk on a daily basis, and write all necessary orders to ensure that appropriate prophylaxis is provided. If this is not the case, an electronic alert is issued (Figure).42 Similar electronic medication administration records, or automated reports, can classify each patient on a ward as being "green" (an order for prophylaxis in place), "yellow" (only mechanical prophylaxis ordered), or "red" (no VTE prophylaxis ordered), ensuring staff awareness of each patient's situation.30

Reasons for Suboptimal Thromboprophylaxis

The reasons for suboptimal thromboprophylaxis and lack of adherence to the guidelines may include lack of awareness, poor understanding of or disagreement with guidelines (either specifically or as a general concept), resistance to changing established practices, and doubt that a new approach will change outcomes.13,43 Additionally, a basic awareness of guidelines does not necessarily mean that physicians have sufficient knowledge to critically evaluate and apply recommendations.26 Other potential barriers include the mistaken belief that a small asymptomatic DVT is unimportant13 and cannot cause clinically significant PE,44 a view fortunately held by only a minority.45 However, in the absence of post-operative venography, subclinical DVT is the main source of PE.44

Due to the often clinically silent nature of VTE, and the low incidence of VTE during the short postoperative hospital stay, the chances of a surgeon witnessing either a major DVT or an acute PE are rare.26 In addition, the trend toward earlier hospital discharge means that many symptomatic events occur post-discharge.16,17 Because patients are often seen by other specialists when referred back to the hospital with a VTE, surgeons are often unaware of the true incidence of VTE in their patients. Another potential barrier to the optimal use of thromboprophylaxis could be the inconvenience of currently available agents.46 Orthopedic surgeons and their patients would benefit from an oral anticoagulant that could be administered in fixed, oral doses, without the need for routine coagulation monitoring.47

Novel Anticoagulants and Their Potential to Reduce "Never Events"

Oral anticoagulants that do not require routine coagulation monitoring are being developed. These agents have the potential to improve adherence to guidelines by providing a more convenient type of prophylaxis.47,48 Unlike established agents, such as VKAs and LMWHs, which target multiple factors in the coagulation cascade, require frequent monitoring, or are administered subcutaneously, these new drugs inhibit a single, specific coagulation factor. This characteristic appears to be translating into clinical benefit in terms of predictability and safety compared with existing agents.47

The most advanced of these emerging agents are dabigatran etexilate,49 an oral, direct thrombin inhibitor, and the oral, direct Factor Xa inhibitors50 rivaroxaban51,52 and apixaban.53 Overall, the pharmacokinetic profiles of dabigatran,54 rivaroxaban,55 and apixaban56 have demonstrated a rapid onset of action, moderate duration of effect, and predictable dose-proportional pharmacokinetics at steady state.

A meta-analysis of data from studies in patients who underwent THA and TKA found no differences in efficacy between dabigatran and the LMWH enoxaparin, the current standard of care.57 Results of the RECORD (REgulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) program58-61 and of a pooled analysis62 showed that rivaroxaban significantly reduced the incidence of the composite of symptomatic VTE and all-cause mortality compared with enoxaparin regimens. In its first phase II study, ADVANCE-1 (Apixaban Dosed Orally Versus Anticoagulation with Injectable Enoxaparin to Prevent Venous Thromboembolism 1), apixaban did not meet non-inferiority margins compared with enoxaparin,63 but a more recent phase II study, ADVANCE-2 (Apixaban Dosed Orally Versus Anticoagulation with Injectable Enoxaparin to Prevent Venous Thromboembolism 2), indicated that apixaban was superior to enoxaparin for preventing VTE after TKA.64

All anticoagulants, by definition, will increase the risk of bleeding. However, primary65-67 and pooled68,69 studies, and meta-analyses57 of data from the dabigatran trials for the prevention of VTE after THA/TKA, found no differences between bleeding rates in the groups receiving dabigatran or enoxaparin. Similarly, primary studies of rivaroxaban58-61 and the pooled analyses70,71

found no differences in bleeding rates compared with the enoxaparin groups after THA/TKA. Finally, the apixaban study ADVANCE-163 found lower bleeding rates, while ADVANCE-264 found no difference in bleeding rates compared with enoxaparin after TKA. It therefore seems that the new agents are largely more effective than the current standard of care, and equally safe.

Drugs in earlier stages of development include the oral direct Factor Xa inhibitors edoxaban, betrixaban, otamixaban, and YM150, and the oral direct thrombin inhibitor AZD0837.72 These new agents should reduce the burden of anticoagulant management. Given their efficacy, these agents may also lead to higher rates of VTE prophylaxis,73 thereby reducing the number of "never events" occurring in hospitals.

Conclusion

VTE following THA and TKA is largely preventable and therefore unacceptable, since it is frequently the result of suboptimal use of thromboprophylaxis. Measures taken by institutions and quality organizations to encourage adherence to evidence-based guidelines can, and should, by creating VTE-free zones, greatly reduce the high clinical and economic burden of this condition. The advent of effective and cost-effective oral anticoagulants, with simpler patient management than the current standard of care, should be very helpful in achieving this goal.

Author Affiliation: Jefferson Medical College and Thomas Jefferson University Hospital, Philadelphia, PA.

Funding Source: Financial support for this supplement was provided by Ortho-McNeil Janssen Scientific Affairs, LLC and Johnson & Johnson Worldwide Market Access.

Author Disclosure: Dr Merli reports consultancy/advisory board assignments with Bayer, Bristol-Myers Squibb, and sanofi-aventis. He has also received grants and lectureship fees from Bayer, Bristol-Myers Squibb, and sanofi-aventis.

Authorship Information: Concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Address correspondence to: Geno J. Merli, MD, FACP, FHM, FSVM, Thomas Jefferson University Hospital, 111 S 11th St, Ste 2210, Philadelphia, PA 19107. E-mail: geno.merli@jefferson.edu.

1. McRae SJ, Ginsberg JS. Initial treatment of venous thromboembolism. Circulation. 2004;110:I3-I9.

2. Lopez JA, Kearon C, Lee AY. Deep venous thrombosis. Hematology Am Soc Hematol Educ Program. 2004:439-456.

3. Heit JA, Silverstein MD, Mohr DN, et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost. 2001;86:452-463.

4. White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107:I4-I8.

5. Nutescu EA. Antithrombotic therapy for the treatment of venous thromboembolism. Am J Manag Care. 2003;9:S103-S114.

6. Lee CH, Hankey GJ, Ho WK, Eikelboom JW. Venous thromboembolism: diagnosis and management of pulmonary embolism. Med J Aust. 2005;182:569-574.

7. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257-2264.

8. Kahn SR, Ginsberg JS. Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med. 2004;164:17-26.

9. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698-707.

10. Jaffer AK. An overview of venous thromboembolism: impact, risks, and issues in prophylaxis. Cleve Clin J Med. 2008;75(suppl 3):S3-S6.

11. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest. 2008; 133:381S-453S.

12. Seagroatt V, Tan HS, Goldacre M, et al. Elective total hip replacement: incidence, emergency readmission rate, and postoperative mortality. BMJ. 1991;303:1431-1435.

13. Kakkar AK, Davidson BL, Haas SK. Compliance with recommended prophylaxis for venous thromboembolism: improving the use and rate of uptake of clinical practice guidelines. J Thromb Haemost. 2004;2:221-227.

14. Dahl OE, Bergqvist D. Current controversies in deep vein thrombosis prophylaxis after orthopaedic surgery. Curr Opin Pulm Med. 2002;8:394-397.

15. Planes A, Vochelle N, Darmon JY, et al. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo. Lancet. 1996;348:224-228.

16. White RH, Romano PS, Zhou H, et al. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med. 1998;158:1525-1531.

17. Kearon C. Duration of venous thromboembolism prophylaxis after surgery. Chest. 2003;124:386S-392S.

18. Comp PC, Spiro TE, Friedman RJ, et al. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group. J Bone Joint Surg Am. 2001;83-A336-A345.

19. Warwick D, Friedman RJ, Agnelli G, et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry. J Bone Joint Surg Br. 2007;89:799-807.

20. Sweetland S, Green J, Liu B, et al. Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study. BMJ. 2009;339:b4583.

21. Agnelli G, Mancini GB, Biagini D. The rationale for long-term prophylaxis of venous thromboembolism. Orthopedics. 2000;23:s643-s646.

22. Friedman RJ. Optimal duration of prophylaxis for venous thromboembolism following total hip arthroplasty and total knee arthroplasty. J Am Acad Orthop Surg. 2007;15:148-155.

23. Nicolaides AN, Breddin HK, Fareed J, et al. Prevention of venous thromboembolism. International Consensus Statement. Guidelines compiled in accordance with the scientific evidence. Int Angiol. 2001;20:1-37.

24. Anderson FA Jr, Hirsh J, White K, Fitzgerald RH Jr. 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.

25. Friedman RJ, Gallus AS, Cushner FD, et al. Physician compliance with guidelines for deep-vein thrombosis prevention in total hip and knee arthroplasty. Curr Med Res Opin. 2008;24:87-97.

26. Caprini JA, Hyers TM. Compliance with antithrombotic guidelines. Manag Care. 2006;15:49-66.

27. 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.

28. Amin A, Spyropoulos AC, Dobesh P, et al. Are hospitals delivering appropriate VTE prevention? The venous thromboembolism study to assess the rate of thromboprophylaxis (VTE start). J Thromb Thrombolysis. 2010;29:326-339.

29. Rahme E, Dasgupta K, Burman M, et al. Postdischarge thromboprophylaxis and mortality risk after hip- or knee-replacement surgery. CMAJ. 2008;178:1545-1554.

30. Arnold DM, Kahn SR, Shrier I. Missed opportunities for prevention of venous thromboembolism: an evaluation of the use of thromboprophylaxis guidelines. Chest. 2001;120:1964-1971.

31. Caprini JA, Tapson VF, Hyers TM, et al. Treatment of venous thromboembolism: adherence to guidelines and impact of physician knowledge, attitudes, and beliefs. J Vasc Surg. 2005;42:726-733.

32. Geerts W. Prevention of venous thromboembolism: a key patient safety priority. J Thromb Haemost. 2009;7(suppl 1):1-8.

33. Michota FA. Prevention of venous thromboembolism after surgery. Cleve Clin J Med. 2009;76(suppl 4):S45-S52.

34. Amin AN, Deitelzweig SB. Optimizing the prevention of venous thromboembolism: recent quality initiatives and strategies to drive improvement. Jt Comm J Qual Patient Saf. 2009;35:558-564.

35. Bratzler DW. Development of national performance measures on the prevention and treatment of venous thromboembolism. J Thromb Thrombolysis. 2010;29:148-154.

36. The National Quality Forum. http://www.qualityforum.org. Accessed November 5, 2010.

37. The Joint Commission. http://www.jointcommission.org. Accessed November 5, 2010.

38. Centers for Medicare & Medicaid Services. http://www.cms.hhs.gov. Accessed November 5, 2010.

39. Office of the Surgeon General of the United States. http://www.surgeongeneral.gov. Accessed November 5, 2010.

40. Physician Quality Reporting Initiative. Centers for Medicare & Medicaid Services. http://www.cms.hhs.gov/PQRI. Accessed November 5, 2010.

41. Bratzler DW, Hunt DR. The surgical infection prevention and surgical care improvement projects: national initiatives to improve outcomes for patients having surgery. Clin Infect Dis. 2006;43:322-330.

42. Merli G. Improving venous thromboembolism performance: a comprehensive guide for physicians and hospitalists. Hosp Pract (Minneap). 2010;38:7-16.

43. Maynard G, Stein J. Designing and implementing effective venous thromboembolism prevention protocols: lessons from collaborative efforts. J Thromb Thrombolysis. 2010;29:159-166.

44. Dahl OE. Continuing out-of-hospital prophylaxis following major orthopaedic surgery: What now? Haemostasis. 2000;30:101-105.

45. Goldhaber SZ, Turpie AGG. Prevention of venous thromboembolism among hospitalized medical patients. Circulation. 2005;111:e1-e3.

46. Eriksson BI, Quinlan DJ. Oral anticoagulants in development: focus on thromboprophylaxis in patients undergoing orthopaedic surgery. Drugs. 2006;66:1411-1429.

47. Weitz JI. Emerging anticoagulants for the treatment of venous thromboembolism. Thromb Haemost. 2006;96:274-284.

48. Borris LC. Barriers to the optimal use of anticoagulants after orthopaedic surgery. Arch Orthop Trauma Surg. 2008;129:1441-1445.

49. Eriksson BI, Smith H, Yasothan U, Kirkpatrick P. Dabigatran etexilate. Nat Rev Drug Discov. 2008;7:557-558.

50. Merli G, Spyropoulos AC, Caprini JA. Use of emerging oral anticoagulants in clinical practice: translating results from clinical trials to orthopedic and general surgical patient populations. Ann Surg. 2009;250:219-228.

51. Borris LC. Rivaroxaban, a new, oral, direct factor Xa inhibitor for thromboprophylaxis after major joint arthroplasty. Expert Opin Pharmacother. 2009;10:1083-1088.

52. Chen T, Lam S. Rivaroxaban: an oral direct factor Xa inhibitor for the prevention of thromboembolism. Cardiol Rev. 2009;17:192-197.

53. Roser-Jones C, Becker RC. Apixaban: an emerging oral factor Xa inhibitor. J Thromb Thrombolysis. 2010;29:141-146.

54. Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64:292-303.

55. Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 - an oral, direct Factor Xa inhibitor - after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61:873-880.

56. Shantsila E, Lip GY. Apixaban, an oral, direct inhibitor of activated Factor Xa. Curr Opin Investig Drugs. 2008;9:1020-1033.

57. Wolowacz SE, Roskell NS, Plumb JM, et al. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A metaanalysis. Thromb Haemost. 2009;101:77-85.

58. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765-2775.

59. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a doubleblind, randomised controlled trial. Lancet. 2008;372:31-39.

60. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776-2786.

61. Turpie AGG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373: 1673-1680.

62. Turpie AGG, Lassen MR, Kakkar AK, et al. A pooled analysis of four pivotal studies of rivaroxaban for the prevention of venous thromboembolism after orthopaedic surgery: effect on symptomatic venous thromboembolism and death, and bleeding. Haematologica. 2009;94(suppl 2):212. Abstract 0522.

63. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:594-604.

64. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375:807-815.

65. Eriksson BI, Dahl OE, Rosencher N, et al. 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.

66. Eriksson BI, Dahl OE, Rosencher N, et al. 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;5:2178-2185.

67. 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. 2009;24:1-9.

68. Eriksson BI, Friedman R. Dabigatran etexilate: pivotal trials for venous thromboembolism prophylaxis after hip or knee arthroplasty. Clin Appl Thromb Hemost. 2009;15:25S-31S.

69. Friedman RJ, Dahl OE, Rosencher N, et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res. 2010;126:175-182.

70. Eriksson BI, Kakkar AK, Turpie AGG, et al. Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement. J Bone Joint Surg Br. 2009;91:636-644.

71. Turpie AGG, Lassen MR, Kakkar A, et al. A pooled analysis of four pivotal studies of rivaroxaban for the prevention of venous thromboembolism after orthopaedic surgery: effect on symptomatic venous thromboembolism, death, and bleeding. Blood. 2008;112. Abstract 36.

72. Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest. 2008;133:234S-256S.

73. Wittkowsky AK. New oral anticoagulants: a practical guide for clinicians. J Thromb Thrombolysis. 2010;29:182-191.