Are Novel Oral Anticoagulants Now the Treatment of Choice for the Prevention of Venous Thromboembolism Following Total Hip or Knee Arthroplasty?

David R. Anderson, M.D., FRCPC
Head/Chief Department of Medicine
Capital Health & Dalhousie University
Halifax, NS

Michael J Dunbar, M.D., FRCSC, Phd
Professor of Biomedical Engineering,
Professor of Community Health and Epidemiolgy
Professor of Surgery, Division of Orthopaedics
Clinical Research Scholar,
Dalhousie University
Halifax, NS

Deep vein thrombosis and pulmonary embolism (collectively known as venous thromboembolism or VTE) are well-recognized complications following total hip or knee arthroplasty1,2. Orthopaedic surgeons have been at the forefront of developing prophylaxis strategies to reduce the risk of these complications, and these innovations have been adopted into routine care in the postoperative period following joint arthroplasty in Canada.


Over the last three decades, numerous studies involving anticoagulant prophylaxis such as unfractionated heparin, warfarin and low-molecular-weight heparin have been performed, demonstrating the effectiveness and safety of these agents. By the late 2000s daily postoperative low-molecular-weight heparin injections became the standard of care for VTE prophylaxis following total hip or knee arthroplasty3. Guidelines recommended these agents be continued for 35 days following total hip arthroplasty and 14 days following total knee arthroplasty3. With use of these strategies, rates of symptomatic VTE complications were less than 1% and fatal pulmonary embolism observed in less than 1/1000 patients4. Bleeding is the most common and serious side-effect of anticoagulant prophylaxis. About 4% of patients undergoing total hip or knee arthroplasty would develop clinically relevant bleeding complications with low molecular weight heparin prophylaxis, usually at the surgical site4.

We are entering an exciting new era of anticoagulant therapy. Since 2008, three novel anticoagulant agents (dabigatran, rivaroxaban, apixaban) have been approved in Canada for venous thromboembolism prophylaxis following total hip or knee arthroplasty. The pharmacokinetics and mechanisms of action of these agents differ but they have the common characteristics of administration in fixed doses with no need for drug monitoring5. These agents also have little food or drug interactions and can be administered to most patients except with those major impairments in kidney and liver function5. The oral formulation of the product offers a major advantage over low-molecular-weight heparin particularly in the outpatient setting. Clinical trials have demonstrated that these agents are at least as effective as low-molecular-weight heparin for the prevention of VTE following total hip or knee arthroplasty4.

As we contemplate whether novel anticoagulants should become the standard of care for VTE prophylaxis following total hip or knee arthroplasty, we need to consider the following questions: "Do we really need to more effective anticoagulant prophylaxis following joint arthroplasty?" and "are there concerns that as we press to find more effective anticoagulant prophylaxis we are going to increase rates of major bleeding and risk the outcome of the arthroplasty procedure in the first place?"

There are hints that we have reached the wall of effectiveness of anticoagulant with the new oral anticoagulants. Meta-analyses have demonstrated that rivaroxaban significantly reduced this risk of symptomatic VTE complications following total hip or nee arthroplasty compared to low-molecular-weight heparin, but show no evidence that it reduced mortality3,4. However, this benefit came at a cost of increased clinically relevant bleeding complications3,4. On the other hand, the two other agents (dabigatran, apixaban) caused similar risk reductions in symptomatic VTE and clinically important bleeding rates compared with low-molecular-weight heparin3,4. One possible explanation for the difference in effectiveness and safety of rivaroxaban compared to other agents is that the first dose of medication was administered on the evening of surgery compared to the following day for the other agents.

In the most recent 2012 guidelines of the American College of Chest Physicians, the recommendation is that low-molecular-weight heparin be the agent of choice for the prevention of VTE following total hip or knee arthroplasty, in preference to novel oral anticoagulants and other prophylaxis modalities given its known effectiveness, relatively low rate of major bleeding and otherwise excellent long-term safety record3. However, this was a relatively weak recommendation that ignored the convenience of the novel anticoagulants.

Our view is that we currently have excellent methods of anticoagulant prophylaxis with low molecular weight heparin and the novel anticoagulants following total hip or knee arthroplasty. Rates of VTE and mortality are very low with currently available prophylaxis strategies. With anticoagulant therapy attempts to further reduce rates of VTE will likely be met with increased rates of major bleeding that are unlikely to be acceptable to patients or orthopedic surgeons. We advocate that further research should focus on strategies for venous thromboembolism prevention following joint arthroplasty that are safer and less expensive than anticoagulant agents. We believe that aspirin and mechanical devices deserve further attention in clinical trials. Previously, American College of Chest Physicians guidelines have dismissed aspirin and minimized the benefit of non-pharmacological innovations for the prevention of venous thromboembolism since the evidence was not as robust as those found in contemporary clinical trials involving anticoagulants2. The 2012 guidelines have rereviewed both older and contemporary studies and have determined there is sufficient evidence to support both aspirin and mechanical methods as effective methods of venous thromboembolism prophylaxis following total hip or knee arthroplasty3. It is also clear that there are countries in the world where a combination of aspirin and mechanical methods are routinely used for VTE prophylaxis and large registries do not report alarming rates of VTE or mortality with these innovations. Whether these aspirin and mechanical methods are as effective and safer than low-molecular-weight heparin or novel anticoagulants requires further study6-8.

Orthopaedic surgeons and patients are in the enviable situation of having a wide variety of effective, generally safe, convenient and guideline-supported antithrombotic agents to choose from following total hip or knee arthroplasty. It is important, as clinicians, that we push the frontiers of practice and evaluate whether safe, convenient and cost-effective modalities may have advantages and, in some situations, even be preferable to newer expensive anticoagulant therapy. In this regard, we believe aspirin and mechanical devices should be the focus of further comparative studies.



  1. Lieberman J.R., Geerts W.H. Prevention of venous thromboembolism after total hip and knee arthroplasty. J Bone Joint Surg Am. 1994 Aug;76(8):1239-50.
  2. Geerts W.H., Bergqvist D., Pineo G., Heit, J.A., Samama C.M., Lassen M.R., Colwell C.W. Prevention of Venous Thromboembolism. Chest 2008; 133:381S-453S.
  3. Falck-Tyyer Y., Francis C., Johanson N.A., Curley C., Dahl O.E., Schulman S. et al. Prevention of VTE in orthopedic surgery patients. Chest 2012;141:e278S-e325S.
  4. Gomez-Outes A., Terleira-Fernandez A.E., Suarez-Gea M.L., Vargas-Castrillon E. Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons. BMJ 2012;344:e3675.
  5. Garcia D., Libby E., Crowther M.A. The new oral anticoagulants. Blood 2010;115:15-20.
  6. Bozic K., Vail T.P., Pekow P.S. et al. Does aspirin have a role in venous thromboembolism prophylaxis in total knee arthroplasty patients? J Arthroplasty 2010;25:1053-1060.
  7. Cusick L.A., Beverland D.E. The incidence of fatal pulmonary embolism after primary hip and knee replacement in a consecutive series of 4253 patients. J Bone Joint Surg Br 2009;91-B:645-648.
  8. Khatod M., Inacio M.S.C., Bini S.A. et al. Pulmonary embolism prophylaxis in more than 30,000 total knee arthroplasty patients: is there a best choice? J Arthroplasty 2012;27:167-72.

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