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Management Brief No. 60

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Management eBriefs
Issue 60March 2013

A Systematic Review: New Oral Anticoagulants vs Standard Anticoagulant Regimens for Thromboprophylaxis Related to Joint Replacement Surgery

Venous thromboembolic (VTE) events are important causes of morbidity in elective total hip replacement (THR) and total knee replacement (TKR) procedures. Current guidelines recommend thromboprophylaxis (measures taken to prevent blood clots) in patients undergoing THR or TKR, although guidelines suggest individual assessment of patients when choosing the specific strategy. Low molecular weight heparin (LMWH) and adjusted-dose warfarin are the most commonly used anticoagulants in the U.S., but a number of other treatment options are available, including unfractionated heparin (UFH), injectable FXa inhibitors, aspirin, mechanical devices, and new oral anticoagulants.

Pharmacological thromboprophylaxis for THR or TKR surgery decreases the risk of VTE by about half, but with the tradeoff of increased bleeding. The risk of bleeding is a concern because it can lead to infections, reoperation, delayed wound healing, and extended hospital stays. New oral anticoagulants were developed with the goal of avoiding the disadvantages of available antithrombotics. The new anticoagulants belong to two drug classes: 1) factor Xa (FXa) inhibitors, and 2) direct thrombin inhibitors (DTIs). Given as fixed oral doses, these drugs have the advantage of a more predictable anticoagulant effect, eliminating the need for the regular monitoring necessary with warfarin. Disadvantages of newer oral anticoagulants include the lack of specific antidotes to reverse their anticoagulant effect in a timely fashion in case of bleeding, and higher drug costs.

Investigators with the VA Evidence-based Synthesis Program, part of the Durham VA Healthcare System, conducted a review of the literature from January 2009 through September 2012, in order to assess emerging data on new oral anticoagulants and compare the effectiveness of the new oral anticoagulants to other classes of antithrombotic agents (i.e., aspirin, warfarin, LMWH, UFH, etc.). Using data from six recently published, high-quality systematic reviews, investigators focused on answering the following questions.

Question #1
For patients undergoing THR or TKR surgery, what is the comparative effectiveness of new oral anticoagulants and standard drug classes (LMWH, injectable factor Xa inhibitors, UFH, warfarin, aspirin) on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, and bleeding outcomes?

  • For all-cause mortality and non-fatal pulmonary embolism, there were no statistically significant differences between oral FXa inhibitors and LMWH (high strength of evidence). Using a base rate of 9 events per 1,000 patients with LMWH, FXa inhibitors were associated with lower symptomatic deep vein thrombosis (4 fewer events per 1,000 patients). Overall, FXa inhibitors were associated with an increased risk of major bleeding, but this outcome did not differ in a clinically or statistically significant way at low and moderate doses (moderate strength of evidence).
  • Based on subgroup analyses, there were no consistent patterns of differences in treatment effects for THR and TKR.
  • There were fewer studies evaluating oral DTIs than oral FXa inhibitors. All trials compared dabigatran (the only FDA-approved oral DTI) with enoxaparin (LMWH). Although estimates of effect were often imprecise, there were no significant differences between dabigatran and enoxaparin for any major outcome.
  • Neither oral FXa inhibitors nor dabigatran have been compared directly with adjusted-dose warfarin, oral antiplatelet drugs, or UFH in existing studies.

Question #2
For patients undergoing THR or TKR surgery, what are the effects of combined pharmacological and mechanical modalities versus pharmacological treatment alone on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, and bleeding outcomes?

  • In the included systematic reviews, no studies were identified that compared the combination of new oral anticoagulants with mechanical thromboprophylaxis versus pharmacological treatment alone.
  • Few studies compared standard antithrombotics (LMWH, oral antiplatelet agents, or UFH) combined with mechanical prophylaxis to pharmacological or mechanical prophylaxis alone.
  • The strength of evidence is insufficient to determine the comparative effectiveness for combined pharmacological and mechanical prophylaxis compared with pharmacological prophylaxis alone for all major outcomes prioritized in this report.

Question #3
For patients undergoing THR or TKR surgery, what is the comparative efficacy of individual new oral anticoagulants on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, and bleeding outcomes?

  • No clinical trials directly compared new oral anticoagulants with each other for thromboprophylaxis in THR or TKR.
  • The included systematic reviews did not estimate the comparative efficacy of new oral anticoagulants for symptomatic deep vein thrombosis, non-fatal pulmonary embolism, all-cause mortality, or surgical site bleeding.
  • Based on indirect comparisons, there were few differences between new oral anticoagulants for the outcomes examined.
    • Rivaroxaban was associated with more major bleeding than apixaban (rivaroxaban and apixaban are the most commonly studied, FDA-approved FXa inhibitors).
    • The risk of symptomatic VTE was lower for rivaroxaban than apixaban or dabigatran, but confidence intervals included the possibility of a chance association.

For THR or TKR, the 35-day rate of symptomatic VTE without thromboprophylaxis is estimated to be 4.3%. Pharmacological thromboprophylaxis decreases VTE by approximately 50%, but with the tradeoff of increased bleeding. New oral anticoagulants have a more convenient route of administration compared with LMWH, and unlike adjusted dose warfarin, they do not require regular laboratory monitoring. Compared with LMWH, FXa inhibitors are associated with a reduced risk of symptomatic deep vein thrombosis, but mortality and non-fatal pulmonary embolism are not significantly different, and the risk of major bleeding episodes is increased.

There are no available studies on head-to-head comparisons of these novel anticoagulants. Longer clinical experience and direct drug-drug comparisons are needed to better assess the risk-to-benefit ratio of new oral anticoagulants for surgical thromboprophylaxis. Based on current evidence, new oral anticoagulants--particularly FXa inhibitors--are a reasonable alternative for thromboprophylaxis in patients undergoing THR or TKR surgery. However, only FXa inhibitors rivaroxaban and apixaban are currently FDA-approved and available in the United States. We caution that similar results in standard VA practice will require careful patient monitoring and selection, excluding those with severe renal disease, liver disease, or increased bleeding risk. Because VA patients, on average, have a higher bleeding risk and greater burden of chronic disease than those with private sector insurance, studies in higher risk populations are needed to determine if the comparative effectiveness is similar to published results in these higher risk groups.

Suggested Evidence-Based Guidance
National evidence-based guidance on the use of newer anticoagulants (dabigatran and rivaroxaban) within the VA healthcare system has been developed by the National Pharmacy Benefits Management Service (PBM). These PBM documents are updated when new information becomes available. Given the rapidly evolving therapeutic area of anticoagulation, please visit the PBM Intranet website directly to access the most recent versions of ( VA National Guidance (***Intranet only***). To view the documents, click on "Clinical Guidance," then "Drug Monographs," "Criteria for Use," or "Clinical Recommendations." Most of these documents also may be found on the PBM Internet website:

This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers -- and to disseminate these reports throughout VA.


Adam SS, McDuffie JR, Lachiewicz PF, Ortel TL, Williams JW Jr. Comparative Effectiveness of Newer Oral Anticoagulants and Standard Anticoagulant Regimens for Thromboprophylaxis in Patients Undergoing Total Hip or Knee Replacement. VA ESP Project #09-010; 2012.

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This report is a product of the HSR&D Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers - and to disseminate these reports throughout VA.

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