The Future of Thromboembolic Prophylaxis Fred D. Cushner, MD,* and Michael P. Nett, MD† For the last 30 years, surgeons have balanced the need for deep-venous thrombosis (DVT) prophylaxis with the need to avoid complications following total joint arthroplasty. Debate continues regarding prophylaxis against venous thromboembolism (VTE). Despite established guidelines and continued research, no consensus exist as to what agent affords the best balance between reducing DVT rates and minimizing the incidence of bleeding and wound complications. New oral anticoagulants offer the ease of oral administration and excellent efficacy, but remain unavailable in the United States and may lead to increased bleeding. New portable pneumatic compression devices look promising. They allow outpatient use and may improve compliance, but their exact role in the future of DVT prophylaxis remains undetermined. Semin Arthro 20:251-254 © 2009 Elsevier Inc. All rights reserved. KEYWORDS deep venous thrombosis, pulmonary embolism, arthroplasty, portable pneumatic compression devices, oral anticoagulation
I
t is quite apparent that no ideal method of deep-venous thrombosis (DVT) prophylaxis exists. Although the merits of chronic prophylaxis are discussed in previous articles, this article will focus on new advances and approaches to prophylaxis.
Oral Agents Certainly, the low molecular weight heparins (LMWHs) have become the gold standard of DVT prophylaxis and treatment across the globe. Although the benefits are well described elsewhere, the main drawback is their subcutaneous route of administration. According to the authors’ experiences, patients may easily learn to self-inject, but it certainly would be beneficial if an oral option existed. New advances have been made in the area of oral prophylaxis. Although some of these agents are available in the global market, they remain unavailable in the United States until the Food and Drug Administration (FDA) application process is completed. Although technically aspirin and warfarin are oral agents, this section will focus on the newer agents that may become available in the near future.
*Division of Orthopedics, Insall Scott Kelly Institute, Southside Hospital, Bay Shore, New York, USA. †Insall Scott Kelly Institute, Southside Hospital, Bay Shore, New York, USA. Address reprint requests to Fred D. Cushner, MD, Insall Scott Kelly Institute for Orthopaedics and Sports Medicine, 301 E. Main St, Bay Shore, NY 11706. E-mail:
[email protected]
1045-4527/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.sart.2009.10.009
Historically, no known oral anticoagulation has been approved for use in the United States since 1954. Ximelagatran (AstraZeneca, London, UK), an oral direct thrombin inhibitor, showed initial promise and was presented to the FDA in 2007. Approval was not received with concerns of hepatotoxicity with long-term use. Rivaroxaban (Xarelto, Bayer) has been studied in orthopedic patients who underwent total knee arthroplasty and total hip arthroplasty. Four pivotal studies, records 1 through 4, as well as a meta-analysis have been completed and presented at academic meetings over the past year, and results of these studies will be discussed in the following paragraphs. Rivaroxaban is a direct Xa inhibitor that is orally administered once daily. The proposed dose in total hip and knee arthroplasty patients is 10 mg daily, starting 6-8 hours postoperatively. Although currently not available in the United States, it has been approved for use in Canada, as well as numerous European countries. The FDA reviewed this drug in July 2009, and additional analysis was requested. Questions were raised regarding the need to better understand bleeding reports, possible liver toxicity, as well as cardiovascular events after cessation of the drug. In the 4 studies evaluated, rivaroxaban has been compared with enoxaparin for hip and knee replacement patients. In these studies, rivaroxaban demonstrated superiority with regard to primary efficacy outcome, the prevention of total venous thromboembolism (VTE), and secondary efficacy outcome, the prevention of major VTE.1-5 In these studies, there was no significant difference in regard to the primary safety outcome of major bleeding compared with enoxaparin. Major bleeding was 251
252 seen in 0.3%-1.3% of patients on rivaroxaban, with daily doses of 10 mg daily or less.1-5 An increased risk of major bleeding was seen with unapproved daily doses ⬍20 mg, which is not recommended.5 Again, in the dose-ranging studies, bleeding complications increase with drug exposure. In the meta-analysis performed by Fisher et al,5 major bleeding occurred in 7% of patients receiving 60 mg of rivaroxaban daily. This was a significant increase compared with 1.7% of patients receiving enoxaparin or 1.3% of patients receiving 10 mg of rivaroxaban daily.5 In addition, although not found to be significant, the bleeding complications were consistently higher with rivaroxaban than enoxaparin in the Record clinical trials, and the bleeding rates were numerically 2 times higher than in the enoxaparin group. It should be noted that most of the increased rate of bleeding was due to extrasurgical site bleeds (intracranial or retroperitoneal), with hemoglobin decrease or transfusion requirements. Close review of the studies shows that when any bleeding was considered, rivaroxaban showed 6.23% in the Record one and 2 hip studies and 8% in the Record 3 and 4 knee studies. This compares with enoxaparin, which showed 5.76% overall bleeding rate for the hip studies and 7.35% for the knee studies. When only major bleeding was considered, the rate for rivaroxaban in the hip studies was 0.2% vs 0.09% for enoxaparin, and 0.62% versus 0.36% for enoxaparin after total knee arthroplasty. Although a small increased bleeding rate was noted, the drug did appear efficacious with regard to the prevention of symptomatic VTE. For example, in Record 3, a dose of 10 mg of rivaroxaban daily had a 0.7% symptomatic rate vs 2% for 40 mg of enoxaparin daily (the European dose). The US study of nearly 2000 patients had a symptomatic VTE rate of 0.7% with 10 mg of rivaroxaban daily as compared with 1.2% for 30 mg of enoxaparin dosed twice daily. Another oral agent that has been studied is Dabigatran etexilate (Boehring Ingelheim, Ingelheim am Rhein, Germany). This is a prodrug that is rapidly converted by a serum esterase to dabigatran, a potent direct thrombin inhibitor. It has a serum half-life of 12-17 hours. In addition, it does not require regular monitoring. In a multicenter double-blind study, nearly 2000 patients having a hip or knee replacement were randomized to either 6-10 days of oral dabigatran etexilate starting 1-4 hours after surgery or 40 mg daily of enoxaparin starting 12 hours after surgery.6 Various doses of dabigatran etexilate were used (50, 150, 225 mg twice daily, 300 mg once daily) and were compared with the standard dose of enoxaparin. In comparison with enoxaparin, VTE was significantly lower in patients receiving 150 mg twice daily, 300 mg once daily, or 225 mg twice daily. VTE was higher in patients receiving the 50 mg twice daily dose compared with enoxaparin, but this was not significant. Major bleeding complications were significantly lower in the 50 mg twice daily group, but elevated with the higher dosing regimens. In a different study, Ericksson et al7 once again evaluated dabigatran vs enoxaparin, comparing the 150 or 220 mg once daily dosing starting 1-4 hours after surgery. Both doses of dabigatran were at least as effective with a similar safety profile as enoxaparin for prevention of VTE after knee re-
F.D. Cushner and M.P. Nett placement in this series. Certainly, questions remain: Will surgeons be comfortable with the early dosing schedule? Will similar results be obtained if dosing is started later in the postoperative period? A third new oral agent that has been recently evaluated is apixaban, which is a specific factor Xa inhibitor. Lassen et al8 recently reported on the results of apixaban after total knee arthroplasty. Patients were randomized to receive either 2.5 mg of apixaban twice daily or 30 mg of enoxaparin subcutaneously every 12 hours. Both medications were started 12-24 hours after surgery and were continued for 10-14 days when a venogram was obtained. Nearly 3000 patients were involved in this series and the overall rate of VTE events were much lower than what was initially anticipated. Results of this study did not show noninferiority compared with enoxaparin while lower rates of clinically relevant bleeding were noted. These results were similar to what Lassen reported in 2007 for a similar cohort of patients.9 Although these 3 agents are navigating through the FDA approval process, the questions remain. Will they be accepted by orthopedic surgeons? Will earlier dosing be beneficial to decreasing VTE and improve efficacy while maintaining an acceptable safety profile? It is believed that the origin of the VTE event is at the time of surgery. It is known that earlier dosing may decrease the amount of VTE, but perhaps at the cost of increased bleeding. For example, Fitzgerald et al10 evaluated enoxaparin at 8 hours rather than 12-24 dosing prescribed in the product label. The result was near elimination of proximal clots and significant decrease in total VTE, but an increased trend toward bleeding was noted. This was also seen in the rivaroxaban studies, with increased bleeding seen with earlier dosing. Because surgical site bleedings were not considered in these trials, many of them may not have been reported. A further complicating issue is that many definitions of bleeding are described in the published data. It is difficult to compare bleeding rates from study to study when bleeding definitions vary widely. Often “major bleed” includes intracranial or retroperitoneal bleeds, but excludes surgical site bleeding. Hull et al11 reviewed bleeding definitions and found nearly 10 different terms used to describe bleeding events. Therefore, no standard criteria exist to assess bleeding. Many studies are not reporting bleeding events that are clinically relevant to orthopedic surgeons (such as an increased hemarthrosis at the site of the joint arthroplasty or prolonged surgical site bleeding). Although many factors play a role in surgical site bleeding, it is often contributed to the VTE prophylaxis agent used. This further complicated issues because it is well recognized that bleeding is multifactorial. Some factors include the use of an uncemented prosthesis, performing extensive soft-tissue releases, and the use of a postoperative drain. All these factors play a role in the postoperative appearance of the wound regardless of the VTE prophylaxis agent used. Although the perception of postoperative bleeding relates to VTE prophylaxis, it should be noted that bleeding events range from 2%-4%, no matter what agents are used. This baseline bleeding rate may be more closely related to the procedure itself than the prophylactic agent used. Patel et al12 reviewed factors associated with
Future of thromboembolic prophylaxis prolonged postoperative drainage in total knee arthroplasty patients. Although VTE prophylaxis played a role in total hip arthroplasty patients, the most important predictive factor for hips and knees was the amount of drainage that occurred in the immediate postoperative period. More drainage in the recovery room led to more drainage on days 2, 3, 4, and 5, and perhaps more emphasis should be placed on control of the bleeding in the immediate postoperative period. This factor occurs well before the initiation of the prophylaxis agents, and hence cannot be related to the prophylaxis agent. At our institution, we have eliminated the immediate use of continuous passive motion (CPM) and focus on immediate wound hemostasis. We now begin CPM on postoperative day 1 and focus on controlling the hemostasis in the immediate postoperative period. In closing, all these new agents are appealing for their ease of use and oral root of administration. However, to some, the perceived risk of bleeding may outweigh these benefits. Surgeons still want to avoid the pharmacologic use of medications during the immediate postoperative period for VTE prophylaxis.
Continuous Enhanced Circulation Therapy A new item that has become available is sequential compression devices that are small, portal, and can be used continuously during the postoperative period. The limitations of mechanical devices have been that they are beneficial only if used nearly 19 hours per day. In addition, to date, this has been an in-hospital modality only, with no method to continue their use on hospital discharge.13 A new, miniature, mobile-battery operated pneumatic system (continuous enhanced circulation therapy [CECT]), combined with lowdose aspirin, has been compared with enoxaparin in a study by Gelfer et al.14 The patients were randomized into 2 groups receiving CECT and aspirin treatment compared with 40 mg daily of enoxaparin. Bilateral venograms were assessed on postoperative day 5 and results concluded that the combination of the CECT device with low-dose aspirin is more effective then enoxaparin in preventing DVT after joint arthroplasty. Some have expressed concern regarding the cost of using continuous compressive devices. This has recently been addressed. Using data published by Botterman et al14 and Ollendorf et al,15 it can be shown that the CECT can actually save hospitals a maximum of $2628.56 per patient.16 Cost analysis must include not only the cost of the device or medications but also the cost of DVTs and the rehospitalizations prevented. Colwell17 evaluated a CECT-type device vs LMWH in total hip arthroplasty patients. Results in this study demonstrated that this mobile miniature compression device reduced thrombolic disease while lowering the incidence of bleeding complications. These authors concluded that this new treatment modality may obviate the need for chemoprophylaxis in patients who undergo hip arthroplasty. These devices have also been proven to be beneficial over the
253 standard sequential compression devices currently in use. Froimson et al18 evaluated venous thromboembolic disease reduction with the portal device compared with the standard device used. The CECT system had increased compliance, lower rates of DVT, reduction in pulmonary embolism, and a shorter length of hospital stay. This portable CECT system was significantly more effective than the standard compression when used in conjunction with LMWH. They may also play a beneficial role in stacking modalities. Edwards et al19 did a preliminary postoperative study to evaluate the portable compression device and LMWH compared with LMWH alone. Patients were screened for DVT using duplex ultrasound at hospital discharge and were followed up clinically for 3 months. In the total knee arthroplasty group, the rate of DVT was 6.6% in the CECT plus LMWH compared with 1 pulmonary embolism and a 19.5% DVT rate in the LMWH only group. In the total hip arthroplasty group, a VTE rate was noted for the 1.5% for this combined therapy vs 3.4% for the LMWH alone group. This study demonstrated significant reduction in the rate of DVT after total knee arthroplasty with CECT device combined with LMWH. To summarize, these new portable devices show some promise. They seem to be effective not only when used in conjunction with currently used prophylaxis agents but also as a stand-alone therapy. Certainly, further studies will show whether the pharmaceutical agents can be abandoned for continuous take-home compression device.
Future Directions The goal of VTE prophylaxis is avoiding bleeding complications while still protecting the patient from VTE. The future direction should provide an improved method of decreasing bleeding in the immediate postoperative period. At our institution, we stack modalities to minimize postoperative bleeding. We reported on the use of lidocaine and epinephrine injection along the arthrotomy site. This combined with a smaller parapatellar incision led to a significant decrease in postoperative blood loss. Other intraoperative measures include the use of tranexamic acid. Tranexamic acid is an antifibrinolytic which helps stop the breaking of fibrinogen. We use a 10 mg/kg dosing for our high-risk patients. Studies show significant decrease in blood loss when this approach is used. Other postoperative measures include the use of fibrin sealants or bipolar cautery devices to minimize postoperative blood loss. This may allow for early hemostasis and less postoperative drainage, which still concerns orthopedists today. Perhaps combining or stacking the modalities will improve wound appearance and reduce surgical site bleeding complications. Improved wound closure also likely plays a role in improving the appearance of the postoperative wound. A recent study at our institution looked at using a bidirectional self-locking suture, Quill (Angiotech, Vancouver, BC), to improve wound appearance, improve operating room (OR) efficiency, and provide a more water-tight seal.
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Conclusions The future studies for VTE prophylaxis will continue to evaluate new oral agents, improved sequential compression devices that can be used at home, and improved methods to decrease postoperative bleeding in the immediate postoperative period. Because these agents are becoming more and more available, we can hope that combining these modalities will decrease VTE rates, reduce bleeding complications, improve wound appearance, and perhaps reduce overall infection rate by minimizing surgical site complications.
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F.D. Cushner and M.P. Nett 8. Lassen MR, Raskob GE, Gallus A, et al: Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 361:594604, 2009 9. Lassen MR, Davidson BL, Gallus A, et al: The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 5:23682375, 2007 10. Fitzgerald RH Jr, Spiro TE, Trowbridge AA, et al: Prevention of venous thromboembolic disease following primary total knee arthroplasty. A randomized, multicenter, open-label, parallel-group comparison of enoxaparin and warfarin. J Bone Joint Surg Am 83:900-906, 2001 11. Hull RD, Yusen RD, Bergqvist D: State-of-the-art review: Assessing the safety profiles of new anticoagulants for major orthopedic surgery thromboprophylaxis. Clin Appl Thromb/Hemost 15:377-388, 2009 12. Patel VP, Walsh M, Sehgal B, et al: Factors associated with prolonged wound drainage after primary total hip and knee arthroplasty. J Bone Joint Surg Am 89:33-38, 2007 13. Westrich GH, Sculco TP: Prophylaxis against deep venous thrombosis after total knee arthroplasty. Pneumatic plantar compression and aspirin compared with aspirin alone. J Bone Joint Surg Am 78:826-834, 1996 14. Gelfer Y, Tavor H, Oron A, et al: Deep vein thrombosis prevention in joint arthroplasties: Continuous enhanced circulation therapy vs low molecular weight heparin. J Arthroplasty 21:206-214, 2006 15. Botteman MF, Caprini J, Stephens JM, et al: Results of an economic model to assess the cost effectiveness of enoxaparin, a LMWH versus warfarin for the prophylaxis of deep vein thrombosis and associated long term complications in total hip replacement surgery in the United States. Clin Ther 24:1960-1986, 2002 16. Ollendorf DA, Vera-Llonch M, Oster G: Cost of venous thromboembolism following major orthopedic surgery in hospitalized patients. Am J Health Syst Pharm 59:1750-1754, 2002 17. Colwell CW: Thrombosis prevention in total hip arthroplasty: A novel compression device versus low –molecular weight heparin. J Bone Joint Surg (in press) 18. Froimson MI, Murray TG, Fazekas AF: Venous thromoembolic disease reduction with a portable pneumatic compression device. J Arthroplasty 24:310-316, 2009 19. Edwards JZ, Pulido PA, Ezzet KA, et al: Portable compression device and low-molecular-weight heparin compared with low-molecularweight heparin for thromboprophylaxis after total joint arthroplasty. J Arthroplasty 23:1122-1127, 2008