Prevention of Venous Thromboembolic Disease After Total Hip and Knee Arthroplasty

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1 1801 CPYRIGHT Ó 2013 BY THE JURNAL F BNE AND JINT SURGERY, INCRPRATED Current Concepts Review Prevention of Venous Thromboembolic Disease After Total Hip an Knee Arthroplasty Jay R. Lieberman, MD, an Michael J. Pensak, MD Investigation performe at the University of Connecticut Health Center, Farmington, Connecticut, an the Keck School of Meicine of the University of Southern California, Los Angeles, California ä The selection of a regimen for venous thromboembolic prophylaxis after total joint arthroplasty is a balance between efficacy an safety. Bleeing may have a negative impact on clinical outcomes. ä Recently, both the American Acaemy of rthopaeic Surgeons (AAS) an the American College of Chest Physicians (ACCP) evelope new evience-base guielines for venous thromboembolic prophylaxis after total joint arthroplasty. ä n the basis of a review of the available literature, the AAS guieline panel was unable to make a recommenation with respect to the selection of a specific prophylaxis regimen or uration of prophylaxis following routine total joint arthroplasty. ä The ACCP panel recommene one of the following moalities as prophylaxis (rather than no prophylaxis at all) for a minimum of fourteen ays: warfarin, low-molecular-weight heparin, fonaparinux, aspirin, rivaroxaban, abigatran, apixaban, or portable mechanical compression. ä Both the AAS an the ACCP guielines recommene against screening with postoperative uplex ultrasonography at the time of ischarge after routine total joint arthroplasty. ä There is renewe interest in the use of mechanical compression as prophylaxis with the avent of portable compression evices, which allow continuation of this type of prophylaxis after hospital ischarge. Although the early ata are promising, appropriately powere ranomize trials are neee to etermine the efficacy of the evices compare with other prophylaxis regimens. Both total hip an knee arthroplasties are extremely successful proceures that improve quality of life. Unfortunately, these proceures are also associate with the evelopment of venous thromboembolic isease, which can increase patient morbiity an mortality. There is general agreement that prophylaxis against venous thromboembolism (VTE) is necessary after total joint arthroplasty, but the ieal prophylactic regimen has not been ientifie. The selection of a prophylactic regimen is a balance between efficacy an safety 1. rthopaeic surgeons are particularly concerne about postoperative bleeing because it may be associate with hematoma, infection, an reoperation, all of which can have a negative impact on outcomes. There is concern that some patients may receive excessive anticoagulation on the basis of their limite risk of eveloping a Disclosure: None of the authors receive payments or services, either irectly or inirectly (i.e., via his or her institution), from a thir party in support of any aspect of this work. ne or more of the authors, or his or her institution, has ha a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomeical arena that coul be perceive to influence or have the potential to influence what is written in this work. No author has ha any other relationships, or has engage in any other activities, that coul be perceive to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitte by authors are always provie with the online version of the article. J Bone Joint Surg Am. 2013;95:

2 1802 VLUME 95-A UMBER 19 CTBER 2, 2013 PREVENTIN F V ENUS T HRMBEMBLIC D ISEASE A FTER TTAL H IP AND K NEE A RTHRPLASTY symptomatic pulmonary embolism (PE) or eep vein thrombosis (DVT). Recently, both the American Acaemy of rthopaeic Surgeons 2 (AAS) an the American College of Chest Physicians 3 (ACCP) evelope new guielines for VTE prophylaxis after total joint arthroplasty. ur purpose was to review the ifferent prophylactic options available toay, elineate the new guielines establishe by the AAS an the ACCP, an explore their potential impact on the selection of a VTE prophylaxis regimen. AAS an ACCP Guielines Both the AAS (September 2011) an the ACCP (February 2012) publishe guielines relate to VTE 2,3. In the past, the orthopaeic community has ha consierable concerns about the recommenations mae by the ACCP 2,4. The major issue of concern was that the ACCP guielines seeme to focus more on efficacy than safety. This was exemplifie by the Grae 1A recommenation against the use of aspirin (ASA; acetylsalicylic aci) an the recommene target international normalize ratio (INR) for warfarin between 2.0 an 3.0. rthopaeic surgeons prefer a target INR of 2.0 to avoi bleeing. In response to these concerns, the AAS evelope its first clinical guieline in ,4,5. This guieline focuse on prevention of symptomatic PE an DVT an the negative impact that bleeing coul have on the outcomes for patients after total joint arthroplasty. Although the guieline recommene risk stratification for VTE an/or bleeing, this is ifficult to o for the iniviual patient because of the lack of evience-base ata in this area. This new AAS clinical VTE practice guieline was base on a systematic review of publishe stuies on the prevention of symptomatic VTE in patients unergoing elective knee an hip arthroplasty 2. Strict criteria were establishe to evaluate the quality of publishe stuies an to avoi bias. There were ten recommenations an each recommenation was grae as strong, moerate, weak, inconclusive, or consensus. A rationale was provie for each recommenation. Unfortunately, on the basis of the available ata, there was only one strong an three moerate recommenations (Table I). Recommenation number 5 hel the most interest for orthopaeic surgeons because it focuse on the type of prophylaxis that coul be use in total joint arthroplasties. n the basis of the available ata, the guieline i not recommen any specific prophylactic regimen after routine total joint arthroplasty. Although there are numerous ranomize trials in the literature, few have compare the efficacy of ifferent agents in preventing symptomatic events an therefore the guieline panel conclue that it coul not make a specific recommenation with respect to the selection of a prophylaxis regimen or the uration of prophylaxis. We briefly review some of the critical issues relate to the other recommenations (Table I). There is no controversy with respect to recommenation number 1. There is general agreement that screening shoul not be performe at the time of hospital ischarge. A similar recommenation was mae in the new ACCP guielines. In recommenation number 4, the panel suggeste that antiplatelet agents (e.g., aspirin an clopiogrel) be iscontinue prior to total joint arthroplasty. This moerate recommenation was mae because there are ata that suggeste these agents are associate with bleeing, but there are no evience-base ata in the arthroplasty literature regaring the optimal management of these patients. This recommenation is probably acceptable if patients are not taking aspirin because of iagnose cariac isease. However, if the patients have a thrombotic risk, it is probably safer to continue the aspirin 6. In aition, if a patient has been prescribe clopiogrel because they have ha a cariac stent, these patients are probably at an increase risk for thrombosis if the clopiogrel is stoppe. Again, there are no evience-base ata in the arthroplasty literature with respect to the optimal treatment of these patients; however, for patients receiving clopiogrel an aspirin, some cariologists have suggeste that the aspirin be continue but that the clopiogrel can be stoppe approximately seven ays prior to the proceure 6.It may have been more appropriate for the guieline panel to suggest that orthopaeic surgeons consult the patient s cariologist or primary care physician to iscuss the overall thrombotic risk for that particular patient an to etermine whether it is safe to procee with elective surgery. It may be appropriate to elay the elective total joint arthroplasty until the clopiogrel can be stoppe, but this may not be pruent in some patients 5. In recommenations number 3 an 7, the work group mae so-calle consensus recommenations that patients be assesse for known bleeing isorers an the presence of active liver isease (recommenation number 3) an that these patients receive only mechanical compression for prophylaxis (recommenation number 7). These were consensus recommenations because there are no evience-base ata available to recommen that all patients have bloo tests to screen for various types of bleeing isorers. In aition, some of these chemoprophylaxis agents are metabolize in the kiney so it may be acceptable for them to be prescribe in patients who have liver isease. The best management may be for the orthopaeic surgeon to review the patient s history with either the primary care physician or appropriate specialist to etermine the safest form of prophylaxis 5. Recently, the ACCP publishe their ninth eition of Antithrombotic Therapy an Prevention of Thrombosis: American College of Chest Physicians Evience-Base Clinical Practice Guielines on Prevention of VTE in rthopeic Surgery Patients. 3 This new guieline represente a major shift in philosophy in comparison with the previous ACCP guielines. The new guieline clearly recognizes that the selection of a prophylactic regimen for total joint arthroplasties is a balance between efficacy an bleeing an that the goal of VTE prophylaxis is to reuce fatal an symptomatic VTE 7. In a clear eparture from prior guielines 8, the ACCP panel i not base its recommenations on the results of venographic screening of asymptomatic events. This alteration in philosophy clearly ha an impact on their ultimate recommenations 7.

3 1803 VLUME 95-A UMBER 19 CTBER 2, 2013 PREVENTIN F V ENUS T HRMBEMBLIC D ISEASE A FTER TTAL H IP AND K NEE A RTHRPLASTY TABLE I AAS Clinical Practice Guielines: Preventing Venous Thromboembolic Disease in Patients Unergoing Elective Hip an Knee Arthroplasty* No. Recommenation Grae 1 Recommenation against routine postoperative uplex ultrasonography screening of patients who unergo elective hip or knee arthroplasty. 2 Patients unergoing elective hip or knee arthroplasty are alreay at high risk for venous thromboembolism. Assessing the risk of venous thromboembolism by etermining whether these patients ha a previous venous thromboembolism shoul be consiere. 3 Patients unergoing elective hip or knee arthroplasty are at risk for bleeing an bleeing-associate complications. The panel recommens that patients be assesse for known bleeing isorers like hemophilia an for the presence of active liver isease, which further increase the risk for bleeing an bleeing-associate complications. 4 The panel suggests that patients iscontinue antiplatelet agents (e.g., aspirin or clopiogrel) before unergoing elective hip or knee arthroplasty. 5 The workgroup suggests the use of pharmacologic agents an/or mechanical compressive evices for the prevention of venous thromboembolism in patients unergoing elective hip or knee arthroplasty, an who are not at elevate risk beyon that of the surgery itself for venous thromboembolism or bleeing. The workgroup cannot recommen for or against a specific prophylactic regimen in these patients since current evience is unclear about which strategy (or strategies) is or are optimal or suboptimal. In the absence of reliable evience regaring the uration of prophylactic strategies, it is the opinion of the panel that patients an physicians iscuss the uration of prophylaxis. 6 In the absence of reliable evience, it is the opinion of the panel that patients unergoing elective hip or knee arthroplasty, who have also ha a previous venous thromboembolism, receive pharmacologic prophylaxis an use mechanical compressive evices. 7 In the absence of reliable evience, it is the opinion of the panel that patients unergoing elective hip or knee arthroplasty, who also have a known bleeing isorer (e.g., hemophilia) an/or active liver isease, use mechanical compressive evices for preventing venous thromboembolism. 8 In the absence of reliable evience, it is the opinion of the panel that patients unergo early mobilization following elective hip an knee arthroplasty. 9 The use of neuraxial (such as intrathecal, epiural, an spinal) anesthesia for patients unergoing elective hip or knee arthroplasty is recommene to help limit bloo loss, even though evience suggests that neuraxial anesthesia oes not affect the occurrence of venous thromboembolic isease. 10 The panel cannot recommen for or against the use of inferior vena cava (IVC) filters as current evience oes not provie clear guiance about whether IVC filters prevent pulmonary embolism in patients unergoing elective hip an knee arthroplasty who also have a contrainication to chemoprophylaxis an/or known resiual venous thromboembolic isease. Strong Weak Inconclusive Moerate Moerate Inconclusive Consensus Consensus Consensus Consensus Moerate Inconclusive *Reprouce, with moification, from Lieberman JR. The new AAS clinical practice guielines on venous thromboembolic prophylaxis: how to aapt them to your practice. J Am Aca rthop Surg Dec;19(12): Reprouce with permission. AAS = American Acaemy of rthopaeic Surgeons. This guieline inclue a rigorous systematic review, an the recommenations mae were base on a prior protocol 8.A Grae-1 recommenation was mae if there was certainty that the benefits of a particular prophylactic regimen i or i not outweigh the risk of burens of that regimen, an a Grae-2 recommenation was given if lower-quality evience was available that le to uncertainty regaring the magnitue of the benefits or complications associate with a particular regimen 8,9. The methoologic quality of the stuies was also assesse. Grae A, B, an C recommenations were given on the basis of the quality of the ranomize trials (A or B), or C, if there were only observational stuies available for review 9. The ninth eition of the ACCP VTE Guieline (Table II) recommens that patients unergoing total joint arthroplasty receive either pharmacologic prophylaxis, incluing aspirin (Grae ), or intermittent pneumatic compression evices (Grae 1C) for fourteen ays instea of no prophylaxis at all. The guieline recommene against screening with uplex ultrasonography prior to hospital ischarge (Grae ). In aition, the panel also recommene starting low-molecular-weight heparin (LMWH) prophylaxis either twelve hours preoperatively or twelve hours postoperatively in orer to limit bleeing (Grae ). The panel also mae several suggestions incluing the use of both a chemoprophylactic agent an intermittent pneumatic compression evices uring the hospital stay (Grae 2C); the use of LMWH in preference to other agents (Graes 2C an ); extening prophylaxis for up to thirty-five ays (Grae ); an avoiance of the use of an inferior vena

4 1804 VLUME 95-A UMBER 19 CTBER 2, 2013 PREVENTIN F V ENUS T HRMBEMBLIC D ISEASE A FTER TTAL H IP AND K NEE A RTHRPLASTY TABLE II Summary of Evience-Base Clinical Practice Guielines on Prevention of VTE in rthopaeic Surgery Patients by the American College of Chest Physicians (Ninth Eition)* Summary of Recommenation In patients unergoing total hip arthroplasty or total knee arthroplasty, one of the following agents shoul be use for a minimum of 10 to 14 ays rather than no antithrombotic prophylaxis: Low-molecular-weight heparin (LMWH) Fonaparinux Apixaban Dabigatran Rivaroxaban Low-ose unfractionate heparin (LDUH) Ajuste-ose vitamin K antagonist (VKA) Aspirin Intermittent pneumatic compression evice (IPCD) For patients unergoing major orthopaeic surgery (total hip arthroplasty, total knee arthroplasty, or hip fracture surgery) an receiving LMWH as thromboprophylaxis, the agent shoul be starte either 12 h preoperatively or 12 h postoperatively rather than 4 h preoperatively or 4 h postoperatively. In patients unergoing total hip arthroplasty or total knee arthroplasty, regarless of the use of an IPCD or length of treatment, LMWH shoul be use in preference to other alternative agents: Fonaparinux Apixaban Dabigatran Rivaroxaban LDUH Ajuste-ose VKA Aspirin For patients unergoing major orthopaeic surgery, thromboprophylaxis shoul be extene in the outpatient perio for up to 35 ays from the ay of surgery rather than for only 10 to 14 ays. In patients unergoing major orthopaeic surgery, ual prophylaxis with an antithrombotic agent an an IPCD uring the hospital stay is recommene. In patients unergoing major orthopaeic surgery with an increase risk of bleeing, an IPCD or no prophylaxis is recommene over pharmacologic treatment. In patients unergoing major orthopaeic surgery an who ecline or are uncooperative with injections or an IPCD, apixaban or abigatran shoul be use (alternatively rivaroxaban or ajuste-ose VKA if apixaban or abigatran are unavailable) rather than alternative forms of prophylaxis. In patients unergoing major orthopaeic surgery, it is not recommene to use an inferior vena cava (IVC) filter for primary prevention over no thromboprophylaxis in patients with an increase bleeing risk or contrainications to both pharmacologic an mechanical thromboprophylaxis. Following major orthopaeic surgery, asymptomatic patients o not nee Doppler (or uplex) ultrasoun (DUS) screening before hospital ischarge. Grae of Recommenation 1C 2C 2C 2C 2C 2C *Moifie from: Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl E, Schulman S, rtel TL, Pauker SG, Colwell CW Jr; American College of Chest Physicians. Prevention of VTE in orthopeic surgery patients: Antithrombotic Therapy an Prevention of Thrombosis, 9th e: American College of Chest Physicians Evience-Base Clinical Practice Guielines. Chest Feb;141(2 Suppl):e278S-325S. cava filter for prophylaxis in patients with contrainications to both chemoprophylaxis an mechanical evices (Grae 2C) 7. The inclusion of aspirin as an alternative to no antithrombotic prophylaxis represente a major shift for the ACCP since, in the eighth eition of the guieline, aspirin ha receive a Grae-1A recommenation against its use 8.Thisnewrecommenation was base mostly on the results of the Pulmonary Embolism Prevention (PEP) Trial 10. The panel conclue that low-ose aspirin for thirty-five ays woul result in seven fewer symptomatic VTE events but with three major bleeing episoes an two aitional nonfatal myocarial infarctions per 1000 patients. Although there was a close balance between the beneficial an averse events associate with aspirin prophylaxis, the panel ecie that there was moerate-quality evience to support the use of aspirin for prophylaxis compare with no prophylaxis at all 3.

5 1805 VLUME 95-A UMBER 19 CTBER 2, 2013 PREVENTIN F V ENUS T HRMBEMBLIC D ISEASE A FTER TTAL H IP AND K NEE A RTHRPLASTY Although there was low-quality evience to assess the efficacy of mechanical intervention compare with no prophylaxis, the panel conclue that there was a relative risk reuction of >50% for both DVT an PE in patients having total joint arthroplasty who receive intermittent pneumatic compression evices as prophylaxis. An obvious avantage with intermittent pneumatic compression evices is that there is no bleeing risk, but patient compliance remains a challenge. Newer battery-powere portable compression evices that can monitor the compliance an that can be use in the hospital an the outpatient setting seem to be an attractive option for these patients. Prophylaxis Following Total Hip an Knee Arthroplasty Both pharmacologic an mechanical approaches have been recommene as prophylactic agents for patients having total joint arthroplasty. Pharmacologic agents presently inclue warfarin, LMWH, fonaparinux, aspirin, rivaroxaban, abigatran, an apixaban. Dabigatran an apixaban have not been approve for use in the Unite States but are approve in Europe. The pharmacologic an mechanical agents have been evaluate in ranomize trials of varying quality. In most of these stuies, venograms were use as a surrogate outcome measure to etermine the efficacy of the agent. The clinical relevance of these asymptomatic istal clots has been questione 1,4. The present review is limite to ranomize clinical trials an meta-analyses that evaluate the results of these trials. In this part of the review, we focus more attention on stuies that influence the evelopment of the ACCP an AAS guielines. Pharmacologic Methos Warfarin Warfarin continues to be frequently prescribe by orthopaeic surgeons because of its long track recor in preventing symptomatic events an because the level of anticoagulation for each patient can be titrate by closely following the INR. Warfarin has been irectly compare with LMWH in a number of ranomize clinical trials in patients having total hip arthroplasty (see Appenix) In each one of the trials, LMWH was more effective in limiting overall asymptomatic clot formation. However, in a multicenter clinical trial comparing the efficacy of warfarin with enoxaparin in preventing symptomatic events after total hip arthroplasty, no ifference was note in the rates of postischarge symptomatic events between the groups manage with warfarin (3.7%; fifty-six of 1495 patients) an LMWH (3.6%; fifty-five of 1516 patients) 15. There have also been a number of multicenter clinical trials comparing the efficacy of warfarin prophylaxis an ifferent LMWHs as prophylactic agents after total knee arthroplasty (see Appenix) 11,13, verall, all trials emonstrate that LMWH was more effective than warfarin in preventing overall DVT formation, but no significant ifferences were note in symptomatic events incluing PE. In general, the bleeing rates were higher in patients who receive LMWH than in those who ha warfarin. Most of these stuies were complete in the 1990s, an therefore the overall rate of asymptomatic DVT was reporte to range from 25% to 54.9% (see Appenix). These values are much higher than those note in more recent stuies assessing the efficacy of the factor Xa or oral thrombin inhibitors (Table III). Low-Molecular-Weight Heparin (LMWH) LMWH functions by inhibiting factor Xa 19,20. The major avantage of LMWH is that no monitoring is require, but it is aministere with a subcutaneous injection. As state previously in a number of ranomize trials in both patients manage with total hip arthroplasty an those manage with total knee arthroplasty, LMWHs were foun to be more effective than warfarin in limiting overall clot formation but not symptomatic events. In all but one stuy 12 comparing LMWH to warfarin, major bleeing rates were equal 13 or higher 11,14,16,18 among the patients receiving LMWH (see Appenix). It shoul be note that the European osing regimen for enoxaparin is 40 mg per ay, beginning the evening before the surgery, an the North American osing regimen is 30 mg twice per ay, beginning twelve to twenty-four hours after the proceure. Enoxaparin has also been compare with fonaparinux an the new factor Xa an thrombin inhibitors, an the results of these trials are reviewe in subsequent sections of this article. Fonaparinux Fonaparinux is a synthetic pentasaccharie an an inirect factor Xa inhibitor 21,22. Subcutaneous aministration of fonaparinux has been shown to be effective as a prophylactic agent in separate ranomize trials assessing patients manage with total joint arthroplasty in which it was irectly compare with enoxaparin (see Appenix). Although fonaparinux is significantly more effective than enoxaparin in limiting asymptomatic clot formation in patients manage with total knee arthroplasty (p < 0.001), the rug has ha limite use in North America because of concerns relate to bleeing 25. Aspirin ver the past three ecaes, there has been an interest in using aspirin as a prophylactic agent after total joint arthroplasty because it is an oral agent that requires no monitoring an is well tolerate by most patients 1. The PEP trial was a ranomize stuy that assesse the efficacy of aspirin (160 mg for five weeks) in preventing symptomatic VTE in 16,000 patients who ha unergone either elective total hip arthroplasty or hip fracture surgery 10. verall, a significant ifference was foun between aspirin an placebo in the hip fracture group with respect to both DVTan PE (p = 0.03 an 0.002, respectively). However, in patients manage with elective total hip arthroplasty, there was no ifference in the rate of symptomatic DVT between the aspirin group (1.1%; twenty-two of 2047 patients) an the placebo group (1.3%; twenty-six of 2041 patients). There were no significant ifferences in bleeing rates, as efine by evacuation of a hematoma, between the patients in the aspirin group (0.4%) an the placebo group (0.4%). The strength of the PEP

6 1806 VLUME 95-A UMBER 19 CTBER 2, 2013 PREVENTIN F V ENUS T HRMBEMBLIC D ISEASE A FTER TTAL H IP AND K NEE A RTHRPLASTY TABLE III Summary of Results from Ranomize Clinical Trials Comparing Enoxaparin with Novel Antithrombotic Agents After Total Knee Arthroplasty ä verall Rate of DVT* Rate of Symptomatic or Major VTE* Stuy* Result P Value Result P Value RECRD-3 (Lassen et al. 28 ; 2008) Enoxaparin (40 mg) 18.2 (160/878) 2.6 (24/925) Rivaroxaban (10 mg) 9.6 (79/824) < (9/908) 0.01 RECRD-4 (Turpie et al. 29 ; 2009) Enoxaparin (30 mg twice a ay) 9.8 (86/878) 1.5 (15/1020) Rivaroxaban (10 mg) 6.3 (55/864) 1.1 (11/1011) 0.45 ADVANCE-1 (Lassen et al. 32 ; 2009) Enoxaparin (30 mg twice a ay) 8.2 (92/1122) 0.8 (13/1596) Apixaban (2.5 mg twice a ay) 7.8 (89/1142) 1.2 (19/1599) ADVANCE-2 (Lassen et al. 33 ; 2010) Enoxaparin (40 mg) 24.4 (243/997) 2.2 (26/1199) Apixaban (2.5 mg twice a ay) 14.6 (142/971) 1.1 (13/1195) RE-MDEL (Eriksson et al. 36 ; 2007) Enoxaparin (40 mg) 36.0 (184/511) 3.5 (18/511) Dabigatran (220 mg) 36.0 (181/503) 2.6 (13/506) 0.38 Dabigatran (150 mg) 39.7 (208/524) 3.8 (20/527) 0.82 RE-MBILIZE (Ginsberg et al. 37 ; 2009) Enoxaparin (30 mg twice a ay) 18.2 (158/868) 1.7 (15/868) Dabigatran (220 mg) 21.1 (181/857) 2.4 (21/857) Dabigatran (150 mg) 25.0 (218/871) 2.3 (20/871 *The values are given as the percentage of patients, with the number affecte ivie by the total number in parentheses. P values are given if they were reporte. DVT = eep venous thrombosis, VTE = venous thromboembolism, PE = pulmonary embolism, RECRD = Regulation of Coagulation in rthopeic Surgery to Prevent Deep Venous Thrombosis an Pulmonary Embolism Investigators, an ADVANCE = Apixaban Dose rally vs. Anticoagulation with Enoxaparin Investigators. Results that ha a significant ifference. Results reporte inicate the rate of major VTE efine as the composite of proximal DVT, nonfatal PE, an VTE-relate eath. Results reporte inicate the rate of symptomatic thromboembolism, efine as the composite of ajuicate symptomatic DVT an nonfatal or fatal PE embolism. #PE rates reporte inicate rates of fatal or nonfatal PE. **PE rates reporte inicate rate of nonfatal PE. trial was that it assesse a large number of patients, an efficacy was evaluate by the number of symptomatic events. When assessing the results in both the patients with a hip fracture an those manage with total joint arthroplasty, there was a moest risk reuction in symptomatic DVT (relative risk, 0.72; 95% confience interval [CI], 0.53 to 0.96) 3. The PEP trial was appropriately powere to evaluate the results in the patients with a hip fracture but not in the patients who ha a hip replacement. To our knowlege, there have been no recent ranomize trials assessing the efficacy of aspirin alone as a prophylactic agent after total knee arthroplasty. n the basis of the results of the PEP trial, the most recent ACCP guielines recommene prophylaxis with low-ose ASA after total joint arthroplasty rather than no prophylaxis at all. Rivaroxaban Rivaroxaban is a irect factor Xa inhibitor that is taken orally an requires no monitoring. The efficacy of rivaroxaban as a prophylactic agent in patients manage with total joint arthroplasty has been assesse in four phase-iii ranomize trials (Tables III an IV), an the rug has been approve for use by the U.S. Foo an Drug Aministration (FDA). In the first total hip arthroplasty stuy, rivaroxaban (10 mg per ay), starte approximately six hours after the surgery, was significantly more effective in preventing total VTE but not symptomatic events than enoxaparin (40 mg) given the night before the operation (p < 0.001) 26. In a subsequent stuy, extene prophylaxis with rivaroxaban for thirty-five ays was significantly more effective in limiting total VTE an symptomatic events than was enoxaparin for ten to fourteen ays (p < ) 27. In patients manage with total knee arthroplasty, oral rivaroxaban (10 mg once aily) was more effective than enoxaparin (40 mg once aily) in reucing overall VTE 28.Ina subsequent stuy comparing oral rivaroxaban (10 mg once aily) with enoxaparin (30 mg every twelve hours), the overall incience of VTE an eath was significantly lower (p = ) in the rivaroxaban group (6.9%; sixty-seven of 965 patients) than in the enoxaparin group (10.1%; ninety-seven of 959 patients) 29 (aitional results are given in Table III).

7 1807 VLUME 95-A UMBER 19 CTBER 2, 2013 PREVENTIN F V ENUS T HRMBEMBLIC D ISEASE A FTER TTAL H IP AND K NEE A RTHRPLASTY TABLE III (continue) Rate of PE* Rate of Major Bleeing Episoes Result P Value Result P Value 0.3 (4/1217) 0.5 (6/1239) (0/1201) (7/1220) 0.5 (8/1508) 0.3 (4/1508) (5/1526) (10/1526) 0.4 (7/1596) 1.4 (22/1588) 1.0 (16/1599) 0.7 (11/1596) (0/1529)# 0.9 (14/1508) 0.26 (4/1528)# 0.6 (9/1501) (1/685)# 1.3 (9/694) 0 (0/675)# 1.5 (10/679) 0.1 (1/696)# 1.3 (9/703) 0.5, (5/868)** 1.4 (12/868) 0.7 (6/857)** 0.6 (5/857) 0 (0/871)** 0.6 (5/871) The major issue of concern relate to the use of rivaroxaban is the timing of the aministration of the first ose of this rug. In these four stuies, the rug was aministrate six to eight hours after surgery; however, it may be safer to aminister this rug the next ay, especially if it oes not have an impact on the evelopment of symptomatic events. In a recent retrospective review, rivaroxaban was associate with a higher rate of reoperation than was LMWH after total knee arthroplasty 30. Apixaban Apixaban is an orally active factor Xa inhibitor, which has been assesse in three separate multicenter ranomize trials in comparison with enoxaparin In a stuy incluing 5407 patients manage with total hip arthroplasty, apixaban (2.5 mg orally twice aily) was associate with a significantly lower overall VTE an eath rate than enoxaparin (40 mg every twenty-four hours) (p < 0.001). Apixaban prevente one episoe of major VTE for each 147 patients treate, without an aitional risk of bleeing 31. Apixaban has been compare with enoxaparin in two ifferent ranomize trials in patients manage with total knee arthroplasty 32,33 (Table III). In a stuy comparing apixaban (2.5 mg twice aily) with enoxaparin (30 mg every twelve hours), the overall DVT rates were extremely low in both groups an the noninferiority criteria were not met for the primary efficacy outcome, which was a composite of any VTE event an eath from any cause (Table III). However, the bleeing rates were significantly lower in the apixaban group (p = 0.05) 32.Ina subsequent ranomize trial, apixaban (2.5 mg twice aily) was compare with enoxaparin (40 mg once aily), an the overall VTE an eath rates associate with apixaban were significantly lower than those in the enoxaparin group (p < ) 33.There was no ifference in major or clinically relevant non-major bleeing episoes (Table III). A comparison of the results of these two stuies with the two ifferent osing regimens for enoxaparin suggests apixaban is more effective than the 40-mg ose of enoxaparin but not the 30-mg twice aily osing regimen. Dabigatran Dabigatran etexilate is an orally aministere irect thrombin inhibitor that has been approve by the FDA for the prevention of stroke an atrial fibrillation but not for VTE prophylaxis. Four ranomize trials in patients manage with total joint arthroplasty evaluate the efficacy of two ifferent oses of abigatran (220 mg an 150 mg), taken orally once aily, compare with enoxaparin (Tables III an IV). In a oubleblin stuy of 3494 patients unergoing total hip arthroplasty, both the 220-mg an 150-mg oses were note not to be inferior to enoxaparin (40 mg aily) 34. In a subsequent ranomize trial assessing patients manage with total hip arthroplasty, oral abigatran (220 mg once aily) was compare with enoxaparin (40 mg once aily). The total VTE an eath rates were similar in both groups (7.7% versus 8.8%), an the superiority of abigatran was not emonstrate 35.

8 1808 VLUME 95-A UMBER 19 CTBER 2, 2013 PREVENTIN F V ENUS T HRMBEMBLIC D ISEASE A FTER TTAL H IP AND K NEE A RTHRPLASTY TABLE IV Summary of Results from Ranomize Clinical Trials Comparing Enoxaparin with New Anticoagulant Agents After Total Hip Arthroplasty ä verall Rate of DVT* Rate of Symptomatic or Major VTE* Stuy* Results P Value Results P Value RECRD1 (Eriksson et al. 26 ; 2008) Enoxaparin (40 mg) 3.4 (53/1558) 2.0, (33/1678) Rivaroxaban (10 mg) 0.8 (12/1595) < (4/1686) <0.001 RECRD2 (Kakkar et al. 27 ; 2008) Enoxaparin (40 mg) 8.2 (71/869) 5.1 (49/962) Rivaroxaban (10 mg) 1.6 (14/864) < (6/961) < ADVANCE-3 (Lassen et al. 31 ; 2010) Enoxaprin (40 mg) 3.6 (68/1911) 0.4 (10/2699) Apixaban (2.5 mg twice a ay) 1.1 (22/1944) 0.1 (4/2708) 0.11 RE-NVATE (Eriksson et al. 34 ; 2007) Enoxaparin (40 mg) 6.3 (56/894) 3.9 (36/917) Dabigatran (220 mg) 4.6 (40/874) 3.1 (28/909) 0.33 Dabigatran (150 mg) 7.2 (63/871) 4.3 (38/888) 0.71 RE-NVATE II (Eriksson et al. 35 ; 2011) Enoxaparin (40 mg) 8.6 (67/783) 0.6 (6/992) Dabigatran (220 mg) 7.6 (60/791) 0.48 <0.1 (1/1001) *The values are given as the percentage of patients, with the number affecte ivie by the total number in parentheses. DVT = eep venous thrombosis, VTE = venous thromboembolism, PE = pulmonary embolism, RECRD = Regulation of Coagulation in rthopeic Surgery to Prevent Deep Venous Thrombosis an Pulmonary Embolism Investigators, an ADVANCE = Apixaban Dose rally vs. Anticoagulation with Enoxaparin Investigators. Results that ha a significant ifference. Results reporte inicate the rate of major VTE efine as the composite of proximal DVT, nonfatal PE, an VTE-relate eath. PE rates reporte inicate rates of fatal or nonfatal PE. #PE rates reporte inicate rate of nonfatal PE. In a ranomize trial assessing patients manage with total knee arthroplasty, both oses of abigatran were not inferior to enoxaparin (40 mg), but neither ose showe superiority over enoxaparin 36. In a secon stuy of patients who ha total knee arthroplasty, the two abigatran oses were compare with enoxaparin (30 mg twice per ay), an the abigatran osage regimens faile to show noninferiority compare with enoxaparin. In aition, there was no significant ifference in major bleeing events between the three groups 37.n the basis of the ata from these four trials, the ACCP panel conclue that abigatran was similar to LMWH with respect to efficacy an ha similar risks of bleeing. Mechanical Methos Intermittent Pneumatic Compression Devices Recently, there has been increase interest in intermittent pneumatic compression evices in patients manage with total hip an knee arthroplasty. The obvious avantage of these evices is that there is no bleeing risk. In the past, the major limitation of intermittent pneumatic compression evices has been that the prophylaxis cease at the time of ischarge, but this is no longer true. The recent evelopment of portable evices allows for the continuation of mechanical prophylaxis after hospital ischarge. Compliance has also been a problem with intermittent pneumatic compression evices, but these newer evices allow the surgeon to etermine how often patients are wearing the evice. Determining the true efficacy of mechanical compression after total joint arthroplasty has been ifficult because these evices have been assesse in small ranomize trials performe in single institutions, an there were often problems with the quality of these trials base on ranomization of the patients, a lack of blining, an susceptibility to a type-ii error 1,38-47.Inthreesmall ranomize trials in patients manage with total hip arthroplasty performe approximately twenty years ago, warfarin was foun to be more effective than pneumatic compression boots in limiting the formation of proximal clots nthebasisoftheresultsof these three stuies, there was a concern that intermittent pneumatic compression evices shoul not be use as the sole means of prophylaxis after total hip arthroplasty 1. However, in a subsequent single-institution ranomize trial comparing the efficacy of intermittent plantar compression with LMWH in patients managewithtotalhiparthroplasty,dvtratesweresimilarinthe foot pump group (18%; twenty-four of 136 patients) an the enoxaparin group (13%; eighteen of 138 patients; p > 0.05) 48. The efficacy of mechanical compression after total knee arthroplasty has been assesse in a variety of small ranomize trials. In four stuies that were performe approximately twenty to thirty years ago, pneumatic compression boots were associate with an overall risk reuction of 56%, but only 110 patients were analyze In four small ranomize trials assessing intermittent plantar compression (172 patients), the overall risk reuction with intermittent plantar compression

9 1809 VLUME 95-A UMBER 19 CTBER 2, 2013 PREVENTIN F V ENUS T HRMBEMBLIC D ISEASE A FTER TTAL H IP AND K NEE A RTHRPLASTY TABLE IV (continue) Rate of PE* Rate of Major Bleeing Episoe Results P Value Results P Value <0.1 (1/1558) 0.37 <0.1 (2/2224) (4/1595) 0.3 (6/2209) 0.5 (4/869) <0.1 (1/1229) 0.1 (1/864) 0.37 <0.1 (1/1228) 0.2 (5/2699)# 0.7 (18/2659) (3/2708)# 0.8 (22/2673) 0.3 (3/1142) 1.6 (18/1154) 0.4 (5/1137) 2.0 (23/1146) <0.1 (1/1156) 1.3 (15/1163) 0.2 (2/992) 0.9 (9/1003) 0.4 <0.1 (1/1001) (14/1010) was 37% 1,8, In more recent stuies assessing the efficacy of intermittent pneumatic compression combine with LMWH compare with LMWH alone in patients manage with total joint arthroplasty, it was note that the combination of LMWH with mechanical compression was more effective in reucing overall DVT rates, but no ifferences were note in the rate of symptomatic events (Table V) However, these stuies inclue both patients who ha total hip arthroplasty an those who ha total knee arthroplasty, an the stuies were not powere to etect ifferences in symptomatic events TABLE V Summary of Results from Trials Investigating the Rates of Venous Thromboembolism an Major Bleeing After Total Knee Arthroplasty an Use of Chemoprophylaxis with an without Mechanical Prophylaxis Stuy verall Rate of DVT* Rate of Symptomatic VTE* Rate of PE* Rate of Major Bleeing Episoe* Ewars et al. 49 (2008) LMWH 19.5 (15/77) 2.6 (2/77) 1.3 (1/77) NA LMWH an continuous enhance circulation therapy 6.5 (5/76) 2.6 (2/76) 1.3 (1/76) NA Eisele et al. 50 (2007) LMWH 7.4 (4/54) NA NA NA LMWH an intermittent pneumatic calf compression 3.8 (3/79) NA NA NA Silbersack et al. 51, (2004) LMWH an grauate compression stockings LMWH an intermittent pneumatic calf compression 40.0 (14/35) NA NA NA 0 (0/35) NA NA NA *The values are given as the percentage, with the number affecte ivie by the total number in parentheses. DVT = eep vein thrombosis, VTE = venous thromboembolism, LMWH = low-molecular-weight heparin, an NA = not available. Results that ha a significant ifference. Note that the combine ifference in DVT rate was significant, with better prevention in the LMWH an intermittent pneumatic calf compression subset for the combine populations of total hip arthroplasty an total knee arthroplasty. Significance was not calculate between the two treatment regimens for the iniviual surgical proceures of total hip arthroplasty or total knee arthroplasty.

10 1810 VLUME 95-A UMBER 19 CTBER 2, 2013 PREVENTIN F V ENUS T HRMBEMBLIC D ISEASE A FTER TTAL H IP AND K NEE A RTHRPLASTY Recently, a multicenter ranomize trial evaluate the efficacy of a mobile compression evice compare with LMWH after total hip arthroplasty 52. This evice can be worn uring walking an after ischarge from the hospital. Sixty-one percent of the patients receive aspirin in aition to the evice. The overall PE an symptomatic DVTrate was 5% in both the mobile compression group (ten of 197 hips) an the LMWH group (ten of 192 hips) (p = 0.953). However, a significant ifference was etecte between the portable compression evice group (0%) an the LMWH group (6%) with regar to bleeing events (p = ). Although these ata look quite promising, the major limitation of this stuy is that it was powere to assess the ifference in bleeing rates rather than the incience of symptomatic events. Further stuy of the efficacy of portable compression as a prophylactic agent after total joint arthroplasty is neee. Surgical Care Improvement Project Guielines Clearly, the new ACCP an AAS guielines allow orthopaeic surgeons a number of ifferent options with respect to the selection of a prophylactic agent. However, it is essential for orthopaeic surgeons who practice in the Unite States to unerstan that it is the Surgical Care Improvement Project for VTE Prophylaxis (SCIP) Guielines that are use to measure quality uring the hospitalization of patients manage with total joint arthroplasty 53. At the present time, LMWH, warfarin, fonaparinux, an rivaroxaban are acceptable agents for both patients having total hip arthroplasty an those having total knee arthroplasty. Mechanical evices alone can be use for patients manage with total knee arthroplasty on the basis of the guieline. The combination of aspirin an a mechanical evice is acceptable after total hip arthroplasty as long as the surgeon writes in the chart that this regimen has been selecte because of concerns regaring bleeing episoes. The SCIP guielines will possibly be moifie in the future to be in alignment with the ACCP an AAS guielines. In conclusion, VTE prophylaxis after total joint arthroplasty is of critical interest to orthopaeic surgeons because of concerns about symptomatic an fatal PE. The number of total joint arthroplasties performe worlwie continues to increase, an the patients receiving these proceures seem to be sicker than in the past. Therefore, the use of effective an safe prophylactic regimens is important. ver the last ecae, it has become apparent that limiting both symptomatic events an bleeing episoes is essential. Although efficacy is important, patients shoul not have excessive anticoagulation because bleeing can have a negative impact on outcomes. Ranomize trials assessing symptomatic events with well-efine parameters relate to bleeing are still neee to select the optimal prophylactic regimen. Effective risk stratification strategies nee to be evelope so that patients receive the appropriate prophylactic regimens. Appenix Tables showing a summary of the results from ranomize clinical trials comparing warfarin an LMWH after total hip arthroplasty an after total knee arthroplasty are available with the online version of this article as a ata supplement at jbjs.org. n Jay R. Lieberman, MD Department of rthopaeic Surgery, Keck School of Meicine of USC, 1520 San Pablo, HCT Suite 2000, Los Angeles, CA Michael J. Pensak, MD Department of rthopaeic Surgery, University of Connecticut Health Center, 263 Farmington Avenue, MARB 4th floor, Farmington, CT References 1. Lieberman JR, Hsu WK. Prevention of venous thromboembolic isease after total hip an knee arthroplasty. J Bone Joint Surg Am Sep;87(9): Mont MA, Jacobs JJ. 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Postoperative fonaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a ranomise ouble-blin trial. Lancet May 18;359(9319): Bauer KA, Eriksson BI, Lassen MR, Turpie AG; Steering Committee of the Pentasaccharie in Major Knee Surgery Stuy. Fonaparinux compare with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Me Nov 1;345(18): Eriksson BI, Borris LC, Frieman RJ, Haas S, Huisman MV, Kakkar AK, Banel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECRD1 Stuy Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Me Jun 26;358(26): Kakkar AK, Brenner B, Dahl E, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECRD2 Investigators. Extene uration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a ouble-blin, ranomise controlle trial. Lancet Jul 5;372(9632): Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Banel TJ, Misselwitz F, Turpie AG; RECRD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Me Jun 26;358(26): Turpie AG, Lassen MR, Davison BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Banel TJ, Benson A, Misselwitz F, Fisher WD; RECRD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECRD4): a ranomise trial. Lancet May 16;373(9676): Jensen CD, Steval A, Partington PF, Ree MR, Muller SD. Return to theatre following total hip an knee replacement, before an after the introuction of rivaroxaban: a retrospective cohort stuy. J Bone Joint Surg Br Jan;93(1): Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Me Dec 23;363(26): Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Me Aug 6;361(6): Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a ranomise ouble-blin trial. Lancet Mar 6;375(9717): Eriksson BI, Dahl E, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Prins MH, Hettiarachchi R, Hantel S, Schnee J, Büller HR; RE-NVATE Stuy Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a ranomise, ouble-blin, non-inferiority trial. Lancet Sep 15;370(9591): Eriksson BI, Dahl E, Huo MH, Kurth AA, Hantel S, Hermansson K, Schnee JM, Frieman RJ; RE-NVATE II Stuy Group. ral abigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NVATE II*). A ranomise, ouble-blin, non-inferiority trial. Thromb Haemost Apr;105(4): Eriksson BI, Dahl E, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Kälebo P, Christiansen AV, Hantel S, Hettiarachchi R, Schnee J, Büller HR; RE-MDEL Stuy Group. ral abigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MDEL ranomize trial. J Thromb Haemost Nov;5(11): Ginsberg JS, Davison BL, Comp PC, Francis CW, Frieman RJ, Huo MH, Lieberman JR, Muntz JE, Raskob GE, Clements ML, Hantel S, Schnee JM, Caprini JA; RE-MBILIZE Writing Committee. ral thrombin inhibitor abigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty Jan;24(1): Bailey JP, Kruger MP, Solano FX, Zajko AB, Rubash HE. Prospective ranomize trial of sequential compression evices vs low-ose warfarin for eep venous thrombosis prophylaxis in total hip arthroplasty. 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Prevention of venous thromboembolism after total knee replacement by high-ose aspirin or intermittent calf an thigh compression. Br Me J Feb 23;280(6213): Hull R, Delmore TJ, Hirsh J, Gent M, Armstrong P, Lofthouse R, MacMillan A, Blackstone I, Ree-Davis R, Detwiler RC. Effectiveness of intermittent pulsatile elastic stockings for the prevention of calf an thigh vein thrombosis in patients unergoing elective knee surgery. Thromb Res. 1979;16(1-2): Blanchar J, Meuwly JY, Leyvraz PF, Miron MJ, Bounameaux H, Hoffmeyer P, Diier D, Schneier PA. Prevention of eep-vein thrombosis after total knee replacement. Ranomise comparison between a low-molecular-weight heparin (naroparin) an mechanical prophylaxis with a foot-pump system. J Bone Joint Surg Br Jul;81(4): Tamir L, Henel D, Neyman C, Eshkenazi AU, Ben-Zvi Y, Zomer R. Sequential foot compression reuces lower limb swelling an pain after total knee arthroplasty. J Arthroplasty Apr;14(3): Westrich GH, Sculco TP. Prophylaxis against eep venous thrombosis after total knee arthroplasty. Pneumatic plantar compression an aspirin compare with aspirin alone. J Bone Joint Surg Am Jun;78(6): Warwick D, Harrison J, Glew D, Mitchelmore A, Peters TJ, Donovan J. Comparison of the use of a foot pump with the use of low-molecular-weight heparin for the prevention of eep-vein thrombosis after total hip replacement. A prospective, ranomize trial. J Bone Joint Surg Am Aug;80(8): Ewars JZ, Pulio PA, Ezzet KA, Copp SN, Walker RH, Colwell CW Jr. Portable compression evice an low-molecular-weight heparin compare with low-molecularweight heparin for thromboprophylaxis after total joint arthroplasty. J Arthroplasty Dec;23(8): Eisele R, Kinzl L, Koelsch T. Rapi-inflation intermittent pneumatic compression for prevention of eep venous thrombosis. J Bone Joint Surg Am May;89(5): Silbersack Y, Taute BM, Hein W, Pohaisky H. Prevention of eep-vein thrombosis after total hip an knee replacement. Low-molecular-weight heparin in combination with intermittent pneumatic compression. J Bone Joint Surg Br Aug;86(6): Colwell CW Jr, Froimson MI, Mont MA, Ritter MA, Trousale RT, Buehler KC, Spitzer A, Donalson TK, Pagett DE. Thrombosis prevention after total hip arthroplasty: a prospective, ranomize trial comparing a mobile compression evice with low-molecular-weight heparin. J Bone Joint Surg Am Mar;92(3): Bratzler DW, Hunt DR. The surgical infection prevention an surgical care improvement projects: national initiatives to improve outcomes for patients having surgery. Clin Infect Dis Aug 1;43(3):

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