Saad Tarabichi, Matthew Sherman, Kerri-Anne Ciesielka, Colin Baker, Javad Parvizi.
Response/Recommendation: Low-dose aspirin (ASA) is currently the most effective and safest method of prophylaxis against venous thromboembolism (VTE) in patients undergoing total joint arthroplasty (TJA). We recommend the use of low-dose ASA as the primary method of VTE prophylaxis in all patients undergoing TJA, including moderate-to high-risk patients.
Strength of Recommendation: Strong.
Rationale: The risk of VTE in orthopaedic surgery patients is well established1. Patients undergoing elective total knee arthroplasty (TKA) or total hip arthroplasty (THA) are considered at high risk for the development of deep venous thrombosis (DVT) and subsequent pulmonary embolism (PE) that can be fatal2. Historical estimates of the incidence of DVT without prophylaxis are between 40% and 84% after TKA and around 39% to 74% after THA3. Recent clinical practice guidelines (CPG) on effective and safe VTE prophylaxis, along with perioperative protocols regarding early post-operative mobilization and spinal anesthesia, have drastically reduced morbidity and mortality secondary to VTE4,5. Nevertheless, the National Institutes of Health (NIH) predicts that the number of patients undergoing TJA and consequently the number of thromboembolic complications is on the rise6.
In 2008 the American Association of Hip and Knee Surgeons (AAHKS) conducted a survey of its members to explore current hospital guidelines for VTE prophylaxis following TJA. 99% of respondents said they routinely utilized either chemical or mechanical prophylaxis following both TKA/THA7. Despite not being able to recommend a specific agent, the 2011 American Academy of Orthopaedic Surgeons (AAOS) CPG advised that all patients undergoing TJA must receive some form of VTE prophylaxis8. However, the more recent American College of Chest Physicians (ACCP) guidelines of 2012 endorsed the use of ASA as an appropriate method of VTE prophylaxis following TJA9. Currently, the selection of a VTE prophylactic agent following arthroplasty is largely determined by individual surgeon preference10. Common anti-coagulants used for the prevention of VTE in orthopaedic patients include ASA, warfarin, injectable agents like low-molecular-weight heparin (LMWH), and the more recently approved Factor Xa inhibitors such as rivaroxaban and apixaban11. The decision of which anticoagulant to use entails achieving an ideal balance of agent efficacy, while also avoiding the adverse side effects brought on by drugs with higher risk profiles12.
Comparative analyses were performed using Network Meta-Analyses (NMA) and odds ratio (OR) with 95% confidence intervals reported. Evaluation of all included studies, levels I-IV, showed that low-dose ASA (100 mg) demonstrated the lowest risk of VTE development13–17. Compared to low-dose ASA, LMWH (postop), LMWH (preop), and rivaroxaban did not significantly differ in their risk of developing VTE, with OR of 1.11 (0.33, 3.76), 1.36 (0.41, 4.50), and 1.38 (0.55, 3.45), respectively. Conversely, high-dose ASA (325 mg) showed the greatest risk of VTE with an OR of 7.90 (2.60, 24.05) followed by heparin (5.94 [2.28, 15.47]) and mechanical prophylaxis (5.76 [1.87, 17.73]), when compared to low-dose ASA. When assessing for bleeding events in all studies, low-dose ASA (81 mg) exhibited the lowest risk estimate and was used as a reference. Mechanical prophylaxis (1.97 [0.04, 94.52]), LMWH 20 mg (2.93 [0.20, 43.80]) and low-dose warfarin (4.32 [0.25, 75.41]) showed the next lowest estimates but did not significantly differ in risk from low-dose ASA. Thrombin inhibitors (23.91 [1.94, 295.06]) were the most likely to be associated with bleeding events, followed by LMWH (postop) (19.66 [1.53, 252.94]) and heparin (18.32 [1.45, 231.39])18–24.
Limiting the analysis to only level I (RCT) studies, rivaroxaban demonstrated the lowest risk of VTE development5,25–28. Low-dose ASA (100 mg), when compared to rivaroxaban, did not significantly differ in risk of VTE development with an OR of 1.61 (0.47, 5.54). Apixaban (2.70 [1.30, 5.62]) and direct thrombin inhibitors (3.49 [1.91, 6.39]) had the next lowest risk of VTE. Additionally, LMWH given post-operatively had an OR of 3.89 (1.38, 10.97). High-dose ASA when compared with rivaroxaban, was found to have the highest OR of VTE development at 26.11 (6.69, 101.90) followed by LMWH 30 mg (15.02 [1.98, 114.01] and low-dose warfarin (13.83 [6.13, 31.18]). LMWH (20 mg) demonstrated the lowest probability of bleeding events in level I studies and was used as a reference. Low-dose warfarin (1.37 [0.25, 7.58]), mechanical prophylaxis (0.69 [0.03, 15.53]), one dose of heparin (3.11 [0.98, 9.89]) and ASA (4.03 [1.02, 15.97]) had relatively low risk of bleeding when compared to LMWH 20 mg. 100 mg ASA (8.67 [2.32, 32.40]), thrombin inhibitors (7.01 [2.50, 19.64] and heparin (6.23 [2.39, 16.21]) increased the risk of bleeding, when compared with LMWH 20 mg13–15,29,30.
The results of our meta-analysis are consistent with currently published scientific literature. We found that in level-I studies, rivaroxaban exhibited slightly lower rates of VTE occurrence when compared to ASA. However, the significance of this is limited, as only four such studies included ASA, none of which directly compared ASA to rivaroxaban5,13,15,29. Overall, we found that low-dose ASA was effective at preventing VTE when compared to other measures. In addition, it exhibited lower rates of bleeding when compared to more commonly used prophylactic agents5,13,15,21,29–33.
In the United States, ASA has emerged as the most commonly used VTE prophylactic agent following TJA7. This widespread adoption of ASA for VTE prophylaxis in TJA has reinforced its standing as a safe and effective agent, that requires no blood test for monitoring1. In a recent meta-analysis of RCT, Matharu et al.34, demonstrated that there was no difference in risk of developing VTE, in patients receiving ASA vs. other anticoagulants following TJA. Furthermore, Rondon et al.35, showed that patients who received ASA, vs. those in the non-ASA cohort, had a 3-fold and 2-fold reduction in risk of death following TJA at 30-days and 1-year, respectively. In addition, ASA has a considerably more benign risk profile when compared to other more potent anticoagulants. Patients receiving ASA experience substantially lower rates of bleeding, hematomas, wound infection, and periprosthetic joint infection1,36.
Recent literature has now discredited previously made determinations that high-dose ASA (325 mg twice a day) provides greater protection against cardiovascular and cerebrovascular events than low-dose ASA (75-100 mg twice a day)37,38. Likewise, the Pulmonary Embolism Prevention trial of 2001 showed that low-dose ASA significantly reduced the incidence of DVT and PE in patients undergoing TJA39. Despite the AAOS guidelines8 recommending high-dose ASA (325 mg twice a day) for VTE prevention following TJA, Parvizi et al.35,40, demonstrated that low-dose (81 mg twice a day) ASA was just as effective at VTE prevention as high-dose ASA, while also exhibiting no difference in mortality rates up to 1 year postoperatively. Moreover, low-dose ASA is also associated with lower rates of bleeding than high-dose ASA and may potentially reduce gastrointestinal toxicity41.
Even with the advent of newer more potent anticoagulants, conventional low-dose ASA remains the most optimal method of VTE prophylaxis following TJA. The results of this meta-analysis, along with previously published literature, reiterate low-dose ASA’s position as an effective, safe, widely available, and inexpensive agent.
Table 1: Studies, design, anticoagulation used, and size of the sample.
| Author’s Last Name | Year of Publication | Type of Design | Type of Surgery | Chemical Name | Sample Size |
| German Hip Arthroplasty Group42 | 1992 | Classic RCT | Hip | Heparin | 168 |
| LMWH | 167 | ||||
| Laguardia18 | 1992 | Classic RCT | Hip | LMWH (Pre-Op) | 19 |
| LMWH (Post-Op) | 21 | ||||
| Leyvraz et al.43 | 1992 | Classic RCT | Hip | Heparin | 139 |
| LMWH | 145 | ||||
| Leyvraz et al.44 | 1991 | Classic RCT | Hip | Heparin | 175 |
| LMWH | 174 | ||||
| Freick45 | 1991 | Classic RCT | Hip | Heparin | 48 |
| LMWH | 52 | ||||
| Planès et al.46 | 1991 | Classic RCT | Hip | LMWH | 65 |
| LMWH (20 mg) | 61 | ||||
| LMWH (40 mg) | 62 | ||||
| Levineet al.26 | 1991 | Classic RCT | Hip | Heparin | 263 |
| LMWH | 258 | ||||
| Eriksson et al.47 | 1991 | Classic RCT | Hip | Heparin | 59 |
| LMWH | 63 | ||||
| Planèset al.48 | 1988 | Classic RCT | Hip | Heparin | 112 |
| LMWH | 107 | ||||
| Planèset al.48 | 1988 | Classic RCT | Hip | Heparin | 113 |
| LMWH | 124 | ||||
| Josefsson et al.29 | 1987 | Classic RCT | Hip | ASA | 40 |
| Heparin | 42 | ||||
| Planès et al.49 | 1986 | Classic RCT | Hip | LMWH (60 mg) | 50 |
| LMWH (30 mg) | 28 | ||||
| LMWH (40 mg) | 50 | ||||
| LMWH (20 mg) | 100 | ||||
| RD Heparin Arthroplasty Group50 | 1994 | Classic RCT | Total Joint | Heparin (Twice) | 328 |
| Heparin (Once) | 320 | ||||
| Warfarin | 321 | ||||
| Menzin et al.51 | 1994 | Classic RCT | Hip | Heparin | 209 |
| LMWH (30 mg) | 195 | ||||
| LMWH (40 mg) | 203 | ||||
| Colwell Jr. Et al.52 | 1994 | Classic RCT | Hip | Heparin | 209 |
| LMWH (30 mg) | 195 | ||||
| LMWH (40 mg) | 203 | ||||
| Hull et al.53 | 1993 | Classic RCT | Total Joint | LMWH | 715 |
| Warfarin | 721 | ||||
| Hull54 | 1997 | Classic RCT | Total Joint | LMWH | 590 |
| Warfarin | 617 | ||||
| Francis et al.55 | 1997 | Classic RCT | Hip | LMWH | 192 |
| Warfarin | 190 | ||||
| Eriksson et al.22 | 1997 | Classic RCT | Hip | LMWH | 1023 |
| Thrombin Inhibitors | 1028 | ||||
| Warwick et al.56 | 1998 | Classic RCT | Hip | Mechanical | 136 |
| LMWH | 138 | ||||
| Colwell Jr. et al.57 | 1999 | Classic RCT | Hip | LMWH | 1516 |
| Warfarin | 1495 | ||||
| Kakkar et al.58 | 2000 | Classic RCT | Hip | Heparin | 134 |
| LMWH | 125 | ||||
| Hull et al.19 | 2000 | Classic RCT | Hip | LMWH (Pre-Op) | 152 |
| LMWH (Post-Op) | 139 | ||||
| Warfarin | 133 | ||||
| Borghi et al.23 | 2002 | Observational Retrospective | Hip | Heparin | 192 |
| LMWH | 457 | ||||
| Turpie et al.24 | 2002 | Classic RCT | Hip | LMWH | 797 |
| Thrombin Inhibitors | 787 | ||||
| Eriksson et al.59 | 2002 | Classic RCT | Total Joint | LMWH | 308 |
| Thrombin Inhibitors | 1169 | ||||
| Eriksson et al.60 | 2003 | Classic RCT | Total Joint | LMWH | 1184 |
| Thrombin Inhibitors | 1141 | ||||
| Colwell Jr. et al.61 | 2003 | Classic RCT | Hip | LMWH | 775 |
| Thrombin Inhibitors | 782 | ||||
| Eriksson et al.60 | 2003 | Classic RCT | Total Joint | LMWH | 1178 |
| Thrombin Inhibitors | 1138 | ||||
| Pitto et al.62 | 2004 | Classic RCT | Hip | Mechanical | 100 |
| LMWH | 100 | ||||
| Enyart63 | 2005 | Observational Prospective | Total Joint | LMWH | 2627 |
| Warfarin | 770 | ||||
| Senaran et al.64 | 2006 | Classic RCT | Hip | Heparin | 50 |
| LMWH | 50 | ||||
| Della Valle et al.5 | 2006 | Observational Prospective | Hip | ASA (325 mg) | 1599 |
| Warfarin | 348 | ||||
| Gelfer et al.13 | 2006 | Classic RCT | Total Joint | ASA (100 mg) | 61 |
| LMWH | 60 | ||||
| Cohen et al.65 | 2007 | Classic RCT | Total Joint | Thrombin Inhibitors | 400 |
| Thrombin Inhibitors (with compression stocks) | 395 | ||||
| Eriksson et al.66 | 2007 | Classic RCT | Hip | Factor Xa Inhibitor (220 mg) | 1146 |
| Factor Xa Inhibitor (150 mg) | 1163 | ||||
| LMWH | 1154 | ||||
| Tian et al.15 | 2007 | Classic RCT | Total Joint | ASA (100 mg) | 100 |
| LMWH | 140 | ||||
| Eriksson et al.28 | 2008 | Classic RCT | Hip | Rivaroxaban | 2209 |
| LMWH | 2224 | ||||
| Kakkar et al.27 | 2008 | Classic RCT | Total Joint | Rivaroxaban | 1228 |
| LMWH | 1229 | ||||
| Colwell Jr. et al.14 | 2010 | Other | Hip | ASA (81 mg) | 199 |
| LMWH | 196 | ||||
| Raskob et al.67 | 2010 | Other | Hip | Factor Xa Inhibitor | 170 |
| Factor Xa Inhibitor | 158 | ||||
| LMWH | 144 | ||||
| Lassen et al.68 | 2010 | Classic RCT | Hip | Apixaban | 1949 |
| LMWH | 1917 | ||||
| Erikssonet al.69 | 2011 | Other | Hip | Factor Xa Inhibitor | 792 |
| LMWH | 785 | ||||
| Intermountain Joint Replacement Center Writing Committee33 | 2011 | Observational Prospective | Total Joint | ASA (325 mg) | 152 |
| Warfarin | 129 | ||||
| Warfarin | 415 | ||||
| Kwong70 | 2011 | Other | Total Joint | Factor Xa Inhibitor | 6183 |
| LMWH | 6200 | ||||
| Khatod et al.71 | 2011 | Observational Retrospective | Hip | ASA | 934 |
| LMWH | 7202 | ||||
| Warfarin | 6063 | ||||
| Jameson et al.25 | 2011 | Observational Retrospective | Total Joint | ASA | 22942 |
| LMWH | 85642 | ||||
| Raskob et al.72 | 2012 | Other | Total Joint | Apixaban | 3394 |
| LMWH | 3394 | ||||
| Nieto et al.73 | 2012 | Other | Total Joint | Factor Xa Inhibitor | 12200 |
| LMWH | 12261 | ||||
| Vulcano et al.32 | 2012 | Observational Retrospective | Total Joint | ASA (325 mg) | 1115 |
| Warfarin | 426 | ||||
| Fuji et al.74 | 2012 | Other | Total Joint | Factor Xa Inhibitor (Low) | 136 |
| LMWH | 82 | ||||
| Factor Xa Inhibitor | 134 | ||||
| Beyer-Westendorf et al.75 | 2012 | Observational Retrospective | Total Joint | Rivaroxaban | 1043 |
| LMWH | 1495 | ||||
| Shoda et al.20 | 2015 | Observational Retrospective | Total Joint | LMWH | 11049 |
| Thrombin Inhibitors | 22727 | ||||
| Charters et al.76 | 2015 | Observational Retrospective | Total Joint | Rivaroxaban | 649 |
| LMWH | 1113 | ||||
| Bonarelli et al.77 | 2015 | Observational Prospective | Hip | Factor Xa Inhibitor | 211 |
| LMWH | 196 | ||||
| Heckmannet al.78 | 2015 | Observational Prospective | Total Joint | Rivaroxaban | 838 |
| LMWH | 464 | ||||
| Özleret al.79 | 2015 | Classic RCT | Total Joint | Rivaroxaban | 60 |
| LMWH | 60 | ||||
| Ricketet al.80 | 2016 | Observational Retrospective | Total Joint | Rivaroxaban | 440 |
| LMWH | 438 | ||||
| Kim81 | 2016 | Other | Hip | Rivaroxaban | 350 |
| LMWH | 351 | ||||
| Huang et al.31 | 2016 | Observational Retrospective | Total Joint | ASA | 796 |
| Warfarin | 6723 | ||||
| Deirmengian30 | 2016 | Observational Retrospective | Hip | ASA | 534 |
| Warfarin | 2463 | ||||
| Yhim et al.21 | 2017 | Observational Retrospective | Hip | ASA | 3654 |
| Rivaroxaban | 4843 | ||||
| LMWH | 13653 | ||||
| Thrombin Inhibitors | 997 | ||||
| Yhimet al.21 | 2017 | Observational Retrospective | Knee | ASA | 24612 |
| Rivaroxaban | 64859 | ||||
| LMWH | 55181 | ||||
| Thrombin Inhibitors | 7721 | ||||
| Lindquist et al.82 | 2018 | Observational Retrospective | Total Joint | ASA (325 mg) | 366 |
| Rivaroxaban | 438 | ||||
| LMWH | 440 | ||||
| Senay et al.83 | 2018 | Observational Prospective | Total Joint | Factor Xa Inhibitor | 904 |
| LMWH | 1468 | ||||
| Tan et al.84 | 2019 | Observational Retrospective | Total Joint | ASA | 13610 |
| LMWH | 17554 | ||||
| Warfarin | 29303 | ||||
| Ghosh et al.85 | 2019 | Observational Prospective | Total Joint | ASA | 6078 |
| Clopidogrel | 56 | ||||
| Factor Xa Inhibitor | 40 | ||||
| LMWH | 995 | ||||
| Warfarin | 105 | ||||
| Kasinaet al.86 | 2019 | Observational Prospective | Hip | Rivaroxaban | 5752 |
| LMWH | 26881 | ||||
| Gage et al.87 | 2019 | Classic RCT | Total Joint | Warfarin (Low) | 804 |
| Warfarin | 793 | ||||
| Cheallaigh et al.88 | 2020 | Observational Retrospective | Total Joint | ASA | 3460 |
| Rivaroxaban | 1212 | ||||
| LMWH | 961 | ||||
| Matharuet al.89 | 2020 | Observational Retrospective | Hip | ASA | 35904 |
| Factor Xa Inhibitor | 29522 | ||||
| Thrombin Inhibitors | 3864 | ||||
| Matharu et al.89 | 2020 | Observational Retrospective | Knee | ASA | 42590 |
| Factor Xa Inhibitor | 30697 | ||||
| Thrombin Inhibitors | 41323 | ||||
| Rahman et al.90 | 2020 | Other | Hip | Rivaroxaban | 80 |
| LMWH | 80 | ||||
| Ren et al.91 | 2021 | Observational Retrospective | Hip | ASA (100 mg) | 34 |
| Rivaroxaban | 36 | ||||
| Bortonet al.92 | 2021 | Observational Retrospective | Hip | ASA | 2560 |
| LMWH | 1049 | ||||
| Warfarin | 193 | ||||
| Uvodichet al.17 | 2021 | Observational Retrospective | Total Joint | ASA (81 mg) | 961 |
| ASA | 2551 | ||||
| Hovik16 | 2021 | Observational Prospective | Total Joint | ASA (81 mg) | 1084 |
| LMWH | 5010 |
RCT=Randomized clinical trial; LMWH=Low-molecular-weight heparin; mg=milligrams: ASA=Aspirin.
References:
1. Parvizi J, Ceylan HH, Kucukdurmaz F, Merli G, Tuncay I, Beverland D. Venous thromboembolism following hip and knee arthroplasty. Journal of Bone and Joint Surgery – American Volume. 2017;99(11):961-972. doi:10.2106/JBJS.16.01253
2. Flevas DA, Megaloikonomos PD, Dimopoulos L, Mitsiokapa E, Koulouvaris P, Mavrogenis AF. Thromboembolism prophylaxis in orthopaedics: an update. EFORT Open Reviews. 2018;3(4):136-148. doi:10.1302/2058-5241.3.170018
3. Westrich GH, Haas SB, Mosca P, Peterson M. Meta-analysis of thromboembolic prophylaxis after total knee arthroplasty. The Journal of Bone and Joint Surgery. 2000;82(6):795-800. doi:10.1302/0301-620X.82B6.9869
4. Gesell MW, Valle AGD, García SB, et al. Safety and Efficacy of Multimodal Thromboprophylaxis Following Total Knee Arthroplasty. The Journal of Arthroplasty. 2013;28(4):575-579. doi:10.1016/j.arth.2012.08.004
5. Valle AGD, Serota A, Go G, et al. Venous Thromboembolism Is Rare with a Multimodal Prophylaxis Protocol after Total Hip Arthroplasty. Clinical Orthopaedics & Related Research. 2006;444:146-153. doi:10.1097/01.blo.0000201157.29325.f0
6. Kurtz S. Prevalence of Primary and Revision Total Hip and Knee Arthroplasty in the United States From 1990 Through 2002. The Journal of Bone and Joint Surgery (American). 2005;87(7):1487. doi:10.2106/JBJS.D.02441
7. Markel DC, York S, Liston MJ, Flynn JC, Barnes CL, Davis CM. Venous Thromboembolism. The Journal of Arthroplasty. 2010;25(1):3-9.e2. doi:10.1016/j.arth.2009.07.021
8. Mont MA, Jacobs JJ, Boggio LN, et al. Preventing Venous Thromboembolic Disease in Patients Undergoing Elective Hip and Knee Arthroplasty. American Academy of Orthopaedic Surgeon. 2011;19(12):768-776. doi:10.5435/00124635-201112000-00007
9. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in Orthopedic Surgery Patients. Chest. 2012;141(2):e278S-e325S. doi:10.1378/chest.11-2404
10. Johanson NA, Lachiewicz PF, Lieberman JR, et al. American Academy of Orthopaedic Surgeons Clinical Practice Guideline on. The Journal of Bone and Joint Surgery-American Volume. 2009;91(7):1755-1757. doi:10.2106/JBJS.I.00511
11. Nutescu EA, Burnett A, Fanikos J, Spinler S, Wittkowsky A. Pharmacology of anticoagulants used in the treatment of venous thromboembolism. Journal of Thrombosis and Thrombolysis. 2016;41(1):15-31. doi:10.1007/s11239-015-1314-3
12. Sharrock NE, Valle AGD, Go G, Lyman S, Salvati EA. Potent Anticoagulants are Associated with a Higher All-Cause Mortality Rate After Hip and Knee Arthroplasty. Clinical Orthopaedics & Related Research. 2008;466(3):714-721. doi:10.1007/s11999-007-0092-4
13. Gelfer Y, Tavor H, Oron A, Peer A, Halperin N, Robinson D. Deep vein thrombosis prevention in joint arthroplasties: continuous enhanced circulation therapy vs low molecular weight heparin. The Journal of arthroplasty. 2006;21(2). doi:10.1016/j.arth.2005.04.031
14. Colwell CW, Froimson MI, Mont MA, et al. Thrombosis prevention after total hip arthroplasty: a prospective, randomized trial comparing a mobile compression device with low-molecular-weight heparin. The Journal of bone and joint surgery American volume. 2010;92(3). doi:10.2106/JBJS.I.00047
15. Tian H, Song F, Zhang K, Liu Y. [Efficacy and safety of aspirin in prevention of venous thromboembolism after total joint arthroplasty]. Zhonghua yi xue za zhi. 2007;87(47).
16. Hovik O, Amlie EJ, Jenssen KK. No Increased Risk of Venous Thromboembolism in High-Risk Patients Continuing Their Dose of 75 mg Aspirin Compared to Healthier Patients Given Low-Molecular-Weight Heparin. The Journal of arthroplasty. 2021;36(10). doi:10.1016/j.arth.2021.06.001
17. Uvodich ME, Siljander MP, Taunton MJ, Mabry TM, Perry KI, Abdel MP. Low-Dose vs Regular-Dose Aspirin for Venous Thromboembolism Prophylaxis in Primary Total Joint Arthroplasty. The Journal of arthroplasty. 2021;36(7). doi:10.1016/j.arth.2021.02.007
18. Laguardia AM, Caroli GC. Prevention of deep vein thrombosis in orthopaedic surgery. Comparison of two different treatment protocols with low molecular weight heparin (‘Fluxum’). Current medical research and opinion. 1992;12(9). doi:10.1185/03007999209111525
19. Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators. Archives of internal medicine. 2000;160(14). doi:10.1001/archinte.160.14.2208
20. Shoda N, Yasunaga H, Horiguchi H, et al. Prophylactic effect of fondaparinux and enoxaparin for preventing pulmonary embolism after total hip or knee arthroplasty: A retrospective observational study using the Japanese Diagnosis Procedure Combination database. Modern rheumatology. 2015;25(4). doi:10.3109/14397595.2014.997424
21. Yhim HY, Lee J, Lee JY, Lee JO, Bang SM. Pharmacological thromboprophylaxis and its impact on venous thromboembolism following total knee and hip arthroplasty in Korea: A nationwide population-based study. PloS one. 2017;12(5). doi:10.1371/journal.pone.0178214
22. Eriksson BI, Wille-Jørgensen P, Kälebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. The New England journal of medicine. 1997;337(19). doi:10.1056/NEJM199711063371901
23. Borghi B, Casati A, Ananesthesia RSG on O. Thromboembolic complications after total hip replacement. International orthopaedics. 2002;26(1). doi:10.1007/s00264-001-0310-8
24. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR, Committee P 2000 SS. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet (London, England). 2002;359(9319). doi:10.1016/S0140-6736(02)08648-8
25. Jameson SS, Charman SC, Gregg PJ, Reed MR, Meulen JH van der. The effect of aspirin and low-molecular-weight heparin on venous thromboembolism after hip replacement: a non-randomised comparison from information in the National Joint Registry. The Journal of bone and joint surgery British volume. 2011;93(11). doi:10.1302/0301-620X.93B11.27622
26. Levine MN, Hirsh J, Gent M, et al. Prevention of deep vein thrombosis after elective hip surgery. A randomized trial comparing low molecular weight heparin with standard unfractionated heparin. Annals of internal medicine. 1991;114(7). doi:10.7326/0003-4819-114-7-545
27. 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 double-blind, randomised controlled trial. Lancet (London, England). 2008;372(9632). doi:10.1016/S0140-6736(08)60880-6
28. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. The New England journal of medicine. 2008;358(26). doi:10.1056/NEJMoa0800374
29. Josefsson G, Dahlqvist A, Bodfors B. Prevention of thromboembolism in total hip replacement. Aspirin versus dihydroergotamine-heparin. Acta orthopaedica Scandinavica. 1987;58(6). doi:10.3109/17453678709146500
30. Deirmengian GK, Heller S, Smith EB, Maltenfort M, Chen AF, Parvizi J. Aspirin Can Be Used as Prophylaxis for Prevention of Venous Thromboembolism After Revision Hip and Knee Arthroplasty. The Journal of arthroplasty. 2016;31(10). doi:10.1016/j.arth.2016.03.031
31. Huang RC, Parvizi J, Hozack WJ, Chen AF, Austin MS. Aspirin Is as Effective as and Safer Than Warfarin for Patients at Higher Risk of Venous Thromboembolism Undergoing Total Joint Arthroplasty. The Journal of arthroplasty. 2016;31(9 Suppl). doi:10.1016/j.arth.2016.02.074
32. Vulcano E, Gesell M, Esposito A, Ma Y, Memtsoudis SG, Valle AGD. Aspirin for elective hip and knee arthroplasty: a multimodal thromboprophylaxis protocol. International orthopaedics. 2012;36(10). doi:10.1007/s00264-012-1588-4
33. Committee IJRCW. A prospective comparison of warfarin to aspirin for thromboprophylaxis in total hip and total knee arthroplasty. The Journal of arthroplasty. 2012;27(1). doi:10.1016/j.arth.2011.03.032
34. Matharu GS, Kunutsor SK, Judge A, Blom AW, Whitehouse MR. Clinical Effectiveness and Safety of Aspirin for Venous Thromboembolism Prophylaxis After Total Hip and Knee Replacement. JAMA Internal Medicine. 2020;180(3):376. doi:10.1001/jamainternmed.2019.6108
35. Rondon AJ, Shohat N, Tan TL, Goswami K, Huang RC, Parvizi J. The Use of Aspirin for Prophylaxis Against Venous Thromboembolism Decreases Mortality Following Primary Total Joint Arthroplasty. Journal of Bone and Joint Surgery. 2019;101(6):504-513. doi:10.2106/JBJS.18.00143
36. Huang R, Buckley PS, Scott B, Parvizi J, Purtill JJ. Administration of Aspirin as a Prophylaxis Agent Against Venous Thromboembolism Results in Lower Incidence of Periprosthetic Joint Infection. The Journal of Arthroplasty. 2015;30(9):39-41. doi:10.1016/j.arth.2015.07.001
37. Hart RG, Harrison MJG. Aspirin Wars. Stroke. 1996;27(4):585-587. doi:10.1161/01.STR.27.4.585
38. Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz JI. Antiplatelet Drugs. Chest. 2012;141(2):e89S-e119S. doi:10.1378/chest.11-2293
39. Group PEP (PEP) trial C. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. The Lancet. 2000;355(9212):1295-1302. doi:10.1016/S0140-6736(00)02110-3
40. Parvizi J, Huang R, Restrepo C, et al. Low-Dose Aspirin Is Effective Chemoprophylaxis Against Clinically Important Venous Thromboembolism Following Total Joint Arthroplasty. Journal of Bone and Joint Surgery. 2017;99(2):91-98. doi:10.2106/JBJS.16.00147
41. Serebruany VL, Steinhubl SR, Berger PB, et al. Analysis of Risk of Bleeding Complications After Different Doses of Aspirin in 192,036 Patients Enrolled in 31 Randomized Controlled Trials. The American Journal of Cardiology. 2005;95(10):1218-1222. doi:10.1016/j.amjcard.2005.01.049
42. Prevention of deep vein thrombosis with low molecular-weight heparin in patients undergoing total hip replacement. A randomized trial. The German Hip Arthroplasty Trial (GHAT) Group. Archives of orthopaedic and trauma surgery. 1992;111(2). doi:10.1007/BF00443477
43. Leyvraz P, Bachmann F, Bohnet J, et al. Thromboembolic prophylaxis in total hip replacement: a comparison between the low molecular weight heparinoid Lomoparan and heparin-dihydroergotamine. The British journal of surgery. 1992;79(9). doi:10.1002/bjs.1800790919
44. Leyvraz PF, Bachmann F, Hoek J, et al. Prevention of deep vein thrombosis after hip replacement: randomised comparison between unfractionated heparin and low molecular weight heparin. BMJ (Clinical research ed). 1991;303(6802). doi:10.1136/bmj.303.6802.543
45. Freick H, Haas S. Prevention of deep vein thrombosis by low-molecular-weight heparin and dihydroergotamine in patients undergoing total hip replacement. Thrombosis research. 1991;63(1). doi:10.1016/0049-3848(91)90276-3
46. Planès A, Vochelle N, Fagola M, Feret J, Bellaud M. Prevention of deep vein thrombosis after total hip replacement. The effect of low-molecular-weight heparin with spinal and general anaesthesia. The Journal of bone and joint surgery British volume. 1991;73(3). doi:10.1302/0301-620X.73B3.1670442
47. Eriksson BI, Kälebo P, Anthymyr BA, Wadenvik H, Tengborn L, Risberg B. Prevention of deep-vein thrombosis and pulmonary embolism after total hip replacement. Comparison of low-molecular-weight heparin and unfractionated heparin. The Journal of bone and joint surgery American volume. 1991;73(4).
48. Planes A, Vochelle N, Mazas F, et al. Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. Thrombosis and haemostasis. 1988;60(3).
49. Planes A, Vochelle N, Ferru J, et al. Enoxaparine low molecular weight heparin: its use in the prevention of deep venous thrombosis following total hip replacement. Haemostasis. 1986;16(2). doi:10.1159/000215285
50. RD heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty. RD Heparin Arthroplasty Group. The Journal of bone and joint surgery American volume. 1994;76(8). doi:10.2106/00004623-199408000-00008
51. Menzin J, Richner R, Huse D, Colditz GA, Oster G. Prevention of deep-vein thrombosis following total hip replacement surgery with enoxaparin versus unfractionated heparin: a pharmacoeconomic evaluation. The Annals of pharmacotherapy. 1994;28(2). doi:10.1177/106002809402800221
52. Colwell CW, Spiro TE, Trowbridge AA, et al. Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. A clinical trial comparing efficacy and safety. Enoxaparin Clinical Trial Group. The Journal of bone and joint surgery American volume. 1994;76(1). doi:10.2106/00004623-199401000-00002
53. Hull R, Raskob G, Pineo G, et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. The New England journal of medicine. 1993;329(19). doi:10.1056/NEJM199311043291902
54. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin vs warfarin for prophylaxis of deep vein thrombosis after hip or knee implantation. An economic perspective. Archives of internal medicine. 1997;157(3).
55. Francis CW, Pellegrini VD, Totterman S, et al. Prevention of deep-vein thrombosis after total hip arthroplasty. Comparison of warfarin and dalteparin. The Journal of bone and joint surgery American volume. 1997;79(9). doi:10.2106/00004623-199709000-00011
56. 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 deep-vein thrombosis after total hip replacement. A prospective, randomized trial. The Journal of bone and joint surgery American volume. 1998;80(8). doi:10.2106/00004623-199808000-00009
57. Colwell CW, Collis DK, Paulson R, et al. Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty. Evaluation during hospitalization and three months after discharge. The Journal of bone and joint surgery American volume. 1999;81(7). doi:10.2106/00004623-199907000-00005
58. Kakkar VV, Howes J, Sharma V, Kadziola Z. A comparative double-blind, randomised trial of a new second generation LMWH (bemiparin) and UFH in the prevention of post-operative venous thromboembolism. The Bemiparin Assessment group. Thrombosis and haemostasis. 2000;83(4).
59. Eriksson BI, Bergqvist D, Kälebo P, et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet (London, England). 2002;360(9344). doi:10.1016/s0140-6736(02)11469-3
60. Eriksson BI, Agnelli G, Cohen AT, et al. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement. Thrombosis and haemostasis. 2003;89(2).
61. Colwell CW, Berkowitz SD, Davidson BL, et al. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study. Journal of thrombosis and haemostasis : JTH. 2003;1(10). doi:10.1046/j.1538-7836.2003.00368.x
62. Pitto RP, Hamer H, Heiss-Dunlop W, Kuehle J. Mechanical prophylaxis of deep-vein thrombosis after total hip replacement a randomised clinical trial. The Journal of bone and joint surgery British volume. 2004;86(5). doi:10.1302/0301-620x.86b5.14763
63. Enyart JJ, Jones RJ. Low-dose warfarin for prevention of symptomatic thromboembolism after orthopedic surgery. The Annals of pharmacotherapy. 2005;39(6). doi:10.1345/aph.1E536
64. Senaran H, Acaroğlu E, Ozdemir HM, Atilla B. Enoxaparin and heparin comparison of deep vein thrombosis prophylaxis in total hip replacement patients. Archives of orthopaedic and trauma surgery. 2006;126(1). doi:10.1007/s00402-005-0079-0
65. Cohen AT, Skinner JA, Warwick D, Brenkel I. The use of graduated compression stockings in association with fondaparinux in surgery of the hip. A multicentre, multinational, randomised, open-label, parallel-group comparative study. The Journal of bone and joint surgery British volume. 2007;89(7). doi:10.1302/0301-620X.89B7.18556
66. 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 (London, England). 2007;370(9591). doi:10.1016/S0140-6736(07)61445-7
67. Raskob G, Cohen AT, Eriksson BI, et al. Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study. Thrombosis and haemostasis. 2010;104(3). doi:10.1160/TH10-02-0142
68. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. The New England journal of medicine. 2010;363(26). doi:10.1056/NEJMoa1006885
69. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thrombosis and haemostasis. 2011;105(4). doi:10.1160/TH10-10-0679
70. Kwong LM. Therapeutic potential of rivaroxaban in the prevention of venous thromboembolism following hip and knee replacement surgery: a review of clinical trial data. Vascular health and risk management. 2011;7. doi:10.2147/VHRM.S4441
71. Khatod M, Inacio MCS, Bini SA, Paxton EW. Prophylaxis against pulmonary embolism in patients undergoing total hip arthroplasty. The Journal of bone and joint surgery American volume. 2011;93(19). doi:10.2106/JBJS.J.01130
72. Raskob GE, Gallus AS, Pineo GF, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials. The Journal of bone and joint surgery British volume. 2012;94(2). doi:10.1302/0301-620X.94B2.27850
73. Nieto JA, Espada NG, Merino RG, González TC. Dabigatran, rivaroxaban and apixaban versus enoxaparin for thomboprophylaxis after total knee or hip arthroplasty: pool-analysis of phase III randomized clinical trials. Thrombosis research. 2012;130(2). doi:10.1016/j.thromres.2012.02.011
74. Fuji T, Nakamura M, Takeuchi M. Darexaban for the prevention of venous thromboembolism in Asian patients undergoing orthopedic surgery: results from 2 randomized, placebo-controlled, double-blind studies. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2014;20(2). doi:10.1177/1076029612457810
75. Beyer-Westendorf J, Lützner J, Donath L, et al. Efficacy and safety of thromboprophylaxis with low-molecular-weight heparin or rivaroxaban in hip and knee replacement surgery: findings from the ORTHO-TEP registry. Thrombosis and haemostasis. 2013;109(1). doi:10.1160/TH12-07-0510
76. Charters MA, Frisch NB, Wessell NM, Dobson C, Les CM, Silverton CD. Rivaroxaban Versus Enoxaparin for Venous Thromboembolism Prophylaxis after Hip and Knee Arthroplasty. The Journal of arthroplasty. 2015;30(7). doi:10.1016/j.arth.2015.02.009
77. Bonarelli S, Bacchin MR, Frugiuele I, Feoli MA, Facchini F, Altimari V. Dabigatran etexilate and LMWH for the prevention of venous thromboembolism in 532 patients undergoing hip surgery. European review for medical and pharmacological sciences. 2015;19(5).
78. Heckmann M, Thermann H, Heckmann F. Rivaroxaban versus high dose nadroparin for thromboprophylaxis after hip or knee arthroplasty. Hamostaseologie. 2015;35(4). doi:10.5482/HAMO-14-12-0078
79. Özler T, Uluçay Ç, Önal A, Altıntaş F. Comparison of switch-therapy modalities (enoxaparin to rivaroxaban/dabigatran) and enoxaparin monotherapy after hip and knee replacement. Acta orthopaedica et traumatologica turcica. 2015;49(3). doi:10.3944/AOTT.2015.14.0219
80. Ricket AL, Stewart DW, Wood RC, et al. Comparison of Postoperative Bleeding in Total Hip and Knee Arthroplasty Patients Receiving Rivaroxaban or Enoxaparin. The Annals of pharmacotherapy. 2016;50(4). doi:10.1177/1060028015626435
81. Kim SM, Moon YW, Lim SJ, Kim DW, Park YS. Effect of oral factor Xa inhibitor and low-molecular-weight heparin on surgical complications following total hip arthroplasty. Thrombosis and haemostasis. 2016;115(3). doi:10.1160/TH15-07-0527
82. Lindquist DE, Stewart DW, Brewster A, et al. Comparison of Postoperative Bleeding in Total Hip and Knee Arthroplasty Patients Receiving Rivaroxaban, Enoxaparin, or Aspirin for Thromboprophylaxis. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2018;24(8). doi:10.1177/1076029618772337
83. Senay A, Trottier M, Delisle J, et al. Incidence of symptomatic venous thromboembolism in 2372 knee and hip replacement patients after discharge: data from a thromboprophylaxis registry in Montreal, Canada. Vascular health and risk management. 2018;14. doi:10.2147/VHRM.S150474
84. Tan TL, Foltz C, Huang R, et al. Potent Anticoagulation Does Not Reduce Venous Thromboembolism in High-Risk Patients. The Journal of bone and joint surgery American volume. 2019;101(7). doi:10.2106/JBJS.18.00335
85. Ghosh A, Best AJ, Rudge SJ, Chatterji U. Clinical Effectiveness of Aspirin as Multimodal Thromboprophylaxis in Primary Total Hip and Knee Arthroplasty: A Review of 6078 Cases. The Journal of arthroplasty. 2019;34(7). doi:10.1016/j.arth.2019.03.021
86. Kasina P, Wall A, Lapidus LJ, et al. Postoperative Thromboprophylaxis With New Oral Anticoagulants is Superior to LMWH in Hip Arthroplasty Surgery: Findings from the Swedish Registry. Clinical orthopaedics and related research. 2019;477(6). doi:10.1097/CORR.0000000000000714
87. Gage BF, Bass AR, Lin H, et al. Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial. JAMA. 2019;322(9). doi:10.1001/jama.2019.12085
88. Cheallaigh SN, Fleming A, Dahly D, et al. Aspirin compared to enoxaparin or rivaroxaban for thromboprophylaxis following hip and knee replacement. International journal of clinical pharmacy. 2020;42(3). doi:10.1007/s11096-020-01032-1
89. Matharu GS, Garriga C, Whitehouse MR, Rangan A, Judge A. Is Aspirin as Effective as the Newer Direct Oral Anticoagulants for Venous Thromboembolism Prophylaxis After Total Hip and Knee Arthroplasty? An Analysis From the National Joint Registry for England, Wales, Northern Ireland, and the Isle of Man. The Journal of arthroplasty. 2020;35(9). doi:10.1016/j.arth.2020.04.088
90. Rahman WA, Habsa GH, Al-Mohrej OA, Hammad M, Selim NM, Hammad A. Incidence of silent venous thromboembolism after total hip arthroplasty: A comparison of rivaroxaban and enoxaparin. Journal of orthopaedic surgery (Hong Kong). 28(2). doi:10.1177/2309499020938865
91. Ren Y, Cao SL, Li Z, Luo T, Feng B, Weng XS. Comparable efficacy of 100 mg aspirin twice daily and rivaroxaban for venous thromboembolism prophylaxis following primary total hip arthroplasty: a randomized controlled trial. Chinese medical journal. 2021;134(2). doi:10.1097/CM9.0000000000001305
92. Borton ZM, Bhangoo NS, Quah CS, Stephen AB, Howard PW. Aspirin monotherapy is a suitable standard thromboprophylactic agent following total hip arthroplasty. Hip international : the journal of clinical and experimental research on hip pathology and therapy. Published online February 2021. doi:10.1177/1120700021990544