100 – What is the most optimal VTE prophylaxis following TKA/THA?

100 – What is the most optimal VTE prophylaxis following TKA/THA?

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 NameYear of PublicationType of DesignType of SurgeryChemical NameSample Size
German Hip Arthroplasty Group421992Classic RCTHipHeparin168
Laguardia181992Classic RCTHipLMWH (Pre-Op)19
LMWH (Post-Op)21
Leyvraz et al.431992Classic RCTHipHeparin139
Leyvraz et al.441991Classic RCTHipHeparin175
Freick451991Classic RCTHipHeparin48
Planès et al.461991Classic RCTHipLMWH65
LMWH (20 mg)61
LMWH (40 mg)62
Levineet al.261991Classic RCTHipHeparin263
Eriksson et al.471991Classic RCTHipHeparin59
Planèset al.481988Classic RCTHipHeparin112
Planèset al.481988Classic RCTHipHeparin113
Josefsson et al.291987Classic RCTHipASA40
  Planès et al.49  1986  Classic RCTHipLMWH (60 mg)50
LMWH (30 mg)28
LMWH (40 mg)50
LMWH (20 mg)100
RD Heparin Arthroplasty Group501994Classic RCTTotal JointHeparin (Twice)328
Heparin (Once)320
  Menzin et al.51  1994  Classic RCT  HipHeparin209
LMWH (30 mg)195
LMWH (40 mg)203
  Colwell Jr. Et al.52  1994  Classic RCT  HipHeparin209
LMWH (30 mg)195
LMWH (40 mg)203
Hull et al.531993Classic RCTTotal JointLMWH715
Hull541997Classic RCTTotal JointLMWH590
Francis et al.551997Classic RCTHipLMWH192
Eriksson et al.221997Classic RCTHipLMWH1023
Thrombin Inhibitors1028
Warwick et al.561998Classic RCTHipMechanical136
Colwell Jr. et al.571999Classic RCTHipLMWH1516
Kakkar et al.582000Classic RCTHipHeparin134
  Hull et al.19  2000  Classic RCT  HipLMWH (Pre-Op)152
LMWH (Post-Op)139
Borghi et al.232002Observational RetrospectiveHipHeparin192
Turpie et al.242002Classic RCTHipLMWH797
Thrombin Inhibitors787
Eriksson et al.592002Classic RCTTotal JointLMWH308
Thrombin Inhibitors1169
Eriksson et al.602003Classic RCTTotal JointLMWH1184
Thrombin Inhibitors1141
Colwell Jr. et al.612003Classic RCTHipLMWH775
Thrombin Inhibitors782
Eriksson et al.602003Classic RCTTotal JointLMWH1178
Thrombin Inhibitors1138
Pitto et al.622004Classic RCTHipMechanical100
Enyart632005Observational ProspectiveTotal JointLMWH2627
Senaran et al.642006Classic RCTHipHeparin50
Della Valle et al.52006Observational ProspectiveHipASA (325 mg)1599
Gelfer et al.132006Classic RCTTotal JointASA (100 mg)61
  Cohen et al.65  2007  Classic RCT  Total JointThrombin Inhibitors400
Thrombin Inhibitors (with compression stocks)395
    Eriksson et al.66    2007    Classic RCT    HipFactor Xa Inhibitor (220 mg)1146
Factor Xa Inhibitor (150 mg)1163
Tian et al.152007Classic RCTTotal JointASA (100 mg)100
Eriksson et al.282008Classic RCTHipRivaroxaban2209
Kakkar et al.272008Classic RCTTotal JointRivaroxaban1228
Colwell Jr. et al.142010OtherHipASA (81 mg)199
  Raskob et al.67  2010  Other  HipFactor Xa Inhibitor170
Factor Xa Inhibitor158
Lassen et al.682010Classic RCTHipApixaban1949
Erikssonet al.692011OtherHipFactor Xa Inhibitor792
Intermountain Joint Replacement Center Writing Committee33  2011  Observational Prospective  Total JointASA (325 mg)152
Kwong702011OtherTotal JointFactor Xa Inhibitor6183
  Khatod et al.71  2011  Observational Retrospective  HipASA934
Jameson et al.252011Observational RetrospectiveTotal JointASA22942
Raskob et al.722012OtherTotal JointApixaban3394
Nieto et al.732012OtherTotal JointFactor Xa Inhibitor12200
Vulcano et al.322012Observational RetrospectiveTotal JointASA (325 mg)1115
  Fuji et al.74  2012  Other  Total JointFactor Xa Inhibitor (Low)136
Factor Xa Inhibitor134
Beyer-Westendorf et al.752012Observational RetrospectiveTotal JointRivaroxaban1043
Shoda et al.202015Observational RetrospectiveTotal JointLMWH11049
Thrombin Inhibitors22727
Charters et al.762015Observational RetrospectiveTotal JointRivaroxaban649
Bonarelli et al.772015Observational ProspectiveHipFactor Xa Inhibitor211
Heckmannet al.782015Observational ProspectiveTotal JointRivaroxaban838
Özleret al.792015Classic RCTTotal JointRivaroxaban60
Ricketet al.802016Observational RetrospectiveTotal JointRivaroxaban440
Huang et al.312016Observational RetrospectiveTotal JointASA796
Deirmengian302016Observational RetrospectiveHipASA534
  Yhim et al.21  2017  Observational Retrospective  HipASA3654
Thrombin Inhibitors997
  Yhimet al.21  2017  Observational Retrospective  KneeASA24612
Thrombin Inhibitors7721
Lindquist et al.822018Observational RetrospectiveTotal JointASA (325 mg)366
Senay et al.832018Observational ProspectiveTotal JointFactor Xa Inhibitor904
  Tan et al.84  2019  Observational Retrospective  Total JointASA13610
    Ghosh et al.85    2019    Observational Prospective    Total JointASA6078
Factor Xa Inhibitor40
Kasinaet al.862019Observational ProspectiveHipRivaroxaban5752
Gage et al.872019Classic RCTTotal JointWarfarin (Low)804
Cheallaigh et al.88  2020  Observational Retrospective  Total JointASA3460
  Matharuet al.89  2020  Observational Retrospective  HipASA35904
Factor Xa Inhibitor29522
Thrombin Inhibitors3864
  Matharu et al.89  2020  Observational Retrospective  KneeASA42590
Factor Xa Inhibitor30697
Thrombin Inhibitors41323
Rahman et al.902020OtherHipRivaroxaban80
Ren et al.912021Observational RetrospectiveHipASA (100 mg)34
Bortonet al.922021Observational RetrospectiveHipASA2560
Uvodichet al.172021Observational RetrospectiveTotal JointASA (81 mg)961
Hovik162021Observational ProspectiveTotal JointASA (81 mg)1084

RCT=Randomized clinical trial; LMWH=Low-molecular-weight heparin; mg=milligrams: ASA=Aspirin.


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