Andrew J. Hughes, Emanuele Chisari, Javad Parvizi.
Response/Recommendation: Proximal deep venous thrombosis (DVT) affecting the popliteal or supra-popliteal vessels carries a high risk of propagation after lower limb orthopaedic surgery. Treatment recommendations consist of anticoagulation for three months in the setting of an acute provoked postoperative proximal DVT.
Strength of Recommendation: Moderate.
Rationale: Venous thromboembolism (VTE) is a major healthcare concern, and those undergoing lower limb orthopaedic surgery are one of the highest risk patient groups1,2. The peak onset of DVT is within 2 and 3 weeks postoperatively3,4, with the risk remaining elevated for 6-12 weeks, and falling gradually thereafter until 4-6 months postoperatively5–8. Proximal DVT, affecting popliteal and supra-popliteal vessels, have been reported to occur in 27% of all DVT following total hip arthroplasty (THA) and 15% of all DVT after total knee arthroplasty (TKA)9,10. Proximal DVT are of particular concern given their tendency to propagate and cause pulmonary embolism (PE) in 40-50% of cases11–16. Such DVTs also display a higher rate of recurrence than their distal counterparts that are isolated to the calf11–16. Given their tendency to propagate, proximal DVT carry a mortality risk of up to 25% in the absence of adequate anticoagulation17.
A high index of suspicion is required when assessing a patient with possible proximal DVT. The American College of Chest Physicians (ACCP) and European Society of Cardiology (ESC) suggest commencing treatment with parenteral anticoagulation in patients with a high clinical suspicion, as well as those with an intermediate clinical suspicion in whom diagnosis may be delayed for longer than 4 hours5,18.
In non-cancer patients with a confirmed acute postoperative proximal DVT, the ACCP, ESC and the American Society of Hematology (ASH) suggest first-line treatment with a direct oral anticoagulant (DOAC), such as dabigatran, rivaroxaban, apixaban or edoxaban18–21. All of these guidelines stipulate that dabigatran and edoxaban must be administered after 5-10 days of parenteral low-molecular-weight heparin (LMWH)18,20,21. The ACCP suggests that a vitamin K antagonist should be favored as second-line over LMWH therapy, following appropriate bridging, with a recommended target international normalized ratio (INR) of 2.0 to 3.0 for the duration of treatment5,20–22. In the setting of an acute provoked postoperative proximal DVT, the ACCP, ESC, and ASH guidelines advocate that anticoagulation is continued for a minimum of 3-months5,18,20,21. The decision for extended treatment beyond 3-months must be based on the risk-benefit ratio for each individual patient18.
Special considerations must be made when dealing with perioperative patients and chronic VTE risk factors, owing to unique challenges warranting hematological consultation. In patients with active cancer and a confirmed acute postoperative DVT, the ACCP and ESC suggest LMWH, given its favorable profile in reducing recurrent episodes of VTE18,20,23. For patients at > 1% risk for developing heparin-induced thrombocytopenia (HIT), or heparin-induced thrombocytopenia and thrombosis (HITT), close monitoring of the platelet count every 2 to 3 days until discontinuation of heparin therapy is recommended5. Development of HITT requires the use of non-heparin anticoagulation5. Pregnant patients are recommended to receive adjusted-dose subcutaneous LMWH instead of unfractionated heparin, vitamin K antagonists, oral direct thrombin inhibitors, and anti-Xa inhibitors5,18,20. In addition, it is recommended that pediatric hematologists with subspecialty expertise in thromboembolism manage pediatric patients with VTE disease5.
Anticoagulation is suggested in favor of catheter-directed thrombolysis, systemic thrombolysis and operative venous thrombectomy, in the setting of non-limb-threatening acute postoperative proximal DVT5,18,20,21,24,25. Adjuvant catheter-directed thrombolysis may also be considered in patients with acute iliofemoral disease, with symptoms less than 14 days, and a life expectancy greater than 1 year18. Inferior vena cava (IVC) filters are suggested only for patients with contraindications to anticoagulation therapy. Routine IVC filter insertion in addition to anticoagulation is not recommended, in light of the risks of access site hematoma, lower limb DVT, filter thrombosis, and the need for subsequent removal with possible retrieval failure5,20,21,26–29. Ambulation is recommended, although severe pain and swelling may require deferral5,18. Compression stockings are not routinely recommended in the setting of an acute provoked postoperative proximal DVT unless providing symptomatic relief, as the literature has not proven any significant benefit in preventing the onset of post-thrombotic syndrome18,20,21.
The primary goal of postoperative VTE treatment is to prevent fatal PE30. In addition, prevention of recurrent VTE is sought, which has proven to be equivocal amongst DOAC and vitamin K antagonists, with indirect comparisons showing that no DOAC is superior to another20,22. The concerns of the orthopaedic community pertain to the perioperative anticoagulation-associated risks of major bleeding, hematoma, wound drainage, and infection31–34. Orthopaedic patients are among the highest risk group to sustain a perioperative bleeding event during a course of anticoagulation35. The risk of bleeding has been shown to be lower in the setting of DOAC therapy compared to that of vitamin K antagonists22,36–39. Of the DOAC’s mentioned within this consensus statement, apixaban has been shown to carry the lowest risk of gastrointestinal bleeding, based on indirect comparisons extrapolated in the setting of atrial fibrillation, however this has not yet been proven in the setting of VTE36–38,40. Based on reduced bleeding risk, the lack of required monitoring, and cost-effectiveness, DOAC have been recently favored over vitamin K antagonists in the published clinical practice guidelines20,21,41,42.
The scope of this consensus statement pertains to the setting of acute provoked postoperative proximal DVT. Guidelines have been formulated to prevent DVT and PE based on generalized population characteristics. It is imperative that hematological advice is sought to clarify an individual’s need for alternative or prolonged therapy while accounting for risk factors for recurrent thrombosis or anticoagulation-associated bleeding. Such scenarios requiring particular consideration in the perioperative setting include, but are not limited to, renal impairment, liver disease, prior VTE, bleeding diatheses, extremes of body weight, and malabsorption18,20. Whilst current guidelines suggest anticoagulation therapy based on population characteristics, patient-specific factors, particularly individual and family preferences voiced after informed consent and shared decision-making, will ultimately determine the optimal treatment choice.
1. Warren JA, Sundaram K, Anis HK, Kamath AF, Higuera CA, Piuzzi NS. Have Venous Thromboembolism Rates Decreased in Total Hip and Knee Arthroplasty? J Arthroplasty. 2020;35(1):259-264. doi:10.1016/j.arth.2019.08.049
2. Keller K, Hobohm L, Barco S, et al. Venous thromboembolism in patients hospitalized for knee joint replacement surgery. Sci Rep. 2020;10(1):22440. doi:10.1038/s41598-020-79490-w
3. Sweetland S, Green J, Liu B, et al. Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study. BMJ. 2009;339:b4583. doi:10.1136/bmj.b4583
4. Kahn SR, Shivakumar S. What’s new in VTE risk and prevention in orthopedic surgery. Res Pract Thromb Haemost. 2020;4(3):366-376. doi:10.1002/rth2.12323
5. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ, American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):7S-47S. doi:10.1378/chest.1412S3
6. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375(9717):807-815. doi:10.1016/S0140-6736(09)62125-5
7. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487-2498. doi:10.1056/NEJMoa1006885
8. Caron A, Depas N, Chazard E, et al. Risk of Pulmonary Embolism More Than 6 Weeks After Surgery Among Cancer-Free Middle-aged Patients. JAMA Surg. 2019;154(12):1126-1132. doi:10.1001/jamasurg.2019.3742
9. Ciccone WJ, Fox PS, Neumyer M, Rubens D, Parrish WM, Pellegrini VD. Ultrasound surveillance for asymptomatic deep venous thrombosis after total joint replacement. J Bone Joint Surg Am. 1998;80(8):1167-1174. doi:10.2106/00004623-199808000-00010
10. Ciccone WJ, Reid JS, Pellegrini VD. The role of ultrasonography in thromboembolic disease management in the orthopaedic patient. Iowa Orthop J. 1999;19:18-25.
11. Masuda EM, Kessler DM, Kistner RL, Eklof B, Sato DT. The natural history of calf vein thrombosis: lysis of thrombi and development of reflux. J Vasc Surg. 1998;28(1):67-73; discussion 73-74. doi:10.1016/s0741-5214(98)70201-0
12. Kazmers A, Groehn H, Meeker C. Acute calf vein thrombosis: outcomes and implications. Am Surg. 1999;65(12):1124-1127; discussion 1127-1128.
13. Palareti G, Cosmi B, Lessiani G, et al. Evolution of untreated calf deep-vein thrombosis in high risk symptomatic outpatients: the blind, prospective CALTHRO study. Thromb Haemost. 2010;104(5):1063-1070. doi:10.1160/TH10-06-0351
14. Kearon C. Natural history of venous thromboembolism. Circulation. 2003;107(23 Suppl 1):I22-30. doi:10.1161/01.CIR.0000078464.82671.78
15. Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation. 2010;121(14):1630-1636. doi:10.1161/CIRCULATIONAHA.109.925214
16. Baglin T, Douketis J, Tosetto A, et al. Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis. J Thromb Haemost. 2010;8(11):2436-2442. doi:10.1111/j.1538-7836.2010.04022.x
17. Markel A. Origin and natural history of deep vein thrombosis of the legs. Semin Vasc Med. 2005;5(1):65-74. doi:10.1055/s-2005-871743
18. Mazzolai L, Aboyans V, Ageno W, et al. Diagnosis and management of acute deep vein thrombosis: a joint consensus document from the European Society of Cardiology working groups of aorta and peripheral vascular diseases and pulmonary circulation and right ventricular function. Eur Heart J. 2018;39(47):4208-4218. doi:10.1093/eurheartj/ehx003
19. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S-e496S. doi:10.1378/chest.11-2301
20. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026
21. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738. doi:10.1182/bloodadvances.2020001830
22. Castellucci LA, Cameron C, Le Gal G, et al. Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA. 2014;312(11):1122-1135. doi:10.1001/jama.2014.10538
23. Carrier M, Cameron C, Delluc A, Castellucci L, Khorana AA, Lee AYY. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res. 2014;134(6):1214-1219. doi:10.1016/j.thromres.2014.09.039
24. Haig Y, Enden T, Grøtta O, et al. Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial. Lancet Haematol. 2016;3(2):e64-71. doi:10.1016/S2352-3026(15)00248-3
25. Garcia MJ, Lookstein R, Malhotra R, et al. Endovascular Management of Deep Vein Thrombosis with Rheolytic Thrombectomy: Final Report of the Prospective Multicenter PEARL (Peripheral Use of AngioJet Rheolytic Thrombectomy with a Variety of Catheter Lengths) Registry. J Vasc Interv Radiol. 2015;26(6):777-785; quiz 786. doi:10.1016/j.jvir.2015.01.036
26. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e278S-e325S. doi:10.1378/chest.11-2404
27. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7):409-415. doi:10.1056/NEJM199802123380701
28. Greenfield LJ. The PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) Randomized Study. Perspect Vasc Surg Endovasc Ther. 2006;18(2):187-188. doi:10.1177/1531003506290863
29. Mismetti P, Laporte S, Pellerin O, et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015;313(16):1627-1635. doi:10.1001/jama.2015.3780
30. Nicholson M, Chan N, Bhagirath V, Ginsberg J. Prevention of Venous Thromboembolism in 2020 and Beyond. J Clin Med. 2020;9(8):E2467. doi:10.3390/jcm9082467
31. Parvizi J, Jacovides CL, Bican O, et al. Is deep vein thrombosis a good proxy for pulmonary embolus? J Arthroplasty. 2010;25(6 Suppl):138-144. doi:10.1016/j.arth.2010.05.001
32. Hill J, Treasure T, National Clinical Guideline Centre for Acute and Chronic Conditions. Reducing the risk of venous thromboembolism in patients admitted to hospital: summary of NICE guidance. BMJ. 2010;340:c95. doi:10.1136/bmj.c95
33. Galat DD, McGovern SC, Hanssen AD, Larson DR, Harrington JR, Clarke HD. Early return to surgery for evacuation of a postoperative hematoma after primary total knee arthroplasty. J Bone Joint Surg Am. 2008;90(11):2331-2336. doi:10.2106/JBJS.G.01370
34. Callaghan JJ, Dorr LD, Engh GA, et al. Prophylaxis for thromboembolic disease: recommendations from the American College of Chest Physicians–are they appropriate for orthopaedic surgery? J Arthroplasty. 2005;20(3):273-274. doi:10.1016/j.arth.2005.01.014
35. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e326S-e350S. doi:10.1378/chest.11-2298
36. van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124(12):1968-1975. doi:10.1182/blood-2014-04-571232
37. Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124(15):2450-2458. doi:10.1182/blood-2014-07-590323
38. Bloom BJ, Filion KB, Atallah R, Eisenberg MJ. Meta-analysis of randomized controlled trials on the risk of bleeding with dabigatran. Am J Cardiol. 2014;113(6):1066-1074. doi:10.1016/j.amjcard.2013.11.049
39. Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med. 2010;152(9):578-589. doi:10.7326/0003-4819-152-9-201005040-00008
40. Kang N, Sobieraj DM. Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism. Thromb Res. 2014;133(6):1145-1151. doi:10.1016/j.thromres.2014.03.035
41. Amin A, Jing Y, Trocio J, Lin J, Lingohr-Smith M, Graham J. Evaluation of medical costs associated with use of new oral anticoagulants compared with standard therapy among venous thromboembolism patients. J Med Econ. 2014;17(11):763-770. doi:10.3111/13696998.2014.950670
42. Amin A, Bruno A, Trocio J, Lin J, Lingohr-Smith M. Real-World Medical Cost Avoidance When New Oral Anticoagulants are Used Versus Warfarin for Venous Thromboembolism in the United States. Clin Appl Thromb Hemost. 2016;22(1):5-11. doi:10.1177/1076029615585991