Deepak Menon, Oussama Abcha, Sofiene Kallel, Hemant Pandit.

Response/Recommendation: Empirical systemic treatment with anticoagulation for suspected venous thromboembolism (VTE) in the post-operative period should only be initiated when timely image-based diagnosis cannot be achieved. Early treatment reduces the risk of VTE-associated morbidity. However, the increased bleeding risk with recent surgery should also be considered. Initiation of anticoagulation is ultimately a clinical decision, and a comprehensive risk-benefit assessment should be undertaken based on individual patient factors. Given the lack of studies reporting the outcomes of initiating vs. delaying therapeutic anticoagulation in patients with suspected VTE in the post-operative period prior to a confirmed diagnosis, further research is therefore necessary.

Strength of Recommendation: Low.

Rationale: Major orthopaedic surgery is a key risk factor for developing VTE¹. The risk of VTE depends on operation type, location, and individual patient factors². The 35-day cumulative risk for symptomatic VTE following total hip arthroplasty (THA), total knee arthroplasty (TKA), and hip fracture surgery is estimated to be 4.3% in the absence of pharmacological prophylaxis³. A high index of suspicion for VTE in the post-operative period is therefore paramount. The American College of Chest Physicians (ACCP) and the National Institute of Health and Care Excellence (NICE) offer clear guidelines for VTE prophylaxis^3,4. This has reduced the incidence of post-operative VTE⁵. VTE diagnosis is based on clinical judgment in combination with the use of a validated pre-test probability scoring system and D-dimer to determine whether further imaging is required². Initiation of antithrombotic medication should always be weighed against the risk of bleeding, particularly in the post-operative period⁶.

A literature search was performed to review the available evidence evaluating the role of starting empirical treatment for suspected VTE in post-operative orthopaedic patients. Guidelines from the ACCP advise empirical initiation of therapeutic dose anticoagulation for suspected acute VTE in cases where there is a high clinical suspicion, or intermediate clinical suspicion when there is an expected delay in diagnostic imaging for at least 4 hours⁷. In patients with a low clinical suspicion of acute VTE where diagnostic imaging is available within 24 hours, initiation of therapeutic anticoagulation is not advised⁷. However, this guidance does not apply to patients following recent surgery who are at increased risk of bleeding post-operatively, and there remains no specific evidence guiding recommendation for the empirical treatment of suspected VTE in the post-operative phase, especially in the orthopaedic patient. Early initiation of therapeutic anticoagulation in the context of a suspected VTE post-operatively is therefore a risk-benefit clinical decision that should be undertaken on a case-by-case basis. This should take into consideration the adverse outcomes associated with major bleeding versus the risk of short- and long-term VTE-associated complications^8,9.

Recent studies have reviewed outcomes associated with empirical treatment of suspected VTE in the absence of diagnostic imaging modalities such as duplex ultrasonography and computed tomography pulmonary angiogram (CTPA)^10–12, although this was not specific to the post-operative period. For example, Obi et al., outlined a protocol based on expert opinion, with initiation of therapeutic anticoagulation based on critical patient status, risk assessment by the Modified Wells’ Score, and individual bleeding risk¹². This protocol advocated empirical treatment of suspected pulmonary embolism (PE) or deep venous thrombosis (DVT) if there was a delay in imaging > 4 hours and > 24 hours, respectively¹².

This protocol and the ACCP guidelines are supported by data from a prospective study by Imberti et al., which reported no adverse events of PE or major bleeding at short-term follow-up after initial administration of a single weight-adjusted therapeutic dose of low-molecular-weight heparin (LMWH) in primary care patients suspected to have a DVT when confirmatory imaging study was not immediately available (within 18 hours)¹³. A 0.7% risk of VTE-associated complications at 3-month follow-up was reported¹³. Fronas et al., report that the initiation of treatment dose rivaroxaban followed by deferment of compression ultrasound for up to 24 hours was safe in patients with suspected lower-limb DVT (based on clinical assessment and a D-dimer ≥ 0.5 mg/L), with no episodes of major bleeding or complications noted at short-term follow-up of 48 hours after the last direct oral anticoagulant (DOAC) dose⁸. Similarly, Siragusa et al., concluded that administering treatment dose LMWH and delaying confirmatory imaging for up to 72 hours in patients with a high pre-test probability or a moderate pre-test probability score and positive D-dimer was safe¹⁴. No major bleeding events were noted at ≤ 72 hours after patient referral, and a 1.2% risk of developing VTE at 3-month follow-up was observed¹⁴.

In a retrospective cohort study, Kim et al., found no significant difference in major or non-major bleeding, transfusion rates or length of stay at 3-month follow-up in hip fracture patients diagnosed with PE pre-operatively relative to a non-PE patient cohort with suspected VTE¹⁵. Of note, 95.6% of the PE cohort received therapeutic anticoagulation post-procedure¹⁵, hence suggesting that peri-operative empirical treatment of VTE may be safe even if early surgery is advocated. However, peri-operative major and non-major bleeding rates remained significant, which were 21.1% and 13.3%, respectively, at 3-month follow-up in the PE cohort¹⁵. Indeed, the proportion of non-PE patients administered therapeutic anticoagulation for suspected VTE pre-operatively was not reported and may have confounded the comparison in this study. Bose et al., found that the incidence of major bleeding events, recurrent VTE, and death in post-operative patients initiated on treatment for PE within a 90-day period was 12%, 4%, and 9%, respectively¹⁶, demonstrating a clear association with increased morbidity.

As the clinical signs of VTE may be unreliable^17,18, clinicians should always be mindful of alternative diagnoses causing respiratory decompensation, even in the presence of imaging confirmed VTE. Further studies are required to determine whether the increased bleeding risk outweighs the benefit of early treatment in cases of suspected post-operative VTE, taking into consideration the type of operation as well as individual patient factors.

References:

1.         Anderson FA, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 Suppl 1):I9-16. doi:10.1161/01.CIR.0000078469.07362.E6

2.         Fleischer AE, Abicht BP, Baker JR, Boffeli TJ, Jupiter DC, Schade VL. American College of Foot and Ankle Surgeons’ clinical consensus statement: risk, prevention, and diagnosis of venous thromboembolism disease in foot and ankle surgery and injuries requiring immobilization. J Foot Ankle Surg. 2015;54(3):497-507. doi:10.1053/j.jfas.2015.02.022

3.         Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in Orthopedic Surgery Patients. 2012;141(2):e278S-e325S. doi:10.1378/chest.11-2404

4.         Perioperative care overview – NICE Pathways. Accessed October 1, 2021. https://pathways.nice.org.uk/pathways/perioperative-care

5.         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

6.         Chan NC, Siegal D, Lauw MN, et al. A systematic review of contemporary trials of anticoagulants in orthopaedic thromboprophylaxis: suggestions for a radical reappraisal. J Thromb Thrombolysis. 2015;40(2):231-239. doi:10.1007/s11239-014-1153-7

7.         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

8.         Fronas SG, Dahm AEA, Wik HS, et al. Safety and feasibility of rivaroxaban in deferred workup of patients with suspected deep vein thrombosis. Blood Adv. 2020;4(11):2468-2476. doi:10.1182/bloodadvances.2020001556

9.         Kruger PC, Eikelboom JW, Douketis JD, Hankey GJ. Deep vein thrombosis: update on diagnosis and management. Med J Aust. 2019;210(11):516-524. doi:10.5694/mja2.50201

10.       Schaefer JK, Henke PK, Barnes GD. Managing suspected venous thromboembolism when a pandemic limits diagnostic testing. Thromb Res. 2020;196:213-214. doi:10.1016/j.thromres.2020.08.029

11.       COVID-19 and Pulmonary Embolism – Hematology.org. Accessed September 29, 2021. https://www.hematology.org:443/covid-19/covid-19-and-pulmonary-embolism

12.       Obi AT, Barnes GD, Wakefield TW, et al. Practical diagnosis and treatment of suspected venous thromboembolism during COVID-19 pandemic. J Vasc Surg Venous Lymphat Disord. 2020;8(4):526-534. doi:10.1016/j.jvsv.2020.04.009

13.       Imberti D, Ageno W, Dentali F, Giorgi Pierfranceschi M, Croci E, Garcia D. Management of primary care patients with suspected deep vein thrombosis: use of a therapeutic dose of low-molecular-weight heparin to avoid urgent ultrasonographic evaluation. J Thromb Haemost. 2006;4(5):1037-1041. doi:10.1111/j.1538-7836.2006.01940.x

14.       Siragusa S, Anastasio R, Porta C, et al. Deferment of objective assessment of deep vein thrombosis and pulmonary embolism without increased risk of thrombosis: a practical approach based on the pretest clinical model, D-dimer testing, and the use of low-molecular-weight heparins. Arch Intern Med. 2004;164(22):2477-2482. doi:10.1001/archinte.164.22.2477

15.       Kim HC, Park J-H, Song J-M, et al. Safety of early orthopedic surgery in patients with intermediate/low- or low-risk pulmonary embolism. J Thorac Dis. 2020;12(3):232-239. doi:10.21037/jtd.2020.01.54

16.       Bose G, Gandara E, Carrier M, Erkens P, Rodger M, Wells P. Outcomes of Pulmonary Embolism In Surgical Patients: A Retrospective Cohort Study. Blood. 2010;116(21):3180. doi:10.1182/blood.V116.21.3180.3180

17.       Mendelson J, Kumar M, Mukherjee V, et al. CT Pulmonary Angiography (CTPA) Frequently Identifies an Alternative Diagnosis in a Post-Orthopedic Population: A Retrospective Review of 372 Consecutive Orthopedic Patients Evaluated for Pulmonary Embolism (PE). CHEST. 2016;150(4):1191A. doi:10.1016/j.chest.2016.08.1300

18.       Murphy CG, Moran DE, Gerstenmaier JF, et al. Evaluation of the incidence of pulmonary embolus in the early postoperative period following cemented hemiarthroplasty. Hip Int. 2016;26(3):295-300. doi:10.5301/hipint.5000341