Aydin Gahramanov, Saad Tarabichi, Charles-Marc Samama.
Response/Recommendation: Duration of immobilization in patients with lower extremity injuries does not influence the choice of venous thromboembolism (VTE) prophylaxis.
Strength of Recommendation: Moderate.
Rationale: Prolonged postoperative immobilization is a well-established risk factor for the development of VTE after surgery1. However, the use of VTE prophylaxis in patients who are immobilized following lower-extremity injuries remains a contentious issue2,3. The 2012 American College of Chest Physicians (ACCP) guidelines recommend against the routine use of VTE prophylaxis in patients with isolated lower-extremity injuries, including immobilized patients4. Despite this, standard practice in Europe is still to routinely administer low-molecular-weight heparin (LMWH) as a method of VTE prophylaxis for all patients immobilized following a lower-extremity injury5. Current clinical practice guidelines have yet to reach a consensus on a reliable treatment algorithm in this setting2,4. Furthermore, whether the duration of immobilization in these patients should influence the choice of VTE prophylaxis remains inadequately investigated.
LMWH has a well-documented adverse side effect profile6. Despite this, it is still commonly used as a method of VTE prophylaxis following lower-extremity injuries7. Recent literature has suggested that it may not be as reliable at preventing VTE in these patients as previously believed. In a study by Lapidus et al.8, participants were randomized to receive either thromboprophylaxis with dalteparin or placebo for 5 weeks after ankle fracture surgery. To be eligible for inclusion, patients had to have received dalteparin for at least 1-week prior to randomization. The mean duration of immobilization was 44 days in both groups. The incidence of radiographically confirmed deep venous thrombosis (DVT) did not significantly differ between the two groups. Additionally, a randomized controlled trial (RCT) by Nemeth et al.9, demonstrated that patients with below-knee cast immobilization administered LMWH, vs. those receiving placebo, demonstrated comparable rates of VTE occurrence. The average immobilization duration in this study was 4.9 weeks. Similarly, Van Adrichem et al.10, conducted two separate clinical trials to investigate the efficacy of dalteparin and nadroparin for the prevention of VTE in patients immobilized following either knee arthroscopy, or after casting of the lower leg. The average duration of immobilization was 4.9 weeks. Patients were randomized to receive either dalteparin, nadroparin, or no-anticoagulation. They found that patients receiving LMWH, vs. patients in the no-anticoagulation group, demonstrated comparable rates of symptomatic VTE occurrence (1.4% and 1.8%, respectively).
Conversely, several studies have demonstrated LMWH ability to cause a relative risk reduction of VTE in this patient population, regardless of the duration of immobilization. Lassen et al.11, conducted a clinical trial to evaluate the safety and efficacy of reviparin in patients immobilized for ³ 5-weeks after a distal leg fracture or achilles tendon rupture. The mean duration of immobilization in the treatment and control groups was 43-days and 44-days, respectively. Radiographically confirmed DVT occurred in 9% of patients randomized to receive reviparin, and 19% of patients randomized to the placebo group. In another study, Otero-Fernandez et al.12, audited the effectiveness of bemiparin in orthopaedic patients managed both surgically and medically. Patients were stratified to receive high-dose (3,500 IU daily) or low-dose (2500 IU/daily) bemiparin based on their individual physician’s assessment of their risk for developing VTE. 6,456 patients were included, 26% of whom were immobilized by plaster cast. Within this sub-group, mean immobilization and duration of treatment was 12.8 days and 21 days, respectively. Patients placed in a cast had a low rate (0.45%) of symptomatic VTE at 30-days.
Following the advent of newer more potent anticoagulants, several studies have been designed in an effort to investigate their safety and efficacy, when compared to more conventional anticoagulation. In one study, Bruntink et al.13, conducted a multicenter RCT of patients with an ankle or foot fracture who required immobilization. Patients were randomized to either the no-treatment group, the nadroparin group (2,850 IU once daily), or the fondaparinux group (2.5 mg once daily). The mean duration of immobilization was 40 days for the no-treatment and nadroparin groups, and 38 days for those receiving fondaparinux. The incidence of DVT was 2.2% in the nadroparin group, 1.1% in the fondaparinux group, and 11.7% in the control group (p = 0.011). Similarly, Samama et al.14, reported on a multicenter study comparing efﬁcacy and safety between fondaparinux and nadroparin. 1,349 patients with an isolated non-surgical, unilateral below-knee injury were randomized into either treatment group. Mean immobilization and treatment durations were 32 days in the fondaparinux group, and 34 days in the nadroparin group. The incidence of DVT in the fondaparinux group and nadroparin group was 2.6% and 8.2%, respectively (p < 0.001). Additionally, The PROphylaxis in NOn-Major Orthopaedic Surgery (PRONOMOS)15 clinical trial compared the effect of rivaroxaban versus enoxaparin in preventing major VTE in patients undergoing lower limb non-major orthopaedic surgery. Patients had to have been scheduled to receive VTE prophylaxis for at least 2 weeks to be eligible for enrollment. The primary outcome studied was the occurrence of symptomatic proximal or distal DVT, pulmonary embolism (PE), and VTE-related death during the treatment period, as well as asymptomatic proximal DVT at the end of treatment. The primary outcome occurred in 0.24% of patients in the rivaroxaban group and in 1.10% of patients in the enoxaparin group (p < 0.05). Bleeding rates were comparable between the rivaroxaban and enoxaparin groups (1.08% and 1.04%, respectively). In conclusion, rivaroxaban proved more effective than enoxaparin in preventing VTE events during a period of immobilization after non-major orthopaedic surgery of the lower limbs, regardless of the duration of immobilization.
The likelihood of VTE complications occurring postoperatively depends on a dynamic interplay between both patient-related and nonpatient-related factors16. Studies have repeatedly shown that prolonged postoperative immobilization does definitively increase a patient’s risk of developing VTE complications17. Guidelines on early and aggressive postoperative mobilization have been established to mitigate the risks it poses to patients18. Currently, the duration of immobilization in patients with lower extremity injuries does not appear to influence the choice of VTE prophylaxis.
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8. J Lapidus L, Ponzer S, Elvin A, et al. Prolonged thromboprophylaxis with Dalteparin during immobilization after ankle fracture surgery: A randomized placebo-controlled, double-blind study. Acta Orthopaedica. 2007;78(4):528-535. doi:10.1080/17453670710014185
9. Nemeth B, van Adrichem R, Nelissen R, le Cessie S, Cannegieter SC. Individualized Thromboprophylaxis in Patients with Lower-Leg Cast Immobilization—A Validation and Subgroup Analysis in the POT-CAST Trial. Thromb Haemost. 2019;119(09):1508-1516. doi:10.1055/s-0039-1693410
10. van Adrichem RA, Nemeth B, Algra A, et al. Thromboprophylaxis after Knee Arthroscopy and Lower-Leg Casting. N Engl J Med. 2017;376(6):515-525. doi:10.1056/NEJMoa1613303
11. Lassen MR, Borris LC, Nakov RL. Use of the Low-Molecular-Weight Heparin Reviparin to Prevent Deep-Vein Thrombosis after Leg Injury Requiring Immobilization. N Engl J Med. 2002;347(10):726-730. doi:10.1056/NEJMoa011327
12. Otero-Fernández R, Gómez-Outes A, Martínez-González J, Rocha E, Fontcuberta J. Evaluation of the Effectiveness and Safety of Bemiparin in a Large Population of Orthopedic Patients in a Normal Clinical Practice. Clin Appl Thromb Hemost. 2008;14(1):75-83. doi:10.1177/1076029607303962
13. Bruntink MM, Groutars YME, Schipper IB, et al. Nadroparin or fondaparinux versus no thromboprophylaxis in patients immobilised in a below-knee plaster cast (PROTECT): A randomised controlled trial. Injury. 2017;48(4):936-940. doi:10.1016/j.injury.2017.02.018
14. Samama CM, Lecoules N, Kierzek G, et al. Comparison of fondaparinux with low molecular weight heparin for venous thromboembolism prevention in patients requiring rigid or semi-rigid immobilization for isolated non-surgical below-knee injury. J Thromb Haemost. 2013;11(10):1833-1843. doi:10.1111/jth.12395
15. Samama CM, Laporte S, Rosencher N, et al. Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery. N Engl J Med. 2020;382(20):1916-1925. doi:10.1056/NEJMoa1913808
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17. Braithwaite I, Healy B, Cameron L, Weatherall M, Beasley R. Lower limb immobilisation and venous thromboembolism risk: combined case–control studies. Postgrad Med J. 2017;93(1100):354-359. doi:10.1136/postgradmedj-2016-134365
18. Pearse EO, Caldwell BF, Lockwood RJ, Hollard J. Early mobilisation after conventional knee replacement may reduce the risk of postoperative venous thromboembolism. The Journal of Bone and Joint Surgery British volume. 2007;89-B(3):316-322. doi:10.1302/0301-620X.89B3.18196