200 – Does the duration of immobilization of patients with lower extremity injuries influence the choice of VTE prophylaxis?

200 – Does the duration of immobilization of patients with lower extremity injuries influence the choice of VTE prophylaxis?

Aydin Gahramanov, 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: Strong.

Rationale: Prolonged postoperative immobilization is a well-studied and established risk factor for the development of VTE following surgery. Whether duration of immobilization of patients with lower extremity injuries influences the choice of VTE prophylaxis remains unclear. Otero-Fernandez et al.1, conducted a large, prospective, observational study auditing the effectiveness of bemiparin in 7,959 patients undergoing orthopaedic procedures with cast immobilization of the leg.  Cast immobilization accounted for 2,052 (28%) of those patients, with bemiparin given for 3–4 weeks. These patients had a mean of 12.8 days of immobilization. Within this sub-population, they found a low rate (0.45%) of symptomatic VTE at 30 days. Low-molecular-weight heparin (LMWH) significantly reduced deep venous thrombosis (DVT) incidence when compared to placebo in these patients.

In a randomized controlled trial (RCT) by Lapidus et al.2, 272 consecutive patients were randomized to receive either thromboprophylaxis with dalteparin (n = 136) or placebo (n = 136) for 5 weeks after ankle fracture surgery. All patients received 1 week of initial treatment with dalteparin before randomization. A unilateral phlebography was performed when the cast was removed.  The mean duration of immobilization was 44 days in both treatment groups. The overall incidence of total DVT was 21% in the dalteparin group, and 28% in the placebo group. The incidence of proximal DVTs was 4% and 3%, respectively. No major bleeding occurred in either patient cohort.

Van Adrichem et al.3, presented the results of two RCT, the POT-KAST trial (patients undergoing knee arthroscopy), and the POT-CAST trial (patients treated with casting).  In the POT-KAST trial, 1,451 patients were included in the intention-to-treat population. VTE occurred in 0.7% of patients in the treatment group vs. 0.4% in the control group. In the POT-CAST trial, 1,435 patients were included in the intention-to-treat population. The average duration of immobilization was 4.9 weeks. VTE occurred in 1.4% of patients in the treatment group, vs. 1.8% in the control group. In both trials, patients in the treatment group received either nadroparin (2,850 IU) or dalteparin (5,000 IU) during the full period of immobilization.

Lapidus et al.4, published a RCT including 105 consecutive patients surgically treated for Achilles’ tendon rupture and subsequently immobilized. Intervention was placebo or dalteparin (5,000 U) given for 6 weeks postoperatively. The mean duration of immobilization was 43 days in both treatment groups. The incidence of DVT was 34% in the dalteparin group and 36% in the placebo group. No pulmonary embolus or major bleeding occurred in either of the groups.

Ali et al.5, compared the results of treatment in two groups of patients with immobilization of the lower extremities with and without rivaroxaban. Adult patients treated with lower limb cast immobilization for different types of lower limb injuries were included in this study. In this study, 518 patients received rivaroxaban 10 mg once daily until they were off the cast. Immobilization duration was 71 days. This was compared with a historical cohort (n = 486), who received no rivaroxaban for thromboprophylaxis. The number of patients developing VTEs in the rivaroxaban group was zero, compared with 6 cases (1.2%) in the non-rivaroxaban group. There were no major or minor bleeding incidents.

Saragas et al.6, studied a prospective cohort of 142 patients who underwent foot and ankle surgery, all of whom required the combination of below-knee immobilization in a cast and no weight-bearing for ≥4 weeks. All patients in the study received 10 mg of rivaroxaban once daily. They found that of the 142, three patients (2.1%) developed a clinically evident DVT, later confirmed by compression ultrasonography. However, a major limitation of their study was that the length of immobilization was not clearly documented.

Bruntink et al.7, conducted a single-blind multicenter RCT that enrolled adults with an ankle or foot fracture who required immobilization. The patients were randomly assigned (1:1:1) to a control group (no thromboprophylaxis) or to one of the intervention groups: daily s/c dose of either nadroparin (2,850 IU) or fondaparinux (2.5 mg). The groups consisted of 154 patients randomly assigned to receive nadroparin, 157 to receive fondaparinux, and 156 to be in the control group. Duration of immobilization was 40.3 days for control, 40.2 days for nadroparin, 38.0 days for fondaparinux group. The incidence of DVT was 2.2% in the nadroparin group, 1.1% in the fondaparinux group, and rose to 11.7% in the control group.

Samama et al.8, reported a multicenter open-label study to compare efficacy and safety between fondaparinux (2.5 mg) and nadroparin (2,850 IU). There were 1,363 patients with an isolated non-surgical unilateral below-knee injury included of whom 1,349 were randomized. Mean immobilization and treatment durations in both groups were 32 and 34 days, respectively. The incidence of DVT was 2.6% in the fondaparinux group, and 8.2% in the nadroparin group.

Lassen et al.9, performed a RCT to evaluate the efficacy and safety of the reviparin (1,750 IU) in 440 patients who required immobilization for at least five weeks after a leg fracture or Achilles’ tendon rupture. Reviparin was given throughout the period of immobilization. DVT was diagnosed in 17 of the 183 patients randomly assigned to receive reviparin (9%) and in 35 of the 188 patients randomly assigned to receive placebo (19%). Two cases of pulmonary embolism (PE) secondary to proximal DVT were reported in the placebo group. The two groups had comparable rates of bleeding and other adverse events. The mean duration of immobilization was 43 days in the reviparin group and 44 days in the placebo group.

Jorgensen et al.10, carried out a RCT on patients treated by immobilization in a plaster cast. All patients over 18 years of age with a planned plaster cast of a lower extremity with ≥38 days of immobilization were included.  300 patients were included (148 in the treatment group and 152 in the control group) and they were randomized to either 3,500 IU of tinzaparin once daily or no treatment. 95 of these patients later withdrew or were subsequently excluded from the study. DVT was diagnosed in 10% of patients in the treatment group and in 17% of patients in the control group.

Goel et al.11, investigated the incidence of DVT and the need for thromboprophylaxis following isolated trauma below the knee. In a RCT, patients who sustained fractures requiring operative fixation were randomized into two groups. Group (1) was treated with dalteparin, and group (2) received placebo with saline injections. The final analysis involved 238 patients, 127 were in the dalteparin-treated group and 111 in the placebo group. All fractures received either post-operative dressing or immobilization in a cast or both, depending on the fracture type. Immobilization duration was 14 days. All patients were reassessed on or around day 14 after surgery and bilateral venography was performed. 14 DVT were identified (12.6%) in the placebo group and 11 DVT (8.7%) in the dalteparin group.

Nemeth et al.12, conducted a multicenter RCT to study the effectiveness of LMWH for the prevention of VTE following below the knee cast immobilization. The average immobilization duration was 4.9 weeks. Patients with a traumatic injury of the leg or foot who were treated with a below-the-knee cast for at least 1 week were eligible for inclusion. 1,519 patients were randomized (1:1) to either a prophylactic dose of LMWH (2,850 IU) or to no treatment. In the treatment group (LMWH prophylaxis), 1.4% of patients developed VTE versus 1.8% of patients in the control group. No major bleeding occurred in either group.

Selby et al.13, conducted a multicenter RCT to study the efficacy of dalteparin in the prevention of VTE after isolated lower leg fractures. Patients with isolated lower leg fractures requiring surgery were randomized to either dalteparin (5,000 IU) or matching placebo with no therapeutic difference, they received treatment once daily for 2 weeks. A total of 258 patients (97%) were included in the primary outcome analysis for effectiveness (130: dalteparin; 128: placebo). Immobilization duration was on average 44 days in the dalteparin group and 42 days in the placebo group. The incidence of VTE in the dalteparin and placebo groups was 1.5% and 2.3%, respectively. There was no fatal PE or major bleeding in either patient cohort.

The largest and most impactful study was produced by Samama et al.14, in 2020. Published in the New England Journal of Medicine, the PROphylaxis in NOn-Major Orthopaedic Surgery (PRONOMOS) clinical trial compared the effect of rivaroxaban versus enoxaparin in preventing major VTE in patients undergoing lower limb non-major orthopaedic surgery. The study was a multicenter RCT. The patient cohort consisted of all adults undergoing non-major surgery of the lower limb. Patients had to have been scheduled to receive VTE prophylaxis for at least 2 weeks to be eligible for trial enrollment. The primary efficacy outcome studied was the occurrence of symptomatic proximal or distal DVT, PE or VTE-related death during the treatment period, or 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. Bleeding rates in the intention-to-treat population did not differ between the rivaroxaban and enoxaparin groups (1.08% and 1.04%, respectively). 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 is a complex interplay of both patient and nonpatient-related factors. Studies have repeatedly shown that prolonged postoperative immobilization does definitively increase a patient`s risk of developing VTE complications15. Guidelines on early and aggressive postoperative mobilization have been established to mitigate the risks immobilization poses to patients16. However, based on current literature, the duration of immobilization in patients with lower extremity injuries does not appear to influence the choice of VTE prophylaxis.

References:

1.         Otero-Fernández R, Gómez-Outes A, Martínez-González J, Rocha E, Fontcuberta J, Bemiparin Cooperative Study Group in Orthopaedic Patients. 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

2.         Lapidus LJ, Ponzer S, Elvin A, et al. Prolonged thromboprophylaxis with Dalteparin during immobilization after ankle fracture surgery: a randomized placebo-controlled, double-blind study. Acta Orthop. 2007;78(4):528-535. doi:10.1080/17453670710014185

3.         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

4.         Lapidus LJ, Rosfors S, Ponzer S, et al. Prolonged thromboprophylaxis with dalteparin after surgical treatment of achilles tendon rupture: a randomized, placebo-controlled study. J Orthop Trauma. 2007;21(1):52-57. doi:10.1097/01.bot.0000250741.65003.14

5.         Ali IA, Elbana H, Farhan M, Qureshi IF, Mubashir A. Venous thromboembolism in trauma patients with lower limb cast immobilization, associated risk reduction and complication using rivaroxaban. Ir J Med Sci. 2021;190(1):169-175. doi:10.1007/s11845-020-02306-3

6.         Saragas NP, Ferrao PNF, Jacobson BF, Saragas E, Strydom A. The benefit of pharmacological venous thromboprophylaxis in foot and ankle surgery. S Afr Med J. 2017;107(4):327-330. doi:10.7196/SAMJ.2017.v107i4.10843

7.         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

8.         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

9.         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

10.       Jørgensen PS, Warming T, Hansen K, et al. Low molecular weight heparin (Innohep) as thromboprophylaxis in outpatients with a plaster cast: a venografic controlled study. Thromb Res. 2002;105(6):477-480. doi:10.1016/s0049-3848(02)00059-2

11.       Goel DP, Buckley R, deVries G, Abelseth G, Ni A, Gray R. Prophylaxis of deep-vein thrombosis in fractures below the knee: a prospective randomised controlled trial. J Bone Joint Surg Br. 2009;91(3):388-394. doi:10.1302/0301-620X.91B3.20820

12.       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(9):1508-1516. doi:10.1055/s-0039-1693410

13.       Selby R, Geerts WH, Kreder HJ, et al. A double-blind, randomized controlled trial of the prevention of clinically important venous thromboembolism after isolated lower leg fractures. J Orthop Trauma. 2015;29(5):224-230. doi:10.1097/BOT.0000000000000250

14.       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

15.       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

16.       Pearse EO, Caldwell BF, Lockwood RJ, Hollard J. Early mobilisation after conventional knee replacement may reduce the risk of postoperative venous thromboembolism. J Bone Joint Surg Br. 2007;89(3):316-322. doi:10.1302/0301-620X.89B3.18196

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