Banne Nemeth, Francisco Palma-Arjona, Alberto D. Delgado-Martinez, James Kigera.
Response/Recommendation: Routine venous thromboembolic (VTE) prophylaxis is not indicated in patients with immobilization of the lower extremity.
Strength of the Recommendation: Moderate.
Rationale: Patients with cast immobilization of the lower extremity may be at an increased risk for developing VTE. Based on one study, patients not receiving thromboprophylaxis have a pooled absolute risk for asymptomatic events of 18.0% (95% confidence interval [CI] 12.9 to 23.1) and a symptomatic risk of 2.0% (95% CI 1.3 to 2.7) (within approximately 3-months)1.
The effectiveness of thromboprophylaxis for the prevention of VTE in these patients has been addressed in multiple small randomized controlled trials (RCT), focusing on asymptomatic events in the past. All trials allocated patients to either no therapy or low-molecular-weight heparin (LMWH). Patients were managed with various types of casts, for a variety of non-surgical problems (fractures treated conservatively, tendon ruptures, and so on). In one of the earlier trials, performed in 1993, 253 patients, aged > 16 years were recruited and conservatively managed with a lower limb cast for at least 7 days2. Patients were randomized between nadroparin or no treatment for 16 days. In the protocol analysis, after 53 post-randomization exclusions, 4.8% of all patients with prophylaxis, and 16.5% of patients without prophylaxis developed asymptomatic deep venous thrombosis (DVT) (defined by compression ultrasound) (risk reduction of 11.7% [95% CI 4.3% – 19.3%]). Kock et al., then published an RCT using similar inclusion criteria, in which 339 patients with a lower limb cast were analyzed3. Upon cast removal, a compression ultrasound and duplex scanning was performed, and suspected asymptomatic events were confirmed with venography. In this trial, much lower incidences were found; 0% in the treated and 4.3% in the non-treated group developed asymptomatic DVT (risk reduction 4.3% [95% CI 1.2%–7.4%]).
Two other trials have been published, but patients undergoing surgery and treated non-operatively were included. In one study4, there was no protective effect of the LMWH (no differences between groups, and no symptomatic DVT in any arm). In the other study5, a significant reduction in asymptomatic DVT (relative risk [RR] 0,45, 95% CI 0,24 to 0,83), but no significant reduction for symptomatic VTE (RR, 0.08, 95% CI 0.00 to 1.36) was detected.
To verify whether patients with lower limb cast immobilization could benefit from thromboprophylaxis, a multi-center high-quality RCT (POT-CAST trial), powered based on symptomatic VTE reduction, was performed6. The trial included 1,519 patients who were assigned to LMWH or no prophylaxis during the full period of immobilization of the lower limb. While most patients (approximately 90%) were treated without surgery, the study did include patients who required surgical intervention. Symptomatic VTE occurred in 10 of the 719 patients (1.4%) in the treatment group and in 13 of the 716 patients (1.8%) in the control group (RR, 0.8; 95% CI, 0.3 to 1.7; absolute difference in risk, -0.4 percentage points; 95% CI, – 1.8 to 1.0). No major bleeding events occurred. The results of this trial indicated that there was no advantage to administration of routine chemoprophylaxis (LMWH) to patients with isolated lower extremity injury that required immobilization.
Several meta-analyses have reviewed the published data on this subject matter7,8. In a Cochrane review7, it was reported that thromboprophylaxis was effective for the prevention of asymptomatic VTE for a pooled RR of 0.49, 95% CI 0.34 to 0.72 (heterogeneity I2 20%, p=0.29). It is important to note that all of these trials were powered for prevention of asymptomatic VTE and are of limited quality. Thus, based on our understanding of the available literature, we do not believe that routine use of thromboprophylaxis is indicated in patients with immobilization of lower extremity, who are not undergoing surgery. With the exception of the POT-CAST trial, studies suffer from extensive heterogeneity of included patients, weak methodologies such as inadequate sample size (underpowered), high rates of loss to follow-up, inclusion of high-risk patients only, and post-randomization exclusions. The latter may also explain why the American College of Chest Physicians (ACCP) guideline also does not recommend routine chemoprophylaxis for patients with isolated lower limb injuries requiring leg immobilization9. Other available guidelines advocate for the use of thromboprophylaxis on an individualized approach by evaluating the risks and benefits of such prophylaxis10.
1. Nemeth B, Cannegieter SC. Venous thrombosis following lower-leg cast immobilization and knee arthroscopy: From a population-based approach to individualized therapy. Thromb Res. 2019;174:62-75. doi:10.1016/j.thromres.2018.11.030
2. Kujath P, Spannagel U, Habscheid W. Incidence and prophylaxis of deep venous thrombosis in outpatients with injury of the lower limb. Haemostasis. 1993;23 Suppl 1:20-26. doi:10.1159/000216905
3. Kock HJ, Schmit-Neuerburg KP, Hanke J, Rudofsky G, Hirche H. Thromboprophylaxis with low-molecular-weight heparin in outpatients with plaster-cast immobilisation of the leg. Lancet. 1995;346(8973):459-461. doi:10.1016/s0140-6736(95)91320-3
4. 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
5. 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
6. 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
7. Zee AA, van Lieshout K, van der Heide M, Janssen L, Janzing HM. Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-limb immobilization. Cochrane Database Syst Rev. 2017;8:CD006681. doi:10.1002/14651858.CD006681.pub4
8. Ettema HB, Kollen BJ, Verheyen CCPM, Büller HR. Prevention of venous thromboembolism in patients with immobilization of the lower extremities: a meta-analysis of randomized controlled trials. J Thromb Haemost. 2008;6(7):1093-1098. doi:10.1111/j.1538-7836.2008.02984.x
9. 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
10. Venous thromboembolism: reducing the risk for patients in hospital | Guidance | NICE. Accessed October 19, 2021. https://www.nice.org.uk/Guidance/CG92