Early Versus Late Initiation of Chemical Venous Thromboembolism Prophylaxis in Adult Patients with Severe Traumatic Brain Injury: A Systematic Review and Meta-analysis

Brij S Karmur; Jennifer A Mann; Alexander A Leung; Andreas H Kramer; Michael M H Yang

doi:10.1007/s12028-025-02404-z

Early Versus Late Initiation of Chemical Venous Thromboembolism Prophylaxis in Adult Patients with Severe Traumatic Brain Injury: A Systematic Review and Meta-analysis

Neurocrit Care. 2025 Nov 14. doi: 10.1007/s12028-025-02404-z. Online ahead of print.

Authors

Brij S Karmur^#¹, Jennifer A Mann^#¹, Alexander A Leung², Andreas H Kramer³, Michael M H Yang⁴

Affiliations

¹ Section of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.
² Department of Medicine and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Canada.
³ Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada.
⁴ Section of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, Calgary, Canada. minhan.yang@ucalgary.ca.

^# Contributed equally.

PMID: 41239163
DOI: 10.1007/s12028-025-02404-z

Abstract

Background: Patients with severe traumatic brain injury (TBI) are at high risk of venous thromboembolism (VTE). However, the optimal timing for initiating chemical VTE prophylaxis (cVTEp) remains controversial due to concerns for intracranial hemorrhage progression.

Methods: Five databases were searched (inception to October 2024) for studies evaluating early versus late cVTEp initiation in severe TBI (defined as Glasgow Coma Scale score ≤ 8 or Abbreviated Injury Scale score ≥ 3). Data were extracted independently and pooled using random-effects models. Early versus late cVTEp initiation and stratified analyses (for cutoffs at ≤ 24, ≤ 48, and ≤ 72 h) were performed, and odds ratios (ORs) were calculated. Outcomes included VTE, hemorrhage progression, neurosurgical intervention, and in-hospital mortality. Absolute risk reduction (ARR) was calculated using control event rates and ORs. Risk of bias was assessed by the Risk of Bias in Non-Randomized Studies-of Interventions tool.

Results: Twenty-one studies were included in the systematic review, with 14 (n = 24,401) included in the meta-analysis. Early compared to late cVTEp initiation was associated with lower odds of VTE (OR 0.47; 95% confidence interval [CI] 0.37-0.60), with consistent benefit at ≤ 48 h (OR 0.39; 95% CI 0.23-0.65) and at ≤ 72 h (OR 0.52; 95% CI 0.39-0.69) but not at ≤ 24 h (OR 0.48; 95% CI 0.14-1.60). The ARR of early vs. late initiation within each stratum was 1.2% for ≤ 24 h, 2.1% for ≤ 48 h, and 3.7% for ≤ 72 h, reflecting differences in the event rates for VTE in each stratum. No significant increase in hemorrhage progression, neurosurgical intervention, or mortality was observed. Notably, mortality was significantly lower for cVTEp initiated at ≤ 48 h (OR 0.74; 95% CI 0.63-0.87). All included studies had moderate to serious risk of bias.

Conclusions: Early cVTEp initiation in severe TBI was associated with lower odds of VTE events and a mortality benefit when initiated at ≤ 48 h. These findings support earlier cVTEp, but the results should be interpreted cautiously due to study heterogeneity and risk of bias, highlighting the need for high-quality prospective research.

Keywords: Chemoprophylaxis; Heparin; Prophylaxis; Traumatic brain injury; Venous thromboembolism.