Venous thromboembolic pharmacological prophylaxis in severe traumatic acute subdural hematomas: Early prophylaxis is effective and safe
Dominik A. Jakob, Elizabeth R. Benjamin*, Gustavo Recinos, Camilla Cremonini, Meghan Lewis, Demetrios Demetriades
Division of Trauma and Critical Care, University of Southern California, Los Angeles, CA, USA
A R T I C L E I N F O
Article history:
Received 31 March 2021 Received in revised form 26 July 2021
Accepted 27 July 2021
A B S T R A C T
Background: The purpose of this study was to evaluate the optimal timing and type of pharmacological venous thromboembolism prophylaxis (VTEp) in patients with severe blunt head trauma with acute subdural hematomas (ASDH).
Methods: Matched cohort study using ACS-TQIP database (2013e2016) including patients with isolated ASDH. Outcomes of matched patients receiving early prophylaxis (EP, ≤48 h) and late prophylaxis (LP, >48 h) were compared with univariable and multivariable regression analysis.
Results: In 1,660 matched cases VTE complications (3.1% vs 0.5%, p < 0.001) were more common in the LP compared to the EP group. Multivariable regression analysis identified EP as an independent protective factor for VTE complications (OR 0.169, p < 0.001) but not mortality (p ¼ 0.260). The adjusted risk for delayed craniectomy was not associated with EP compared to LP (p ¼ 0.095). LMWH was independently associated with a lower mortality (OR 0.480, p ¼ 0.008) compared to UH.
Conclusions: Early VTEp (≤48 h) does not increase the risk for craniectomies and is independently associated with fewer VTE complications in patients with isolated ASDH. LMWH was independently associated with a lower mortality compared to UH.
Keywords:
Venous thromboembolism Subdural hematoma Prophylaxis
1. Introduction
Traumatic brain injury (TBI) remains the leading cause of death in the United States with an annual average of 53,000 deaths.1 Patients with severe TBI are associated with high risk for venous thromboembolism (VTE), which may occur soon after the traumatic event.2 Procoagulants, namely tissue factors are rich in the brain tissue and may trigger a hypercoagulable state after systemic release.3e5 Early pharmacological prophylaxis reduces this risk of VTE but there are concerns about the risk of progression of intra- cranial bleeding.
The presence of associated extracranial injuries complicates any interpretation of efficacy and safety of VTE pharmacological pro- phylaxis (VTEp). In addition, there is evidence that different types of intracranial hemorrhage may be associated with different risks of VTE complications.2 Also, the type of intracranial hemorrhage can affect the hemodynamic presentation of the patient, which could complicate the analysis. For example, SAH is very often is associated with tachycardia, EKG abnormalities, elevated Troponin levels and fever, which could complicate the interpretation of the data. To minimize these problems, the present study evaluated the efficacy and safety of early prophylaxis in patients with isolated severe blunt TBI and acute subdural hemorrhage (ASDH).
Furthermore, heparinoids might have neuroprotective proper- ties. We hypothesized that LMWH is superior to UH in patients with severe TBI and ASDH.
2. Material and methods
The study was approved by the Institutional Review Board of the University of Southern California.
2.1. Patient selection and data collection
This cohort-matched study used the American College of Sur- geons Trauma Quality Improvement Program (ACS TQIP) database. The database was queried to identify all adult patients ( 16 years old) who sustained isolated TBI that resulted in ASDH over a 4 years period (2013e2016). Isolated severe TBI was defined as head Abbreviated Injury Scale (AIS) 3, excluding patients with extra- cranial body part (neck, chest, abdomen, spine and extremities) AIS 3. Specific intracranial injuries were identified using AIS predot codes, in order to exclude patients with other associated intracranial hemorrhages (epidural, subarachnoid, intra- parenchymal and intra-ventricular hemorrhages). Additionally, patients were excluded if they died or were discharged within 72 h from admission or were transferred from another facility. Other exclusion criteria were: patients who received any pharmacological venous thromboembolic other than unfractionated heparin (UH) or low molecular weight heparin (LMWH) and patients with a history of bleeding diathesis or with missing data regarding VTEp and complications. Furthermore, patients who underwent a craniec- tomy or an ICP monitor placement before the initiation of VTEp were also excluded.
Variables extracted from the TQIP database included patient demographics, vitals and Glasgow Coma Score (GCS) on admission, head AIS, injury severity score (ISS), timing and type of VTE pro- phylaxis. In addition, interventions after initiation of VTEp, such as delayed craniectomy (including 2nd craniectomy) and delayed intracranial pressure monitoring (ICP) were collected. Primary outcomes of interest were pulmonary embolism (PE), deep venous thrombosis (DVT) summarized as VTE complications (PE DVT) and mortality. Secondary outcomes were intensive care unit (ICU) admission, ICU and hospital length of stay (LOS), as well as dispo- sition after hospital discharge. Patients were finally divided in two groups based on timing of VTEp initiation: early prophylaxis, defined as 48 h (EP), or late, defined as > 48 h (LP) after admission.
2.2. Cohort matching
A 1:1 cohort matching of patients receiving EP vs LP was per- formed on the basis of the following criteria: age ( 65, <65 years), gender, hypotension (SBP <90 mmHg), tachycardia (HR > 120 bpm), GCS, head AIS and the type of VTEp (LMWH, UH). The matching tolerance was 0 for all matching criteria. Matching was performed without replacement.
2.3. Statistical analysis
Normality of distribution was assessed using histograms, skewness, kurtosis, and the Shapiro-Wilk test. Univariate analysis was performed to identify differences between the EP and LP group. Pearson’s chi-squared or Fischer Exact test was used to compare proportions for categorical variables, while the Mann-Whitney U test was used to compare continuous variables. Results were re- ported as numbers and percentages for categorical variables or medians and interquartile ranges (IQR) for continuous variables.
In the matched cohorts the effect of timing and type of VTEp was further analyzed with logistic regression analysis. Outcomes (VTE complications including DVT and PE; mortality and delayed cra- niectomy) were included as dependent variables in the logistic regression analysis. Clinically important predictor variables (Age>65, gender, hypotension, tachycardia, GCS <9, AIS head, VTE type) were correlated with the dependent variables using Pearson's chi-squared or Fischer Exact as appropriate and entered in the regression models if the p value was <0.2. Correlation between variables were tested with multicollinearity analysis. Results were reported as odds ratio (OR) and 95% confidence interval (CI). Regression model performance was assessed using goodness of fit, Snell's R-square, and adjusted R-square. Variables with p value < 0.05 were considered significant. All statistical analysis was performed using SPSS version 23.0 (SPSS Inc., Chicago, IL).
3. Results
3.1. Unmatched cohort characteristics
A total of 4,680 patients with isolated blunt TBI with ASDH met the inclusion criteria (Fig. 1). Of these, 1,941 patients (41.5%) received EP and 2,739 (58.5%) received LP. A 1:1 cohort matching resulted in 1660 matched cases, which formed the basis of the present study. All matching variables [age ( 65, <65 years), gender, hypotension (SBP<90 mmHg), tachy- cardia (HR > 120bpm), GCS, head AIS and the type of VTEp (LMWH, UH)] were equally distributed between patients receiving EP and LP. As well, the ISS between the two groups was similar [1716e21 vs 17,16e21 p ¼ 0.454] (Table 1).
3.2. Interventions and outcomes
In the matched cohorts interventions (delayed ICP monitor, delayed craniectomy, 2nd craniectomy rate) were not significantly different between the two groups. VTE complications (3.1% vs 0.5%, p < 0.001) including PE (0.6% vs 0.1%, p 0.007) and DVT (2.7% vs 0.5%, p < 0.007) were more common in the LP compared to the EP group. ICU admission rate (78.3% vs 66.4%, p < 0001) was higher in the LP group, including longer ICU LOS [42e7 vs 32e4 days, p < 0.001] and hospital LOS [85e13 vs 53e8 days, p < 0.001] compared to the EP group. The majority of patients were discharged home with a higher per- centage when receiving EP compared to LP (61.7% vs 45.4%, p < 0.001). Mortality in patients with isolated ASDH was 1.7% when receiving EP and 2.3% when receiving LP. (p ¼ 0.267) (Table 2).
3.3. Adjusted effect of timing and type of VTEp
The adjusted effect of EP in patients with isolated subdural he- matomas is outlined in Table 3. EP compared with LP was inde- pendently associated with fewer VTE complications (OR 0.169, CI 0.083e0.346) including PE (OR 0.098, CI 0.012e0.769) and DVT (OR 0.176, CI 0.083e0.376). The timing of the VTEp had no independent effect on mortality (p 0.587) or delayed craniectomy (p 0.095). LMWH was identified as an independent protective factor for mortality compared to UH (OR 0.480, CI 0.280e0.824) but not for VTE complications (p 0.550) or delayed craniectomy (p 0.995) No significant collinearity was detected between the predictor variables of the regression models. The VIF was smaller than 1.5 for all variables included in the regression models. The model perfor- mances are outlined in Table 2 and 3.
4. Discussion
Traumatic brain injury is associated with a high mortality1 and an increased risk of VTE complications, without administration of VTEp reported as high as 53.8%.6,7 Pharmacological prophylaxis reduces this risk of VTE complications8e10 but there are concerns that it may increase the risk of progression of intracranial bleeding, especially in severe TBI when applied early.11 The American College of Surgeons recommends in the best practice guidelines for the management of TBI that VTEp should be considered within the first
Abbreviations: AIS, abbreviated injury score; TBI, traumatic brain injury; SAH, subarachnoid hemorrhage; EDH, epidural hemorrhage; IPH, intra-parenchymal hemorrhage; IVH, intra-ventricular hemorrhage; ICP, intra cranial pressure; VTEp, venous thromboembolism prophylaxis
72 h following TBI in most cases.12 A recently published systematic review of patients with TBI and intracranial hemorrhage supports these guidelines: early VTEp at 24e72 h in patients with stable repeat computed tomography scans was associated with reduced VTE incidence without a corresponding increase of intracranial hemorrhage.13 However, there is evidence that an even earlier prophylaxis may be safe and more effective.9,10,14
Most studies in patients with TBI evaluating the optimal timing of VTEp include all types of intracranial hemorrhages. However, it is well known that different types of intracranial hemorrhage are associated with a different risk of VTE2 and may therefore respond differently to pharmacological prophylaxis. The optimal type and timing for initiating pharmacological prophylaxis, especially in the different types of intracranial hemorrhages remains controversial and leading to a wide variability in clinical practice amongst sur- geons and institutions.15e17
Furthermore, LMWH may be superior to unfractionated heparin in patients with TBI due to neuroprotective properties.
The current study was designed to evaluate the optimal timing and type of VTEp after isolated severe TBI with ASDH. We found that VTEp 48 h after admission was independently associated with decreased VTE complications without increased need for craniectomy after initiation of VTEp. Moreover, LMWH has shown a mortality benefit compared to UH. Although the VTE rate including the rate of PE was lower in the group receiving EP, we did not show an independently associated mortality benefit for patients receiving EP. This may be explained by the low number of total patients reported with PE.11
In line with our findings, Byrne et al., in a retrospective pro- pensity matched cohort study identified early initiation of VTEp (<72 h) as superior compared to late prophylaxis (>72 h) in patients with severe isolated traumatic brain injury. The authors reported a
Table 1
Patients Characteristics and Clinical Data after case control matching.
Total
3320 (%) ≤ 48 h
1660 (%) > 48 h
1660 (%)
P value
DEMOGRAPHICS
Age (years)a
58 (37e74)
58 (35e74)
59 (39e73)
0.567
≥ 65 years Gender 1316 (39.6) 658 (39.6) 658 (39.6) 1.000
Male 2094 (63.1) 1047 (63.1) 1047 (63.1) 1.000
PHYSIOLOGIC DATA AND ADMISSION VITALS SIGNS
Hypotension, SBP <90 16 (0.5) 8 (0.5) 8 (0.5) 1.000
Tachycardia, HR > 120 146 (4.4) 73 (4.4) 73 (4.4) 1.000
GCSa 1514,15 1514,15 1514,15 1.000
GCS ≤ 8 288 (8.7) 144 (8.8) 144 (8.8) 1.000
AIS Head
3 740 (22.3) 370 (22.3) 370 (22.3) 1.000
4 2294 (69.1) 1147 (69.1) 1147 (69.1)
5 286 (8.6) 143 (8.6) 143 (8.6)
ISSa 1716e21 1716e21 1716e21 0.454
reported similar findings. In patients with isolated severe TBI an initiation of VTEp after 72 h was independently associated with more VTE complications. Furthermore, early prophylaxis (within 48 h) was independently associated with lower mortality. In addition, LMWH was shown to be superior to UH.10 Again, no subanalysis within the different types of intracranial hemorrhages was performed.
Other retrospective studies reported reduced DVT rates following initiation of VTEp as early as 24 h.19,20 Phelan et al.21 reported in a randomized double-blinded placebo-controlled pilot trial, which included 60 patients, that TBI progression rates after starting LMWH 24 h after the injury were similar to those of the placebo group in low-risk patients. One DVT occurred in the pla- cebo group (28 patients), whereas no VTE complication occurred in the LMWH group (32 patients). All these studies were limited by heterogenous injury patterns and small sample sizes and as well did not distinguish between the different types of intracranial hemorrhages. Today, it is a common practice in many centers to start VTEp within 24 h after the demonstration of a stable intra- cranial injury by computed tomography.22,23
The protective effect of LMWH over UH is in line with previous
UH 1634 (49.2) 817 (49.2) 817 (49.2) 1.000 trauma studies.10,24,25 Especially in the setting of traumatic brain
LMWH 1686 (50.8) 843 (50.8) 843 (50.8) injuries LMWH may be associated with neuroprotective proper-
Values are numbers (percentages) unless indicated otherwise.
Abbreviations: SBP, systolic blood pressure; HR, heart rate; GCS, glasgow coma scale; AIS, abbreviated injury score; UH, unfractionated heparin; LMWH, low mo- lecular weight heparin. a Reported as IQR.
Table 2
Interventions and outcomes of patients after case control matching.
Home 1742 (53.6) 1006 (61.7) 736 (45.4) < 0.001
Rehabilitation center 671 (20.6) 275 (16.9) 396 (24.4)
Nursing home 591 (18.2) 244 (15.0) 374 (21.4)
Extended care facility 32 (1.0) 11 (0.7) 21 (1.3)
other 217 (6.7) 95 (5.8) 122 (7.5)
Mortality 67 (2.0) 29 (1.7) 38 (2.3) 0.267
Abbreviations: ICP, intra cranial pressure; PE, pulmonary embolism; DVT, deep vein thrombosis; VTE, venous thromboembolism; ICU, intensive care unit; LOS, length of stay.
Values are numbers (percentages) unless indicated otherwise.
a Reported as IQR.
b Defined as performed after initiation of VTE prophylaxis.
c Reported only for patients who were admitted to ICU.
decreased risk of pulmonary embolism and deep vein thrombosis but no increase in risk of late neurosurgical intervention or death.18 The propensity score matching included the different types of intracranial hemorrhages. However, a subanalysis of VTE compli- cations or mortality within the different types of hemorrhages was not performed.
ties.26e30 Moreover, anti-inflammatory effects31 and the reported lower rate of PE associated with LMWH may have also contributed to better outcomes. Byrne et al. performed a propensity score- matched analysis of major trauma patients from the TQIP data- base. In this study, LMWH was associated with significantly lower risk of PE compared to UH and was therefore recommended as the anticoagulant agent of choice for prevention of PE in patients with major trauma.32 Other studies found lower rates of VTE complica- tions associated with LMWH compared to UH.8,33
Despite the benefits associated with LMWH compared to UH, many institutions still choose UH over LMWH due to a perceived lower bleeding risk. The rationale for this practice is the easy reversibility of the UH with protamine sulfate while LMWH has no specific antidote. In the present study UH was used in nearly half the patients receiving VTEp. A large database study from the United States published similar rates of heparin use (49.1%) in patients with blunt traumatic brain injuries receiving VTEp.10 The wide- spread use of UH may be further explained by the current nonspecific guideline recommendations. The Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition34 gives a Level III recommendation for the use of either LMWH or UH to prevent VTE complications, without making a recommen- dation for one or the other agent.
This is the first study addressing the question of the optimal timing and type of VTEp in patients with TBI and ASDH. A strength of the present study includes the extended matching with the exclusion of patients with extracranial injuries and intracranial hemorrhages other than ASDH in order to minimize confounding effects of heterogenous injury patterns with regard to venous thromboembolic prophylaxis. This strength is also a limitation, because severe subdural hemorrhage is often associated with additional head and extracranial injuries thus making this a very specific subgroup of the population. There are inherent limitations associated with the retrospective study design, based on a large database. First, the findings of the repeat CT scan are not available and could not be considered for the decision-making process of the initiation of the VTEp. Second, duration and held doses after initi- ation of the VTEp are not recorded by the TQIP database. Third, surrogate markers for safety of early prophylaxis included rate of delayed craniectomy and mortality. Subclinical hemorrhage pro- gression or adverse neurological outcomes are not reported by the TQIP database and could not be considered as safety markers.
Table 3
Adjusted effect of early VTEp in patients with isolated subdural hematomas compared to late VTEp.
OR 95% CI (upper/lower) p value Goodness of fit p Cox & Snell R2 Nagelkerke R2
VTE complicationsa
0.169 0.083 0.346 <0.001 0.527 0.017 0.106
PEa
0.098 0.012 0.769 0.027 0.974 0.007 0.160
DVTa
0.176 0.083 0.376 <0.001 0.469 0.013 0.091
Mortalityb
0.752 0.457 1.235 0.260 0.088 0.019 0.107
Delayed craniectomyc
1.937 0.891 4.211 0.095 0.922 0.011 0.117
Abbreviations: VTEp, venous thromboembolism prophylaxis; OR, odds ratio; CI, confidence interval; VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; GCS, glasgow coma score; AIS, abbreviated injury score.
Logistic regression analysis.
a Adjusted for tachycardia, GCS, head AIS.
b Adjusted for age, GCS, head AIS, VTE type.
c Adjusted for gender, GCS, head AIS.
Table 4
Adjusted effect of LMWH as VTEp in patients with isolated subdural hematomas compared to UH.
OR 95% CI (upper/lower) p value Goodness of fit p Cox & Snell R2 Nagelkerke R2
VTE complicationsa
0.852 0.503 1.442 0.550 0.654 0.018 0.106
PEa
0.574 0.163 2.017 0.387 0.874 0.007 0.166
DVTa
0.906 0.516 1.589 0.729 0.564 0.014 0.091
Mortalityb
0.480 0.280 0.824 0.008 0.115 0.019 0.105
Delayed craniectomyc
1.003 0.471 2.136 0.995 0.857 0.011 0.117
Abbreviations: LMWH, low molecular weight heparin; VTEp, venous thromboembolism prophylaxis; UH, unfractionated heparin; OR, odds ratio; CI, confidence interval; VTE venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; GCS, glasgow coma score; AIS, abbreviated injury score.
Logistic regression analysis.
a Adjusted for tachycardia, GCS, head AIS, timing of VTE prophylaxis.
b Adjusted for age, GCS, head AIS.
c Adjusted for gender, GCS, head AIS, timing of VTE prophylaxis.
Finally, the use of UH and LMWH was not randomized and the choice in administration may have contributed to bias in our results.
5. Conclusion
Early VTEp ( 48 h) does not increase the risk for craniectomies and is independently associated with fewer thromboembolic events in isolated severe head injuries with subdural hemorrhage. LMWH is independently associated with lower mortality. These data suggest initiation of early VTEp with LMWH in patients with isolated severe head injuries with acute subdural hemorrhage in the appropriate clinical setting.
Grant support
None.
Statement of human rights
The study was approved by the Institutional Review Board of the University of Southern California.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
All authors declare no potential conflict of interest.
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