Is It Safe to Use Tranexamic Acid for Chronic Subdural Hematoma: A Systematic Review and Meta-Analysis

Abstract

Trans-4-(aminomethyl)-cyclohexane-1-carboxylic acid, also known as tranexamic acid (TXA), has occasionally been used to prevent postoperative recurrence of chronic subdural hematoma (CSDH) after burr hole craniotomy (BC). However, there is a lack of data about the safety and efficacy of TXA administration after BC. This systematic review and meta-analysis adhered to the Cochrane Handbook Standards Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searching databases up to January 2024 for randomized controlled trials and cohort studies evaluating TXA. The primary outcome was CSDH recurrence and reoperation. The secondary outcome was thrombosis risk and mortality rate. Ten studies were included, comprising 14,836 patients with CSDH who underwent surgical treatment. Five studies were randomized controlled trials, while the other two case series and three cohort studies. The overall pooled hematoma recurrence rate in the group of patients who used TXA as an adjuvant treatment to the surgical intervention (TXA group), compared with patients who only used surgery to treat CSDH (control group), was 0.05 (95% confidence interval [0.03–0.08], p < 0.01), indicating a significant reduction in recurrence with TXA treatment. TXA, as an adjuvant treatment to the surgical intervention, reduces the risk of postoperative hematoma recurrence, reoperation, thromboembolic complication, and mortality related to CSDH after BC in elderly patients.

Keywords

chronic subdural hematoma - craniotomy - subdural hematoma - tranexamic acid

Introduction

Chronic subdural hematoma (CSDH) commonly occurs in elderly patients, and in the aging population, the incidence is expected to increase.[1] The burr hole craniotomy (BC) is the standard management, which shows promising outcomes. However, the risk of hematoma recurrence varies by 10 to 29% in 1 to 8 weeks.[2] [3] However, since the development of the endovascular technique, middle meningeal artery embolization demonstrated high efficacy as an alternative or adjunctive approach in the management of CSDH.[4] [5] Regarding the promising results of different surgery techniques and patient selection,[6] the major concern about the priority of modalities and patient selection is still not proven.

In addition, nonsurgical techniques and drug prescriptions, including dexamethasone,[7] [8] angiotensin-converting enzyme inhibitors,[9] tranexamic acid (TXA),[10] [11] and herbal medicine,[12] have been reported in the literature. It is still unknown which of these drugs are safe and suitable for the elderly, given their high incidence of frailty to be prescribed with multiple medications. In the CSDH cavity, inflammatory mediators stimulate vascular permeability and release tissue plasminogen activators from endothelial cells, increasing plasminogen conversion to plasmin.[13] TXA reversibly binds to plasminogen, preventing the binding of plasmin to fibrin and degradation of fibrin, subsequently.[14] Although previous studies have reported a preventative effect of oral TXA for CSDH,[15] hyperfibrinolysis contributes to continuous bleeding in the cavity and the recurrence of hematoma.[16] This study aimed to investigate the safety and efficacy of TXA as an adjunct option of surgery on CSDH.

Materials and Methods

Protocol and Registration

This systematic review and meta-analysis are formulated by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. The study has not been registered in either PROSPERO or another systematic reviews database.

Database and Search Strategy

A comprehensive literature search, spanning from inception to January 2024, was performed across the following databases: PubMed, SCOPUS, EMBASE, and Web of Science from inception to September 21, 2023. The following search terms, “Tranexamic acid,” “recurrence,” and “Chronic Subdural Hematoma,” were combined using Boolean operators and truncation ([Table 1]). The search was limited to English-language or available English translation publications.

Table 1 Search strategies for various databases

Database	Search strategy	Number
PubMed	#1 “tranexamic acid”[MeSH Terms] OR (“tranexamic”[All Fields] AND “acid”[All Fields]) OR “tranexamic acid”[All Fields] #3 “Hematoma, Subdural”[Mesh] OR “Hematoma, Subdural, Intracranial”[Mesh] OR “Hematoma, Subdural”[Mesh] OR “subdural hematoma”[tiab] OR “subdural haematoma”[tiab] OR “subdural hematoma”[tiab] OR “haematoma, subdural”[tiab] OR “haematoma, subdural”[tiab] OR “haemorrhage, subdural”[tiab] OR “hematoma, subdural”[tiab] OR “hemorrhage, subdural”[tiab] OR “subdural bleeding”[tiab] OR “subdural haematoma”[tiab] OR “subdural haemorrhage”[tiab] OR “subdural hemorrhage”[tiab] OR “subdural hematoma”[tiab] #4 #1 AND #2 AND #3	54
SCOPUS	#1 TITLE-ABS-KEY (“tranexamic acid” OR (“tranexamic” AND “acid”) OR “tranexamic acid”) #3 TITLE-ABS-KEY (“subdural hematoma” OR “subdural haematoma” OR “subdural hematoma” OR “haematoma, subdural” OR “haemorrhage, subdural” OR “hematoma, subdural” OR “hemorrhage, subdural” OR “subdural bleeding” OR “subdural haematoma” OR “subdural haemorrhage” OR “subdural hemorrhage” OR “subdural hematoma”) #4 #1 AND #2 AND #3	158
Embase	#1 'tranexamic acid'/exp OR 'tranexamic acid':ti,ab OR ('tranexamic':ti,ab AND 'acid':ti,ab) #2 'subdural hematoma'/exp OR 'subdural haematoma':ti,ab OR 'subdural hematoma':ti,ab OR 'haematoma, subdural':ti,ab OR 'haematoma, subdural, intracranial':ti,ab OR 'hemorrhage, subdural':ti,ab OR 'hematoma, subdural':ti,ab OR 'hematoma, subdural, acute':ti,ab OR 'hematoma, subdural, intracranial':ti,ab OR 'hemorrhage, subdural':ti,ab OR 'subdural bleeding':ti,ab OR 'subdural haematoma':ti,ab OR 'subdural hemorrhage':ti,ab OR 'subdural hemorrhage':ti,ab OR 'subdural hematoma':ti,ab #4 #1 AND #2 AND #3	184
WOS	#1 TI= (“tranexamic acid” OR (“tranexamic” AND “acid”) OR “tranexamic acid”) #2 TI= (“subdural hematoma” OR “subdural haematoma” OR “subdural hematoma” OR “haematoma, subdural” OR “haematoma, subdural” OR “haemorrhage, subdural” OR “hematoma, subdural” OR “hemorrhage, subdural” OR “subdural bleeding” OR “subdural haematoma” OR “subdural haemorrhage” OR “subdural hemorrhage” OR “subdural hematoma”) #4 #1 AND #2 AND #3	17

Abbreviations: MeSH: Medical Subject Headings; WOS, Web of Science.

Note: 219 duplicates removed. September 21, 2023.

The inclusion and exclusion criteria were applied to screen the titles and abstracts of the identified studies. Full-text assessments followed for potentially eligible studies, along with manual screening of reference lists of these articles to identify other relevant studies. The cohort studies, randomized controlled trials, or propensity-matched cohorts that administered TXA were included. Conference data, review papers, case reports with less than 10 patients, studies where TXA was used as the primary medical management, and study protocols were excluded. Of note, papers including patients with recurrent CSDH, such as dural arteriovenous fistula, were excluded from the final investigation.

Study Selection

Two independent reviewers performed complete screening to ensure the accuracy and study relevance. Initially, the title and abstract of the selected research were examined to identify and remove any unrelated sources. Then, the full texts of the papers were comprehensively reviewed, facilitating subsequent assessment by two authors meticulously. The manuscript that met the predetermined inclusion criteria of the study was chosen for data extraction. Additionally, to reduce the effect of the viewpoint of the two authors, a third reviewer resolved the disparities. A thorough examination of the references cited within the selected papers was conducted to identify more relevant papers.

Data Extraction

Two reviewers conducted the data extraction process. The information included the author's name, study period, study designation, number of patients, demographic data, hematoma characteristics, complications, mortality, hematoma volume, and follow-up period. The primary outcomes were hematoma recurrence, reoperation rate, and hematoma reduction, and the secondary outcomes were thrombosis, serious adverse events (SAEs), and mortality.

Statistical Analysis

The statistical analysis was performed with STATA V.17. The primary outcome, the rate of recurrence, and the secondary outcome, the rate of thrombosis, were pooled using 95% confidence intervals (CIs) and a random effects model. Subgroup analysis was conducted to explore the outcome based on the study type (randomized control trial and propensity-matched cohorts and case series with more than 10 patients). Heterogeneity was assessed using the I ² test, and an I ² < 30% was defined as low heterogeneity. All statistical tests were two-sided; a p-value of < 0.05 was considered statistically significant. Means are reported as mean (95% CI). Egger's test was used to assess publication bias.

Results

Study Selection Process

The initial search strategy yielded 413 articles in the PubMed, Embase, Scopus, and Web of Science databases. A total of 219 articles were deduplicated, and the remaining 194 articles underwent title/abstract screening, of which 172 articles were removed. A total of 22 articles underwent full-text screening, and studies that did not fully meet the inclusion criteria were excluded (n = 12). Finally, we included 10 studies in the systematic review. Five of the included studies were randomized control trials.[17] [18] [19] [20] [21] The remaining two studies were propensity-matched cohorts[22] [23] and three retrospective study.[10] [11] [24] All the included studies were recently published, encompassing the time frame from 2012 to 2023. [Fig. 1] outlines the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the study selection process.

Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of the study selection process.

Baseline Characteristics

This study included 14,836 patients with subdural hematoma who underwent bur hole hematoma evacuation and received TXA. A total of 7,450 patients only used surgery to treat CSDH (control group), and 7,386 patients received TXA as an adjuvant treatment for the surgical intervention (TXA group). The mean age of the patients was reported in nine studies. The median follow-up of patients was 6 months (range 1–12 months). The duration of TXA administration for patients reported in five studies varied from 21 days to 6 moths.[11] [17] [19] [20] [21] Most studies utilized 750 mg/day of TXA daily,[10] [17] [21] [22] [23] [24] and the remaining studies used 650 mg/day,[11] 1,000 mg/day of TXA,[18] [19] and 1,500 mg/day.[20] [Table 2] represents the baseline characteristics of the included study.

Table 2 Included studies summary

Author, year	Study type	No of patients (control)	% Male (control)	Age (control)	Follow-up (mo)
de Paula et al, 2023[17]	RCT	50 (26)	62 (61.5)	75.8 ± 11.8 (72.6 ± 11.9)	9.4
Kageyama et al, 2013[10]	Retrospective	21	12	72.0 (71.5)	10
Miyakoshi et al, 2023[22]	PSM	930 (465)	65.1 (65.1)	81.3 ± 7.3 (81. 1 ± 6.9)	6
Perel et al, 2012[18]	RCT	270 (137)	228 (85.4)	36 ± 14 (37 ± 14)	1
Wan et al, 2020[19]	RCT	90 (49)	66.7 (48.9)	69.57 ± 13.69 (72.02 ± 11.79)	6
Shibahashi et al,2022[23]	PSM	13,128 (6,564)	4,523 (68.9)	Not specified	12
Tanweer et al, 2016[11]	Retrospective	14	12	56.4 ± 16	3
Workewych, 2018[20]	RCT	24 (13)	41.6 (46.1)	70.18 ± 12.03 (70.85 ± 9.31)	2–3
Yamada and Natori, 2020[21]	RCT	154 (82)	64.9 (69.5)	78.2 ± 9.8 (78.8 ± 10.8)	3
Yang et al, 2023[24]	Retrospective	155 (114)	77.4 (76.3)	72.0 (71.5)	10

Abbreviations: PSM, propensity score matching; RCT, randomized clinical trial.

Primary Outcome

Recurrence

In the five studies that reported hematoma recurrence, the pooled recurrence rate in the TXA group was found to be 0.02 (95% CI [0.00–0.04], I ²: 6.16%, p-value = 0.32) and the control group 0.08 (95% CI [0.05–0.11], I ²: 0.01%, p-value: 0.66). Test of group difference revealed that adjuvant TXA to surgical management was associated with significant decrease in recurrence rate (p-value < 0.001) ([Fig. 2]).

Fig. 2 The recurrence rate between adjuvant tranexamic acid (TXA) to surgery (TXA group) and surgical management only (control group).

Reoperation

Three studies included the required reoperation rate (two cohort studies and one randomized clinical trial [RCT]). The overall reoperation rate in the TXA group was 0.05 (95% CI [0.00–0.10], I ²: 92.59%, p-value < 0.001) and in the control group was 0.12 (95% CI [0.03–0.20], I ²: 91.7%, p-value < 0.001). Test of group difference showed no significant difference between adjuvant TXA compared with the control group (p-value: 0.18) ([Fig. 3]).

Fig. 3 The reoperation rate between adjuvant tranexamic acid (TXA) to surgery (TXA group) and surgical management only (control group).

Hematoma Volume Reduction

Two RCT studies evaluated the hematoma reduction, the overall SDH volume was –0.36 (95% CI [–0.66 to –007], I ²: 98%, p-value = 0.98), lower in the TXA group than the control group, which was significantly different (p-value < 0.02) ([Fig. 4]).

Fig. 4 The hematoma reduction between adjuvant tranexamic acid (TXA) to surgery (TXA group) and surgical management only (control group).

Secondary Outcome

Mortality Rate

Three studies evaluated the mortality rate (two RCTs and one cohort study), the mortality rate in the TXA group was 0.06 (95% CI [0.03–0.10], I ²: 49.70%, p-value = 0.15), and in the control group was 0.07 (95%CI [–0.03 to 0.18], I ²: 98.87%, p-value < 0.001). The overall mortality rate was reduced in the TXA group compared with the control group but the difference was not statistically significant (p-value: 0.87) ([Fig. 5]).

Fig. 5 The comparison of mortality rate between adjuvant tranexamic acid (TXA) to surgery (TXA group) and surgical management only (control group).

Serious Adverse Events

Three RCTs categorized the SAEs, including new onset or growth of the intracranial hemorrhage, the need for neurosurgery, or death. The SAE in the TXA group was found to be 0.20 (95% CI [–0.05 to 0.40], I ²: 96.25%, p-value < 0.001) and 0.19 (95% CI [–0.19 to 0.57], I ²: 100%, p-value < 0.001) in the control group. Test of group difference was shown and no significant difference was present between the TXA and control group ([Fig. 6]).

Fig. 6 The forest plot of serious adverse events between adjuvant tranexamic acid (TXA) to surgery (TXA group) and surgical management only (control group). Complications were not significantly different between the two groups (p-Value: 0.96).

Fig. 7 The forest plot of thromboembolic complication rate between adjuvant tranexamic acid (TXA) to surgery (TXA group) and surgical management only (control group).

Thromboembolic Complications

Four studies (two RCTs and two cohort studies) evaluated thromboembolic complications (TCs). TC in the TXA group was found to be 0.05 (95% CI [–0.02 to 0.11], I ²: 100%, p-value < 0.001) and 0.04 (95% CI [–0.04 to 0.12], I ²: 100%, p-value < 0.001) in the control group.

Publication Bias

The publication bias of the studies was also evaluated by regression, Egger test. No significant publication bias was present in the reoperation rate (t = 1.50, p-value = 0.2072), mortality rate (t = 2.01, p-value = 0.1146), SAE rate (t = 1.24, p-value = 0.2841), and TCs rate (t = 2.29, p-value = 0.0619). However, the recurrence rate had a significant publication bias (t = 2.67, p-value = 0.0282), which means the publication bias affected the recurrence rates in the present study.

Discussion

The outcomes evaluated in this study have two main results: adhering to the primary outcomes, the hematoma recurrence rate is lower in the TXA group than in the control group. Additionally, TXA has not affected the mortality rate or TCs.

In our meta-analysis, the hematoma recurrence rate after surgery is 8%; however, in the previous meta-analysis on the only RCTs and propensity score-matched studies performed by Albalkhi et al found the rate of recurrence to be approximately 13.6%.[25] It should be noted that the risk of hematoma recurrence after drilling surgery varies from 3 to 39%.[26] [27] [28] Our study shows a lower rate of hematoma recurrence than the Japanese studies with 60,000 participants, which found a rate of 13.1%.[29] The results of the present study attributed the high effect of Shibahashi et al, which included 13,128 patients in their observational study, scored match study of 149,543 patients with 1-year follow-up in 1,100 hospitals. In the score-matched retrospective study, the rate of hematoma recurrence that needed reoperation was significantly reduced (TXA: 1.9% vs. surgery group: 6.1%, p-value < 0.001).[23] The major concern is that reoperation after hematoma recurrence is recommended for symptomatic patients or radiological findings of cerebral compression.[30] Moreover, controversial results exist on the bias risk of different techniques in the burr hole surgery.[3] [31] So, findings should be consistent after sensitivity analysis.[23] In another large population cohort study, Miyakoshi et al included 465 patients in each group of their research after the matching of 6,647 patients. They found a reduction of relative risk of hematoma recurrence in the TXA versus control group (6.5% vs. 16.8%) in the 6 months of follow-up.[22] Furthermore, the retrospective study by Tanweer et al on the role of TXA after surgical evacuation found a 91.3% reduction in residual hematoma volume in patients who received oral TXA, with no hematoma recurrence in the 3-month follow-up.[11] On the other hand, the randomized trial study by Wan et al found no postoperative recurrence of hematoma in the TXA group. However, the was not large enough and 30% of participants were lost to follow-up.[19] The discrepancy in results may be associated with the duration of follow-up, which varies from 1 to 12 months.

The routine follow-up computed tomography (CT) scan is contemporary, while it cannot predispose any other comorbidities related to the mortality,[32] and the hematoma recurrence is mainly affected by clinical symptomatic recurrence following TXA or surgery alone.

In this study, no factors were associated with hematoma recurrence. However, several factors have been demonstrated to be associated with the likelihood risk of hematoma recurrence, including postoperative residual hematoma volume, the use of anticoagulants, greater preoperative midline shift, and lack of intraoperative irrigation.[33] [34] Zhu et al found male gender, bilateral hematoma, and drainage as significant predictors of hematoma recurrence.[35] Also, Hamou et al[36] found expansion of hematoma as a predictor of hematoma recurrence. The anatomical variations unifying system, for example, the Oslo CSDH Grading System, which includes post- and preoperative hematoma volume and density changes in the CT scan,[37] could be considered to predict the hematoma recurrence.[38]

In our meta-analysis, the SDH volume reduction was only assessed in two studies[20] [21] in which significant volume depletion was found. Gao et al's systematic review and meta-analysis on 3,102 patients with traumatic brain injuries found that TXA significantly reduced the hematoma volume.[39] Moreover, Yan et al, in their meta-analysis on the efficacy of TXA, found a reduction of hematoma expansion of intracranial hemorrhage compared with the placebo.[40] However, another study on the efficacy of TXA in nontraumatic intracranial bleeding found that TXA does not affect the severity of bleeding of subarachnoid hemorrhage and intracranial hemorrhage.[41] It should be noted that the use of TXA in complex spine and pelvic surgeries was effective in reducing blood loss in the case group rather than the control group.[42] [43]

The secondary endpoint in our study was to examine if the administration of TXA as an adjunct therapy increases the risk of thrombotic events in patients with CSDH. Theoretically, TXA can promote thromboembolic events; however, previous large trials have found that at doses 1 to 2 g, this adverse effect was not clinically significant.[44] [45] In our analysis, four studies reported thrombosis in patients receiving TXA as an adjunct treatment.[17] [20] [21] [22] [23] Our analysis found no association between TXA and the TC rate. Murao et al conducted a meta-analysis on the effects of TXA on thrombotic events in bleeding patients and found no evidence linking TXA to an increased risk of thrombotic events.[46] Another meta-analysis by Hariharan et al concluded that TXA was not associated with an increased risk of thrombotic events.[47]

Although cranial surgery increases the 6-month mortality of CSDH,[48] our study showed that TXA after burr hole surgery has not affected the mortality rate and SAEs of CSDH.[17] [18] [22] Furthermore, administration of TXA in traumatic brain injury did not affect the mortality rate.[39] However, in the emergency settings, TXA reduced the 1-month mortality.[49] Future studies will be prompted to unify the scoring system of mortality and adverse events in the setting of CSDH management. For instance, Zaki et al found beneficial outcome prediction of mortality frailty index (mFI-5) in CSDH patients who underwent cranial surgery.[50] Sastry et al also found mFI-5 as a prediction model of 90 days mortality in atraumatic CSDH.[51]

Compared with other potential treatments, dexamethasone increased the adverse outcomes following 6 months.[8] Additionally, in the systematic review and meta-analysis by Agrawal et al on 653 patients who received primary dexamethasone, 356 patients underwent surgery with an odds ratio of 7.16%.[7] Furthermore, a previous meta-analysis conducted by Wang et al on 611 patients found that atorvastatin was an effective option to reduce hematoma volume[9]; however, the inhibition of cytochrome P450[52] in high doses raises a concern about potential interactions. The results of our study confirmed previous findings on the safety profile and known TXA interaction with other drugs as the higher risk of polypharmacy in elderly patients with CSDH.[1] [53]

Limitations

Although the results of our study showed promising results for the role of TXA as an adjunctive therapy to the surgical evacuation of CSDH, the variation of follow-up time in the studies and the number of patients lost in the clinical course is the notable limitation of this study. Additionally, the long-term outcomes of TXA on the hematoma recurrence have not been described in the studies included in our analysis. Finally, the study's results may be affected by factors such as the hematoma pattern, the history of CSDH, and existing comorbidities. Relying on these important covariation factors and inadequate reporting of the outcomes related to these factors, subgroup analysis was not feasible enough. So, future studies should note the role of comorbidities that influence the outcome of surgery for CSDH patients.

Conclusion

This study indicated that TXA as an adjunct treatment to BC is a safe option to reduce postoperative hematoma recurrence and reoperation, and it has not increased the rate of TCs and SAEs.

Conflict of Interest

None declared.

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Publication History

Article published online:
10 January 2025