Article, Neurology

Tranexamic acid for traumatic brain injury: a systematic review and meta-analysis

a b s t r a c t

Objective: The antifibrinolytic agent Tranexamic acid (TXA) has demonstrated clinical benefit in trauma patients with severe bleeding, but its effectiveness in patients with Traumatic brain injury is unclear. We conducted a systematic review to evaluate the following research question: In ED patients with or at risk of intracranial hem- orrhage (ICH) secondary to TBI, does TXA compared to placebo improve patients’ outcomes?

Methods: MEDLINE, EMBASE, CINAHL, and other databases were searched for randomized controlled trial (RCT) or quasi-RCT studies that compared the effect of TXA to placebo on outcomes of TBI patients. The main outcomes of interest included mortality, neurologic function, Hematoma expansion, and adverse effects. We used “Grading quality of evidence and strength of recommendations” to assess the quality of trials. Two authors independently abstracted data using a data collection form. Results from studies were pooled when appropriate.

Results: Of 1030 references identified through the search, 2 high-quality RCTs met inclusion criteria. The effect of TXA on mortality had a pooled relative risk of 0.64 (95% confidence interval [CI], 0.41-1.02); on unfavorable func- tional status, a relative risk of 0.77 (95% CI, 0.59-1.02); and on ICH progression, a relative risk of 0.76 (95% CI, 0.58- 0.98). No serious adverse effects (such as Thromboembolic events) associated with TXA group were reported in the included trials.

Conclusion: Pooled results from the 2 RCTs demonstrated statistically significant reduction in ICH progression with TXA and a nonstatistically significant improvement of clinical outcomes in ED patients with TBI. Further ev- idence is required to support its routine use in patients with TBI.

Introduction

traumatic brain injury is a major cause of death and disability in the United States, accounting for an estimated 1.4 million emergency department (ED) visits, 275000 hospitalizations, and 52000 deaths each year [1]. It also exerts substantial burden on the cost of health care in the United States with an estimated cost of 60 billion dollars annually [2].

Secondary brain injury from progressive Intracranial bleeding, cere- bral edema, increased intracranial pressure, and subsequent cerebral is- chemia is the primary cause of morbidity and mortality after TBI [3-6]. Secondary brain injury is worsened by posttraumatic coagulopathy, which occurs in a third of brain injured patients and is associated with a 10-fold increase in risk of death [4,7,8].

* Corresponding author. Department of Emergency Medicine, SUNY Downstate Medical Center, 450 Clarkson Ave, Box: 1228, Brooklyn, NY 11203. Tel.: +1 718 245 2973; fax: +1 718 245 4799.

E-mail addresses: [email protected] (S. Zehtabchi), [email protected] (S.G. Abdel Baki), [email protected] (L. Falzon), [email protected] (D.K. Nishijima).

Recently, the antifibrinolytic agent Tranexamic acid demon- strated improved mortality compared with placebo in severely bleeding trauma patients in the CRASH-2 trial, which enrolled 20211 patients in 40 countries [9]. In addition to the robust data demonstrating clinical benefit in trauma patients with severe bleeding, TXA also has an excel- lent safety profile [10] and has been shown to be cost-effective [11]. Be- cause of the mechanistic potential for TXA to decrease secondary brain injury, it has been considered as a possible therapy to improve Clinically important outcomes in patients with TBI.

The objective of this systematic review was to address the following research question: In ED patients with or at risk of TBI (patients) does administration of TXA (intervention) compared to placebo (compari- son) improve patients’ outcomes such as reduction in mortality, neuro- logic function, and hemorrhage progression (outcome)?

Methods

This systematic review was conducted following the “Preferred Reporting Items for Systematic Reviews and Meta-Analysis” recom- mendation [12]. The authors followed a predesigned protocol for

http://dx.doi.org/10.1016/j.ajem.2014.09.023

literature search, trial selection, data abstraction, quality assessment of trials, and reporting the results.

The following Inclusion/exclusion criteria were applied for selecting eligible trials:

Participants ED patients with or at risk of Intracranial Hemorrhage secondary to TBI. We considered any plausible definition for TBI and “at risk of ICH” used by original articles.

Intervention Intervention consisted of TXA administra- tion at any dose, route, and time after TBI.

Control Placebo administration.

Outcomes The primary outcome measures were (a) death due to any cause after TBI assessed at the end of the follow-up period sched- uled by original studies (eg, inhospital, 30-day, 6-month, etc) and (b) neurologic outcomes measured by any criteria pro- posed by the original studies such as Glas- gow Outcome Score and discharge status. The secondary outcomes included hemor- rhage progression, transfusion requirement, the need for neurosurgical intervention, and adverse effects (such as thromboembolic events) associated with the use of TXA. We also considered additional radiologic outcomes such as development of new hemorrhage, mass effect, and Midline shift, if reported by the original studies.

Study designs Only Randomized controlled trials or quasi-RCTs that compared the impact of TXA compared to placebo on outcomes of TBI patients were considered for inclusion.

Literature search Using a predesigned search strategy devel-

oped by an expert medical librarian (LF), da- tabases including MEDLINE (1946 to March 2014), EMBASE (1980 to March 2014),

CINAHL (1981 to March 2014), and the Cochrane Library were searched. Additional databases searched included web of Science, Google Scholar, and clinicaltrials.gov. The authors also searched the proceedings of emergency medicine, hematology, trauma, neurology, and neurosurgery conferences to look for relevant presented abstracts. In addition, we reviewed the bibliographies of pertinent articles for citations of eligible studies not identified in the electronic data- bases. Lastly, the experts in the field were contacted to solicit information about possi- ble ongoing, unpublished studies. The MEDLINE and EMBASE search strategies are presented in the Appendix A.

Two authors (SZ and SGA), working inde- pendently, reviewed all references and ob- tained the full text of potentially relevant articles. Disagreements were resolved by consensus. The search identified a total of 1030 citations from the databases. After excluding nonrelevant articles based on their titles and abstracts (Fig. 1), 19 full text articles were reviewed. Two RCTs met the eligibility criteria [13,14]. Searching the gray literature identified no additional stud- ies. However, contacting the experts and searching the clinical trials registration

web site revealed an ongoing large multicen- ter trial (CRASH-3) on the topic with esti- mated completion date of 2016 [15]. We also identified a new trial (not recruiting yet) on www.clinicaltrials.gov website that is planning to test the impact of Pre-hospital administration of TXA on the clinical out- comes of TBI patients (trial registraion # NCT01990768).

Data extraction Data from the identified studies were ab- stracted independently by 2 of the authors (SZ and SGA) using a standardized form. When more than 1 technique was used to measure an outcome, data on all measures used were extracted separately. For studies with incomplete quantitative information available, attempts were made to obtain data from the study authors.

The dichotomous outcomes were reported by percentages and 95% confidence intervals (CIs) and Relative risks. Data reported as con- tinuous variables (eg, size of hematoma) were summarized as mean with SD or me- dians with quartiles, whichever used in the original studies.

Quality assessment We used “Grading quality of evidence and

strength of recommendations” criteria to as- sess the quality of the included trial and rate the Level of evidence [16]. Two authors (SZ and DKN) independently assessed the

Fig. 1. Flow diagram of study Selection process for systematic review.

Table 1

Characteristics of the included trials

Study	Patients	Intervention	Comparison	Outcomes
CRASH-2	Institution: 10 hospitals in India and Colombia	TXA 1 gram intravenously	Matching	Primary: Total hemorrhage growth from the first (before
Intracranial Bleeding Study, 2011, [13]	Population: 270 adult (>=16 years old) Inclusion criteria: CRASH-2 inclusion criteria (trauma with significant hemorrhage [SBP b90 mm Hg or heart rate N 110 or both] or at risk for significant hemorrhage, within 8 h of injury) plus TBI (GCS <=14 and a brain CT compatible with TBI) Exclusion criteria: pregnant women and patients for whom a second brain CT was not possible	(IV) over 10 minutes followed by an IV infusion of 1 gram over 8 hours	Placebo	randomization) to second CT scan (24-48 h later) Secondary: (1) Significant of hemorrhage growth defined as an increase by >=25% of total hemorrhage in relation to its initial volume, (2) new ICH, (3) change in subarachnoid hemorrhage grade, (4) mass effect, (5) new focal cerebral ischemia, and (6) clinical outcomes (death from any cause, dependency, and need for neurosurgical intervention) Clinical outcomes were measured upon discharge, at 28 d, or at death, whichever came first
Yutthakasemsunt	Institution: single-center study in Thailand	TXA 1 g IV over 30 minutes	Matching	CT outcomes were measured in 249 patients who had first and second CT. Clinical outcomes were measured in all patients (n = 270) Primary: 1. Progression of ICH revealed by CT scan at
et al, 2013 [14]	Population: 240 adult (N 16 years old) Inclusion criteria: nonPenetrating TBI (GCS score 4- 12) within 8 h of onset and with no indication for emergency neurosurgical intervention	followed by an IV infusion of 1 g over 8 h	placebo	24 h (defined as new ICH on second CT, expansion of existing ICH by 25% or more); 2. increase in pressure effect (increase in midline shift of greater than 1 mm or increase in basal cistern between first and second CT)
	Exclusion criteria: patients with coagulopathy and an elevated serum creatinine (N 2 mg/dL)			Secondary: Inhospital mortality, Glasgow Outcome Scale at hospital discharge, blood transfusion requirement, neurosurgical intervention, and any inhospital thromboembolic events

Abbreviations: SBP, systolic blood pressure.

quality of the included trials. Their agree- ment on the assessment criteria was mea- sured by ?.

Quantitative data synthesis The effect of TXA on dichotomous outcomes

was assessed using a random effects model because the trials were expected to be heterogeneous in their design and patient populations. Relative risk and 95% CIs were calculated. We quantitatively synthesized 3 outcome measures from the 2 randomized trials-inhospital mortality, unfavorable functional status, and significant hemorrhage growth. The definitions of significant ICH and inhospital mortality differed slightly between the 2 trials [13,14]. Because both trials used slightly different measures of functional sta- tus at hospital discharge, we defined the out- come of unfavorable functional status as death, vegetative statue, fully dependent re- quiring constant attention, or dependent but not requiring constant attention.

Statistical heterogeneity was examined using the ?² and I² tests for heterogeneity. Data were analyzed using STATA 11.0 statistical software (STAT Corp, College Station, TX) with weighting for size of the trial.

Results

Two RCTs met the inclusion criteria [13,14]. The characteristics of the included trials are listed in Table 1.

Both studies were of high quality. ? representing the agreement of the 2 authors on elements of quality assessment was 1.0. The details of the quality assessment of the 2 trials are listed in Table 2.

The results of the included trials are summarized in Table 3. CRASH- 2 Intracranial Bleeding Study (ICB) [13] also adjusted the outcomes by Glasgow Coma Scale score, age, time from injury to first comput- ed tomography (CT), time from injury to second CT, and initial hemor- rhage volume. The results of the adjusted outcome analysis are presented in Table 4.

The forest plots representing the Pooled analysis of data pertaining to the main outcomes are shown in Fig. 2.

Table 2

Quality assessment of the included trials

Criteria CRASH-2, 2011 [13] Yutthakasemsunt et al, 2013 [14]

Randomization Yes, patient randomization was balanced by center and with an allocation sequence based ona block size of 8, generated with a computer random number generator.

Concealment Yes, allocations were masked. Both randomization and allocation assignments were kept in a different city by an international coordinating center. The study drug and the placebo ampoules were indistinguishable.

Yes, computer randomization with random block size.

Yes, group assignments were kept in opaque sealed envelopes.

Intention-to-treat analysis Yes Yes

Blinding Yes, double blinded (subjects and investigators). Yes, subjects, caregivers, and outcome assessors were blinded.

Follow-up 270/270 (100%) with clinical follow-up

249/270 (92.2%) for CT outcomes (21 missed: 10 in treatment group and 11 in placebo group)

227/238 (95.4%) had primary outcome analyzed

(11 missed [5 in treatment group and 6 in placebo]: 2 inappropriate consent, 7 dead, 1 agitated, 1 refused)

Outcome reporting bias None identified None identified

Quality of evidence High High

Table 3

Summary of the reported outcomes by the included trials comparing TXA to placebo in ED patients with TBI

Study Outcomes TXA, n/N; % (95% CI) Placebo, n/N; % (95% CI) Relative risk (95% CI) CRASH-2 ICB Study, 2011 [13] Total hemorrhage growth (mean +- SD) ^a 5.9 mL (+-27) 8.1 mL (+-29) ^b

Significant hemorrhage growth ^c 44/123; 36% (28%-45%) 56/126; 44% (36%-53%) 0.80 (0.59-1.09) Area of new hemorrhage on repeat CT (not seen on initial CT) 13/123; 11% (6%-17%) 20/126; 16% (11%-23%) 0.66 (0.35-1.28)

Change in subarachnoid hemorrhage grade -0.11 -0.12 ^d

	Presence of mass effect on CT	58/123; 47% (39%-56%)	76/126; 60% (52%-68%)	0.78 (0.06-0.99)
	New focal cerebral ischemia	6/123; 5% (2%-10%)	12/126; 10% (6%-16%)	0.51 (0.19-1.32)
	Mortality at discharge or 28 d (whichever came first)	14/133; 11% (6%-17%)	24/137; 18% (12%-26%)	0.60 (0.33-1.11)
	Dependency in survivors ^e	26/119; 22% (15%-30%)	29/113; 26% (19%-34%)	0.85 (0.54-1.35)
	Need for neurosurgical intervention at discharge or 28 d	20/133; 15% (10%-22%)	21/137; 15% (10%-22%)	0.98 (0.56-1.72)
	Composite outcome ^f	60/133 45% (36%-54%)	80/137; 58% (50%-67%)	0.77 (0.61-0.98)
Yutthakasemsunt et al, 2013 [14]	Significant hemorrhage growth ^g	21/120; 18% (12%-25%)	32/118; 27% (20%-36%)	0.65 (0.39-1.05)
	Increase in intracranial pressure effect ^h	11/114; 10% (5%-16%)	12/115; 11% (6%-17%)	0.92 (0.60-1.40)
	Improved GCS motor score at 24 h	37/120; 31% (23%-40%)	37/118; 31% (23%-41%)	0.98 (0.67-1.40)
	Inhospital mortality	12/120; 10% (6%-17%)	17/118; 14% (9%-22%)	0.69 (0.35-1.39)
	Unfavorable Glasgow Outcome Scale at hospital discharge ⁱ	21/120; 18% (12%-25%)	27/118; 23% (16%-31%)	0.76 (0.46-1.27)
	Blood transfusion requirement	31/120; 26% (19%-34%)	33/118; 28% (21%-37%)	0.92 (0.60-1.40)
	Need for neurosurgic intervention	3/120; 3% (1%-7%)	0/118; 0% (0%-3%) ^j	5.95 (0.30-117)
	Inhospital thromboembolic events	0/120; 0% (0%-3%) ^j	4/118; 3% (1%-8%)	0.12 (0.01-2.28)

^a Defined as change in total volume from all Hemorrhagic lesions between initial and repeat CT (at 24-48 hours).

^b Unadjusted: reduction of -2.1 mL, 95% CI -9.8 to 5.6; adjusted: reduction of -3.8 mL, 95% CI, -11.5 to 3.9, P = 0.33.

^c Defined as greater than or equal to 25% increase in total volume from all hemorrhagic lesions between initial and repeat CT (at 24-48 hours).

^d P = 0.93.

^e Measured using the 5-point modified Oxford Handicap Score and dichotomized into dependent (fully dependent required attention day and night or dependent not requiring constant attention) or independent (some restriction in lifestyle but independent, minor symptoms, or no symptoms).

^f Significant hemorrhage growth, area of new hemorrhage, new focal cerebral ischemic lesion, need for neurosurgical intervention, and death.

^g Defined as greater than or equal to 25% increase of ICH in any dimension (height, length, or width) or new ICH between initial and repeat CT (at 24 +- 8 hours).

^h Defined as increase in midline shift of greater than 1 mm or an increase in basal cistern between the first and second CT scan.

ⁱ Defined as death, Persistent vegetative state, and severe disability.

^j 0.5 added to both cells to obtain CIs.

No adverse events related to TXA was reported in CRASH-2 ICB [13]. In the study by Yutthakasemsunt et al [14], 4 cases of inhospital throm- boembolic events were documented in the placebo group, but none was reported in the TXA group.

We were not able to examine the impact of TXA on outcome of TBI patients with isolated head injury alone. In the study of Yutthakasemusunt et al [14], 17% (n = 20) and 14% (n = 16) of pa- tients in TXA and placebo groups had isolated head injury, respec- tively. The authors did not evaluate the outcomes in this subgroup because of the small sample size. Similarly, the CRASH-2 ICB [13] au- thors also indicated that only a small number of patients in their study had isolated head injury and the outcomes could not be assessed in this particular subgroup.

Discussion

Improving the outcome of brain injury patients largely depends on minimizing the secondary brain insults because the extent of primary brain damage after TBI cannot be modified. Secondary insults include hematoma expansion, cerebral edema, increased intracerebral pressure, infection, hypoxia, and coagulopathy. The brain tissue contains large amounts of thromboplastin. This substance is released in high concen- tration into the blood stream after Physical trauma to the parenchyma, causing disturbance in coagulation processes [17,18]. In addition, dam- aged cerebral endothelium activates platelets as well as clotting cas- cades to produce intravascular thrombosis and depletion of coagulation factors [19,20].

Table 4

The adjusted analysis of the reported outcomes in the CRASH-2 Intracranial Bleeding Study, comparing TXA to placebo in ED patients with TBI

Study	Outcomes	TXA, n/N; % (95% CI)	Placebo, n/N; % (95% CI) Adjusted odds ratio ^a (95%CI)
CRASH-2 ICB Study, 2011 [13]	Total hemorrhage growth (mean +- SD)^b	5.9 mL (+-27)	8.1 mL (+-29) ^c
Significant hemorrhage growth^d		44/123; 36% (28%-45%)	56/126; 44% (36%-53%)	0.67 (0.40-1.13)
Area of new hemorrhage on repeat CT		13/123; 11% (6%-17%)	20/126; 16% (11%-23%)	0.62 (0.28-1.35)
(not seen on initial CT) Presence of mass effect on CT		58/123; 47% (39%-56%)	76/126; 60% (52%-68%)	0.59 (0.35-0.97) ^e
New focal cerebral ischemia		6/123; 5% (2%-10%)	12/126; 10% (6%-16%)	0.49 (0.18-1.44)
Mortality at discharge or 28 d		14/133; 11% (6%-17%)	24/137; 18% (12%-26%)	0.47 (0.21-1.04)
(whichever came first) Dependency in survivors^f		26/119; 22% (15%-30%)	29/113; 26% (19%-34%)	0.66 (0.32-1.36)
Need for neurosurgical intervention at		20/133; 15% (10%-22%)	21/137; 15% (10%-22%)	0.98 (0.45-1.93)
discharge or 28 d Composite outcome^g		60/133 45% (36%-54%)	80/137; 58% (50%-67%)	0.57 (0.33-0.98)

^a Adjusted by GCS score, time from injury to first CT, time from injury to second CT, and initial hemorrhage volume.

^b Defined as change in total volume from all hemorrhagic lesions between initial and repeat CT (at 24-48 hours).

^c Reduction of -3.8 mL, 95% CI, -11.5 to 3.9, P = .33.

^d Defined as greater than or equal to 25% increase in total volume from all hemorrhagic lesions between initial and repeat CT (at 24-48 hours).

^e Adjusted by GCS score, time from injury to first CT, time from injury to second CT, initial hemorrhage volume, and initial mass effect.

^f Measured using the 5-point modified Oxford Handicap Score and dichotomized into dependent (fully dependent required attention day and night or dependent not requiring constant attention) or independent (some restriction in lifestyle but independent, minor symptoms, or no symptoms).

^g Significant hemorrhage growth, area of new hemorrhage, new focal cerebral ischemic lesion, need for neurosurgical intervention, and death.

In-hospital mortality
Unfavorable functional status at hospital discharge a

Progression of hemorrhage b

a - defined as death, vegetative state, or fully dependent requiring attention day and night or dependent but not requiring constant attention

b - defined as ? 25% increase in total volume from all hemorrhagic lesions between initial and repeat CT (at 24-48 hours)

Abbreviations: RR, relative risk; CI, confidence intervals; df, degrees of freedom

Fig. 2. Forest plots representing the effect of TXA on outcome of patients with TBI. A, Inhospital mortality. B, Unfavorable functional status at hospital discharge. C, Progression of hemorrhage.

Tranexamic acid, a lysine analog, functions by inhibiting plasminogen activation. This action allows mature fibrin clots to be maintained and coagulation to continue uninhibited. The use of TXA for TBI to improve clinical outcomes is based on the theory that TXA may limit secondary brain injury through 2 mechanisms. First, TXA, as an antifibrinolytic agent, may limit fibrinolysis and thus ICH progression. Fibrinolysis is common in TBI and has been shown to be a strong independent predictor of ICH progression [21]. Second, TXA may inhibit the effect of tissue plasminogen activator, which plays a role in perilesional edema [22].

We identified 2 high-quality clinical trials that tested the hypothesis that administration of TXA to patients with TBI would reduce hematoma growth compared with placebo [13,14]. Both trials were powered to de- tect a difference in ICH progression (initial and repeat Head CT.) but also evaluated clinical outcomes as secondary outcome measures [13,14].

Although not statistically significant, both trials did demonstrate a trend toward decreased ICH progression in the TXA cohort compared with placebo [13,14]. This trend was noted in a number of different measures of ICH progression including total volumetric growth, propor- tion with significant (25%) hemorrhage growth, new area of hemor- rhage, and the presence of mass effect. Both trials also demonstrated a slight trend (nonstatistically significant) toward improved mortality in the TXA cohort [13,14].

After pooling the data pertaining to the 3 outcomes of inhospital mor- tality, functional status, and hemorrhage progression, the meta-analysis revealed a statistically significant reduction in hemorrhage progression in TBI patients receiving TXA. The pooled relative risks for inhospital mortality and functional status were not statistically significant.

The results of these 2 trials suggesting a trend toward decreased ICH progression with early administration of TXA should be viewed with caution. Hematoma expansion has been associated with poor outcome in patients with TBI [23]. Although this outcome likely lies on the causal pathway to clinical outcomes such as functional status and mortality, surrogate outcomes do not always translate into actual clinical outcomes [24]. For example, although an initial phase II clinical trial demonstrated reduction in the hematoma growth and mortality after administration of activated factor VII to patients with nontraumatic ICH [25], subsequent phase III trial confirmed the reduction in hematoma growth but failed to show improved survival or functional outcomes [26].

Limitations

Some limitations exist in the current body of evidence. We did not identify any studies that were adequately powered to detect any clinical outcomes. There was some heterogeneity between identified studies, particularly in the inclusion criteria. The CRASH-2 Intracranial Bleeding Study [13] enrolled a broader range of TBI, with 45% having mild TBI (GCS score, 13-15), compared to Yutthakasemsunt et al [14], which en- rolled patients with moderate to severe TBI (GCS score, 4-12). Almost all patients in the CRASH-2 Intracranial Bleeding Study [13] had significant extracranial injuries. Because TXA has proven Mortality benefit in pa- tients with significant hemorrhage [9], the trend toward improved mor- tality in this study may be a result of limiting extracranial hemorrhage progression by TXA, and the benefits might not be the same in patients with Isolated TBI. CRASH-2 ICB [13] study also had a Protocol deviation leading to enrollment of 31 patients (11%) with a GCS score of 15 and 7 patients (3%) with a normal initial head CT. Tranexamic acid would un- likely have any clinical benefit in these patients. This issue could have diluted the results of study.

Neither trial was able to examine the outcomes in patients with iso- lated head injury due to the small number of such patients in both trials. Therefore, it is difficult to distinguish the effects of TXA in TBI from that of polytrauma.

The included studies did not account for patients receiving anticoag- ulants or Antiplatelet agents. Such therapies can significantly increase hemorrhage progression post TBI and thus interfere with TXA effects. However, the mean age of the patients recruited in both studies was

younger than 38 years and, therefore, a population less frequently treat- ed with antiplatelet and anticoagulant therapy [13,14].

Although the study by Yutthakasemsunt et al [14] only enrolled nonpenetrating TBI, the CRASH-2 ICB [13] did not categorize TBI into blunt or penetrating. The mechanism of injury could be a confounder that needs to be examined in future trials.

Lastly, the meta-analysis was performed with only 2 trials. Although this fact limits the generalizability of the findings, the high quality of the included trials and absence of significant heterogeneity validate the analysis.

Conclusion

Pooled results from the 2 RCTs demonstrated statistically significant reduction in ICH progression with TXA and a nonstatistically significant improvement of clinical outcomes in ED patients with TBI. Despite an excellent safety profile, further evidence is required to support the rou- tine use of TXA in patients with TBI. An ongoing, international, multi- center, phase III trial (CRASH-3) [15] evaluating the use of TXA on death and disability in patients with TBI with a planned enrollment of 10000 patients will certainly shed light on this particular question.

Conflict of interest

SZ, LF, and DKN have no conflict of interest to report. SGA owns stock options in Bio-Signal Group Corporation and is a coinventor on US pat- ents pending 61/554, 743 and 13/284, and 886. He is also the principal investigator of a National Institutes of Health-funded trial 5R41HD072881-02.

Appendix A

Search strategy for MEDLINE and EMBASE Ovid MEDLINE (1946 to March 1, 2014)

exp Brain Injuries/ (48229)
craniocerebral trauma/ (18742)

(traumatic brain adj (injur$ or concussion$ or contusion$ or laceration$)).tw. (16260)

(traumatic cerebral adj (injur$ or concussion$ or contusion$ or laceration$)).tw. (41)

(tbi or tbis).tw. (11582)

exp intracranial hemorrhages/ (54594)

((brain or basal ganglia or cerebral or cranial or intracranial or posterior fossa or Subarachnoid) adj2 (bleed$ or h?emorrhag$)).tw. (29410)

Pituitary apoplexy.tw. (738)

or/1-8 (127629)

Antifibrinolytic agents/ (3910)

Tranexamic Acid/ (1882)

txa.tw. (833)

amca.tw. (229)

amcha.tw. (113)

amchafibrin.tw. (0)

amikapron.tw. (1)

amstat.tw. (0)

anexan.tw. (0)

antivoff.tw. (0)

caprilon.tw. (0)

(cl 65336 or cl65336).tw. (0)

cy?lo?apron.tw. (46)

exacyl.tw. (5)

fibrinon.tw. (0)

frenolyse.tw. (1)

hemostan.tw. (0)

hexa?apron.tw. (0)

kabi 2161.tw. (2)

kalnex.tw. (0)

lysteda.tw. (6)

micranex.tw. (0)

rikaparin.tw. (0)

ronex.tw. (0)

Appendix A (continued)

Ovid MEDLINE (1946 to March 1, 2014)

spotof.tw. (0)
t-amcha.tw. (41)

theranex.tw. (0)

tramic.tw. (0)

tranex.tw. (0)

tranexam.tw. (8)

tranexa?ic acid.tw. (1807)

tranexic.tw. (0)

trans achma.tw. (0)

trans amcha.tw. (15)

transamin.tw. (14)

transexamic acid.tw. (5)

traxamic.tw. (0)

trenaxin.tw. (0)

ugurol.tw. (5)

or/10-48 (6206)

9 and 49 (328)

Embase (1980 to March 11, 2014)

exp brain injury/ (112797)
head injury/ (36287)

(traumatic brain adj (injur$ or concussion$ or contusion$ or laceration$)).tw. (24818)

(traumatic cerebral adj (injur$ or concussion$ or contusion$ or laceration$)).tw. (52)

(tbi or tbis).tw. (19172)

exp Brain hemorrhage/ (82666)

((brain or basal ganglia or cerebral or cranial or intracranial or posterior fossa or Subarachnoid) adj2 (bleed$ or h?emorrhag$)).tw. (39870)

Pituitary Apoplexy.tw. (902)

or/1-8 (229865)

antifibrinolytic agent/ (3841)

tranexamic acid/ (6543)

txa.tw. (527)

amca.tw. (271)

amcha.tw. (90)

amchafibrin.tw. (19)

amikapron.tw. (3)

amstat.tw. (1)

anexan.tw. (0)

antivoff.tw. (0)

caprilon.tw. (9)

(cl 65336 or cl65336).tw. (1)

cy?lo?apron.tw. (435)

exacyl.tw. (103)

fibrinon.tw. (0)

frenolyse.tw. (13)

hemostan.tw. (0)

hexa?apron.tw. (11)

kabi 2161.tw. (4)

kalnex.tw. (0)

lysteda.tw. (33)

micranex.tw. (0)

rikaparin.tw. (0)

ronex.tw. (0)

spotof.tw. (6)

t-amcha.tw. (33)

theranex.tw. (0)

tramic.tw. (0)

tranex.tw. (17)

tranexam.tw. (12)

tranexa?ic acid.tw. (2691)

tranexic.tw. (0)

trans achma.tw. (0)

trans amcha.tw. (5)

transamin.tw. (59)

transexamic acid.tw. (12)

traxamic.tw. (0)

trenaxin.tw. (0)

ugurol.tw. (44)

or/10-48 (9852)

9 and 49 (698)

References

AJEM

Tranexamic acid for traumatic brain injury: a systematic review and meta-analysis

a b s t r a c t

Introduction

Methods

Results

Discussion

In-hospital mortality
Unfavorable functional status at hospital discharge a

Progression of hemorrhage b

Limitations

Conclusion

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Tranexamic acid for traumatic brain injury: a systematic review and meta-analysis

a b s t r a c t

Introduction

Methods

Results

Discussion

In-hospital mortality Unfavorable functional status at hospital discharge a Progression of hemorrhage b

Limitations

Conclusion

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In-hospital mortality
Unfavorable functional status at hospital discharge a

Progression of hemorrhage b