What evidence supports the use of tranexamic acid in patients with traumatic brain injury?
Introduction
Traumatic brain injury (TBI) is a substantial cause of disability in the United States with over 2.5 million TBI-related emergency department visits each year.1 Further, TBI results in about 30% of all injury-related deaths. Permanent disability is common after TBI.2 Traumatic brain injury can be defined as any injury to the head that disrupts normal brain function as evidenced by any of the following: alteration in mental state at the time of injury, decreased or loss of consciousness, loss of memory, or neurological deficit. The Glasgow Coma Scale (GCS) is used for grading TBI severity by assessing verbal responses, the patient’s ability to open their eyes voluntarily or in response to external commands from the provider, and motor function. Scores range from 3 to 15 with severe injury identified as a GCS score between 3 and 8, moderate between injury between 9 and 12, and mild injury between 13 and 15. Intracranial hemorrhages (ICH) are common in TBI due to the rupture of small cortical arteries or veins after trauma to the skull which potentially allows for bleeding into the intracranial space. This bleeding is associated with an increased intracranial pressure and neurological deterioration that can be life threatening depending on the severity of the head injury. Such bleeding can be identified through CT imaging and can help serve as a predictor of patient survival following TBI. Recently, tranexamic acid (TXA) has been proposed as a treatment option to improve outcomes in patients with TBI.
Tranexamic acid is a synthetic derivative of the amino acid lysine that works by inhibiting fibrinolysis. Although there are few Food and Drug Administration (FDA)-approved uses for TXA, it is frequently used via multiple routes of administration (ie, oral, intravenous, or topical) for a variety of uses including orthopedic surgery, epistaxis, gastrointestinal bleeding, and uterine bleeding. It has also become routine care in bleeding trauma patients.3 A brief review of TXA in trauma patients is provided below followed by a more in-depth review of TXA for patients with TBI.
TXA in Trauma
Interest in the use of TXA for TBI originated from its efficacy in bleeding, general trauma patients. The primary trial supporting the use of TXA in trauma patients with major bleeding is the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage-2, or CRASH-2, trial which was a randomized controlled trial including 20,211 trauma patients who were significantly bleeding or at risk of significant bleeding.4 The objective of CRASH-2 was to evaluate the effects of TXA on death, vascular occlusive events, and the need for blood transfusion in trauma patients. This randomized trial included adult trauma patients with significant hemorrhage (defined as a systolic blood pressure less than 90 mm Hg or heart rate greater than 110 beats per minute or both) who were within 8 hours of injury. Patients received either 1 gram of TXA infused over 10 minutes, followed by an intravenous (IV) infusion of 1 gram over 8 hours or matching placebo. The primary outcome, all-cause mortality within 4 weeks of injury, was significantly reduced with TXA. The relative risk (RR) of death with TXA was 0.91 (95% CI, 0.85 to 0.97; p=0.0035). Vascular occlusive events did not differ significantly between groups (1.7% in TXA group versus 2.0% in placebo group). Additionally, receipt of blood product transfusions did not differ significantly between groups with 50.4% of TXA patients receiving transfusion versus 51.3% of placebo treated patients receiving blood transfusions. The authors concluded that early administration of TXA to trauma patients significantly reduced all-cause mortality with no significant increase in vascular occlusive events or blood transfusion receival. In the subgroup that received TXA more than 3 hours after the injury, TXA was shown to increase the risk of death due to bleeding which may indicate that treatment with TXA greater than 3 hours after injury is not beneficial.5
TXA in TBI
Until recently, studies evaluating use of TXA in patients with TBI were limited. Many of the studies were small, single-center studies. A summary of these studies can be found in Table 1. In addition, 2 recent meta-analyses of randomized controlled trials evaluated the efficacy and safety of TXA in TBI.6,7 All studies included in these analyses are summarized in Table 1 with one exception. In the 2019 meta-analysis by Chen et al, the authors included a publication from CRASH-2 that was not exclusive to patients with TBI and potentially affects the applicability of this meta-analysis; therefore, no further discussion of this meta-analysis is included.6 Overall results from a meta-analysis by Weng et al, found lower total hemorrhage growth with TXA compared with placebo but failed to find mortality benefit.7 The authors completed a sensitivity analysis excluding 1 low quality study (see Chakroun-Walha in Table 1). In this analysis, mortality was significantly improved with TXA (RR, 0.64; 95% CI, 0.41 to 1.00; p=0.05).
| Table 1. Randomized controlled trials with TXA administration in patients presenting with TBI.8-13 | ||||
|---|---|---|---|---|
| Citation and study design | Subjects | Interventions | Results | Conclusions |
| Mousavinejad 20208 DB, RCT | N=40 patients diagnosed with a contusion and IPH within 8 hours of injury onset requiring surgery Excluded patients with significant extradural hemorrhage | TXA Placebo TXA bolus of 1 g in 500 mL of NS over 10 min followed by a maintenance dose of 1 g in 500 mL of NS | Endpoints: · ICH volume after surgery (cm3): 921.68 TXA vs. 1032.61 placebo; p=0.62 · Mean hemoglobin reduction during surgery (cm3): 0.07 TXA vs. 0.23 placebo; p=0.89; · Mean hemoglobin reduction 6 hours after surgery (cm3): 0.04 TXA vs. 0.12 placebo; p=0.97 · Both groups had a 15% mortality rate | No statistically significant difference between placebo and TXA Limitations: · The trial included only 40 patients · Unclear information regarding maintenance infusion duration |
| Chakroun-Walha 20199 OL, RCT | N=180 patients with TBI and ICH presenting within 24 hours of trauma Excluded patients with significant extracranial bleeding | TXA No TXA TXA bolus of 1 g in 100 mL of NS over 10 min followed by a maintenance dose of 1 g in 500 mL of NS over 8 hours | Primary endpoints: · 28-day mortality: 28.1% TXA vs. 22.6% placebo; p=0.4 · On day 1, numerically more units of PRBC, FFP, and platelets were transfused in the TXA group (p=not significant) Secondary endpoints: · PE: 11.5% TXA vs. 2.4% placebo; p=0.02 · Neurosurgery: 24% TXA vs. 19% placebo; p=0.4 | TXA did not significantly reduce mortality or the need for transfusion or surgery Limitations: · Small sample size · OL · Single center in Tunisia · About half of the patients were treated within the first 8 hours · Numerically more neurosurgeries as well as units of FFP, PRBC, and platelets (on day 1) were required in the TXA group which may mean this group was sicker at baseline |
| Fakharian 201810 DB, RCT | N=149 patients with TBI and ICH arriving within 8 hours of trauma Excluded patients with major organ damage requiring surgical intervention within 8 hours | TXA Placebo TXA bolus of 1 g in 100 mL of NS over 10 min followed by a maintenance dose of 1 g in 1,000 mL of NS over 8 hours | Endpoints: · Growth of ICH: 20.5% TXA vs. 22.7% placebo; p=0.87 · Need for surgery: 10.8% TXA vs. 16% placebo; p=0.35 · Death: 2.7% TXA vs. 4% placebo; p=1 · Unfavorable outcome at discharge: 10.8 TXA vs. 17.3 placebo; p=0.25 | TXA non significantly reduced the growth of hemorrhagic lesion due to TBI Limitations: · Small sample size · Single-center study conducted in Iran |
| Jokar 201711 SB, RCT | N=80 patients within 2 hours of TBI with acute ICH (volume <30 mL) Extensive exclusion criteria including: GCS 30 mL, focal neurologic deficits, SAH, cerebral edema, TXA within 14 days | TXA Placebo TXA bolus of 1 g in 100 mL of NS over 10 min followed by a maintenance dose of 1 g in 500 mL of NS over 8 hours | Primary endpoint: · ICH growth at 48 hours: 1.7 mL TXA vs. 4.3 mL placebo; p<0.001 | TXA reduces ICH growth after TBI and reduces ICH progression Limitations: · No evaluation of safety/AEs · Small sample size · Short time of 2 hours chosen as inclusion time between trauma occurrence and TXA administration · Extensive exclusion |
| Yutthakasemsunt 201312 DB, RCT | N=238 patients with moderate to severe TBI (GCS 4 to 12) presenting within 8 hours of injury without need for immediate surgery | TXA Placebo TXA bolus of 1 g over 30 min followed by a maintenance dose of 1 g infused over 8 hours | Primary endpoint: · Progressive ICH:18%. TXA vs. 27% placebo (RR, 0.65; 95% CI, 0.40 to 1.05) Secondary endpoints: · Death: 14% TXA vs. 10% placebo (RR, 0.69; 95% CI, 0.35 to 1.39) · Unfavorable outcome: 21% TXA vs 27% placebo (RR, 0.76; 95% CI, 0.46 to 1.27) | TXA was not shown to significantly improve clinical outcomes; however, there was no evidence of increased risk of thrombotic AEs Limitations: · Single center in Thailand |
| Perel 201213 Subset of patients from CRASH-2 Study DB, RCT | N=270 patients with TBI and GCS ≤14 with significant hemorrhage who were within 8 hours of injury | TXA Placebo TXA bolus of 1 g over 10 min followed by maintenance dose of 1 g over 8 hours | Primary endpoint: · Total hemorrhage growth: 5.9 mL TXA vs. 8.1 mL placebo; adjusted difference -3.8 mL; 95% CrI, -11.5 to 3.9 mL Clinical outcomes: · Death: 10.5% TXA vs. 17.5% placebo (adjusted OR, 0.49; 95% CrI, 0.22 to 1.06) · Neurosurgery: 15% TXA vs. 15.3% placebo (adjusted OR, 0.98; 95% CrI, 0.50 to 1.91) · Poor outcome: 45.1% TXA vs. 58.4% placebo (adjusted OR, 0.59; 95% CrI, 0.37 to 0.96) | TXA administration might improve outcomes in TBI patients Limitations: · Subgroup of CRASH-2 |
| Abbreviations: AEs=adverse events; CI=confidence interval; CrI=credibility interval; DB=double blind; FFP=fresh frozen plasma; GCS=Glasgow Coma Scale; ICH=intracranial hemorrhage; IPH=Intraparenchymal hemorrhage; S=normal saline; OL=open label; OR=odds ratio; PE=pulmonary embolism; PRBC=packed red blood cells; RCT=randomized control trial; RR=relative risk; SAH=subarachnoid hemorrhage; SB=single-blind; TBI=traumatic brain injury; TXA=tranexamic acid. | ||||
CRASH-3
The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage-3, or CRASH-3, was a multicenter, randomized, international trial designed to compare TXA to placebo in patients with TBI.14 Adults with TBI (within 3 h of injury), a GCS score of 12 or lower, and evidence of intracranial bleeding on CT scan were included. Patients were excluded if they had major extracranial bleeding upon presentation. Patients were randomly allocated to receive a loading dose of 1 g of TXA infused over 10 min (which was started immediately after randomization) followed by an IV infusion of 1 g over 8 hours or matching placebo. The primary endpoint was head injury-related death within 28 days. There were numerous secondary endpoints including head injury-related death within 24 hours of injury, all-cause mortality, disability, vascular occlusive events, neurosurgery, seizures, intensive care unit stay (in days), and adverse events.
Of the 12,737 patients enrolled, 9202 (72.2%) of patients had follow-up data available.14 Baseline subject characteristics were similar between groups where most participants were men (80%), mean age was approximately 40 years old, and the mean time since injury was 1.9 hours. Head injury-related death occurred in 18.5% of patients in the TXA group versus 19.8% in the placebo group (855 versus 892 events; risk ratio [RR], 0.94; 95% confidence interval [CI], 0.86 to 1.02). The researchers also conducted a sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline. Among these patients, the primary endpoint occurred in 12.5% of the tranexamic acid group versus 14.0% in the placebo group (485 versus 525 events; RR, 0.89; 95% CI, 0.80 to 1.00). When stratified by GCS score and pupil reactivity, there was a significant reduction in the risk of the primary outcome with tranexamic acid use in patients with mild-to-moderate head injury (GCS 9 to 15) but no clear reduction in those with severe head injury (GCS 3 to 8). Additionally, there was a significant reduction seen in patients who had bilateral reactive pupils. There were few significant differences between groups in terms of secondary endpoints, but head injury-related death within 24 hours was significantly reduced with TXA (RR, 0.81; 95% CI, 0.69 to 0.95). Importantly, TXA did not increase the risk of thromboembolic events (RR, 0.98; 95% CI, 0.74 to 1.28).
The researchers concluded that administration of TXA to patients with TBI within 3 hours of injury reduces head injury-related death specifically in those with mild to moderate head injury. Additionally, there was no evidence of increased adverse effects or complications with TXA use compared with that of placebo. It should be noted that the original protocol was designed to include patients who presented within 8 hours of injury; however, this protocol was changed based on other evidence suggesting worse outcomes in patients who present later.
Discussion
CRASH-3 is a large, well-designed controlled trial that did not find a significant reduction in head injury-related death among patients with TBI presenting within 3 hours of injury.14 However, TXA was beneficial in a subgroup of patients with mild to moderate TBI. Importantly, TXA did not appear to increase the risk of thromboembolic events in these patients. Although CRASH-3 is a large, well-designed controlled trial, some important limitations exist and should be considered prior to widespread incorporation of TXA in clinical practice. First, the results were only significant in a subgroup of patients with mild to moderate injury; thus, these findings should be considered hypothesis generating and further study in patients with mild to moderate TBI should be conducted. In addition, the use of head injury-related death rather than overall mortality may be considered suspicious. Although the authors do report mortality in the overall population (a nonsignificant reduction), they do not report overall mortality in the subgroup of patients with mild to moderate TBI. It should be noted that overall mortality was the original primary endpoint stated in the protocol and on which the sample size was based.
Other trials (Table 1) evaluating TXA use in TBI are small and few conclusions can be drawn based on this literature.8-13 However, these trials do generally support a reduction in ICH growth with TXA but fail to find much difference in clinical outcomes.7,8-13 Although these trials indicate that the benefits of TXA in TBI patients appear to be small, the risks also appear minimal. Only 1 study found a significant increase of thromboembolic events (see Chakroun-Walha 2019) and limitations of this trial have been noted.9 Other adverse events were not well-addressed in these clinical trials.8-13
Conclusion
From the data available at this time, there does not appear to be a mortality benefit with TXA in the overall TBI population; however, based on the results of CRASH-3, TXA can be considered to improve injury-related death in patients with mild to moderate TBI. If TXA is used in TBI, a 1 g bolus dose followed by a 1 g infusion should be used as other dosing regimens have not been studied at this time.
References
- Severe TBI. Center for Disease Control and Prevention. https://www.cdc.gov/traumaticbraininjury/severe.html. Updated April 2, 2019. Accessed March 2, 2020.
- Manley GT, Hauser SL, McCrea M. Concussion and other traumatic brain injuries. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20thNew York, NY: McGraw-Hill; http://accesspharmacy.mhmedical.com/content.aspx?bookid=2129§ionid=192533001. Accessed March 02, 2020.
- Nishida T, Kinoshita T, Yamakawa K. Tranexamic acid and trauma-induced coagulopathy. J Intensiv Care. 2017;5:5.
- CRASH-2 trial collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376(9734):23-32.
- CRASH-2collaborators, Roberts I, Shakur H, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377(9771):1096-1101.
- Chen H, Chen M. The efficacy of tranexamic acid for brain injury: a meta-analysis of randomized controlled trials [published online ahead of print]. Am J Emerg Med. 2019; pii:S0735-6757(19):30648-5. doi: 1016/j.ajem.2019.158499.
- Weng S, Wang W, Wei Q, Lan H, Su J, Xu Y. Effect of tranexamic acid in patients with traumatic brain injury: a systematic review and meta-analysis. World Neurosurg. 2019; 123:128-135.
- Mousavinejad M, Mozafari J, Ilkhchi RB, Hanafi MG, Ebrahimi P. Intravenous tranexamic acid for brain contusion with intraparenchymal hemorrhage: randomized, double-blind, placebo-controlled trial. Rev Recent Clin Trials.2020; 15(1):70-75.
- Chakroun-Walha O, Samet A, Jerbi M, et al. Benefits of the tranexamic acid in head trauma with no extracranial bleeding: a prospective follow-up of 180 patients. Eur J Trauma Emerg Surg.2019; 45(4):719-726.
- Fakharian E, Abedzadeh-Kalahroudi M, Atoof F. Effect of tranexamic acid on prevention of hemorrhagic mass growth in patients with traumatic brain injury. World Neurosurg. 2018; 109:e748-e753.
- Jokar A, Ahmadi K, Salehi T, Sharif-Alhoseini M, Rahimi-Movaghar V. The effect of tranexamic acid in traumatic brain injury: a randomized controlled trial. Chin J Traumatol. 2017; 20(1):49-51.
- Yutthakasemsunt S, Kittiwatanagul W, Piyavechvirat P, Thinkamrop B, Phuenpathom N, Lumbiganon P. Tranexamic acid for patients with traumatic brain injury: a randomized, double-blinded, placebo-controlled trial. BMC Emerg Med. 2013;13:20.
- Perel P, Al-Shahi Salman R, Kawahara T, et al. CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: the effect of tranexamic acid in traumatic brain injury–a nested randomised, placebo-controlled trial. Health Technol Assess. 2012;16(13): iii-xii, 1-54.
- Roberts I, Shakur-Still H, Aeron-Thomas A, et al. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019 Nov 9; 394(10210):1713-1723.
Prepared by:
John Dicristofano, PharmD
PGY1 Pharmacy Practice Resident
April 2020
The information presented is current as of March 2, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.