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Missingness matters: a secondary analysis of thromboelastography measurements from a recent prehospital randomized tranexamic acid clinical trial
Donohue, J. K., Iyanna, N., Lorence, J. M., Brown, J. B., Guyette, F. X., Eastridge, B. J., Nirula, R., Vercruysse, G. A., O'Keeffe, T., Joseph, B., et al
Trauma surgery & acute care open. 2024;9(1):e001346
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Editor's Choice
Abstract
BACKGROUND Tranexamic acid (TXA) has been hypothesized to mitigate coagulopathy in patients after traumatic injury. Despite previous prehospital clinical trials demonstrating a TXA survival benefit, none have demonstrated correlated changes in thromboelastography (TEG) parameters. We sought to analyze if missing TEG data contributed to this paucity of findings. METHODS We performed a secondary analysis of the Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport Trial. We compared patients that received TEG (YES-TEG) and patients unable to be sampled (NO-TEG) to analyze subgroups in which to investigate TEG differences. TEG parameter differences across TXA intervention arms were assessed within subgroups disproportionately present in the NO-TEG relative to the YES-TEG cohort. Generalized linear models controlling for potential confounders were applied to findings with p<0.10 on univariate analysis. RESULTS NO-TEG patients had lower prehospital systolic blood pressure (SBP) (100 (78, 140) vs 125 (88, 147), p<0.01), lower prehospital Glascow Coma Score (14 (3, 15) vs 15 (12, 15), p<0.01), greater rates of prehospital intubation (39.4% vs 24.4%, p<0.01) and greater mortality at 30 days (36.4% vs 6.8%, p<0.01). NO-TEG patients had a greater international normalized ratio relative to the YES-TEG subgroup (1.2 (1.1, 1.5) vs 1.1 (1.0, 1.2), p=0.04). Within a severe prehospital shock cohort (SBP<70), TXA was associated with a significant decrease in clot lysis at 30 min on multivariate analysis (β=-27.6, 95% CI (-51.3 to -3.9), p=0.02). CONCLUSIONS Missing data, due to the logistical challenges of sampling certain severely injured patients, may be associated with a lack of TEG parameter changes on TXA administration in the primary analysis. Previous demonstration of TXA's survival benefit in patients with severe prehospital shock in tandem with the current findings supports the notion that TXA acts at least partially by improving clot integrity. LEVEL OF EVIDENCE Level II.
PICO Summary
Population
Patients at risk for haemorrhage receiving tranexamic acid before hospitalization, enrolled in the Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport (STAAMP) Trial (n= 903).
Intervention
Prehospital tranexamic acid (TXA) (n= 447).
Comparison
Placebo (n= 456).
Outcome
This study was a secondary analysis of the STAAMP trial, comparing patients that received thromboelastography (TEG) (YES-TEG, n= 837) and patients unable to be sampled (NO-TEG, n= 66) to analyze subgroups in which to investigate TEG differences. NO-TEG patients had lower prehospital systolic blood pressure (SBP) (100 (78, 140) vs. 125 (88, 147)), lower prehospital Glascow Coma Score (14 (3, 15) vs. 15 (12, 15)), greater rates of prehospital intubation (39.4% vs. 24.4%) and greater mortality at 30 days (36.4% vs. 6.8%). NO-TEG patients had a greater international normalized ratio relative to the YES-TEG subgroup (1.2 (1.1, 1.5) vs. 1.1 (1.0, 1.2)). Within a severe prehospital shock cohort (SBP< 70), TXA was associated with a significant decrease in clot lysis at 30 min on multivariate analysis (β= -27.6; 95% CI [-51.3, -3.9].
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Tranexamic acid in pediatric hemorrhagic trauma
Borgman, M. A., Nishijima, D. K.
The Journal of Trauma and Acute Care Surgery. 2023;94(1S Suppl 1):S36-s40
Abstract
There is strong evidence in adult literature that tranexamic acid (TXA) given within 3 hours from injury is associated with improved outcomes. The evidence for TXA use in injured children is limited to retrospective studies and one prospective observational trial. Two studies in combat settings and one prospective civilian US study have found association with improved mortality. These studies indicate the need for a randomized controlled trial to evaluate the efficacy of TXA in injured children and to clarify appropriate timing, dose and patient selection. Additional research is also necessary to evaluate trauma-induced coagulopathy in children. Recent studies have identified three distinct fibrinolytic phenotypes following trauma (hyperfibrinolysis, physiologic fibrinolysis, and fibrinolytic shutdown), which can be identified with viscohemostatic assays. Whether viscohemostatic assays can appropriately identify children who may benefit or be harmed by TXA is also unknown.
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Prehospital Tranexamic Acid for Severe Trauma
Gruen, R. L., Mitra, B., Bernard, S. A., McArthur, C. J., Burns, B., Gantner, D. C., Maegele, M., Cameron, P. A., Dicker, B., Forbes, A. B., et al
The New England journal of medicine. 2023
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Editor's Choice
Abstract
BACKGROUND Whether prehospital administration of tranexamic acid increases the likelihood of survival with a favorable functional outcome among patients with major trauma and suspected trauma-induced coagulopathy who are being treated in advanced trauma systems is uncertain. METHODS We randomly assigned adults with major trauma who were at risk for trauma-induced coagulopathy to receive tranexamic acid (administered intravenously as a bolus dose of 1 g before hospital admission, followed by a 1-g infusion over a period of 8 hours after arrival at the hospital) or matched placebo. The primary outcome was survival with a favorable functional outcome at 6 months after injury, as assessed with the use of the Glasgow Outcome Scale-Extended (GOS-E). Levels on the GOS-E range from 1 (death) to 8 ("upper good recovery" [no injury-related problems]). We defined survival with a favorable functional outcome as a GOS-E level of 5 ("lower moderate disability") or higher. Secondary outcomes included death from any cause within 28 days and within 6 months after injury. RESULTS A total of 1310 patients were recruited by 15 emergency medical services in Australia, New Zealand, and Germany. Of these patients, 661 were assigned to receive tranexamic acid, and 646 were assigned to receive placebo; the trial-group assignment was unknown for 3 patients. Survival with a favorable functional outcome at 6 months occurred in 307 of 572 patients (53.7%) in the tranexamic acid group and in 299 of 559 (53.5%) in the placebo group (risk ratio, 1.00; 95% confidence interval [CI], 0.90 to 1.12; P = 0.95). At 28 days after injury, 113 of 653 patients (17.3%) in the tranexamic acid group and 139 of 637 (21.8%) in the placebo group had died (risk ratio, 0.79; 95% CI, 0.63 to 0.99). By 6 months, 123 of 648 patients (19.0%) in the tranexamic acid group and 144 of 629 (22.9%) in the placebo group had died (risk ratio, 0.83; 95% CI, 0.67 to 1.03). The number of serious adverse events, including vascular occlusive events, did not differ meaningfully between the groups. CONCLUSIONS Among adults with major trauma and suspected trauma-induced coagulopathy who were being treated in advanced trauma systems, prehospital administration of tranexamic acid followed by an infusion over 8 hours did not result in a greater number of patients surviving with a favorable functional outcome at 6 months than placebo. (Funded by the Australian National Health and Medical Research Council and others; PATCH-Trauma ClinicalTrials.gov number, NCT02187120.).
PICO Summary
Population
Adult patients with severe trauma and at risk for trauma induced coagulopathy, enrolled in the PATCH-Trauma trial in 15 emergency medical services in Australia, New Zealand, and Germany (n= 1,310).
Intervention
Tranexamic acid (n= 661).
Comparison
Placebo (n= 646).
Outcome
Survival with a favorable functional outcome at 6 months occurred in 307 of 572 patients (53.7%) in the tranexamic acid group and in 299 of 559 (53.5%) in the placebo group (risk ratio, 1.00; 95% confidence interval (CI), [0.90, 1.12]. At 28 days after injury, 113 of 653 patients (17.3%) in the tranexamic acid group and 139 of 637 (21.8%) in the placebo group had died (risk ratio, 0.79; 95% CI [0.63, 0.99]. By 6 months, 123 of 648 patients (19.0%) in the tranexamic acid group and 144 of 629 (22.9%) in the placebo group had died (risk ratio, 0.83; 95% CI [0.67, 1.03]. The number of serious adverse events, including vascular occlusive events, did not differ meaningfully between the groups.
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Association of Fibrinolysis Phenotype with Patient Outcomes following Traumatic Brain Injury
Durbin, S., Brito, A., Johnson, A., Cotton, B., Rowell, S., Schreiber, M.
The journal of trauma and acute care surgery. 2023
Abstract
BACKGROUND Impaired coagulation is associated with elevated risk of mortality in trauma patients. Prior studies have demonstrated increased mortality in patients with hyperfibrinolysis (HF) and fibrinolysis shutdown (SD). Additionally, prior studies have demonstrated no effect of tranexamic acid (TXA) on fibrinolysis phenotypes. We examined the association of admission fibrinolysis phenotype with traumatic brain injury (TBI) patient outcomes. METHODS Data were extracted from a placebo-controlled multicenter clinical trial. Patients ≥15 years old with TBI (Glasgow Coma Scale 3-12) and systolic blood pressure ≥ 90 mmHg were randomized in the out-of-hospital setting to receive placebo bolus/placebo infusion (Placebo), 1 gram (g) TXA bolus/1 g TXA infusion (Bolus Maintenance [BM]); or 2 g TXA bolus/placebo infusion (Bolus Only [BO]). Fibrinolysis phenotypes on admission were determined by clot lysis at 30 minutes (LY30): SD ≤0.8%, physiologic 0.9-2.9%, HF ≥3%. Logistic regression was used to control for age, sex, penetrating injury, ISS, maximum head AIS, and TXA treatment group. RESULTS 747 patients met inclusion criteria. Fibrinolysis shutdown was the most common phenotype in all treatment groups and was associated with increased age, ISS and presence of intracranial hemorrhage (ICH). Inpatient mortality was 15.2% for SD and HF, and 10.6% for physiologic (p = 0.49). No differences in mortality, disability rating scale at 6 months, acute kidney injury, acute respiratory distress syndrome, or multi-organ failure were noted between fibrinolysis phenotypes. CONCLUSION SD is the most common phenotype expressed in moderate to severe TBI. In TBI, there is no association between fibrinolysis phenotype and mortality or other major complications. LEVEL OF EVIDENCE diagnostic test/criteria, III.
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Prehospital tranexamic acid is associated with a dose-dependent decrease in syndecan-1 after trauma: A secondary analysis of a prospective randomized trial
Gruen DS, Brown JB, Guyette FX, Johansson PI, Stensballe J, Li SR, Leeper CM, Eastridge BJ, Nirula R, Vercruysse GA, et al
The journal of trauma and acute care surgery. 2023
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Editor's Choice
Abstract
BACKGROUND In the Study of Tranexamic Acid During Air and Ground Prehospital Transport (STAAMP) Trial, prehospital tranexamic acid (TXA) was associated with lower mortality in specific patient subgroups. The underlying mechanisms responsible for a TXA benefit remain incompletely characterized. We hypothesized that TXA may mitigate endothelial injury and sought to assess whether TXA was associated with decreased endothelial or tissue damage markers among all patients enrolled in the STAAMP Trial. METHODS We collected blood samples from STAAMP Trial patients and measured markers of endothelial function and tissue damage including syndecan-1, soluble thrombomodulin (sTM), and platelet endothelial cell adhesion molecule-1 (PECAM-1) at hospital admission (0 hours) and 12, 24, and 72 hours after admission. We compared these marker values for patients in each treatment group during the first 72 hours, and modeled the relationship between TXA and marker concentration using regression analysis to control for potential confounding factors. RESULTS We analyzed samples from 766 patients: 383 placebo, 130 abbreviated dosing, 119 standard dosing, and 130 repeat dosing. Lower levels of syndecan-1, TM, and PECAM measured within the first 72 hours of hospital admission were associated with survival at 30 days (P < 0.001). At hospital admission, syndecan-1 was lower in the TXA group (28.30 [20.05, 42.75] vs. 33.50 [23.00, 54.00] P = 0.001) even after controlling for patient, injury, and prehospital factors (P = 0.001). For every 1 g increase in TXA administered over the first 8 hours of prehospital transport and hospital admission, there was a 4 ng/mL decrease in syndecan-1 at 12 hours controlling for patient, injury, and treatment factors (P = 0.03). CONCLUSIONS Prehospital TXA was associated with decreased syndecan-1 at hospital admission. Syndecan-1 measured 12 hours after admission was inversely related to the dose of TXA received. Early pre- and in-hospital TXA may decrease endothelial glycocalyx damage or upregulate vascular repair mechanisms in a dose-dependent fashion. LEVEL OF EVIDENCE Level II, Secondary analysis of a prospective randomized trial.
PICO Summary
Population
Injured patients who received prehospital tranexamic acid (TXA) and were at risk for haemorrhage enrolled in the STAAMP randomised controlled trial (n= 766).
Intervention
Abbreviated dose: 1g of TXA (n= 130). Standard dose: 2g of TXA (n= 119). Repeat dose: 3g of TXA (n= 130).
Comparison
Placebo (saline), (n= 383).
Outcome
Blood samples were collected to measure markers of endothelial function and tissue damage including syndecan-1, soluble thrombomodulin (sTM), and platelet endothelial cell adhesion molecule-1 (PECAM-1) at hospital admission and 12, 24, and 72 hours after admission. Lower levels of syndecan-1, TM, and PECAM measured within the first 72 hours of hospital admission were associated with survival at 30 days. At hospital admission (mean ng/mL [IQR]), syndecan-1 was lower in the TXA group than the placebo group (28.30 [20.05, 42.75] vs. 33.50 [23.00, 54.00]) even after controlling for patient, injury, and prehospital factors. For every 1g increase in TXA administered over the first 8 hours of prehospital transport and hospital admission, there was a 4 ng/mL decrease in syndecan-1 at 12 hours controlling for patient, injury, and treatment factors.
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TXA does not affect levels of TBI-related biomarkers in blunt TBI with ICH: A secondary analysis of the Prehospital TXA for TBI Trial
Hoefer, L. E., Benjamin, A. J., Polcari, A. M., Schreiber, M. A., Zakrison, T. L., Rowell, S. E.
The journal of trauma and acute care surgery. 2023
Abstract
BACKGROUND Brain specific biomarkers such as glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein-2 (MAP-2) have been identified as tools for diagnosis in traumatic brain injury (TBI). Tranexamic acid (TXA) has been shown to decrease mortality in patients with intracranial hemorrhage (ICH). The effect of TXA on these biomarkers is unknown. We investigated whether TXA affects levels of GFAP, UCH-L1, and MAP-2, and whether biomarker levels are associated with mortality in patients receiving TXA. METHODS Patients enrolled in the prehospital TXA for TBI trial had GFAP, UCHL-1 and MAP-2 levels drawn at 0 and 24 hours post injury(n = 422). Patients with ICH from blunt trauma with a GCS <13 and SBP >90 were randomized to placebo, 2 g TXA bolus, or 1 g bolus +1 g/8 hrs TXA infusion. Associations of TXA and 24-hour biomarker change were assessed with multivariate linear regression. Association of biomarkers with 28-day mortality was assessed with multivariate logistic regression. All models were controlled for age, GCS, ISS, and AIS head. RESULTS Administration of TXA was not associated with a change in biomarkers over 24 hours post-injury. Changes in biomarker levels were associated with AIS head and age. On admission, higher GFAP (OR 1.75, CI 1.31-2.38, p < 0.001) was associated with increased 28-day mortality. At 24 hours post injury, higher levels of GFAP (OR 2.09, CI 1.37-3.30, p < 0.001 and UCHL-1(OR 2.98, CI 1.77-5.25, p < 0.001) were associated with mortality. A change in UCH levels from 0 to 24 hours post-injury was also associated with increased mortality (OR 1.68, CI 1.15-2.49, p < 0.01). CONCLUSION Administration of TXA does not impact change in GFAP, UCHL-1, or MAP-2 during the first 24 hours after blunt TBI with ICH. Higher levels of GFAP and UCH early after injury may help identify patients at high risk for 28-day mortality. LEVEL OF EVIDENCE II, therapeutic/care management.
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Prehospital tranexamic acid in trauma patients: a systematic review and meta-analysis of randomized controlled trials
Acharya, P., Amin, A., Nallamotu, S., Riaz, C. Z., Kuruba, V., Senthilkumar, V., Kune, H., Bhatti, S. S., Sarlat, I. M., Krishna, C. V., et al
Frontiers in medicine. 2023;10:1284016
Abstract
BACKGROUND Prehospital tranexamic acid (TXA) may hold substantial benefits for trauma patients; however, the data underlying its efficacy and safety is scarce. METHODS We searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov from inception to July 2023 for all randomized controlled trials (RCTs) investigating prehospital TXA in trauma patients as compared to placebo or standard care without TXA. Data were pooled under a random-effects model using RevMan 5.4 with risk ratio (RR) and mean difference (MD) as the effect measures. RESULTS A total of three RCTs were included in this review. Regarding the primary outcomes, prehospital TXA reduced the risk of 1-month mortality (RR 0.82, 95% CI 0.69-0.97) but did not increase survival with a favorable functional outcome at 6 months (RR 1.00, 95% CI 0.93-1.09). Prehospital TXA also reduced the risk of 24-h mortality but did not affect the risk of mortality due to bleeding and traumatic brain injury. There was no significant difference between the TXA and control groups in the incidence of RBC transfusion, and the number of ventilator- and ICU-free days. Prehospital TXA did not increase the risk of adverse events except for a small increase in the incidence of infections. CONCLUSION Prehospital TXA is useful in reducing mortality in trauma patients without a notable increase in the risk of adverse events. However, there was no effect on the 6-month favorable functional status. Further large-scale trials are required to validate the aforementioned findings. SYSTEMATIC REVIEW REGISTRATION PROSPERO (CRD42023451759).
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Effect of age on the efficacy of tranexamic acid: An analysis of heterogeneity of treatment effect within the CRASH-2 dataset
Manoukian, M. A. C., Tancredi, D. J., Nishijima, D. K.
The American Journal of Emergency Medicine. 2022;53:37-40
Abstract
BACKGROUND Trauma is a major cause of morbidity and mortality in older adults and will become more common as the population ages. Tranexamic acid (TXA) is a lysine analogue frequently used in the setting of significant trauma with hemorrhage. The aim of this study is to investigate the heterogeneity of treatment effect of TXA as it relates to patient age during trauma care. METHODS We included patients from the CRASH-2 trial who were randomized within 3 h of injury. Patients were stratified into age groups <26 years, 26 to 35 years, 36 to 45 years, 46 to 55 years, and >55 years. Multiple logistic regression models were utilized to evaluate adjusted odds ratios (OR) with 95% confidence intervals (CI) for mortality. Heterogeneity of treatment effect was evaluated using Akaike and Bayesian information criteria to determine the optimum logistic regression model after which a Wald Chi-square test was utilized to evaluate statistical significance. RESULTS On univariate analysis, TXA administration decreased mortality within the <26 years cohort (decrease of 2.1%, 95% CI 0.2 to 4.0), 46 to 55 years cohort (decrease 6.7%, 95% CI 2.7 to 10.7), and >55 years cohort (decrease of 5.3%, 95% CI 0.4 to 10.3). On adjusted analysis, when compared to the 36 to 45 years cohort, the <26 year cohort experienced a decreased mortality (OR 0.72, 95% CI 0.62 to 0.85) whereas the >55 year cohort experienced increased mortality (OR 1.8, 95% CI 1.5 to 2.2). Assessment for heterogeneity of treatment effect of TXA administration between groups approached but did not reach statistical significance (p = 0.11). CONCLUSIONS Mortality related to trauma increases with age, however, there does not appear to be heterogeneity of treatment effect for TXA administration among different age groups.
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Intranasal Topical Application of Tranexamic Acid in Atraumatic Anterior Epistaxis: A Double-Blind Randomized Clinical Trial
Hosseinialhashemi, M., Jahangiri, R., Faramarzi, A., Asmarian, N., Sajedianfard, S., Kherad, M., Soltaniesmaeili, A., Babaei, A.
Annals of Emergency Medicine. 2022;80(3):182-188
Abstract
STUDY OBJECTIVE To determine the effectiveness of intranasal topical application of tranexamic acid in reducing the need for anterior nasal packing and determine the number of episodes of rebleeding in adult patients presenting with spontaneous atraumatic anterior epistaxis. METHODS This study was a double-blind randomized trial conducted from September to November 2021 in the ears, nose, and throat (ENT) emergency department (ED), Khalili Hospital, Shiraz, Iran. Cotton pledgets soaked in either phenylephrine and lidocaine (control group) or tranexamic acid with phenylephrine and lidocaine (intervention group) were inserted into the patients' nostrils for 15 minutes. The primary outcome was the need for anterior nasal packing. The secondary outcomes were staying in the ED for more than 2 hours, needing electrical cauterization, and rebleeding within 24 hours and 1 to 7 days of the first referral to the ED. The trial was registered with the Iranian Registry of Clinical Trials (IRCT20210403050815N1). RESULTS A total of 240 patients (120 in each group) were enrolled in this study. Tranexamic acid was associated with a lower rate of need for anterior nasal packing (50.0% versus 64.2%; odds ratio [OR], 0.56; 95% confidence interval [CI], 0.33 to 0.94). There were no significant differences between the 2 groups in terms of the need for electrical cauterization and the rate of rebleeding within 1 to 7 days. Tranexamic acid was associated with a lower rate of stay in the ED for more than 2 hours (9.2% versus 20.8%; OR, 0.38; 95% CI, 0.18 to 0.82) and rebleeding in 24 hours (15.0% versus 30%; OR, 0.41; 95% CI, 0.22 to 0.78) compared with the rates in the control group. CONCLUSION Intranasal topical application of tranexamic acid is associated with a lower rate of need for anterior nasal packing and a shortened stay in the ED; it may be considered a part of the treatment for atraumatic anterior epistaxis.
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A cost-effectiveness and value of information analysis to inform future research of tranexamic acid for older adults experiencing mild traumatic brain injury
Williams, J., Ker, K., Roberts, I., Shakur-Still, H., Miners, A.
Trials. 2022;23(1):370
Abstract
BACKGROUND Tranexamic acid reduces head injury deaths in patients with CT scan evidence of intracranial bleeding after mild traumatic brain injury (TBI). However, the cost-effectiveness of tranexamic acid for people with mild TBI in the pre-hospital setting, prior to CT scanning, is uncertain. A large randomised controlled trial (CRASH-4) is planned to address this issue, but the economic justification for it has not been established. The aim of the analysis was to estimate the likelihood of tranexamic acid being cost-effective given current evidence, the treatment effects required for cost-effectiveness, and the expected value of performing further research. METHODS An early economic decision model compared usual care for mild TBI with and without tranexamic acid, for adults aged 70 and above. The evaluation was performed from a UK healthcare perspective over a lifetime time horizon, with costs reported in 2020 pounds (GBP) and outcomes reported as quality-adjusted life years (QALYs). All analyses used a £20,000 per QALY cost-effectiveness threshold. RESULTS In the base case analysis, tranexamic acid was associated with an incremental cost-effectiveness ratio of £4885 per QALY gained, but the likelihood of it being cost-effective was highly dependent on the all-cause mortality treatment effect. The value of perfect information was £22.4 million, and the value of perfect information for parameters that could be collected in a trial was £21.9 million. The all-cause mortality risk ratio for tranexamic acid and the functional outcomes following TBI had the most impact on cost-effectiveness. CONCLUSIONS There is a high degree of uncertainty in the cost-effectiveness of tranexamic acid for older adults experiencing mild TBI, meaning there is a high value of performing future research in the UK. The value in a global context is likely to be far higher.