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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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Re-analysis of the PolyHeme Phase III trial dataset: Lessons for future haemoglobin-based oxygen carrier trauma trials
Mackenzie CF, Dubé GP, Pitman AN
Injury. 2023
Abstract
INTRODUCTION To assist design of future HBOC clinical trials for pre-hospital and prolonged field care, the haemoglobin-based-oxygen carrier (HBOC) Phase III trauma trial database comparing PolyHeme to blood transfusion was re-analysed to identify causes of adverse early outcomes versus the 30-day mortality outcome of the original trial. We questioned if failure of PolyHeme (10 g/dl) to increase haemoglobin concentration and dilutional coagulopathy versus blood, caused higher Day 1 mortality in the PolyHeme arm of the trial. METHODS New analyses of the original trial database, including Fisher's exact test, examined impact of interval changes in total haemoglobin [THb], coagulation, fluid volumes administered and mortality on Day 1 in the Control (pre-hospital crystalloids, then blood after trauma centre admission) and PolyHeme arms of the trial. RESULTS Admission [THb] was significantly greater (p<0.05) in PolyHeme (12.3 [SD = 1.8] g/dl) versus Control (11.5 [SD= 2.9] g/dl) patients. This early [THb] advantage was reversed within 6 h. Early mortality was negatively correlated with [THb] and maximum 1.4 h after hospital admission (17/365 for Control vs. 5/349 for PolyHeme). The mortality trend began reversing, when Control arm received blood. Coagulopathy was more common in the PolyHeme arm. Mortality rate was 2-fold greater for patients with coagulopathy in the control arm (18% vs. 9%, p = 0.1008) and 4-fold greater in PolyHeme arm (33% vs. 8.5%, p < 0.001). In a subgroup analysis of patients with major haemorrhage (n = 55), mortality was significantly higher in PolyHeme patients [12/26 (46.2%) versus 4/29 (13.8%) in control cohort (p = 0.018)], related to mean 10 liters more IV fluid administration and more severe anaemia (6.2 g/dL vs. 9.2 g/dL) in the PolyHeme cohort. CONCLUSIONS PolyHeme (10 g/dL) diminished pre-hospital anaemia. The inability of PolyHeme to reverse acute anaemia in a subset of major haemorrhage patients was due to volume overload secondary to high PolyHeme doses, resulting in dilution of clotting factors and low circulating THb (versus transfused controls) during the first 12 h of the trial. Haemodilution was associated with prolonged administration of PolyHeme, while blood transfusion was available to Control patients following hospital admission. Coagulopathy exacerbated bleeding, anaemia, contributing to excess mortality in the PolyHeme arm. Future trials for prolonged field care should evaluate HBOC with higher haemoglobin concentration, lower volume administration and transition upon trauma centre admission to blood plus coagulation factors or whole blood.
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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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Role of single-dose intravenous iron therapy for the treatment of anaemia after orthopaedic trauma: protocol for a pilot randomised controlled trial
Peterson, D. F., McKibben, N. S., Hutchison, C. E., Lancaster, K., Yang, C. J., Dekeyser, G. J., Friess, D. M., Schreiber, M. A., Willett, N. J., Shatzel, J. J., et al
BMJ open. 2023;13(3):e069070
Abstract
INTRODUCTION Orthopaedic trauma and fracture care commonly cause perioperative anaemia and associated functional iron deficiency due to a systemic inflammatory state. Modern, strict transfusion thresholds leave many patients anaemic; managing this perioperative anaemia is an opportunity to impact outcomes in orthopaedic trauma surgery. The primary outcome of this pilot study is feasibility for a large randomised controlled trial (RCT) to evaluate intravenous iron therapy (IVIT) to improve patient well-being following orthopaedic injury. Measurements will include rate of participant enrolment, screening failure, follow-up, missing data, adverse events and protocol deviation. METHODS AND ANALYSIS This single-centre, pilot, double-blind RCT investigates the use of IVIT for acute blood loss anaemia in traumatically injured orthopaedic patients. Patients are randomised to receive either a single dose infusion of low-molecular weight iron dextran (1000 mg) or placebo (normal saline) postoperatively during their hospital stay for trauma management. Eligible subjects include adult patients admitted for lower extremity or pelvis operative fracture care with a haemoglobin of 7-11 g/dL within 7 days postoperatively during inpatient care. Exclusion criteria include history of intolerance to intravenous iron supplementation, active haemorrhage requiring ongoing blood product resuscitation, multiple planned procedures, pre-existing haematologic disorders or chronic inflammatory states, iron overload on screening or vulnerable populations. We follow patients for 3 months to measure the effect of iron supplementation on clinical outcomes (resolution of anaemia and functional iron deficiency), patient-reported outcomes (fatigue, physical function, depression and quality of life) and translational measures of immune cell function. ETHICS AND DISSEMINATION This study has ethics approval (Oregon Health & Science University Institutional Review Board, STUDY00022441). We will disseminate the findings through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER NCT05292001; ClinicalTrials.gov.
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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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Efficacy of the Military Tactical Emergency Tourniquet for Lower Extremity Arterial Occlusion Compared with the Combat Application Tourniquet: A Randomized Crossover Study
Samutsakorn DK, Carius BM
Journal of special operations medicine : a peer reviewed journal for SOF medical professionals. 2023
Abstract
INTRODUCTION Extremity bleeding and subsequent hemorrhagic shock is one of the main causes of preventable battlefield death, leading to mass-fielding of modern tourniquets, such as the Combat Application Tourniquet (CAT; Composite Resources). Numerous look-alike tourniquets, such as the Military Tactical Emergency Tourniquet (MTET; SZCTKlink), flood commercial markets, offering visually near-identical tourniquets for drastically reduced prices. We examined the performance of the MTET compared with that of the CAT. METHODS We undertook a randomized crossover trial to observe self-applied tourniquets to the lower extremity by combat medics, comparing the CAT to the MTET in application time and success rates, proven by loss of distal pulse assessed by Doppler ultrasound in <1 minute. RESULTS All 50 participants (100%) successfully applied the CAT versus 40 participants (80%) using the MTET (p = .0001). Median application time for the CAT (29.03 seconds; range, 18.63 to 59.50 seconds) was significantly less than those of successful MTET applications (35.27 seconds; range, 17.00 to 58.90 seconds) or failed MTET applications (72.26 seconds; range, 62.84 to 83.96 seconds) (p = .0012). Of 10 MTET failures, three (30%) were from application time >1 minute and seven (70%) from tourniquet mechanical failure. CONCLUSION The MTET performed worse than the CAT did in all observed areas. Despite identical appearance, look-alike tourniquets should not be assumed to be equivalent in quality or functionality to robustly tested tourniquets.
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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).