Efficacy and Safety of Tranexamic Acid in Emergency Trauma: A Systematic Review and Meta-Analysis

In trauma patients, bleeding can lead to coagulopathy, hemorrhagic shock, and multiorgan failure, and therefore is of fundamental significance in regard to early morbidity. We conducted a meta-analysis to evaluate the efficacy and safety of tranexamic acid (TXA) in civil and military settings and its impact on in-hospital mortality (survival to hospital discharge or 30-day survival), intensive care unit and hospital length of stay, incidence of adverse events (myocardial infarct and neurological complications), and volume of blood product transfusion. The systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic review of the literature using PubMed, Scopus, EMBASE, Web of Science, and the Cochrane Central Register and Controlled Trials (CENTRAL) database was conducted from inception to 10 January 2021. In-hospital mortality was reported in 14 studies and was 15.5% for the TXA group as compared with 16.4% for the non-TXA group (OR = 0.81, 95% CI 0.62–1.06, I2 = 83%, p = 0.12). In a civilian TXA application, in-hospital mortality in the TXA and non-TXA groups amounted to 15.0% and 17.1%, respectively (OR = 0.69, 95% CI 0.51–0.93, p = 0.02, I2 = 78%). A subgroup analysis of the randomized control trial (RCT) studies showed a statistically significant reduction in in-hospital mortality in the TXA group (14.3%) as compared with the non-TXA group (15.7%, OR = 0.89, 95% CI 0.83–0.96, p = 0.003, I2 = 0%). To summarize, TXA used in civilian application reduces in-hospital mortality. Application of TXA is beneficial for severely injured patients who undergoing shock and require massive blood transfusions. Patients who undergo treatment with TXA should be monitored for clinical signs of thromboembolism, since TXA is a standalone risk factor of a thromboembolic event and the D-dimers in traumatic patients are almost always elevated.

All trauma patients with ongoing significant hemorrhage (systolic blood pressure less than 90 mmHg and/or heart rate more than 110 beats per minute), or who are considered to be at risk of significant hemorrhage, and are within 8 hours of the injury, are eligible for trial entry if they appear to be at least 16 years old. Although entry is allowed up to 8 hours from injury, the earlier that patients can be treated the better.
The fundamental eligibility criterion is the responsible doctor's 'uncertainty' as to whether or not to use an antifibrinolytic agent in a particular adult with traumatic hemorrhage. Patients for whom the responsible doctor considers there is a clear indication for antifibrinolytic therapy should not be randomized. Likewise, patients for whom there is considered to be a clear contraindication to antifibrinolytic therapy (such as, perhaps, those who have clinical evidence of a thrombotic disseminated intravascular coagulation) should not be randomized. Where the responsible doctor is substantially uncertain as to whether or not to use an antifibrinolytic, all these patients are eligible for randomization and should be 1 g of tranexamic acid infused over 10 min, followed by an intravenous infusion of 1 g over 8 h, or matching placebo (0·9% saline).
Death in hospital within 4 weeks of injury.
Tranexamic acid safely reduced the risk of death in bleeding trauma patients in this study. On the basis of these results, tranexamic acid should be considered for use in bleeding trauma patients. considered for the trial. There are no other pre-specified exclusion criteria El-Menyar et al. 2020 All patients of both genders aged 16 to 80 years old treated with TXA during the prehospital phase.
All patients receiving the first dose of TXA at the ED. Patients <16 and >80 years of age, vulnerable population (prisoners and pregnant patients), traumatic brain injury with exposed brain, isolated drowning or hanging victims.
1-g in the first 3 hours after injury followed by a 1 g infusion over 8 hours.

Patient characteristics.
Prehospital TXA administration is associated with less in-hospital blood transfusion and massive transfusion protocol (MTP). There is no significant increase in the thromboembolic events and mortality.

Ghawnni et al. 2018
Patients 16 years of age or older who met one or more of the following criteria: (1) tachycardia (defined as a heart rate [HR] ≥110 beats per minute on arrival to the emergency department [ED]); (2) hypo-tension (defined as a systolic blood pressure [SBP] ≤90 on ED arrival); and/or (3) requiring at least 1 unit of PRBCs in the ED.
Patients who received TXA at a peripheral hospital.
1g over 10 min followed by an infusion of 1 g over 8 hours.
The compliance rate of TXA administration.
Compliance with TXA administration to trauma patients with suspected major bleeding was low. Quality improvement strategies aimed at increasing appropriate use of TXA are warranted.
Guyette et al.

"STAAMP"
Injured patients at risk for hemorrhage transported from the scene or transferred from an outside emergency department to a participating site within an estimated 2 hours of the time of injury were eligible for enrollment if they experienced at least 1 episode of hypotension (systolic blood pressure ≤90 mm Hg) or tachycardia (heart rate ≥110 beats per minute) before arrival at a participating center.
Age older than 90 years or younger than 18 years, lack of intravenous or intraosseous access, isolated fall from standing, documented cervical cord injury, known prisoner or pregnancy, traumatic arrest of more than 5 minutes, penetrating brain injury, isolated drowning or hanging, objection to study voiced at scene, or wearing a STAAMP study opt-out bracelet.
1-g of tranexamic acid infused during 8 hours, or a bolus of 1-g of tranexamic acid followed by 1-g of tranexamic acid infused during 8 hours 30-day mortality.
In injured patients at risk for hemorrhage, tranexamic acid administered before hospitalization did not result in significantly lower 30-day mortality. The prehospital administration of tranexamic acid after injury did not result in a higher incidence of thrombotic complications or adverse events. Tranexamic acid given to injured patients at risk for hemorrhage in the prehospital setting is safe and associated with survival benefit in specific subgroups of patients. Howard et al. 2017 Patients had to have been injured in combat in Afghanistan, been admitted to a role 3 MTF, and received a blood transfusion of at least one unit. Preliminary evidence from the Cal-PAT study suggests that TXA administration may be safe in the prehospital setting with no significant change in adverse events observed and an associated decreased use of blood products in cases of traumainduced hemorrhagic shock. Given the current sample size, a statistically significant decrease in mortality was not observed. Additionally, this study demonstrates that it may be feasible for paramedics to identify and safely administer TXA in the prehospital setting.
Major amputation of any extremity above the wrists and above the ankles Neeki et al. 2018 The prehospital and hospital use of TXA should be considered for all trauma patients that meet any of the following criteria: •Blunt or penetrating trauma with signs and symptoms of hemorrhagic shock within three hours of injury.
-Systolic blood pressure of less than 90 mmHg at scene of injury, during air and/or ground medical transport, or upon arrival to designated trauma centers. -Heart rate > 120.
-Estimated blood loss of 500 milliliters in the field. -Bleeding not controlled by direct pressure or tourniquet. •Major amputation of any extremity above the wrists and above the ankles.
•Any patient <18 years of age. •Any patient more than three hours post-injury.
•Any patient with an active thromboembolic event (within the last 24 hours) -i.e., active stroke, myocardial infarction or pulmonary embolism.
•Any patient with a hypersensitivity or anaphylactic reaction to TXA. •Traumatic arrest with more than five minutes of cardiopulmonary resuscitation without return of vital signs.
•Penetrating cranial injury. •Traumatic brain injury with brain matter exposed.
•Isolated drowning or hanging victims.
•Documented cervical cord injury with motor deficits.
Mortality measured at 24 hours, 48 hours, and 28 days.
Findings from the Cal-PAT study suggest that TXA use in the civilian prehospital setting may safely improve survival outcomes in patients who have sustained traumatic injury with signs of hemorrhagic shock.

Ng et al. 2019
Trauma patient >16 years of age, significant hemorrhage defined as systolic blood pressure <90 mm Hg and/or heart rate >110 bpm, and presentation within 8 h of injury.
Patients with a history of cardiovascular disease, thromboembolic events, bleeding diathesis, renal failure with Cr > 250micromol/L, or those that were pregnant or on anticoagulants.
1-g IV/10 min bolus and 1-g IV/8 h infusion. Trauma patients 18 years or older who met triage criteria for serious injury and at least one of the following: 1) hypotension (systolic blood pressure <90 mm Hg) upon presentation, 2) massive transfusion guideline Patients who were transferred from another hospital or injured more than 3 hours previously.
1-gr bolus infusion over 10 minutes followed by a 1-g infusion over 8 hours.
Death within 24 hours; death during hospitalization; venous thromboembolic events (VTE) (deep In civilian trauma, early TXA administration confers early survival advantage without affecting blood product usage but may increase the risk of DVT/PE and AKI. activation in the Emergency Department (ED), or 3) transport directly to the operating room (OR) or interventional radiology (IR) suite from the ED. vein thrombosis or pulmonary embolism); myocardial infarction (MI); stroke; acute kidney injury (AKI); and blood product usage. Valle et al. 2014 All adult patients who underwent emergency OR directly from the resuscitation area were prospectively entered into a registry.
OR for isolated orthopedic and/or neurosurgical indications and minor trauma operations such as those for complex wound closures. This is the first civilian study, to our knowledge, in which the effect of prehospital TXA use in trauma patients has been examined. TXA was associated with prolonged time to death and significantly improved early survival.
exclusion of trauma centers from other countries) Legend: MT = Massive transfusion defined as having received ≥10 units of packed red blood cells (PRBC) and/or whole blood (WB) in the first 24 hours after injury; TXA = tranexamic acid; VTE = venous thromboembolism; NS = Not specified.  Figure S1. Forest plot of patients age in TXA vs. Control group. The center of each square represents the weighted mean differences for individual trials, and the corresponding horizontal line stands for a 95% confidence interval. The diamonds represent pooled results. Figure S2. Forest plot of patient patients' sex (male) in TXA vs. Control group. The center of each square represents the weighted odds ratios for individual trials, and the corresponding horizontal line stands for a 95% confidence interval. The diamonds represent pooled results. Figure S3. Forest plot of injury severity score at admission in TXA vs. Control group. The center of each square represents the weighted mean differences for individual trials, and the corresponding horizontal line stands for a 95% confidence interval. The diamonds represent pooled results. Figure S4. A summary table of review authors' judgements for each risk of bias item for each randomized study. Figure S5. A plot of the distribution of review authors' judgements across randomized studies for each risk of bias item. Figure S6. A summary table of review authors' judgements for each risk of bias item for each non-randomized study. Figure S7. A plot of the distribution of review authors' judgements across non-randomized studies for each risk of bias item.