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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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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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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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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.
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Tranexamic acid is not inferior to placebo with respect to adverse events in supected tbi patients not in shock with a normal head ct: A retrospective study of a randomized trial
Harmer J, Dewey EN, Meier EN, Rowell SE, Schreiber MA
The journal of trauma and acute care surgery. 2022
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BACKGROUND A 2-gram bolus of tranexamic acid (TXA) has been shown to reduce 28-day mortality in a RCT. This study investigates whether out-of-hospital TXA use is associated with adverse events or unfavorable outcomes in suspected TBI when intracranial hemorrhage (ICH) is absent on initial CT. METHODS This study utilized data from a 2015-2017, multicenter, randomized trial studying the effect of the following TXA doses on moderate to severe TBI: 2-gram bolus, 1-gram bolus plus 1-gram infusion over 8 hours, and a placebo bolus with placebo infusion. Of the 966 participants enrolled, 395 with an initial CT negative for ICH were included in this analysis. Fifteen adverse events (28-day incidence) were studied: MI, DVT, seizure, pulmonary embolism, ARDS, cardiac failure, liver failure, renal failure, CVA, cardiac arrest, cerebral vasospasm, "any thromboembolism", hypernatremia, AKI, and infection. Other unfavorable outcomes analyzed include mortality at 28 days & 6 months, GOSE ≤4 at discharge & 6 months, ICU-free days, ventilator-free days, hospital-free days, and combined unfavorable outcomes. In both study drug groups the incidence of dichotomous outcomes and quantity of ordinal outcomes were compared to placebo. RESULTS No statistically significant increase in adverse events or unfavorable outcomes was found between either TXA dosing regimen and placebo. Demographics and injury scores were not statistically different other than two methods of injury which were overrepresented in the 1-gram TXA bolus +1-gram TXA infusion. CONCLUSIONS Administration of either a 2-gram TXA bolus or a 1-gram TXA bolus plus 1-gram TXA 8-hour infusion in suspected-TBIs without ICH is not associated with increased adverse events or unfavorable outcomes. Because the out-of-hospital 2-gram bolus is associated with a mortality benefit it should be administered in suspected-TBI. LEVELS OF EVIDENCE Level II, Therapeutic.
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Traumatic injury clinical trial evaluating tranexamic acid in children (TIC-TOC): a pilot randomized trial
Nishijima DK, VanBuren JM, Linakis SW, Hewes HA, Myers SR, Bobinski M, Tran NK, Ghetti S, Adelson PD, Roberts I, et al
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2022
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Editor's Choice
Abstract
BACKGROUND The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage; however, the drug has not been evaluated in a trial in injured children. We evaluated the feasibility of a large-scale trial evaluating the effects of TXA in children with severe hemorrhagic injuries. METHODS Severely injured children (0 up to 18(th) birthday) were randomized into a double-blind randomized trial of 1) TXA 15 mg/kg bolus dose, followed by 2 mg/kg/hr infusion over 8 hours, 2) TXA 30 mg/kg bolus dose, followed by 4 mg/kg/hr infusion over 8 hours, or 3) normal saline placebo bolus and infusion. The trial was conducted at 4 pediatric Level I trauma centers in the United States between June 2018 and March 2020. We enrolled patients under federal exception from informed consent (EFIC) procedures when parents were unable to provide informed consent. Feasibility outcomes included the rate of enrollment, adherence to intervention arms, and ability to measure the primary clinical outcome. Clinical outcomes included global functioning (primary), working memory, total amount of blood products transfused, intracranial hemorrhage progression, and adverse events. The target enrollment rate was at least 1.25 patients per site per month. RESULTS A total of 31 patients were randomized with a mean age of 10.7 years (standard deviation [SD] 5.0 years) and 22 (71%) patients were male. The mean time from injury to randomization was 2.4 hours (SD 0.6 hours). Sixteen (52%) patients had isolated brain injuries and 15 (48%) patients had isolated torso injuries. The enrollment rate using EFIC was 1.34 patients per site per month. All eligible enrolled patients received study intervention (9 patients TXA 15 mg/kg bolus dose, 10 patients TXA 30 mg/kg bolus dose, and 12 patients placebo) and had the primary outcome measured. No statistically significant differences in any of the clinical outcomes were identified. CONCLUSION Based on enrollment rate, protocol adherence, and measurement of the primary outcome in this pilot trial, we confirmed the feasibility of conducting a large-scale, randomized trial evaluating the efficacy of TXA in severely injured children with hemorrhagic brain and/or torso injuries using EFIC.
PICO Summary
Population
Severely injured children enrolled in the TIC-TOC trial across four centers in US (n= 31).
Intervention
15 mg/kg of tranexamic acid (TXA) dose, followed by 2 mg/kg/hr infusion (n= 9).
Comparison
30 mg/kg of TXA dose, followed by 4 mg/kg/hr infusion (n= 10). Saline placebo and infusion (n= 12).
Outcome
All patients had their primary outcome measured. Feasibility outcomes included the rate of enrollment, adherence to intervention arms, and ability to measure the primary clinical outcome. Clinical outcomes included global functioning (primary), working memory, total amount of blood products transfused, intracranial hemorrhage progression, and adverse events. The mean time from injury to randomization was 2.4 hours (SD 0.6 hours). Sixteen (52%) patients had isolated brain injuries and 15 (48%) patients had isolated torso injuries. No statistically significant differences in any of the clinical outcomes were identified.
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Comparison of the therapeutic efficacy of topical tranexamic acid, epinephrine, and lidocaine in stopping bleeding in non-traumatic epistaxis: a prospective, randomized, double-blind study
Ekmekyapar, M., Sahin, L., Gur, A.
European Review for Medical and Pharmacological Sciences. 2022;26(9):3334-3341
Abstract
OBJECTIVE Nasal packing is used to stop bleeding in cases of epistaxis. Different topical drugs are preferred to these packs in the emergency department. In this study, we aimed to compare the efficacy of lidocaine, epinephrine and tranexamic acid (TXA) in stopping bleeding in patients with epistaxis. PATIENTS AND METHODS Patients with non-traumatic epistaxis were evaluated in three treatment groups as topical lidocaine, epinephrine, and TXA. These treatments were applied prospectively in a double-blind manner and randomized manner. The bleeding stop times of the patients were recorded with bleeding time parameters. RESULTS A total of 108 patients were included in the study. The mean age of the patients was 55.7±17.7 years. When the bleeding stop times were compared between the groups, there was no statistically significant difference (lidocaine vs. epinephrine, p=0.870; lidocaine vs. TXA, p=0.502; and epinephrine vs. TXA, p=0.242). The systolic blood pressure value statistically significantly differed between the lidocaine and epinephrine groups (p=0.034) and between the epinephrine and TXA groups (p=0.003). There was also a statistically significant difference between the diastolic blood pressure values of the epinephrine and TXA groups (p=0.020). CONCLUSIONS We found that nasal packing with lidocaine, epinephrine and TXA was not superior to each other in terms of stopping bleeding time.
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The Effects of Timing of Prehospital Tranexamic Acid on Outcomes after Traumatic Brain Injury; Sub Analysis of a Randomized Controlled Trial
Brito AMP, Schreiber MA, El Haddi J, Meier EN, Rowell SE
The journal of trauma and acute care surgery. 2022
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BACKGROUND Tranexamic acid (TXA) is an antifibrinolytic that has shown some promise in improving outcomes in traumatic brain injury (TBI), but only when given early after injury. We examined the association between timing of prehospital TXA administration and outcomes in patients with moderate to severe TBI. METHODS Patients enrolled in the multi-institutional, double-blind randomized Prehospital TXA for TBI Trial with blunt or penetrating injury and suspected TBI (GCS ≤12, SBP ≥90) received either a 2 g TXA bolus or a 1 g bolus plus 1 g 8 h infusion within 2 hours of injury were analyzed. Outcomes were compared between early administration (<45 minutes from injury) and late administration (> 45 minutes from injury) using a Chi Square, Fischers Exact Test, t-test, or Mann Whitney U test as indicated. Logistic regression examined time to drug as an independent variable. P < 0.05 was considered significant. RESULTS 649 Patients met inclusion criteria (354 early and 259 late). 28-day and 6-month mortality, 6-month Glasgow Outcome Scale - Extended (GOSE) and disability rating scale scores were not different between early and late administration. Late administration was associated with higher rates of DVT (0.8 vs 3.4%, p = 0.02), cerebral vasospasm (0% vs 2%, p = 0.01), as well as prolonged EMS transport and need for a prehospital airway (p < 0.01). CONCLUSIONS In patients with moderate or severe TBI who received TXA within two hours of injury, no mortality benefit was observed in those who received treatment within 45 minutes of injury, although lower rates of select complications were seen. These results support protocols that recommend TXA administration within 45 minutes of injury for patients with suspected TBI. LEVEL OF EVIDENCE Level 1, Therapeutic.
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Tranexamic acid and reduction of blood transfusion in lower limb trauma surgery: a randomized controlled study
Kaur G, Selhi HS, Delmotra NJ, Singh J
Sicot-J. 2021;7:53
Abstract
INTRODUCTION Post-operative blood loss in lower limb trauma fractures increases morbidity. Very few studies have evaluated the efficacy of Tranexamic Acid (TXA) in reducing blood loss and the consequent requirement of blood transfusion in the Indian population. METHODS This was a randomized controlled study of 100 patients with lower limb trauma. Fifty patients were given 1 g of TXA before surgery, and 50 patients were not given TXA. The requirement of blood transfusion, fall in Hb, the number of days admitted in the hospital after surgery were recorded, and evidence of deep vein thrombosis (DVT) was monitored. RESULTS Baseline demographics between the groups were comparable. The required blood transfusion and fall in Hb in patients receiving intra-operative TXA were significantly lower than those not given TXA (p < 0.0001). There was no significant difference in the length of hospital stay between the two groups (p = 0.6). There was no significant difference in the incidence of DVT in both groups. DISCUSSION TXA helps reduce the morbidity of trauma patients by reducing the requirement for blood transfusion. Its use is safe in lower limb trauma surgery and lowers the cost of therapy to the patient.
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Efficacy and safety of the second in-hospital dose of tranexamic acid after receiving the prehospital dose: double-blind randomized controlled clinical trial in a level 1 trauma center
El-Menyar A, Ahmed K, Hakim S, Kanbar A, Mathradikkal S, Siddiqui T, Jogol H, Younis B, Taha I, Mahmood I, et al
European journal of trauma and emergency surgery : official publication of the European Trauma Society. 2021
Abstract
BACKGROUND Prehospital administration of tranexamic acid (TXA) to injured patients is increasing worldwide. However, optimal TXA dose and need of a second infusion on hospital arrival remain undetermined. We investigated the efficacy and safety of the second in-hospital dose of TXA in injured patients receiving 1 g of TXA in the prehospital setting. We hypothesized that a second in-hospital dose of TXA improves survival of trauma patients. METHODS A prospective, double-blind, placebo-controlled randomized, clinical trial included adult trauma patients receiving 1 g of TXA in the prehospital settings. Patients were then blindly randomized to Group I (second 1-g TXA) and Group II (placebo) on hospital arrival. The primary outcome was 24-h (early) and 28-day (late) mortality. Secondary outcomes were thromboembolic events, blood transfusions, hospital length of stay (HLOS) and organs failure (MOF). RESULTS A total of 220 patients were enrolled, 110 in each group. The TXA and placebo groups had a similar early [OR 1.000 (0.062-16.192); p = 0.47] and late mortality [OR 0.476 (95% CI 0.157-1.442), p = 0.18].The cause of death (n = 15) was traumatic brain injury (TBI) in 12 patients and MOF in 3 patients. The need for blood transfusions in the first 24 h, number of transfused blood units, HLOS, thromboembolic events and multiorgan failure were comparable in the TXA and placebo groups. In seriously injured patients (injury severity score > 24), the MTP activation was higher in the placebo group (31.3% vs 11.10%, p = 0.13), whereas pulmonary embolism (6.9% vs 2.9%, p = 0.44) and late mortality (27.6% vs 14.3%, p = 0.17) were higher in the TXA group but did not reach statistical significance. CONCLUSION The second TXA dose did not change the mortality rate, need for blood transfusion, thromboembolic complications, organ failure and HLOS compared to a single prehospital dose and thus its routine administration should be revisited in larger and multicenter studies. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03846973.