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
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.
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
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.
Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury
Rowell SE, Meier EN, McKnight B, Kannas D, May S, Sheehan K, Bulger EM, Idris AH, Christenson J, Morrison LJ, et al
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IMPORTANCE Traumatic brain injury (TBI) is the leading cause of death and disability due to trauma. Early administration of tranexamic acid may benefit patients with TBI. OBJECTIVE To determine whether tranexamic acid treatment initiated in the out-of-hospital setting within 2 hours of injury improves neurologic outcome in patients with moderate or severe TBI. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blinded, randomized clinical trial at 20 trauma centers and 39 emergency medical services agencies in the US and Canada from May 2015 to November 2017. Eligible participants (N = 1280) included out-of-hospital patients with TBI aged 15 years or older with Glasgow Coma Scale score of 12 or less and systolic blood pressure of 90 mm Hg or higher. INTERVENTIONS Three interventions were evaluated, with treatment initiated within 2 hours of TBI: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (bolus maintenance group; n = 312), out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (bolus only group; n = 345), and out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (placebo group; n = 309). MAIN OUTCOMES AND MEASURES The primary outcome was favorable neurologic function at 6 months (Glasgow Outcome Scale-Extended score >4 [moderate disability or good recovery]) in the combined tranexamic acid group vs the placebo group. Asymmetric significance thresholds were set at 0.1 for benefit and 0.025 for harm. There were 18 secondary end points, of which 5 are reported in this article: 28-day mortality, 6-month Disability Rating Scale score (range, 0 [no disability] to 30 [death]), progression of intracranial hemorrhage, incidence of seizures, and incidence of thromboembolic events. RESULTS Among 1063 participants, a study drug was not administered to 96 randomized participants and 1 participant was excluded, resulting in 966 participants in the analysis population (mean age, 42 years; 255 [74%] male participants; mean Glasgow Coma Scale score, 8). Of these participants, 819 (84.8%) were available for primary outcome analysis at 6-month follow-up. The primary outcome occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group (difference, 3.5%; [90% 1-sided confidence limit for benefit, -0.9%]; P = .16; [97.5% 1-sided confidence limit for harm, 10.2%]; P = .84). There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%; difference, -2.9% [95% CI, -7.9% to 2.1%]; P = .26), 6-month Disability Rating Scale score (6.8 vs 7.6; difference, -0.9 [95% CI, -2.5 to 0.7]; P = .29), or progression of intracranial hemorrhage (16% vs 20%; difference, -5.4% [95% CI, -12.8% to 2.1%]; P = .16). CONCLUSIONS AND RELEVANCE Among patients with moderate to severe TBI, out-of-hospital tranexamic acid administration within 2 hours of injury compared with placebo did not significantly improve 6-month neurologic outcome as measured by the Glasgow Outcome Scale-Extended. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01990768.
Out-of-hospital patients with traumatic brain injury aged 15 years or older (n= 1280).
Bolus maintenance group: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (n = 312).
Bolus only group: out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (n = 345). Placebo group: out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (n = 309).
A total of 819 participants were available for primary outcome analysis at 6-month follow-up. The primary outcome (favorable neurologic function at 6 months) occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group. There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%); 6-month Disability Rating Scale score (6.8 vs 7.6); or progression of intracranial hemorrhage (16% vs 20%).
TXA Administration in the Field Does Not Affect Admission TEG after Traumatic Brain Injury
Dixon AL, McCully BH, Rick EA, Dewey E, Farrell DH, Morrison LJ, McMullan J, Robinson BRH, Callum J, Tibbs B, et al
The journal of trauma and acute care surgery. 2020
BACKGROUND No FDA-approved medication improves outcomes following traumatic brain injury (TBI). A forthcoming clinical trial that evaluated the effects of two prehospital tranexamic acid (TXA) dosing strategies compared with placebo demonstrated no differences in thromboelastography (TEG) values. We proposed to explore the impact of TXA on markers of coagulation and fibrinolysis in patients with moderate to severe TBI. METHODS Data were extracted from a placebo-controlled clinical trial in which patients ≥15 years old with TBI (Glascow Coma Scale 3-12) and systolic blood pressure ≥90 mmHg were randomized prehospital to receive placebo bolus/placebo infusion (Placebo), 1 gram (g) TXA bolus/1g TXA infusion (Bolus Maintenance [BM]); or 2g TXA bolus/placebo infusion (Bolus Only [BO]). TEG was performed and coagulation measures including prothrombin time (PT), activated partial thromboplastin time (aPTT), international ratio (INR), fibrinogen, D-dimer, plasmin anti-plasmin (PAP), thrombin anti-thrombin (TAT), tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) were quantified at admission and six hours later. RESULTS Of 966 patients receiving study drug, 700 had labs drawn at admission and six hours later. There were no statistically significant differences in TEG values, including LY30, between groups (p>0.05). No differences between PT, aPTT, INR, fibrinogen, TAT, tPA, and PAI-1 were demonstrated across treatment groups. Concentrations of D-dimer in TXA treatment groups were less than placebo at six hours (p<0.001). Concentrations of PAP were less in TXA treatment groups than placebo on admission (p<0.001) and six hours (p=0.02). No differences in D-dimer and PAP were observed between BM and BO. CONCLUSION While D-dimer and PAP levels reflect a lower degree of fibrinolysis following prehospital administration of TXA when compared to placebo in a large prehospital trial of patients with TBI, TEG obtained on admission and six hours later did not demonstrate any differences in fibrinolysis between the two TXA dosing regimens and placebo. LEVEL OF EVIDENCE III; Diagnostic.