1.
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
Jama. 2020;324(10):961-974
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Abstract
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.
PICO Summary
Population
Out-of-hospital patients with traumatic brain injury aged 15 years or older (n= 1280).
Intervention
Bolus maintenance group: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (n = 312).
Comparison
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).
Outcome
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%).
2.
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
Abstract
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.
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Severely injured trauma patients with admission hyperfibrinolysis: Is there a role of tranexamic acid? Findings from the PROPPR trial
Khan M, Jehan F, Bulger EM, O'Keeffe T, Holcomb JB, Wade CE, Schreiber MA, Joseph B, PROPPR Study Group
The Journal of Trauma and Acute Care Surgery. 2018;85((5)):851-857.
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Abstract
INTRODUCTION Administration of tranexamic acid (TXA) in coagulopathy of trauma gained popularity after the CRASH-2 trial. The aim of our analysis was to analyze the role of TXA in severely injured trauma patients with admission hyperfibrinolysis. METHODS We reviewed the prospectively collected Pragmatic, Randomized Optimal Platelet and Plasma Ratios database. We included patients with admission hyperfibrinolysis (Ly30 >3%) on thromboelastography. Patients were stratified into two groups (TXA and No-TXA) and were matched in 1:2 ratio using propensity score matching for demographics, admission vitals, and injury severity. Primary outcome measures were 6-, 12-, and 24-hour and 30-day mortality; 24-hour transfusion requirements; time to achieve hemostasis; and rebleeding after hemostasis requiring intervention. Secondary outcome measures were thrombotic complications. RESULTS We analyzed 680 patients. Of those, 118 had admission hyperfibrinolysis, and 93 patients (TXA: 31 patients; No-TXA: 62 patients) were matched. Matched groups were similar in age (p = 0.33), gender (p = 0.84), race (p = 0.81), emergency department (ED) Glasgow Coma Scale (p = 0.34), ED systolic blood pressure (p = 0.28), ED heart rate (p = 0.43), mechanism of injury (p = 0.45), head Abbreviated Injury Scale score (p = 0.68), injury severity score (p = 0.56), and blood products ratio (p = 0.44). Patients who received TXA had a lower 6-hour mortality rate (34% vs. 13%, p = 0.04) and higher 24-hour transfusion of plasma (15 vs. 10 units, p = 0.03) compared with the No-TXA group. However, there was no difference in 12-hour (p = 0.24), 24-hour (p = 0.25), and 30-day mortality (p = 0.82). Similarly, there was no difference in 24-hour transfusion of RBC (p = 0.11) or platelets (p = 0.13), time to achieve hemostasis (p = 0.65), rebleeding requiring intervention (p = 0.13), and thrombotic complications (p = 0.98). CONCLUSION Tranexamic acid was associated with increased 6-hour survival but does not improve long-term outcomes in severely injured trauma patients with hemorrhage who develop hyperfibrinolysis. Moreover, TXA administration was not associated with thrombotic complications. Further randomized clinical trials will identify the subset of trauma patients who may benefit from TXA. LEVEL OF EVIDENCE Therapeutic study, level III.