Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury | Traumatic Brain Injury | JAMA | JAMA Network
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Visual Abstract. Tranexamic Acid and Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury
Tranexamic Acid and Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury
Figure 1.  Flow of Participants in a Study of the Effect of Tranexamic Acid vs Placebo on Neurologic Outcomes in Patients With Traumatic Brain Injury
Flow of Participants in a Study of the Effect of Tranexamic Acid vs Placebo on Neurologic Outcomes in Patients With Traumatic Brain Injury

aPatients for whom the blinded study drug was not infused are not included in analyses.

bPatients in this category may have had a seizure prior to study drug administration or seizure-like behavior that was not managed and thus are not necessarily adverse events.

cIncorrect in-hospital assignment was made for 1 patient, who received approximately 125 mg of tranexamic acid prior to infusion being stopped.

Figure 2.  Post Hoc Descriptive Analysis of Mortality Through 28 Days in a Study of the Effect of Tranexamic Acid vs Placebo on Neurologic Outcomes in Patients With Traumatic Brain Injury
Post Hoc Descriptive Analysis of Mortality Through 28 Days in a Study of the Effect of Tranexamic Acid vs Placebo on Neurologic Outcomes in Patients With Traumatic Brain Injury

Survival data to 28 days was available for 91% of participants in the bolus maintenance group, 92% in the bolus only group, and 92% in the placebo group. Participants who were lost to follow-up after discharge or study withdrawal prior to 28 days and who were notified themselves about their study enrollment rather than family member notification were assumed to survive through 28 days for this plot (n = 52). The remaining participants were censored before 28 days: 5 [2%] in the bolus maintenance group, 9 [3%] in the bolus only group, and 12 [4%] in the placebo group. The shaded areas represent pointwise 95% CIs for each treatment group. The median (interquartile range) observation time for all 3 groups was 28 (28-28) days.

Table 1.  Baseline Characteristics of Patients in a Study of the Effect of Tranexamic Acid vs Placebo on Neurologic Outcomes in Patients With Traumatic Brain Injury
Baseline Characteristics of Patients in a Study of the Effect of Tranexamic Acid vs Placebo on Neurologic Outcomes in Patients With Traumatic Brain Injury
Table 2.  Hospital Course and Outcomesa in a Study of the Effect of Tranexamic Acid vs Placebo on Neurologic Outcomes in Patients With Traumatic Brain Injury
Hospital Course and Outcomesa in a Study of the Effect of Tranexamic Acid vs Placebo on Neurologic Outcomes in Patients With Traumatic Brain Injury
Table 3.  Adjusted Analyses of Primary and Select Secondary Outcomes in the Tranexamic Acid Groups vs Placebo Group in a Study of the Effect of Tranexamic Acid on Neurologic Outcomes in Patients With Traumatic Brain Injury
Adjusted Analyses of Primary and Select Secondary Outcomes in the Tranexamic Acid Groups vs Placebo Group in a Study of the Effect of Tranexamic Acid on Neurologic Outcomes in Patients With Traumatic Brain Injury
Table 4.  Adjusted Analyses of Select Secondary Outcomes and Adverse Events in a Study of the Effect of Tranexamic Acid vs Placebo on Neurologic Outcomes in Patients With Traumatic Brain Injury
Adjusted Analyses of Select Secondary Outcomes and Adverse Events in a Study of the Effect of Tranexamic Acid vs Placebo on Neurologic Outcomes in Patients With Traumatic Brain Injury
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Original Investigation
September 8, 2020

Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury

Author Affiliations
  • 1Department of Surgery, Oregon Health & Science University, Portland
  • 2Department of Surgery, Duke University School of Medicine, Durham, North Carolina
  • 3Department of Biostatistics, University of Washington, Seattle
  • 4Department of Surgery, University of Washington, Seattle
  • 5Department of Emergency Medicine, University of Texas Southwestern Medical Center, Dallas
  • 6Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
  • 7Department of Emergency Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  • 8Providence Health Care Research Institute, Vancouver, British Columbia, Canada
  • 9Rescu, Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, Ontario, Canada
  • 10Division of Emergency Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 11Department of Emergency Medicine, Regions Hospital, St Paul, Minnesota
  • 12Department of Surgery, University of Alabama, Birmingham
  • 13Department of Surgery, University of Arizona, Phoenix
  • 14Department of Emergency Medicine, Medical College of Wisconsin, Milwaukee
  • 15Department of Surgery, University of Cincinnati, Cincinnati, Ohio
  • 16Department of Surgery, McGovern Medical School, University of Texas Health Science Center, Houston
  • 17Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada
  • 18Department of Emergency Medicine, University of Cincinnati, Cincinnati, Ohio
  • 19Department of Surgery, Regions Hospital, St Paul, Minnesota
  • 20Trauma Surgery, Texas Health Presbyterian Hospital, Dallas
  • 21Department of Emergency Medicine, John Peter Smith Health Network, Ft Worth, Texas
  • 22Johns Hopkins School of Medicine, Baltimore, Maryland
  • 23British Columbia Emergency Health Services, Vancouver, British Columbia, Canada
  • 24Department of Emergency Medicine, Baylor University Medical Center, Dallas, Texas
  • 25Department of Surgery, Mayo Clinic, Rochester, Minnesota
  • 26Department of Surgery, John Peter Smith Health Network, Ft Worth, Texas
  • 27Department of Emergency Medicine, Oregon Health & Science University, Portland, Oregon
  • 28Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota
  • 29Department of Surgery, St Michael’s Hospital, Toronto, Ontario, Canada
  • 30Department of Emergency Medicine, Medical City Plano, Plano, Texas
  • 31Emergency Medicine, Methodist Dallas Medical Center, Dallas, Texas
  • 32National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
  • 33Trauma Surgery, Texas Health Harris Methodist Hospital, Ft Worth
JAMA. 2020;324(10):961-974. doi:10.1001/jama.2020.8958
Key Points

Question  Does early administration of tranexamic acid to patients with moderate or severe traumatic brain injury improve neurologic outcome at 6 months?

Findings  In this randomized multicenter clinical trial that included 966 participants enrolled in the out-of-hospital setting by paramedics, treatment with tranexamic acid as an out-of-hospital bolus with or without in-hospital infusion, compared with placebo as an out-of-hospital bolus and in-hospital infusion, resulted in a favorable neurologic outcome (defined as Glasgow Outcome Scale-Extended score >4) in 65% vs 62% of patients at 6 months, a difference that was not statistically significant.

Meaning  Among participants suspected of having moderate or severe traumatic brain injury, out-of-hospital administration of tranexamic acid compared with placebo did not significantly improve 6-month neurologic recovery.

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

Introduction

In 2016, an estimated 27 million people worldwide sustained a traumatic brain injury (TBI), an increase of 47% since 1990.1 In 2014, there were an estimated 288 000 TBI-related hospitalizations and more than 56 000 TBI-related deaths in the US alone.2 Effective management for TBI represents a significant unmet need and has the potential to affect morbidity and mortality worldwide. Despite decades of well-designed clinical trials, no drug has been approved by the US Food and Drug Administration to manage acute TBI.3-5

Quiz Ref IDTranexamic acid is a synthetic derivative of the amino acid lysine that acts by competitively inhibiting plasminogen activation and, at higher concentrations, noncompetitively inhibiting plasmin.6 Tranexamic acid binding blocks the interaction of plasminogen with fibrin, preventing breakdown of fibrin clot.6 The clinical use of tranexamic acid to control bleeding was first described in 1966,6 and its use has expanded over the past 50 years to multiple clinical settings.7,8 Because results from the CRASH-2 trial in 2010 demonstrated a survival benefit for patients at risk for traumatic hemorrhage who received tranexamic acid, its use has become common for patients with severe hemorrhagic shock.9 Until publication of the CRASH-3 trial in 2019, which examined the use of tranexamic acid in more than 12 000 patients with TBI, the use of tranexamic acid in patients with TBI has been limited to retrospective analyses and small clinical trials.10-12 The current trial was designed to examine whether tranexamic acid administered within 2 hours of injury would result in improved 6-month neurologic outcome in patients with moderate or severe TBI.

Methods
Trial Design and Oversight

The Prehospital TXA for TBI Trial was a randomized, double-blind, 3-group, multicenter phase II trial designed to examine the efficacy and safety of out-of-hospital administration of tranexamic acid compared with placebo in participants with moderate or severe TBI who were not in shock. Outcomes were compared between patients who received tranexamic acid initiated in the out-of-hospital setting within 2 hours of injury and those who received placebo. With the exception of tranexamic acid administration, treatment was not altered during transport or after arrival to the trauma center. Out-of-hospital tranexamic acid administration for TBI was not standard care at any participating site during the trial. The full trial protocol and statistical analysis plan are available in Supplement 1. The trial used the infrastructure of the Resuscitation Outcomes Consortium, a North American clinical trials network dedicated to conducting clinical trials in out-of-hospital cardiac arrest and severe traumatic injury. The study took place in 12 regions, including 20 trauma centers and 39 emergency medical services (EMS) agencies across the US and Canada (eFigure in Supplement 2).

The trial was conducted under US regulations for Exception From Informed Consent Requirements for Emergency Research (21 CFR §50.24) and the Canadian Tri-Council Policy Statement 2 (Ethical Conduct for Research Involving Humans). As required, all individual site ethics review boards and the Human Research Protection Office of the US Department of Defense reviewed and approved the local community consultation process, public disclosure plans, and conduct of the study. Participants or their legally authorized representative were notified of enrollment as soon as feasible and were asked to provide written informed consent for continued participation in the trial. Safety oversight for the trial was performed by a data and safety monitoring board and an independent medical monitor.

Eligible Patients

Quiz Ref IDThe target population for the trial was patients aged 15 years or older with moderate or severe blunt or penetrating TBI, a Glasgow Coma Scale (GCS) score of 3 to 12, at least 1 reactive pupil, and systolic blood pressure of at least 90 mm Hg prior to randomization. EMS agencies were provided centralized video and hands-on training to ensure GCS assessment standardization across sites. It was instructed to obtain the GCS score prior to intubation. Patients were eligible only if an intravenous (IV) catheter was in place, the study drug could be administered within 2 hours of injury, and the predefined EMS transport destination was a participating trauma center. Detailed exclusion criteria are provided in the protocol (Supplement 1).

Randomization and Masking

Participants were randomly assigned to study groups in a 1:1:1 ratio using a computer-generated allocation sequence programmed by the data coordinating center. Identical-appearing out-of-hospital study drug kits were packaged in numerical order according to a permuted block design of variable block size (3 and 6) and shipped to EMS agencies for placement on EMS vehicles in random order. Each EMS vehicle or helicopter carried only 1 study kit at a time containing either 2 g of tranexamic acid, 1 g of tranexamic acid, or placebo solution (saline). Any kits that were opened but not used were discarded and a new kit was supplied to each vehicle for the next trip. The order in which kits were used could not be controlled because the location of injury and EMS availability determined which agency and vehicle responded. As a result, the effective randomization was complete rather than a permuted block.

Neither opening the study kit nor administering the study drug revealed the group assignment. Group assignment was blinded to all EMS agencies, pharmacists, coordinators, and providers throughout the study. Emergency unblinding by the coordinating center was performed only when the treating physician determined open-label tranexamic acid was indicated as an adjunct for hemorrhage control.

Study Intervention

Participants were randomly assigned to 1 of 3 treatment groups: 1-g IV tranexamic acid bolus in the out-of-hospital setting followed by a 1-g tranexamic acid IV infusion initiated upon hospital arrival and infused over 8 hours (bolus maintenance group), 2-g IV tranexamic acid bolus in the out-of-hospital setting followed by a placebo infusion (bolus only group), or IV placebo bolus in the out-of-hospital setting followed by an IV placebo infusion (placebo group). The bolus maintenance dose was chosen based on the observed decreased mortality in the CRASH-2 trial using this dose and because it is widely considered standard of care in patients with traumatic hemorrhage. The bolus only dose was chosen as an alternative dosing regimen that could be more feasible in prehospital and military settings. The out-of-hospital bolus was initiated by EMS prior to arrival and completed either out of hospital or in the emergency department. Following completion of the out-of-hospital bolus, the in-hospital infusion was initiated in the emergency department and administered over 8 hours. Infusion stopping rules established to protect patient safety are listed in the protocol (Supplement 1). Adverse events that occurred during the initial 28 days of hospitalization were recorded. A biospecimen and imaging repository was created and maintained at the clinical coordinating center (Supplement 1).

Study Outcomes

The primary outcome was functional neurologic outcome measured 6months after injury using the Glasgow Outcome Scale-Extended (GOSE)13-15 and dichotomized into favorable (GOSE score >4 [moderate disability or good recovery]) and poor (GOSE score ≤4 [severe disability, vegetative state, or death]). Prespecified secondary outcomes included 28-day mortality, 6-month Disability Rating Scale (DRS) score (range, 0 [no disability] to 30 [death]),14,15 progression of intracranial hemorrhage (ICH; defined as >33% increase in the combined volume of subdural, epidural, and intraparenchymal hematomas), discharge GOSE score, discharge DRS score, Marshall and Rotterdam scores on initial head computed tomographic imaging, incidence of neurosurgical interventions, hospital-free days, intensive care unit–free days, ventilator-free days, and fibrinolysis at hospital admission. Additional prespecified secondary outcomes included adverse events potentially associated with tranexamic acid administration: incidence of seizures (defined as observed seizure-like activity and administration of antiseizure medication or electroencephalogram confirmation) and incidence of thrombotic events (cerebral ischemia, myocardial infarction, deep vein thrombosis, and pulmonary embolism). Although complete data on all secondary outcomes are reported by treatment group in this study, statistical analyses are only performed on 6-month GOSE score (primary outcome), 28-day mortality, 6-month DRS score, progression of ICH, and the safety-related outcomes. Analyses for other secondary outcomes are planned to be reported separately.

The initial trial design involved a comparison of each of the 2 tranexamic acid dosing regimens separately with placebo, rather than a comparison of the combined tranexamic acid groups with the placebo group. However, the protocol review committee had a concern with study power and the analytic plan was revised by combining the 2 tranexamic acid treatment groups with a comparison of the combined group with the placebo group. The protocol review committee and the data and safety monitoring board approved this change in 2014, and all subsequent protocols have this as the prespecified analytic approach. In addition, the primary outcome measure was the GOSE score 6 months after injury, dichotomized as a favorable neurologic outcome (GOSE score >4) or unfavorable outcome (GOSE score ≤4). This outcome was prespecified in the original protocol and was unchanged in all subsequent versions of the protocol.

At the time of manuscript preparation, we recognized that the original trial registry entry on ClinicalTrials.gov (November 2013) lacked sufficient detail and did not correctly represent the planned 2-group comparison as the primary analysis and did not specify that the GOSE score outcome was to be dichotomized. This analytic plan and this outcome, which were established and prespecified prior to the beginning of trial enrollment, were included in the updated ClinicalTrials.gov entry (July 2018).

Sample Size

The planned sample size of 963 analysis population participants provided 80% power for tests of benefit at a 0.071 absolute higher proportion with favorable outcomes in the combined group of tranexamic acid–treated patients and harm at a 0.095 absolute lower proportion with favorable outcomes in the combined group of tranexamic acid–treated patients. Because no previous studies have evaluated long-term neurologic outcome in patients with TBI who received tranexamic acid, these differences were chosen as part of an overall strategy to use this phase II trial to identify potential treatments for a phase III trial. Because a subsequent phase III trial could test for benefit at conventional levels, power was computed for an asymmetric 2-sided test conducted at the 10% level for benefit and at the 2.5% level for harm under a grouped sequential design that included 1 interim futility analysis. Additional detail of the grouped sequential design and power analysis is available in the protocol (Supplement 1).

Statistical Analysis

In this double-blind study, because caregivers would not be able to discern the contents of study drug containers, our protocol-specified analysis included only participants who received the study drug. This design was chosen to avoid diluting the analysis population with participants who had no potential to benefit from treatment. No follow-up data were collected for participants who received no study drug. The prespecified primary analysis compared the percentage of participants in the analysis population with a favorable neurologic outcome (GOSE score >4) 6 months after injury between the combined tranexamic acid treatment group and the placebo group using logistic regression adjusted for study site after multiply imputing missing outcome data using fully conditional specification.16 The primary analysis pooled both treatment groups because this comparison provided greater power to detect a benefit of tranexamic acid treatment. Because odds ratios derived from logistic regression can provide a misleading representation of risk when the base rate is high, we instead present adjusted differences in the percentages of participants with favorable neurologic outcome using linear regression with robust standard errors; logistic regression results are reported in Supplement 2. Sensitivity analyses were conducted on a GCS-stratified dichotomous GOSE outcome.17 Additional details of the multiple imputation methods are included in eTables 1 to 3 in Supplement 2.

Secondary analyses comparing the combined tranexamic acid treatment group with the placebo group were performed for 28-day mortality, 6-month DRS score, and progression of ICH. Pairwise comparisons between individual treatment groups were also performed for the primary outcome and select secondary outcomes in the full analysis population and in the following 2 exploratory subgroups: participants with unimputed outcomes and participants with ICH on initial computed tomographic imaging. Absolute percent differences or mean differences and 95% CIs are presented for all secondary analyses. Analyses of the full analysis population were adjusted for site only. Subgroup analyses include prespecified adjustment for site, age, sex, penetrating injury, out-of-hospital GCS score, Injury Severity Score (ISS), and Abbreviated Injury Scale (AIS) head score. Imputed outcomes were used for all analyses except for analyses of the progression of ICH and analyses of the unimputed outcomes subgroup.

This National Institutes of Health–sponsored trial required the collection of race and ethnicity data, which were obtained through the medical record of participating sites. Study staff transcribed information from the medical record into fixed categories on the trial case report form.

Statistical analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing) and the R packages mice version 3.6.0, miceadds 3.8-9, mitools 2.4, and sandwich 2.5-1. Because of the potential for type I error due to multiple comparisons, findings for secondary outcomes and secondary analyses of the primary outcome should be interpreted as exploratory.

Results
Study Participants and Enrollment

Between May 2015 and March 2017, a total of 1063 participants were randomized. The study drug was not administered to 96 randomized participants and 1 participant was excluded based on being in police custody prior to enrollment, resulting in 966 participants included in the analysis population (mean age, 42 years; 255 [74%] male participants; mean GCS score, 8) (Figure 1). The study groups were well balanced with respect to demographics and baseline anatomic and physiologic characteristics, with the exception of fewer penetrating injuries in the bolus only group. Injury severity was similar between groups based on the out-of-hospital GCS score, the ISS, and the AIS head score (Table 1). The median estimated time from injury to out-of-hospital study drug administration ranged from 40 to 43 minutes across groups, and the bolus completion percentage ranged from 93% to 95%. The median time from out-of-hospital bolus completion to start of the in-hospital infusion ranged from 86 to 94 minutes, and the in-hospital dose completion percentage ranged from 69% to 77%. (Table 1). Emergency unblinding occurred in 3% of patients, of whom 53% received open-label tranexamic acid.

Complete data on all prespecified primary and secondary outcomes are presented by treatment group in Table 2. Results from the prespecified primary statistical analysis and exploratory analyses reporting treatment group comparisons for select secondary outcomes and for select subgroups follow.

Primary Analysis

The primary outcome was obtained in 819 of the 966 participants (85%) treated with the study drug. The percentage of patients who completed follow-up was higher in the placebo group (87%) than in both the bolus maintenance (84%) and bolus only (83%) groups. The primary reasons for failure to follow-up were participant withdrawal from the study and inability to locate the participant 6 months after injury (Figure 1). Participants lost to follow-up were less severely injured and had better outcomes at discharge than other discharged participants (eTable 4 in Supplement 2). The site-adjusted absolute difference in the primary outcome of favorable neurologic outcome (GOSE score >4) between the combined tranexamic acid group and the placebo group was −3.5% (65% vs 62%; [90% 1-sided confidence limit for benefit, −0.9%]; P = .16; [97.5% 1-sided confidence limit for harm, 10.2%]; P = .84) (Table 3). Logistic regression models for the primary outcome yielded similar results (eTable 5 in Supplement 2). Results for the stratified dichotomy of GOSE score based on the qualifying GCS score were similar to those of the GOSE score greater than 4 (eTable 6 in Supplement 2).

Secondary Outcomes

The overall 28-day mortality in this trial was 16%, of which 87% was attributed to neurologic injury (eTable 7 in Supplement 2). The all-cause 28-day mortality was 14% in the combined tranexamic acid group and 17% in the placebo group (adjusted difference, −2.9% [95% CI, −7.9% to 2.1%]; P = .26; Table 3); 28-day mortality was 12% for the bolus only group and 17% for the bolus maintenance group (bolus maintenance vs placebo: adjusted difference, −0.09% [95% CI, −6.1% to 5.9%]; P = .98; bolus only vs placebo: adjusted difference, −5.4% [95% CI, −10.9% to 0.05%]; P = .05; bolus only vs bolus maintenance: adjusted difference, −5.3% [95% CI, −10.8% to 0.1%]; P = .06). Although these mortality differences did not reach statistical significance, they were apparent early (Figure 2) and may have influenced treatment group differences in the rates of adverse events.

The difference in the DRS score at 6 months was not statistically significant between tranexamic acid–treated and placebo-treated participants (6.8 vs 7.6; adjusted difference, −0.9 [95% CI, −2.5 to 0.7]; P = .29; Table 3). Among participants with multiple head computed tomographic scans, 16% of tranexamic acid–treated participants experienced progression of ICH compared with 20% of placebo-treated participants (adjusted difference, −5.4% [95% CI, −12.8% to 2.1%]; P = .16; Table 3). Pairwise comparisons of the 3 treatment groups for GOSE score greater than 4, DRS score, and progression of ICH revealed no statistically significant differences (Table 3).

Adverse Events

Table 2 and Table 3 list predefined adverse events potentially associated with tranexamic acid administration. Overall, thrombotic events were more frequently observed in the bolus only (9%) and placebo (10%) groups than in the bolus maintenance group (4%). Participants in the bolus only group were more likely to experience seizures (5%) than participants in the bolus maintenance group (2%) or placebo group (2%). In patients without ICH, 6% developed seizures in the bolus only group compared with no patients in the bolus maintenance group and 2% of patients in the placebo group (eTable 8 in Supplement 2). The total numbers of other adverse events were similar between groups (Table 4). Additional details about adverse events are provided in eTable 9 in Supplement 2.

Exploratory Analyses of Subgroups

Results from between-group comparisons of favorable 6-month neurologic outcome (GOSE score >4), DRS score, and 28-day mortality in the subgroup of participants for whom the outcomes did not need to be imputed were similar to the results of analyses of all patients’ data (Table 4 and eTable 5 in Supplement 2). Among patients who were determined while in the hospital to have had an ICH, 28-day mortality was 18% in the bolus only group, 26% in the bolus maintenance group, and 27% in the placebo group (bolus maintenance vs placebo: adjusted difference, −0.8% [95% CI, −7.0% to 8.7%]; P = .84; bolus only vs placebo: adjusted difference, −8.2% [95% CI, −16.6% to −0.8%]; P = .03; bolus only vs bolus maintenance: adjusted difference, −9.0% [95% CI, −16.1% to −1.8%]; P = .01). Additional subgroup analyses are shown in eTable 10 in Supplement 2.

Resuscitation and Coagulation

Crystalloid volume administered by 24 hours was similar between groups. Participants in the bolus only group received fewer blood transfusions than patients in the other 2 groups. Among those who received a blood transfusion, participants in the bolus only group received less volume (Table 2). Values for all thromboelastography parameters were similar among groups (Table 2 and eTable 11 in Supplement 2).

Discussion

Quiz Ref IDIn this phase II trial of patients with moderate or severe traumatic brain injury, there was no statistically significant difference in 6-month neurologic outcome between the combined group of participants with moderate or severe TBI who received either a 1-g out-of-hospital tranexamic acid bolus followed by a 1-g in-hospital tranexamic acid infusion or a 2-g out-of-hospital tranexamic acid bolus followed by an in-hospital placebo infusion compared with participants who received an out-of-hospital placebo bolus followed by an in-hospital placebo infusion.

There are now 2 randomized trials that have examined the use of tranexamic acid in patients with TBI, both of which demonstrated no statistically significant difference in their primary end point comparing participants who received tranexamic acid with those who received placebo.10 This adds to the growing list of neutral trials in individuals with TBI and underscores the importance of developing improved methods for patient selection. In 2019, the CRASH-3 trial collaborators published the results of a pragmatic, placebo-controlled trial that randomized 12 737 adult participants from 29 countries with moderate or severe TBI to receive either a 1-g tranexamic acid bolus (initiated within 3 hours of injury) followed by a 1-g tranexamic acid 8-hour infusion or placebo and found no statistically significant difference in their primary outcome of risk of death from head injury at 28 days (18.5% of patients in the tranexamic acid group vs 19.8% in the placebo group).10 In this trial, similar to the CRASH-3 trial results, all-cause mortality at 28 days was not different between groups (14% for tranexamic acid–treated patients vs 17% for placebo-treated patients). Despite no statistically significant difference in the primary outcome in either trial, there were important differences and findings from both trials that warrant consideration and future investigation. Although this trial did not independently examine patients with less severe injuries, the CRASH-3 trial reported a significantly lower risk of head injury–related death in less severely injured patients (with mild and moderate TBI) who received tranexamic acid compared with placebo (risk ratio, 0.78).10

In contrast to CRASH-3, this trial examined 2 different dosing regimens of tranexamic acid and performed exploratory analyses on the subset of patients with ICH based on the known ability of tranexamic acid to decrease bleeding. Although the CRASH-3 trial investigators did not report the number of participants with ICH and did not independently examine this subset of patients, it is likely that the number of patients enrolled in CRASH-3 with ICH was higher than in this trial because participants were enrolled after imaging was obtained in the hospital setting. Similar to the findings in CRASH-3, most of the mortality difference in this trial was observed by 24 hours after injury. No statistically significant difference in ICH progression was observed between patients who received tranexamic acid and those who received placebo in this trial, suggesting that the antifibrinolytic effect of tranexamic acid on bleeding may be less important than alternative mechanisms in this patient population. Although these findings are only exploratory, future analyses examining different tranexamic acid dosing regimens to determine the true effect of tranexamic acid in both less severely injured patients as well as those with ICH is warranted.

Quiz Ref IDOne of the primary concerns surrounding tranexamic acid administration relates to the potential for seizures and thrombotic complications.18-21 Consistent with multiple trials (including CRASH-3), this trial demonstrated no statistically significant difference in the rate of seizures between participants in the bolus maintenance group (the same tranexamic acid dose used in CRASH-3) and the placebo group, with a seizure rate of approximately 2% across groups in both trials. However, this is the first large-scale trial to administer a 2-g bolus of tranexamic acid, and 5% of participants in that group developed seizures, which is similar to previous studies in different patient populations that demonstrated an association between higher tranexamic acid levels and increased seizures.19-21 Although too few patients experienced seizures to draw meaningful conclusions, any potential benefit for tranexamic acid administration in patients with ICH should be balanced by the potential increased seizure risk.

Limitations

Quiz Ref IDThis study has several limitations. First, the early mortality difference observed between treatment groups has the potential to lead to survival bias, in which severely injured patients who survived longer in the bolus only group may have lived long enough to experience more complications. Second, determining time of injury prior to hospital arrival is challenging. Although this trial excluded participants without an estimated time of injury, because the actual time of injury is rarely known, the initial 911 call is often used as a surrogate for injury time, which is standard for out-of-hospital trials. Although the time from injury to tranexamic acid administration was well balanced between groups, inaccuracies related to the time from injury to tranexamic acid administration are still likely. Third, enrolling patients in the out-of-hospital setting using the GCS to determine severity of injury has important limitations. Because the GCS has limited ability to discriminate between ICH and other central nervous system depressed states (eg, intoxication, sedation, shock), a fairly low percentage of patients with ICH were enrolled in this trial, which may have diluted treatment differences. Fourth, despite standardized EMS training, 20% of participants enrolled in the trial had a GCS score of 13 or higher on admission, potentially contributing further to an overall low injury severity. Fifth, obtaining 6-month follow-up in participants with TBI enrolled in the out-of-hospital setting, prior to consent, is challenging. In this trial, 15% of participants were lost to follow-up due to study withdrawal or the inability to locate transient participants 6 months after injury. Although considerable prognostic data on participants lost to follow-up were used to impute outcomes, the potential for bias remains. Sixth, participants with both blunt and penetrating injuries were enrolled in this trial to reflect military and civilian populations, potentially introducing heterogeneity into the outcomes. However, because only 3% of participants in this trial experienced penetrating injury, the results may not be generalizable to patients with penetrating TBI. Seventh, several secondary subgroup analyses were based on comparisons of small numbers of participants, potentially leading to a type II error. Eighth, statistical significance was not corrected for multiple testing, potentially leading to type I error; the secondary analyses of the primary outcome as well as the analyses of secondary outcomes should therefore be interpreted with caution.

Conclusions

Among patients with moderate or severe TBI, out-of-hospital tranexamic acid administration within 2 hours of injury did not improve 6-month neurologic outcome as measured by the GOSE.

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Article Information

Corresponding Author: Susan Rowell, MD, MBA, Division of Trauma and Critical Care Surgery, Department of Surgery, Duke University School of Medicine, 2301 Erwin Rd, Durham, NC 27707 (susan.rowell@duke.edu).

Accepted for Publication: May 8, 2020.

Correction: This article was corrected on October 27, 2020, to correct Table 2 to indicate the number of participants in the bolus only group that had more than 3% of clot lysed at 30 minutes following maximum amplitude as 31. The Table has been corrected and now indicates 31 participants.

Author Contributions: Dr McKnight and Mr Meier had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Rowell, McKnight, Kannas, May, Sheehan, Bulger, Christenson, Morrison, Colella, Weisfeldt, Zielinski, Auderheide, Williams, Schreiber.

Acquisition, analysis, or interpretation of data: Rowell, Meier, McKnight, Kannas, May, Bulger, Idris, Morrison, Frascone, Bosarge, Colella, Johannigman, Cotton, Callum, McMullan, Dries, Tibbs, Richmond, Tallon, Garrett, Auderheide, Gandhi, Schlamp, Robinson, Jui, Klein, Rizoli, Gamber, Fleming, Hwang, Vincent, Hendrickson, Simonson, Klotz, Sopko, Witham, Ferrara, Schreiber.

Drafting of the manuscript: Rowell, Meier, McKnight, Cotton, Garrett, Zielinski, Auderheide, Schlamp, Robinson, Fleming, Simonson, Sopko, Schreiber.

Critical revision of the manuscript for important intellectual content: Rowell, Meier, McKnight, Kannas, May, Sheehan, Bulger, Idris, Christenson, Morrison, Frascone, Bosarge, Colella, Johannigman, Cotton, Callum, McMullan, Dries, Tibbs, Richmond, Weisfeldt, Tallon, Garrett, Zielinski, Auderheide, Gandhi, Schlamp, Robinson, Jui, Klein, Rizoli, Gamber, Hwang, Vincent, Williams, Hendrickson, Klotz, Sopko, Witham, Ferrara, Schreiber.

Statistical analysis: Meier, McKnight, May, Hwang, Simonson.

Obtained funding: Rowell, McKnight, Kannas, May, Idris, Christenson, Weisfeldt, Schreiber.

Administrative, technical, or material support: Kannas, Sheehan, Bulger, Christenson, Frascone, Bosarge, Callum, McMullan, Dries, Tibbs, Richmond, Weisfeldt, Tallon, Gandhi, Schlamp, Robinson, Jui, Gamber, Williams, Hendrickson, Simonson, Witham, Ferrara, Schreiber.

Supervision: McKnight, Kannas, May, Christenson, Bosarge, Colella, Cotton, Callum, Tibbs, Weisfeldt, Garrett, Zielinski, Schlamp, Robinson, Gamber, Klotz, Schreiber.

Other - conducting the study at St Michael's Hospital in Toronto: Rizoli.

Other - supervised the implementation of the randomized trial in my site (University of Toronto): Morrison.

Other - patient enrolment and site PI: Callum.

Conflict of Interest Disclosures: Dr Rowell reported receiving grants from the US Department of Defense (DoD) and the National Institutes of Health (NIH) during the conduct of the study and personal fees from Portola Phamaceuticals outside the submitted work. Dr McKnight reported receiving grants from DoD and NIH during the conduct of the study. Dr May reported receiving grants from DoD and NIH during the conduct of the study. Dr Sheehan reported receiving grants from DoD and NIH during the conduct of the study. Dr Bulger reported receiving grants from NIH during the conduct of the study. Dr Idris reported receiving grants from NIH during the conduct of the study. Dr Christenson reported receiving grants from NIH during the conduct of the study. Dr Morrison reported receiving grants from NIH, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation Canada during the conduct of the study and endowed chair salary support from the Robert and Dorothy Pitts Chair in Acute Care and Emergency Medicine outside the submitted work. Dr Frascone reported receiving grants from DoD and NIH during the conduct of the study. Dr Bosarge reported receiving grants from DoD during the conduct of the study and personal fees from Avanos outside the submitted work. Dr Cotton reported receiving grants from DoD during the conduct of the study. Dr Callum reported receiving grants from Octapharma and the Canadian Blood Services outside the submitted work. Dr McMullan reported receiving grants from NIH during the conduct of the study. Dr Dries reported receiving grants from DoD and NIH during the conduct of the study. Dr Tibbs reported receiving grants from NIH during the conduct of the study. Dr Weisfeldt reported receiving grants from Johns Hopkins University during the conduct of the study. Dr Auderheide reported receiving grants from the Medical College of Wisconsin during the conduct of the study. Dr Schlamp reported receiving wages paid for duties rendered as a research assistant for the purpose of this trial from the Resuscitation Outcomes Consortium. Dr Williams reported receiving grants from DoD during the conduct of the study. Dr Klotz reported receiving grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Schreiber reported receiving grants from DoD, NIH, Health Canada, and the American Heart Association and personal fees from Haemonetics during the conduct of the study and personal fees from CSL Behring, Tricol, Velico Medical, and Arsenal Medical outside the submitted work. No other disclosures were reported.

Funding/Support: The Resuscitation Outcomes Consortium institutions participating in the trial were supported by a series of cooperative agreements from the National Heart, Lung and Blood Institute administered by the US Army Medical Research & Material Command (W81XWH-13-2-0090), including U01 HL077863 (University of Washington Data Coordinating Center), U01 HL077866 (Medical College of Wisconsin), U01 HL077871 (University of Pittsburgh), U01 HL077873 (Oregon Health and Science University), U01 HL077881 (University of Alabama at Birmingham), and U01 HL077887 (University of Texas Southwestern Medical Center/Dallas).

Role of the Funder/Sponsors: The US Army Medical Research & Material Command and the National Heart, Lung, and Blood Institute had input in the study design but had no role in the study conduct; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. However, Dr Sopko and Dr Pearson are employed by the National Heart, Lung, and Blood Institute and participated in the review and approval of the manuscript. The American Heart Association has also cosponsored Resuscitation Outcome Consortium research activities and did not participate in any of the above or influence the decision to publish the manuscript.

Group Information: The Resuscitation Outcome Consortium Investigators are listed in the eAppendix in Supplement 2.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of DoD, the National Heart, Lung and Blood Institute, or NIH and should not be construed as an official DoD/US Army policy unless designated by other documentation. No official endorsement should be made.

Meeting Presentations: This study was presented at the Military Health Systems Research Symposium; August 22, 2018, Orlando, Florida; at the American Academy of Neurology Plenary Session; May 5, 2019; Philadelphia, Pennsylvania; and at the TXA in Trauma Symposium; July 5, 2019; Melbourne, Australia.

Data Sharing Statement: See Supplement 3.

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