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

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.

Conflict of interest statement

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.

Figures

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

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

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.