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

Educational Objective
To learn whether tranexamic acid is beneficial for patients with moderate to severe traumatic brain injury.
1 Credit CME
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

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

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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