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Does prehospital administration of tranexamic acid compared with placebo result in lower 30-day mortality in patients at risk for hemorrhage after trauma?
In this multicenter randomized clinical trial of 927 patients, patients who received tranexamic acid compared with placebo in the prehospital setting did not have a significantly lower rate of 30-day mortality (8.1% vs 9.9%). There were no differences in the incidence of pulmonary embolism, deep vein thrombosis, seizures, or adverse events, including thrombotic complications, across arms.
Prehospital administration of tranexamic acid is safe but does not significantly reduce mortality in patients at risk for hemorrhage after injury.
In-hospital administration of tranexamic acid after injury improves outcomes in patients at risk for hemorrhage. Data demonstrating the benefit and safety of the pragmatic use of tranexamic acid in the prehospital phase of care are lacking for these patients.
To assess the effectiveness and safety of tranexamic acid administered before hospitalization compared with placebo in injured patients at risk for hemorrhage.
Design, Setting, and Participants
This pragmatic, phase 3, multicenter, double-blind, placebo-controlled, superiority randomized clinical trial included injured patients with prehospital hypotension (systolic blood pressure ≤90 mm Hg) or tachycardia (heart rate ≥110/min) before arrival at 1 of 4 US level 1 trauma centers, within an estimated 2 hours of injury, from May 1, 2015, through October 31, 2019.
Patients received 1 g of tranexamic acid before hospitalization (447 patients) or placebo (456 patients) infused for 10 minutes in 100 mL of saline. The randomization scheme used prehospital and in-hospital phase assignments, and patients administered tranexamic acid were allocated to abbreviated, standard, and repeat bolus dosing regimens on trauma center arrival.
Main Outcomes and Measures
The primary outcome was 30-day all-cause mortality.
In all, 927 patients (mean [SD] age, 42  years; 686 [74.0%] male) were eligible for prehospital enrollment (460 randomized to tranexamic acid intervention; 467 to placebo intervention). After exclusions, the intention-to-treat study cohort comprised 903 patients: 447 in the tranexamic acid arm and 456 in the placebo arm. Mortality at 30 days was 8.1% in patients receiving tranexamic acid compared with 9.9% in patients receiving placebo (difference, –1.8%; 95% CI, –5.6% to 1.9%; P = .17). Results of Cox proportional hazards regression analysis, accounting for site, verified that randomization to tranexamic acid was not associated with a significant reduction in 30-day mortality (hazard ratio, 0.81; 95% CI, 0.59-1.11, P = .18). Prespecified dosing regimens and post-hoc subgroup analyses found that prehospital tranexamic acid were associated with significantly lower 30-day mortality. When comparing tranexamic acid effect stratified by time to treatment and qualifying shock severity in a post hoc comparison, 30-day mortality was lower when tranexamic acid was administered within 1 hour of injury (4.6% vs 7.6%; difference, −3.0%; 95% CI, −5.7% to −0.3%; P < .002). Patients with severe shock (systolic blood pressure ≤70 mm Hg) who received tranexamic acid demonstrated lower 30-day mortality compared with placebo (18.5% vs 35.5%; difference, −17%; 95% CI, −25.8% to −8.1%; P < .003).
Conclusions and Relevance
In injured patients at risk for hemorrhage, tranexamic acid administered before hospitalization did not result in significantly lower 30-day mortality. The prehospital administration of tranexamic acid after injury did not result in a higher incidence of thrombotic complications or adverse events. Tranexamic acid given to injured patients at risk for hemorrhage in the prehospital setting is safe and associated with survival benefit in specific subgroups of patients.
ClinicalTrials.gov Identifier: NCT02086500
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Accepted for Publication: June 13, 2020.
Published Online: October 5, 2020. doi:10.1001/jamasurg.2020.4350
Correction: In Figures 2 and 3 in the Original Investigation titled “Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury: A Double-blind, Placebo-Controlled, Randomized Clinical Trial,” published online October 5, 2020, the labels of the forest plots, which showed “Favors placebo” on the left and “Favors tranexamic acid” on the right, have been reversed. This article was corrected online on December 2, 2020.
Corresponding Author: Jason L. Sperry, MD, MPH, Department of Surgery, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA 15213 (email@example.com).
Author Contributions: Dr Zenati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Guyette, Brown, Zenati, Early-Young, Adams, Eastridge, O’Keeffe, Joseph, Alarcon, Zuckerbraun, Neal, Rosengart, Yealy, Peitzman, Sperry.
Acquisition, analysis, or interpretation of data: Guyette, Brown, Zenati, Adams, Eastridge, Nirula, Vercruysse, O’Keeffe, Alarcon, Callaway, Neal, Forsythe, Billiar, Yealy, Sperry.
Drafting of the manuscript: Guyette, Eastridge, Callaway, Rosengart, Yealy, Sperry.
Critical revision of the manuscript for important intellectual content: Guyette, Brown, Zenati, Early-Young, Adams, Eastridge, Nirula, Vercruysse, O’Keeffe, Joseph, Alarcon, Callaway, Zuckerbraun, Neal, Forsythe, Rosengart, Billiar, Yealy, Peitzman.
Statistical analysis: Brown, Zenati.
Obtained funding: Guyette, Zenati, Sperry.
Administrative, technical, or material support: Guyette, Zenati, Early-Young, Adams, Eastridge, Nirula, O’Keeffe, Alarcon, Callaway, Zuckerbraun, Neal, Forsythe, Billiar, Peitzman.
Supervision: Adams, Nirula, O’Keeffe, Joseph, Zuckerbraun, Rosengart, Yealy, Sperry.
Conflict of Interest Disclosures: Dr Guyette reported receiving grants from the US Department of Defense (DOD) during the conduct of the study. Dr Zenati reported receiving grants from the DOD during the conduct of the study and grants from the National Institutes of Health (NIH) and the DOD outside the submitted work. Dr Adams reported receiving grants from the DOD during the conduct of the study. Dr Callaway reported receiving grants from the DOD to the University of Pittsburgh during the conduct of the study and grants from the NIH outside the submitted work. Dr Neal reported receiving grants from the DOD, National Institute of General Medical Sciences, and the National Heart, Lung, and Blood Institute during the conduct of the study and grants and personal fees from Janssen Pharmaceuticals and Haemonetics, grants from Instrumentation Laboratories, funding from Haima Therapeutics, and personal fees from CSL Behring outside the submitted work. Dr Sperry reported receiving grants from the DOD during the conduct of the study and outside the submitted work. No other disclosures were reported.
Funding/Support: This research was funded by grant W81XWH 13-2-0080 from the US Army Medical Research and Material Command, Fort Detrick, Maryland.
Role of the Funder/Sponsor: The funding source had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The writing team and the statistician had full access to all the data in the study and had final responsibility for the decision to submit for publication.
The STAAMP Study Group Collaborators: University of Pittsburgh, Presbyterian Hospital; clinical coordinating center and enrolling site: Meghan L. Buck, Ashley M. Ryman, Elizabeth A. Gimbel, Erin G. Gilchrist, Meghan Buhay, Tianyuan Xu, Multidisciplinary Acute Care Research Organization (MACRO) MACRO Research Specialists, MACRO Clinical Trials Research Associates; Investigational Drug Services—University of Pittsburgh Medical Center, Presbyterian Hospital: Sean Barrett; University of Texas Health San Antonio: Mark DeRosa, Rachelle Babbitt Jonas, Naresh Talathoti, Stephanie DeMoor, Santiago Pedraza, Lauran Barry, Danielle Cobb, Meenakshi Rani, Kristen Rocchi, Ryan Wallace, John C Myers, Caroline Zhu, Hyelin Oh; Investigational Drug Services—University of Texas Health San Antonio: Jennifer Hillman, Armando Garcia; University of Utah: Katie Birkas, Zachery Robinson, Sarah Puig-Holzman; Investigational Drug Services—University of Utah: Rian Davis; University of Arizona: Andrea Seach, David Bradford, Laurel L. Rokowski; Investigational Drug Services—University of Arizona: Jennifer Hoiles, Elena Issaian.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank all the prehospital personnel and research personnel at all enrolling sites, who were essential for the successful execution of the trial.
Meeting Presentation: This paper was presented at ACS Clinical Congress 2020; October 5, 2020; online presentation.
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