Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury: A Double-blind, Placebo-Controlled, Randomized Clinical Trial

Abstract

Importance: 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.

Objective: 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.

Interventions: 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.

Results: In all, 927 patients (mean [SD] age, 42 [18] 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.

Trial registration: ClinicalTrials.gov Identifier: NCT02086500.

Conflict of interest statement

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.

Figures

Figure 1.. Flow of Patients in the Study of Tranexamic Acid During Air and Ground Prehospital Transport (STAAMP) Trial

Screening, randomization, and follow-up of the study participants. Per site institutional review board requirements, data from participants who withdrew consent or were excluded based on ineligibility in certain situations could not be included for the intention-to-treat analysis. Multiple imputation was performed for the 9 participants missing the primary outcome for the primary analysis as prespecified in the study protocol. Dose response analyses were performed on those with 30-day mortality data available.

Figure 2.. Survival and Subgroup Analysis for 30-Day Mortality

A, Kaplan-Meier estimates of 30-day survival rate among patients randomized to the prehospital tranexamic acid or placebo intervention. The time when qualifying vital signs occurred in the prehospital environment represents time zero. B, Risk ratio of 30-day mortality in the 7 prespecified subgroups. The diamond represents the point estimate of the risk ratio, and horizontal bars represent the 95% CI. The dotted vertical line represents a risk ratio of 1.0, indicating no difference in mortality between standard care and plasma groups. The dashed vertical line represents the overall treatment risk ratio in the intention-to-treat cohort for patients not missing the primary outcome of 30-day mortality. Adjusted P values are for the interaction term between each subgroup and treatment group in a logistic regression model with 30-day mortality as the outcome to determine whether there was a significantly different effect of treatment group across the levels of each subgroup on the outcome, adjusted for multiple comparisons using false discovery rate correction. TBI indicates traumatic brain injury.

Figure 3.. Prespecified Tranexamic Acid Dose Response Analysis, Time to Intervention, and Shock Severity Post Hoc Subgroup Analysis for 30-Day Mortality

A, Risk of 30-day mortality across tranexamic acid prespecified dosing regimens, accounting for site clustering. All risk ratios are in reference to the placebo group. The abbreviated dose represents a single 1-g bolus dose. The standard dose represents a 2-g dose administered as a 1-g bolus dose followed by a 1-g infusion during 8 hours. The repeat dose represents a 3-g dose administered as 2 separate 1-g boluses followed by a 1-g infusion during 8 hours. The repeat dose had lower risk of 30-day mortality than placebo group. B, Risk of 30-day mortality of the tranexamic acid group compared with placebo accounting for site clustering across post hoc subgroups for time of tranexamic acid administration from injury and shock severity based on qualifying inclusion vital signs. The dotted vertical line represents a risk ratio of 1.0 (no difference between groups). The squares represent the point estimate of the risk ratio, with the horizontal solid lines representing the 95% CIs. Time of tranexamic acid administration from injury was stratified by 1 hour or less and greater than 1 hour. The risk of 30-day mortality was lower in the tranexamic acid group when the drug was administered within 1 hour of injury. The risk of 30-day mortality was lower in the tranexamic acid group among patients in severe shock with systolic blood pressure less than 70 mm Hg based on qualifying inclusion vital signs. SBP indicates systolic blood pressure.