Early Prehospital Tranexamic Acid Following Injury Is Associated With a 30-day Survival Benefit

A Secondary Analysis of a Randomized Clinical Trial

Shimena R. Li, MD; Francis Guyette, MD, MPH; Joshua Brown, MD, MSc; Mazen Zenati, MD, MPH, PhD; Katherine M. Reitz, MD, MSc; Brian Eastridge, MD; Raminder Nirula, MD, MPH; Gary A. Vercruysse, MD; Terence O'Keeffe, MD; Bellal Joseph, MD; Matthew D. Neal, MD; Brian S. Zuckerbraun, MD; Jason L. Sperry, MD, MPH

Disclosures

Annals of Surgery. 2021;274(3):419-426. 

In This Article

Discussion

Hemorrhage and acute traumatic coagulopathy are leading causes of death following traumatic injury.[1–6] How one is resuscitated and the adjuncts utilized in addition to blood and blood component is important. Previous studies demonstrate that early use of TXA in injured patients at risk for bleeding improves survival.[8,10,14] A recent randomized clinical trial showed that prehospital TXA administration is safe, but did not result in statistically significant survival benefit between treatment arms.[18] The results of the current secondary analysis demonstrate a significant survival benefit in patients with at least mild to moderate shock who received prehospital TXA within 1 hour from injury. This survival benefit remained robust after multivariate adjustment, with a 65% lower hazard for 30-day mortality in patients that received EARLY prehospital TXA when compared to placebo.

Previous investigations demonstrate that injured patients with shock index >0.9 have higher mortality rates and risk for critical bleeding.[26,27] Additionally, a prospective cohort study evaluating the differential effect of TXA in patients with and without shock showed that TXA reduced mortality and MOF only in patients with shock.[28] Because patients enrolled in the primary STAAMP trial demonstrated a broad spectrum of injury and shock severity, only patients with initial prehospital shock index >0.9 were included for this secondary analysis to capture those at highest risk for hemorrhage and mortality. After exclusion of patients without evidence of shock, EARLY prehospital TXA was associated with not only a 30-day survival benefit, but also reduced incidence of MOF and lower 6-hour and 24-hour transfusion volumes. Shock index can be easily calculated and used as a stratification tool in the prehospital setting to identify patients that may benefit from prehospital TXA following injury. These findings can help guide appropriate patient selection and timing of prehospital TXA administration after injury.

Although the majority of studies examining the effect of TXA in injured patients are limited to the in-hospital setting, the importance of timing in TXA administration is a common theme.[8,11,14,17,29] The CRASH-2 trial is the largest randomized control trial evaluating the effect of in-hospital TXA within 8 hours of injury on mortality. This study showed significant reduction in overall mortality in those randomized to TXA.[8] Importantly, a post-hoc exploratory analysis showed that those receiving TXA within 1 hour of injury had the greatest reduction in mortality due to bleeding.[14] Further analysis confirmed that the time-dependent effect of TXA was not explained by differences in mechanism of injury, GSC, or blood pressure.[29] Extrapolating from the knowledge that early TXA administration improves survival and that the majority of deaths from traumatic hemorrhage occur within the first hours following injury, characterizing appropriate protocols and patient selection for prehospital TXA administration is paramount.

The time-dependent effect of TXA on survival may be explained by the timing of biological response following injury. Acute traumatic coagulopathy (ATC) involves a cascade of events following tissue trauma and hypoperfusion resulting in the activation of anticoagulant and fibrinolytic pathways.[30–32] ATC has been identified as a distinct entity present at the time of injury and is associated with poor outcomes.[30,32,33] TXA occupies binding sites on tissue plasminogen activator (tPA)-activated plasminogen, preventing the conversion to plasmin and blocking the interaction with fibrin. tPA reaches peak concentration approximately 30 minutes following injury with subsequent peak levels of plasminogen at 1 hour.[29,34] Administration of TXA before peak plasminogen concentration, ameliorating the downstream fibrinolytic and inflammatory effects of plasmin, may explain the observed benefits when TXA is given early. The EARLY subgroup in this analysis had a median time to treatment of 47 minutes with improved clinical outcomes, solidifying that early administration of TXA confers maximum benefit.

The magnitude of shock and a dysfunctional inflammatory response following traumatic injury have also been implicated in the development of postinjury MOF.[35,36] By reducing the activation of plasmin and preventing downstream plasmin-mediated proinflammatory cytokine release, TXA has been postulated to have an anti-inflammatory effect.[37] The present results demonstrate that EARLY prehospital TXA was associated with significantly decreased incidence of MOF (4.2% vs 12.5%, P = 0.02).

TXA following injury has been shown to have varying effect on transfusion requirements.[8,9,38,39] In this analysis, we observed decreased volume of 6-hour and 24-hour blood and blood component transfusion in patients receiving EARLY prehospital TXA, with no significant observed differences in transfusion requirements in the DELAYED group. Further, EARLY prehospital TXA was associated with reduced massive packed red blood cell transfusion (2.5% vs 9.2%, P = 0.03), which was not observed in the DELAYED group. Timely administration of TXA in the prehospital phase is associated with a reduced risk of blood product transfusion after injury.

Evidence surrounding measures of coagulopathy after TXA administration in traumatic injury is limited.[9,19,40] There were no differences across randomization arms in the primary STAAAMP trial and no differences found in INR in the current secondary analysis. TEG measurements occurred in-hospital after either EARLY or DELAYED prehospital TXA was administered. The current subgroup results of decreased α angle (EARLY TXA vs placebo) and LY30 in (DELAYED TXA vs placebo) do not provide a underlying mechanism for the outcomes demonstrated. Additionally, the observed differences in alpha angle may not be clinically significant. It may be that in-hospital thromboelastography may be unable to appropriately characterized differences in LY30 following a prehospital TXA intervention. Further prospective analysis comparing measures of coagulopathy and fibrinolysis following prehospital TXA treatment are needed to provide clarity.

Although we were not able to comment on changes in coagulation parameters due to study design, previous investigations have suggested improved measures of coagulopathy after TXA administration. In particular, Kunze-Szikszay et al[40] assessed the effects of prehospital TXA on rotational thrombelastometry and showed no significant changes in parameters following TXA treatment. This was in contrast to a study by Theusinger et al[41] which compared coagulation status in trauma patients at the scene and on arrival to the emergency department and showed dramatic deterioration in measures of coagulation between the two time points.

Most importantly, we report no significant increase in adverse effects, including VTE and seizure, across treatment arms in both EARLY and DELAYED groups. This corresponds to the primary trials results[18] and demonstrates the safety of prehospital TXA as has been documented in other recent prehospital clinical trials focused on traumatic brain injury.[19]

Although this secondary analysis has robust findings, there are several limitations. This was a post-hoc secondary analysis that was not prespecified in the primary STAAMP trial protocol. The study was not randomized across EARLY and DELAYED patients, and there were significant differences between the two subgroups. Although we adjusted for these differences and confounding variables across the groups using a multivariate Cox proportional model, potential for residual confounding exists. Additionally, the primary STAAMP trial included patients from multiple trauma centers, which could affect conclusions based on differences across participating sites. However, analyses from both the primary STAAMP trial and the current secondary analysis were adjusted for enrollement site, and results are independent of major differences across participating centers. To capture those at risk for hemorrhage, we excluded patients with a shock index of ≤0.9, which limits the external validity of our results. Thromboelastography measurements were unable to be obtained in all patients and the comparison results are associated with missingness which limits the ability to draw appropriate conclusions. Lastly, this study was not powered to definitively conclude what was demonstrated for DELAYED group patients.

The results of this analysis adds to mounting evidence that minimizing the time between injury and TXA administration is critical for maximal outcome benefits.[5,15,19] Capitalizing on the prehospital phase of care allows for the delivery of this life-saving treatment as close to the time of injury as possible.[42] These findings underscore the multifactorial therapeutic action TXA confers in trauma patients at risk for hemorrhage. The combination of anti-fibrinolytic and anti-inflammatory effects of TXA serves as a powerful tool to combat the cascade of events triggered by endothelial damage and resulting inflammation following injury. Additionally, the findings from this study offer guidance for appropriate patient selection for prehospital TXA, with pronounced benefit in those who receive TXA within 1 hour of injury with evidence of shock.

In conclusion, we characterized a subgroup of patients that have significant benefit from prehospital TXA. Patients with shock index >0.9 who received prehospital TXA within 1 hour of injury had lower 30-day mortality, incidence of MOF, and lower 6-hour and 24-hour blood product transfusion requirements without an increased risk of adverse effects. These current results suggest TXA is safe in the prehospital setting and should be administered as close to the time of injury as possible for maximal outcome benefits.

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