Tranexamic Acid in Trauma Improves Mortality

By Frannie Rudolf

For years there has been talk in the EM community surrounding the use of tranexamic acid in trauma. Tranexamic acid has been used in surgery to reduce blood loss, and it has been hypothesized that it could be used in trauma to reduce hemorrhage and fibrinolysis that may become pathologic in trauma situations. TXA, a derivative of lysine, works by blocking binding sites on plasminogen, inhibiting plasminogen’s conversion to plasmin, which can potentially inhibit trauma-induced coagulopathy caused by fibrinolysis. 

The EMCrit Podcast with Dr. Tim Coates of the CRASH-2 trial nicely summarizes the available evidence. The CRASH-2 trial, originally published in The Lancet in 2010, showed that the use of tranexamic acid in trauma patients with significant hemorrhage reduced all cause mortality. This trial remains the most significant TXA study, however, there is still uncertainty surrounding the benefits and proper use of TXA. To clarify the data out there and try to make sense of what you need to know for actual practice and application we’ll briefly analyze a review article published in the Annals of Emergency Medicine which ties together the literature regarding TXA since the CRASH-2 trial. 

And now onto the study...

"Does the Use of Tranexamic Acid Improve Trauma Mortality?" Annals of Emergency Medicine 63.4 (2014): 460-62. Web.

The Review:

• Clinical question: Does the use of tranexamic acid reduce mortality in trauma patients and which patients benefit most?
• Article search strategy: Pubmed and Cochrane collaboration search using the key words “transexamic acid and trauma”. Only originally published articles looking at mortality and transexamic acid were included and they identified four articles that fit the bill. Three of the four articles included in the review are based off date from the CRASH-2 trial. We’ll take a more detailed look at that study, and then summarize the key points of the other studies. 
• Article Summaries:
  • CRASH-2:
    • Study design: double-blind, prospective, randomized, placebo-controlled trial in 274 hospitals in 40 countries
    • Population: enrolling 20,211 adult trauma patients with or at risk of significant bleeding

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Trial Profile 

• • • Intervention Protocol: Patients were randomly given either a standard dose of Tranexamic acid (n=10,060) or matched placebo (n=10,067) within 8 hours of injury. (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were included if the responsible doctor was substantially uncertain about whether or not to treat with transexamic acid (ie, entry was governed by the uncertainty principle).
      • Results: All-cause mortality was significantly reduced with tranexamic acid (1463 [14·5%] tranexamic acid group vs. 1613 [16·0%] placebo group). The risk of death due to bleeding was significantly reduced (489 [4·9%] vs. 574 [5·7). Tranexamic acid given greater than 8 hours after injury resulted in an increased incidence of death due to hemorrhage compared to placebo (4.4% vs. 3.1%).
      • Primary Outcomes: Death within 4 weeks, cause of death further classified by bleeding, vascular occlusion (pulmonary embolism, stroke, or myocardial infarction), multi-organ failure, head injury, and other. Results of the primary outcomes were subdivided into 4 baseline characteristics: (1) estimated hours since injury, (2) systolic blood pressure, (3) Glasgow Coma Scale (GCS) score, and (4) type of injury (blunt versus penetrating).

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Death by Cause

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All-cause Mortality by Subgroups

• • • Interpretations: Tranexamic acid reduces all cause mortality and significantly reduces the risk of death from bleeding if given within 3 hours of the injury. 
    • Strengths: 1) Blinding and randomization: both staff and study participants were blinded. Patient’s randomized in blocks of 8 with computer random generator, with a minimization algorithm balancing for sex, age, time since injury, type of injury (blunt or penetrating), Glasgow Coma Score, systolic blood pressure, respiratory rate, central capillary refill time, and country. 2) Intention to treat analysis. 3) Big study population with generalizable results, given study spanned 40 countries. 
    • Weaknesses: 1) Size. Some argue that the size is actually a negative in this study given that it makes the study easier to power and may result in detection of statistically significant results that are not clinically important. 2) Protocol: Patient’s were admitted to the study if physicians were “reasonably certain anti-fibrinolytics were indicated”. Though this is a subjective entry point, the study also included objective criteria, like signs of massive hemorrhage (systolic bp <90 mmhg or HR >110 bpm). 3) Effect size depends on time of administration, and study showed TXA was actually harmful after 3 hours. Authors proposed these results could be due to chance or TXA may be contraindicated late in trauma do to thrombotic disseminated intravascular coagulation that can occur, but this is an area of TXA use that is not fully understood. 
  • Roberts et al:  A pre specified analysis of the CRASH-2 trial data to determine how the effects of treatment with tranexamic acid varied according to a trauma patient's baseline risk of death by stratifying the data into baseline risk of death (<6%, 6% to 20%, 21% to 50%, and >50%). Data showed that in each baseline risk of death, there were fewer total deaths and fewer deaths caused by bleeding in the tranexamic acid arm, although the effect was not significant in the lowest-risk group.
  • CRASH-2 Intracranial Bleeding Study: Smaller study within the CRASH-2 trial that quantified the effect of tranexamic acid on intracranial hemorrhage in patients with traumatic brain injury. The trial included 270 patients who fulfilled inclusion criteria for the CRASH-2 trial and had a TBI and looked at progression of intracranial hemorrhage on CT in patients given tranexamic acid v. a placebo. Results showed no statistically significant reduction in hemorrhage size on CT or adverse outcomes in the TXA, concluding that TXA was neither helpful nor harmful in TBI. 
  • Morrison et al: Retrospective, observational, cohort study enrolling 896 patients with combat related injuries admitted to a surgical hospital in Afghanistan. Researchers looked at the reduction in in-hospital mortality after implementation of a “major hemorrhage protocol” which included administration of a standard dose of TXA to trauma patients requiring blood products or with evidence of hyperfibrinolysis. Patient’s were divided into those who received tranexamic acid within 1 hour of injury ( n = 293) and those who did not receive tranexamic acid ( n = 603). Data was further subdivided into a massive hemorrhage group, which looked at those who received 10 or more units of pRBCs within 24 hours. The primary outcome was in-hospital mortality. Results showed an absolute reduction in hospital mortality in the TXA group of 6.5% and an absolute reduction of 13.7% in the massive transfusion group. 
• Conclusion of Literature Review: 
  • Our articles showed a mortality benefit in bleeding trauma patients with the use of tranexamic acid. 
  • There also seems to be no significant increase in serious pro-thrombotic complications if administered within 3 hours of injury. 
  • Based on the CRASH-2 intracranial bleeding study, there is no evidence that it is beneficial in TBI. 
  • Authors recommend tranexamic acid in trauma patients (other than isolated TBI patients) at risk for serious hemorrhage (SBP < 90 mm Hg, heart rate > 110 beats per minute), and if they receive resuscitation with blood products.  

Original Article 

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On the Horizon: The findings of the CRASH-2 trial have been demonstrated outside of this study and evidence since supports its claims to a reduction in death from hemorrhage in trauma situations. Furthermore, economic evaluations have shown that TXA is cheap and cost effective. Given all the available data it seems likely that we will start seeing TXA used for at least severely ill trauma patients within the 3-hour time frame. 

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References:

1. CRASH-2 Collaborators:  Effects of transexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): a randomized, placebo-controlled trial.  Lancet 376. 23-32.2010.
2. Harvey, Virginia, Jeanmarie Perrone, and Patrick Kim. "Does the Use of Tranexamic Acid Improve Trauma Mortality?" Annals of Emergency Medicine 63.4 (2014): 460-62. Web.