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Date: July 1, 2023

Reference: PATCH-Trauma Investigators and ANZICS Clinical Trial Group. Prehospital Tranexamic Acid for Severe Trauma. NEJM 2023.

Guest Skeptic: Dr. Salim Rezaie is a community emergency physician in San Antonio, TX.  He is the Creator and founder of REBEL EM, a free, critical appraisal blog that tries to cut down knowledge translation gaps of research to bedside clinical practice (https://rebelem.com).

Case: A 48-year-old man involved in a motor vehicle collision (MVC) is being evaluated by paramedics. He was entrapped in his vehicle for over one hour, had an initial blood pressure of 78/46 mmHg, and appeared to have a seat belt sign with deformities to bilateral lower extremities.  His Glasgow Coma Scale (GCS) score is 13 with obvious head trauma as well.  Emergency Medical Services (EMS) calls in ahead of time to warn the facility that they are 20 minutes out, to give report about the patient, and ask whether they should give tranexamic acid (TXA) pre-hospital.

Background: We have looked at the use of TXA many times on the SGEM. Most of the times the RCTs we critically appraised did not demonstrate superiority for their primary outcome. This has included:

There is some evidence of efficacy for TXA in epistaxis (SGEM#55, SGEM#210, and SGEM#395). There is also the CRASH-2 trial from 2010 which was reviewed with our good friend Dr. Anand Swaminathan (SGEM#80). That classic practice changing paper showed a 1.5% absolute decrease in death in trauma patients receiving TXA vs placebo (NNT = 66).

Despite these results, many clinicians remained skeptical of the benefit of TXA in trauma patients.  One of the major criticisms of the CRASH-2 trial was it was performed in under-resourced trauma systems and therefore may not be generalizable to care in advanced trauma systems.

Clinical Question: In advanced trauma systems, does the prehospital use of TXA increase the rate of survival with a favorable functional outcome in patients at risk for trauma-induced coagulopathy?

Reference: PATCH-Trauma Investigators and ANZICS Clinical Trial Group. Prehospital Tranexamic Acid for Severe Trauma. NEJM 2023.

  • Population: Adults (>18 years of age) with suspected severe traumatic injuries at risk for trauma induced coagulopathy (Assessed using the Coagulopathy of Severe Trauma [COAST] score) that could receive TXA within three hours of injury.

Coagulopathy of Severe Trauma (COAST Score)

  • Intervention: TXA 1g intravenous (IV) bolus over 10 minutes followed by 1g over 8 hours
  • Comparison: 9% saline (same volume as TXA) administered as bolus and infusion over 8 hours
  • Outcome:
    • Primary Outcome: Survival with a favorable functional outcome at six months assessed using the Glasgow Outcome Scale – Extended (GOS-E)
    • Secondary Outcomes: Death within 24 hours, 28 days, and 6 months after injury
    • Safety: Risk of thromboembolic phenomenon (deep vein thrombosis, pulmonary embolism, myocardial infarction, or stroke)

Glasgow Outcome Scale – Extended (GOS-E)

  • Type of Study: International, randomized, double-blind, placebo-controlled trial

Authors’ Conclusions: “Among adults with major trauma and suspected trauma-induced coagulopathy who were being treated in advanced trauma systems, prehospital administration of tranexamic acid followed by an infusion over 8 hours did not result in a greater number of patients surviving with a favorable functional outcome at 6 months than placebo.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. No
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. No
  12. Financial Conflicts of Interest. No

Results: They included 1,310 trauma patients. The mean age was 44 years, 70% male, 92% had blunt trauma and the median Injury Severity Score was 29.

Key Results: No statistical difference in favourable functional outcome at six months.

  • Primary Outcome: Favorable functional outcome at six months
    • TXA (53.7%) vs Placebo (53.5%); Risk Ratio (RR) 1.00; 95% CI 0.9 to 1.12
  • Secondary Outcomes:
    • 24 Hour Mortality: TXA (9.7%) vs Placebo (14.1%); RR 0.69; 95% CI 0.51 to 0.94
    • 28 Day Mortality: TXA (17.3%) vs Placebo (21.8%); RR 0.79; 95% CI 0.63 to 0.99
    • 6 Month Mortality: TXA 19.0% vs Placebo (22.9%); RR 0.83; 95% CI 0.67 to 1.03
  • Safety Outcome: No statically significant difference in safety outcomes (deep vein thrombosis, pulmonary embolism, myocardial infarction, or stroke)

1. Primary Outcome:

  • Survival with a favorable functional outcome at 6 months assessed using the Glasgow Outcome Scale – Extended (GOS-E)
  • Would we expect a one-time dose of a drug to have a significant impact on 6-month outcomes?
  • TXA’s role is in immediate clot stabilization and thus a short-term outcome may have been more relevant
  • For example, although secondary outcomes we do see statistically significant outcomes in mortality at 24hrs and 28days in patients receiving TXA

2. Dosing:

  • In this study TXA given as 1g over 10minutes, followed by 1g over 8hrs
  • There is now evidence for giving a 2g bolus over 10 minutes without follow up infusion
  • Many military and civilian trauma centers have moved to this dosing strategy
  • It is unclear whether 2g bolus in this trial would have made a difference in the primary outcome

3. Protocol Violations:

  • 35% of patients had protocol violations in this trial
  • 17% of patients assigned to receive placebo received open-label TXA
  • 21% of patients assigned to receive TXA did not receive the second dose
  • Overall, this could bias the results towards the null

4. Increased Survival with Poor Neurologic Outcome:

  • Although 24hr and 28-day mortality were secondary outcomes there were statistically significant outcomes in both groups
  • Additionally, the 28-day mortality in this trial (RR 0.79; 95% CI 0.63 TO 0.99) is similar to that observed in CRASH-2 (RR 0.91; 95% CI 0.85 to 0.97) with a better risk reduction but larger 95% CI
  • It seems TXA had its greatest effect on reducing deaths in the short-term window however with greater neurologic disability at 6 months
  • Would we withhold a treatment that saves lives in the short-term because survivors may be severely disabled at 6 months?

5. Do the Results of This Study Change Clinical Practice?

  • This is a relatively small trial with 1300 patients from 21 hospitals over 7 years compared to previous evidence
  • For comparison, CRASH-2 recruited 20,000 patients and did show a statistically significant difference in patients who got TXA
  • Do the results of a smaller RCT, trump the results of a significantly larger RCT…it all depends. Each study needs to be considered with their individual limitations.
  • We are unsure if the results of this study will change clinical practice

Comment on Authors’ Conclusion Compared to SGEM Conclusion: Agree with the author’s conclusion that there was no superiority for good neurologic outcomes at 6-months in patients receiving TXA who were being treated in advanced trauma systems.

SGEM Bottom Line: There is more uncertainty on whether TXA should be routinely given to all trauma patients being treated in an advanced trauma system.

Case Resolution: You tell the paramedics since the patient is at risk of trauma induced coagulopathy, within three hours of injury, and hypotensive, to go ahead and give the TXA.

Dr. Salim Rezaie

Clinical Application: It is unlikely this data will change much in terms of clinical management.  Data on TXA in major trauma consistently demonstrates improved short-term mortality with an excellent safety profile. Those who are convinced of the efficacy of TXA will continue to use this medication and those who are more skeptical will continue to question the potential benefit of TXA.

What Do I Tell the Patient? TXA has consistently been shown to decrease short-term mortality across multiple studies which gives you the best chance for recovery. However, it does not improve longer term functional outcome.  Functional outcome could potentially be improved however with further rehabilitation.

Dr. Simon Carley

Simon Says: When we were preparing this episode, we reached out to Dr. Simon Carley from St. Emlyn’s. He is a very smart person and knows the TXA literature very well. It is wise to listen when Simon speaks. Our question was how he was going to clinically apply the PATCH-Trauma into his practice. You can hear his response on the SGEM podcast.

 Keener Kontest: Last weeks’ winner was Shawn Murphy a PA from Parry Sound. He knew fentanyl can cause something called wooden chest syndrome.

Listen to the podcast this week to hear the keener question. If you think you know the answer then send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed:

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.