CRASH-2: Tranexamic Acid in Bleeding Trauma Patients (2010)

“We conclude that tranexamic acid can be used in bleeding trauma patients to reduce the risk of death due to bleeding, with no evidence of an increase in vascular occlusive events.”

  • The CRASH-2 Trial Collaborators

1. Publication Details

  • Trial Title: Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial
  • Citation: CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376(9734):23-32. DOI: 10.1016/S0140-6736(10)60835-5
  • Published: July 3, 2010, in The Lancet
  • Author: The CRASH-2 trial collaborators
  • Funding: UK National Institute for Health Research Health Technology Assessment programme; and others.

2. Keywords

  • Trauma, Hemorrhage, Tranexamic Acid (TXA), Antifibrinolytic, Randomized Controlled Trial

3. The Clinical Question

  • In adult trauma patients with or at risk of significant hemorrhage (Population), does early administration of tranexamic acid (TXA) (Intervention) compared to placebo (Comparison) reduce all-cause mortality at 28 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Uncontrolled bleeding is a major cause of death in trauma patients. Tranexamic acid is an antifibrinolytic agent that reduces bleeding by preventing the breakdown of blood clots. It had been shown to be effective in reducing blood loss in elective surgery.
  • Knowledge Gap: Despite its known mechanism, there was no high-quality evidence from a large randomized controlled trial to determine if tranexamic acid could improve survival in the chaotic and complex setting of acute trauma.
  • Proposed Hypothesis: The authors hypothesized that the early administration of a short course of tranexamic acid would reduce mortality in bleeding trauma patients.

5. Study Design and Methods

  • Design: A very large, international, multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 274 hospitals in 40 countries.
  • Trial Period: Enrollment ran from May 2005 to January 2010.
  • Population:
    • Inclusion Criteria: Adult trauma patients (≥16 years) with significant hemorrhage (defined as systolic blood pressure < 90 mm Hg, or heart rate > 110 bpm, or both) or who were considered to be at risk of significant hemorrhage, and who were within 8 hours of injury.
    • Exclusion Criteria: Included patients for whom the clinician was certain that tranexamic acid was either indicated or contraindicated.
  • Intervention: Patients received a loading dose of tranexamic acid (1g over 10 minutes) followed by an infusion of 1g over 8 hours.
  • Control: Patients received a matching intravenous placebo (0.9% saline).
  • Management Common to Both Groups: All other aspects of trauma care, including resuscitation and blood product transfusion, were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 20,000 patients would provide 90% power to detect a 2% absolute risk reduction in mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 28 days.
    • Secondary Outcomes: Included death due to bleeding, vascular occlusive events (e.g., myocardial infarction, stroke, pulmonary embolism), and the need for blood transfusion.

6. Key Results

  • Enrollment and Baseline: 20,211 patients were randomized (10,060 to TXA and 10,067 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: All-cause mortality at 28 days was significantly lower in the tranexamic acid group: 1463 of 10,060 patients (14.5%) died, compared with 1613 of 10,067 patients (16.0%) in the placebo group (p=0.0035).
  • Secondary Outcomes: The risk of death due to bleeding was significantly lower in the TXA group (4.9% vs. 5.7%; p=0.0077). Importantly, there was no significant increase in the risk of vascular occlusive events (e.g., blood clots) in the TXA group.
  • Adverse Events: The incidence of adverse events, particularly fatal and non-fatal vascular occlusive events, was similar between the two groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for all-cause death: 0.91 (95% CI, 0.85 to 0.97; P-value: 0.0035).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 0.91.
      • Clinical Meaning: The RR of 0.91 means that patients in the TXA group had a 9% lower relative risk of dying at 28 days compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.85 to 0.97.
      • Clinical Meaning: Since this entire range is below the line of no effect (1.0), it confirms that the result is statistically significant. Clinically, this means we can be 95% confident that the true benefit of TXA is a risk reduction of somewhere between 3% and 15%.
    • P-value: The p-value of 0.0035 is well below the 0.05 threshold, indicating the result is statistically significant and unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 16.0% – 14.5% = 1.5%.
      • Clinical Meaning: For every 1000 trauma patients with significant bleeding treated with TXA, about 15 additional deaths were prevented.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.015 = 67.
      • Clinical Meaning: You would need to treat 67 bleeding trauma patients with TXA to prevent one additional death.
  • Subgroup Analyses: A pre-specified subgroup analysis showed that the benefit of TXA was greatest when given early. Treatment given within 1 hour of injury significantly reduced the risk of death due to bleeding, but this benefit was lost if treatment was delayed beyond 3 hours.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard and provided a massive amount of high-quality data.
  • Generalizability: The pragmatic design with broad inclusion criteria and enrollment across 40 diverse countries makes the findings highly generalizable to trauma patients worldwide.
  • Statistical Power: The enormous sample size provided definitive power to detect a small but clinically important difference in mortality.
  • Patient-Centered Outcomes: The primary outcome of all-cause mortality is a robust, objective, and highly relevant endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The findings are highly generalizable to a broad population of trauma patients with significant hemorrhage.
  • Other: The cause of death was not always formally adjudicated, but this is unlikely to have biased the results for all-cause mortality.

10. Conclusion of the Authors

  • The authors concluded that tranexamic acid safely reduces the risk of death in bleeding trauma patients and should be given as early as possible after injury.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided definitive evidence for a simple, inexpensive, and life-saving intervention. It led to the immediate and universal adoption of tranexamic acid into trauma resuscitation guidelines worldwide.
  • Specific Recommendations:
    • Patient Selection: For adult trauma patients with or at risk of significant hemorrhage, within 3 hours of injury.
    • Actionable Intervention: Administer tranexamic acid (1g over 10 minutes, followed by 1g over 8 hours).
    • Expected Benefit: This intervention can be expected to prevent approximately one death for every 67 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that TXA should be given to all trauma patients, only those with evidence of significant bleeding. The subgroup analysis suggests it may be harmful if given after 3 hours.
  • Implementation Caveats: The key takeaway is the importance of early administration. The benefit is time-dependent and is lost if treatment is delayed.

12. Context and Related Studies

  • Building on Previous Evidence: The CRASH-2 trial (2010) was a direct successor to the CRASH trial (2004), which had shown harm with corticosteroids in head injury. The CRASH-2 investigators used the same successful large, pragmatic trial methodology to test a different drug.
  • Influence on Subsequent Research: The definitive positive result of this trial led to the design of the WOMAN trial (2017) in postpartum hemorrhage and the CRASH-3 trial (2019) in isolated traumatic brain injury, both of which also showed benefits for tranexamic acid.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question.
  • Future Directions: The results of this trial have spurred research into the use of tranexamic acid in other bleeding conditions, such as gastrointestinal bleeding and postpartum hemorrhage.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a leading cause of preventable death worldwide with a simple, inexpensive intervention.
  • Methods: The very large, multicenter, double-blind RCT design was of the highest quality and was essential for reliably detecting a small but important treatment effect. The pragmatic design ensured high external validity.
  • Results: The study reported a statistically significant and clinically important reduction in mortality. The finding of no increase in vascular occlusive events was a critical safety outcome that addressed the main concern with using an antifibrinolytic drug.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in evidence-based medicine and public health, demonstrating that a simple, low-cost intervention can save thousands of lives when applied on a global scale. Its findings are highly applicable worldwide.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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