CRASH-3: Tranexamic Acid in Traumatic Brain Injury (2019)

“Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Treatment should be given as soon as possible after injury.”

  • The CRASH-3 Trial Collaborators

1. Publication Details

  • Trial Title: Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial
  • Citation: The CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019;394(10210):1713-1722. DOI: 10.1016/S0140-6736(19)32233-0
  • Published: October 14, 2019, in The Lancet
  • Author: The CRASH-3 trial collaborators
  • Funding: UK National Institute for Health Research Health Technology Assessment programme; and others.

2. Keywords

  • Traumatic Brain Injury (TBI), Head Injury, Tranexamic Acid (TXA), Antifibrinolytic, Intracranial Hemorrhage, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute traumatic brain injury (TBI) (Population), does early administration of tranexamic acid (TXA) (Intervention) compared to placebo (Comparison) reduce the risk of head injury-related death at 28 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Intracranial bleeding is a common and devastating complication that can worsen after the initial injury. The CRASH-2 trial (2010) had already proven that tranexamic acid, an antifibrinolytic agent, reduces mortality in trauma patients with extracranial bleeding.
  • Knowledge Gap: It was unknown if the benefits of TXA would extend to patients with isolated traumatic brain injury. There were theoretical concerns that by preventing clot breakdown, TXA could increase the risk of stroke or other vascular occlusive events in the brain.
  • Proposed Hypothesis: The authors hypothesized that the early administration of tranexamic acid would reduce the risk of head injury-related death in patients with TBI.

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: 175 hospitals in 29 countries.
  • Trial Period: Enrollment ran from July 2012 to January 2019.
  • Population:
    • Inclusion Criteria: Adult patients (≥16 years) with acute TBI who were within 3 hours of injury, had a Glasgow Coma Scale (GCS) score of 12 or less, or had any intracranial bleeding on CT scan.
    • Exclusion Criteria: Included patients with major extracranial bleeding (who would have been eligible for CRASH-2).
  • 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 TBI care were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 10,000 patients would provide 90% power to detect a 1.5% absolute risk reduction in head injury-related death. (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: Head injury-related death in hospital within 28 days of injury.
    • Secondary Outcomes: Included all-cause mortality, disability, and the incidence of vascular occlusive events (e.g., myocardial infarction, stroke, pulmonary embolism).

6. Key Results

  • Enrollment and Baseline: 12,737 patients were randomized, but the primary analysis was restricted to the 9,202 patients treated within 3 hours of injury (4,649 to TXA and 4,553 to placebo). The groups were well-matched.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: In the primary analysis of patients treated within 3 hours, there was no statistically significant difference in head injury-related death. 855 of 4649 patients (18.5%) in the TXA group died, compared with 892 of 4553 patients (19.8%) in the placebo group (p=0.08).
  • Secondary Outcomes: There was no significant difference in all-cause mortality or disability. Importantly, there was no significant increase in the risk of vascular occlusive events 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 head injury-related death between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for head injury-related death: 0.94 (95% CI, 0.86 to 1.02; P-value: 0.14). Note: The abstract reports a different RR after excluding patients with GCS 3 or bilateral unreactive pupils.
  • 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 0.94.
      • Clinical Meaning: An RR of 0.94 suggests a non-significant 6% lower relative risk of head injury-related death in the TXA group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.86 to 1.02.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. The true effect could range from a 14% benefit to a 2% harm.
    • P-value: The p-value of 0.14 is higher than the 0.05 threshold, indicating the result is not statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the primary outcome was not met, ARR and NNT are not applicable to the overall population.
  • Subgroup Analyses: In a pre-specified subgroup analysis, among patients with mild-to-moderate head injury (GCS 9-15), TXA significantly reduced the risk of head injury-related death (RR 0.78; 95% CI 0.60–1.00). This benefit was not seen in patients with severe head injury (GCS 3-8).

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 29 diverse countries makes the findings highly generalizable to a wide range of patients with TBI.
  • Statistical Power: The enormous sample size provided definitive power to detect even a small but clinically important difference.
  • Patient-Centered Outcomes: The primary outcome of head injury-related death is a robust and patient-centered 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 patients with TBI.
  • Other: The primary outcome of the trial was technically negative. The positive finding was in a pre-specified subgroup, which, while more robust than a post-hoc analysis, should still be interpreted with some caution.

10. Conclusion of the Authors

  • The authors concluded that tranexamic acid is safe in patients with TBI and that treatment within 3 hours of injury reduces head injury-related death, particularly in patients with mild-to-moderate head injury.

11. To Summarize

  • Impact on Current Practice: This trial provided important evidence on the role of TXA in isolated TBI. While the primary outcome was not met, the positive signal in the large subgroup of patients with mild-to-moderate injury, combined with the strong evidence of safety, has led many guidelines to recommend its use.
  • Specific Recommendations:
    • Patient Selection: For adult trauma patients with isolated mild-to-moderate traumatic brain injury (GCS 9-15) within 3 hours of injury.
    • Actionable Intervention: Administer tranexamic acid (1g over 10 minutes, followed by 1g over 8 hours).
  • What This Trial Does NOT Mean: This trial does NOT mean that TXA is beneficial for patients with severe TBI (GCS 3-8), where no benefit was seen.
  • Implementation Caveats: As with CRASH-2, the key is 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-3 trial (2019) was a direct follow-up to the successful CRASH-2 trial (2010), designed to see if the benefits of TXA in extracranial hemorrhage would translate to intracranial hemorrhage.
  • Influence on Subsequent Research: The findings of the CRASH trials have solidified the role of early TXA administration in the management of major hemorrhage, whether extracranial or intracranial.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The lack of benefit in severe TBI is an important finding that requires further investigation to understand the underlying pathophysiology.
  • Future Directions: Future research may focus on different dosing regimens or on combining TXA with other neuroprotective strategies in TBI.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a simple, inexpensive intervention for a leading cause of death and disability.
  • Methods: The very large, multicenter, double-blind RCT design was of the highest quality. The main methodological point for discussion is the interpretation of the primary outcome versus the subgroup analysis.
  • Results: The study’s primary analysis was negative. The positive finding was in a large, pre-specified subgroup (mild-to-moderate TBI), which lends it more credibility than a post-hoc analysis. The confirmation of safety (no increase in vascular occlusive events) was a critical finding.
  • Conclusions and Applicability: The authors’ conclusion, which emphasizes the subgroup finding, is a reasonable interpretation given the pre-specified nature of the analysis and the strong signal of benefit in that group. The trial provides strong evidence to support the use of early TXA in patients with mild-to-moderate TBI.

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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