CRASH-3

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Roberts I, et al. "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". The Lancet. 2019. :.
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Clinical Question

What are the effects of tranexamic acid on head injury-related death, disability, and adverse events in patients with traumatic brain injury?

Bottom Line

  • CRASH-3 is generally a negative study that did not demonstrate that tranexamic acid reduces mortality from head injury-related death at 28 days. For a specific, narrow subgroup of patients seen within 3 hours, mild to moderate head injury (GCS 9 – 15), and intracranial hemorrhage, the risk of death related to head injury was reduced. Tranexamic acid reduced the risk of head injury-related death within 24 hours of injury, but this benefit was not shown at 28 days.

Major Points

Guidelines

As of June 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=12,737 randomized patients
    • Intervention (n=6406)
    • Placebo (n=6331)
  • Setting: 175 hospitals in 29 countries
  • Enrollment: July 20, 2012 and January 31, 2019
  • Follow-up: 28 days
  • Analysis: Intention-to-treat
  • Primary Outcome: head injury-related death in hospital within 28 days of injury in patients randomly assigned within 3 hours of injury

Population

Inclusion Criteria

  • Adults with TBI who were within 3 h of injury
  • Glasgow Coma Scale (GCS) score of 12 or lower
  • Any intracranial bleeding on CT scan

Exclusion Criteria

  • Major extracranial bleeding
  • TBI with a GCS score of 3 and those with bilateral unreactive pupils (prespecified sensitivity analysis)

Baseline Characteristics

  • Demographics: 80% male in both groups
  • Age: Mean 41.7 years (TXA group), 41.9 years (placebo group)
  • Groups were generally matched evenly for systolic blood pressure, Glasgow Coma Scale, and pupil reaction

Interventions

  • 1 g of tranexamic acid infused over 10 min followed by an intravenous infusion of 1 g over 8 h vs. matching placebo

Outcomes

Primary Outcomes

  • Head injury-related death in hospital within 28 days of injury in patients randomly assigned within 3 h of injury: 18.5% with TXA and 19.8% with placebo; RR 0·94; 95% CI 0·86–1·02
  • Excluding patients with GCS score of 3 or bilateral unreactive pupils: 12.5% vs. 14.0%; RR 0·89; 95% CI 0·80–1·00

Secondary Outcomes

  • All-cause mortality RR 0·96; 95% CI 0·89–1·04
  • Early head injury-related death (within 24 h after injury) RR 0·81; 95% CI 0·69–0·95
  • Non-head injury-related deaths RR 1·31; 95% CI 0·93–1·85
  • Cause-specific mortality
  • Disability
  • Vascular occlusive events (myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism)
  • Seizures
  • Complications
  • Neuro​surgery
  • Days in intensive care unit
  • Adverse events within 28 days of randomization

Subgroup Analysis

  • Head injury-related death
    • Mild-to-moderate head injury RR 0·78; 95% CI 0·64–0·95
    • Severe head injury RR 0·99; 95% CI 0·91–1·07
    • Reactive pupils RR 0·87; 95% CI 0·77–0·98
    • Non-reactive pupils RR 1·03; 95% CI 0·94–1·13

Adverse Events

  • No statistically significant differences between groups in disability or vascular occlusive events

Strengths

  • Asks a relevant clinical question
  • Builds on previous studies
  • Intention-to-treat study design
  • Very large patient recruitment for both treatment and control populations
  • Trial demonstrated safety data for tranexamic acid

Criticisms

  • CRASH-3 enrolled many sick patients who may have been unlikely to benefit from tranexamic acid administration
  • Benefits seen in the subgroup analysis refer to a specific, narrow group of patients and extrapolation to practice may be difficult as the results should be interpreted as hypothesis-generated in the context of negative findings for the primary outcome

Funding

  • Run in phase (first 500 patients): The JP Moulton Charitable Trust
  • Main phase: the National Institute for Health Research Health Technology Assessment (NIHR HTA; 14/190/01), and Joint Global Health Trials, Medical Research Council, Department for International Development, Global Challenges Research Fund, and the Wellcome Trust (MRM0092111)
  • New Brunswick Trauma Program grant of $10 000 CAD to support the trial in Canada

Further Reading