What is the role of tranexamic acid (TXA) in traumatic brain injury (TBI) based on the Crash 3 trial?

CRASH-3 Trial: Tranexamic Acid in Traumatic Brain Injury

The CRASH-3 trial demonstrated that tranexamic acid (TXA) reduces head injury-related death by 22% in mild-to-moderate traumatic brain injury when administered within 3 hours of injury, with the greatest benefit seen when treatment occurs within 1 hour. 1, 2

Key Trial Findings

The CRASH-3 trial randomized 12,737 TBI patients to receive either TXA (1g loading dose over 10 minutes, followed by 1g infusion over 8 hours) or placebo. 2 The trial specifically enrolled patients within 3 hours of injury with GCS ≤12 or intracranial bleeding on CT scan, excluding those with significant extracranial bleeding. 2

Primary Outcome Results

• Overall mortality reduction: Among patients treated within 3 hours, head injury-related death was 18.5% in the TXA group versus 19.8% in placebo (RR 0.94,95% CI 0.86-1.02). 2

• Benefit in mild-to-moderate TBI: When excluding moribund patients (GCS 3 or bilateral unreactive pupils), TXA reduced head injury-related death from 14.0% to 12.5% (RR 0.89,95% CI 0.80-1.00). 2

• Strongest effect in mild-to-moderate injury: TXA reduced death by 22% in patients with mild-to-moderate TBI (RR 0.78,95% CI 0.64-0.95), but showed no benefit in severe TBI (RR 0.99,95% CI 0.91-1.07). 1, 2

Critical Timing Considerations

Time to treatment is the single most important factor determining TXA effectiveness in TBI. 1

• Within 1 hour: Patients treated within 1 hour had 65% lower 30-day mortality (HR 0.35,95% CI 0.19-0.65). 1

• Progressive decline: Treatment benefit decreases by approximately 10% for every 15-minute delay in administration. 1

• After 3 hours: Administration beyond 3 hours may actually increase mortality risk (RR 1.44,95% CI 1.12-1.84) and is contraindicated. 1

Mechanism of Action Insights

Exploratory analysis revealed that TXA's benefit occurs primarily through reduction of early deaths within 24 hours of injury. 3

• Early mortality reduction: TXA reduced deaths within 24 hours from 3.9% to 2.9% (RR 0.74,95% CI 0.58-0.94). 3

• No late effect: Deaths occurring beyond 24 hours showed no difference between TXA and placebo groups (11.5% vs 11.7%). 3

• Consistent across severity: The early mortality benefit was consistent regardless of TBI severity or country income level when moribund patients were excluded. 3

Patient Selection Algorithm

Appropriate candidates for TXA:

• Mild-to-moderate TBI (GCS >3 with at least one reactive pupil) 1
• Within 3 hours of injury, ideally within 1 hour 1
• No significant extracranial bleeding 2

Patients who should NOT receive TXA:

• Severe TBI with GCS 3 and bilateral unreactive pupils (no demonstrated benefit) 1
• More than 3 hours post-injury (potential harm) 1
• Active disseminated intravascular coagulation 4

Dosing Protocol

The standard evidence-based regimen is:

• Loading dose: 1g IV over 10 minutes 1, 2
• Maintenance dose: 1g IV infusion over 8 hours 1, 2

A 2024 network meta-analysis suggested that a 2g bolus may be superior to the standard CRASH-3 regimen, showing lower mortality compared to both placebo (RR 1.53,95% CI 1.08-2.17) and the 1g+1g regimen (RR 1.44,95% CI 1.02-2.03). 5 However, this finding is based on limited data from a single study and requires further validation. 5

Safety Profile

• Vascular occlusive events: No significant increase in thrombotic complications (RR 0.98,95% CI 0.74-1.28). 2

• Seizures: No increased risk compared to placebo (RR 1.09,95% CI 0.90-1.33). 2

• Overall safety: TXA is safe in TBI patients when administered within the appropriate time window. 3

Implementation Pitfalls to Avoid

• Delaying for diagnostics: Do not wait for CT imaging or advanced testing if clinical suspicion exists—administer TXA empirically before diagnostic workup to maximize the time-dependent benefit. 1

• Treating moribund patients: Resources should not be allocated to TXA in patients with GCS 3 and bilateral unreactive pupils, as no benefit has been demonstrated. 1

• Late administration: Never administer TXA beyond 3 hours post-injury, as this may increase mortality. 1

Cost-Effectiveness

TXA is highly cost-effective for mild-to-moderate TBI, with cost per life-year gained ranging from $48 in low-income countries to $64 in high-income countries. 1 This exceptional cost-effectiveness supports widespread implementation, particularly in resource-limited settings where TBI burden is highest. 2

Pre-Hospital Considerations

Pre-hospital administration should be strongly considered to ensure treatment within the critical 1-hour window, given that effectiveness decreases substantially with each 15-minute delay. 1