In people with mild-to-moderate traumatic brain injury, tranexamic acid (a drug which reduces bleeding) given within three hours of injury reduces the risk of death by 22%. This effect is seen in a subgroup of those who are less severely affected.
This NIHR-funded multi-centre international trial randomised 12,737 adults with intracranial bleeding to receive either tranexamic acid or a placebo. Overall, there was no difference in risk of death within 28 days between the two groups. However, when split by the severity of brain injury according to the Glasgow Coma Scale (GCS), those scoring above 9 out of 15 benefited.
Tranexamic acid reduces bleeding by inhibiting the breakdown of blood clots. The drug is already included in guidelines for pre-hospital care of patients with trauma and for adults with extracranial bleeding.
This trial found that it was also safe and effective with no increased incidence of stroke or blood clots in the lungs or deep veins when used in people with intracranial bleeding.
Why was this study needed?
Globally, around 10 million people die every year after a traumatic brain injury. In the UK, traumatic brain injury is estimated to cost £15 billion a year.
In patients with trauma and major extracranial bleeding, it has already been shown that when tranexamic acid is given within three hours it can reduce deaths from bleeding by a third. However, the effect of tranexamic acid on patients with intracranial bleeding has previously only been researched in two small trials. Although results were encouraging, they needed to be validated in a larger trial.
This trial was the first large multicentre trial to investigate the effect of tranexamic acid on head-injury related death, as well as disability and adverse events.
What did this study do?
The CRASH-3 randomised control trial compared two doses of tranexamic acid with placebo for adults with traumatic brain injury. Amongst the 12,737 people randomised to either group, the researchers managed to treat 9,202 (72.2%) within three hours of injury.
Eligible patients had a GCS score of 12 or lower or any intracranial bleeding, and no major extracranial bleeding. The treating clinician had to be uncertain as to the appropriateness of tranexamic acid treatment. Patients were an average age of 42 years.
The trial recruited patients from 29 countries of low, middle and high incomes, so the results are likely to be reproducible. In addition, patients and clinicians were blinded to the treatment allocation, which increases reliability in the results.
What did it find?
When tranexamic acid or placebo was given within three hours of the head injury:
- Overall, tranexamic acid had no effect on the risk of death within 28 days due to head injury. Deaths occurred in 18.5% (855/4,613) of the tranexamic acid group compared with 19.8% (892/4,514) of the placebo group, (relative risk [RR] 0.94, 95% confidence interval [CI] 0.86 to 1.02).
- There were fewer head-injury related deaths for those with mild-to-moderate head injury severity (GCS 9 to 15) given tranexamic acid, at 5.8% (166/2,846) compared with 7.5% (207/2,769) of those given placebo (RR 0.78, 95% CI 0.64 to 0.95). A smaller reduction in risk was found for people in whom both pupils were reactive to light.
- There was no reduction in head-injury related deaths for people with more severe head injury (GCS 3 to 8), with 39.6% (689/1,739) deaths in the tranexamic acid group compared with 40.1% (685/1,710) of the placebo group (RR 0.99, 95% CI 0.91 to 1.07). Similarly, there was no difference in risk for people with no pupil reactivity in one or both eyes.
- Tranexamic acid had no effect on the risk of disability. According to the Disability Rating Scale (range 0 to 30), those given tranexamic acid scored on average 4.99 compared with 5.03 in the placebo group, indicating moderate severity in both groups.
- There was no difference in complications such as stroke, deep vein thrombosis (DVT), pulmonary embolus (clot in the lung) or seizures.
What does current guidance say on this issue?
The NICE 2016 guideline recommends using tranexamic acid in patients with major trauma. NICE recommends against using it more than three hours after injury.
The guideline for head injuries (updated in 2019) focuses on the initial assessment, such as when to perform a scan, resuscitation and restoring blood volume after heavy bleeding. It does not cover the use of anti-bleeding medicines for head injury.
What are the implications?
This trial adds to the current guidelines for the treatment of major trauma, providing evidence that tranexamic acid is safe to administer within three hours of traumatic brain injury. It is likely to reduce mortality when given to adults with mild-to-moderate head injury.
It remains unclear whether the benefits would outweigh the risks for older adults. The evidence showing the benefits of this cheap and easy to administer drug may inform future head injury guidance.
Citation and Funding
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;394:1713-23.
This trial was funded by NIHR Health Technology Assessment Programme (project number 14/190/01), JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and the Wellcome Trust (Joint Global Health Trials scheme).
CRASH-2 Collaborators, Shakur H, Roberts I et al. 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;376:23-32.
CRASH-3 website. About the trial. London: London School of Hygiene and Tropical Medicine; 2019.
NICE. Major trauma: assessment and initial management. NG39. London: National Institute of Health and Care Excellence; 2016.
NICE. Head injury: assessment and early management. CG176. London: National Institute of Health and Care Excellence; 2014, updated 2019.
Parsonage M. Traumatic brain injury and offending; an economic analysis. London: Centre for Mental Health; 2016.
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