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tranexamic acid

NIHR Signal Tranexamic acid is safe to use following mild-to-moderate traumatic brain injury and reduces deaths

Published on 29 January 2020

doi: 10.3310/signal-000870

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.

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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).

Bibliography

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.

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).

Bibliography

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.

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

Published on 19 October 2019

The CRASH-3 trial collaborators

Lancet , 2019

BACKGROUND: Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. METHODS: This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). RESULTS: Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50.3%] or placebo [6331 [49.7%], of whom 9202 (72.2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18.5% in the tranexamic acid group versus 19.8% in the placebo group (855 vs 892 events; risk ratio [RR] 0.94 [95% CI 0.86-1.02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12.5% in the tranexamic acid group versus 14.0% in the placebo group (485 vs 525 events; RR 0.89 [95% CI 0.80-1.00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0.78 [95% CI 0.64-0.95]) but not in patients with severe head injury (0.99 [95% CI 0.91-1.07]; p value for heterogeneity 0.030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0.005) but time to treatment had no obvious effect in patients with severe head injury (p=0.73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0.98 (0.74-1.28). The risk of seizures was also similar between groups (1.09 [95% CI 0.90-1.33]). INTERPRETATION: 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. Patients should be treated as soon as possible after injury. FUNDING: National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme). TRANSLATIONS: For the Arabic, Chinese, French, Hindi, Japanese, Spanish and Urdu translations of the abstract see Supplementary Material.

Expert commentary

This trial provides robust data to address an important question. The changes to the protocol and subgroup analysis will undoubtedly lead to debate over the findings, but it seems reasonable to conclude that tranexamic acid given within three hours of injury reduces deaths in adults with mild-to-moderate head injury and bleeding on CT scan.

The relatively young age of the cohort raises concerns about applying the findings to older patients with other medical problems and causes of reduced consciousness. Tranexamic acid should not be used indiscriminately in all head-injured patients, but selectively in those likely to benefit.

Professor Steve Goodacre, Health Services Research, School of Health and Related Research (ScHARR), University of Sheffield

The commentator chairs the NIHR HTA Commissioning Committee and is Deputy Director of the HTA Programme which funded the CRASH-3 trial