An appraisal of: Use of tranexamic acid in major trauma: a sex-disaggregated analysis of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2 and CRASH-3) trials and UK trauma registry (Trauma and Audit Research Network) data

British Journal of Anaesthesia, 129 (2): 191e199 (2022)
doi: 10.1016/j.bja.2022.03.032 

Internal Validity

  • This paper carries out a secondary data analysis on the CRASH-2 (2005-2010) and CRASH-3 (2012-2019) studies combined, as well as inspects data collected in the Trauma and Audit Research Network (TARN).
  • Both CRASH studies were large randomized, double-blinded, placebo-controlled trials. They recruited >20,000 and >10,000 patients respectively across >175 hospitals and from between 29-40 countries. 
  • Inclusion population;
    – CRASH-2 evaluated adults with significant bleeding or at risk of significant bleeding (SBP <90 or HR >100) within 8 hours of major trauma.
    – CRASH-3 evaluated adult patients who sustained traumatic brain injury within 3 hours of presentation (GCS <12 or evidence of intracranial bleed on CT without major extracranial bleeding). Any patient with GCS <3 or bilateral unreactive pupils was excluded due to poor baseline prognosis.
    – This paper combines both CRASH datasets, notably excluding any patient who was randomized and received intervention 3 hours after injury. 
  • Intervention; in both CRASH trails a loading dose of 1 g of TXA infused over 10 min, followed by an intravenous infusion of 1 g over 8 h was used. Normal saline was infused in placebo controls.  
  • Primary outcome = mortality within 24hours of injury after administration of TXA in major trauma (a sex-disaggregated analysis). 
  • Patients in both CRASH trials were followed up for 28days after traumatic injury however this paper only presents analysis after 24hours of injury. 
  • Secondary analysis examined whether there was a difference in receipt of TXA by sex. This was carried out on data taken from the TARN registry, which covers patients of all ages in England and Wales, who sustain injury resulting in hospital admission for longer than 3 days, critical care admission, death within 30 days of hospital arrival and transfer to a tertiary or specialist centre. All patients registered in 2017 to 2020 (inclusive) were included. 


  • Primary outcome analysis was performed on an intention to treat basis (missing data was minimal < 1%). 
  • A total of 13,530 patients in CRASH-2 trial and 7,694 patients in CRASH-3 trial fulfilled the inclusion criteria. An equal proportion of each sex received TXA vs placebo in the combined dataset (50:50). 
  • Pooled data from both CRASH studies showed TXA reduced the risk of death by 20-30% in both males and females. There was no significant heterogeneity by sex (P=0.34). The risk reduction (RR) in females patients was 0.69 [95% CI = 0.52-0.91] and in males 0.80 [95% CI = 0.71-0.90] with no significant heterogeneity (p=0.57). 
  • Potential confounders – age, time to treatment and baseline risk of death – were controlled for. 
  • Secondary analysis was carried out using imputed data as 20-31% of data for pre-hospital physiological variables and prehospital time was missing from TARN registry.
  • Total of 216,364 patients records were pooled from the TARN registry (46% female: 54% male); TXA was received by 7198 (7.3% [95% CI = 7.1-7.4%]) of the females and 19,697 (16.8% [95% CI = 16.6-17.0%]) of the males. The odds ratio for receipt of TXA was 0.39 [95% CI = 0.38-0.40].
  • Again potential confounders were addressed – logistic regression models were used to explore the potential interaction of age and baseline risk of death as result of bleeding (estimated by the BATT score) with TXA administration. They found females were less likely to receive TXA across all ages but that the disparity between TXA administration in men and women increased as the risk of death caused by bleeding decreased (P < 0.001). 
  • Mechanism of injury was not controlled for due to potential of causing over-adjustment bias but a stratified analysis was performed which showed females were less frequently given TXA than males for all injuries except motor vehicle crashes.

External Validity

  • The population analysed here is representative of our patients in the NHS; firstly the combined CRASH dataset was sufficiently large covering a population across multiple countries worldwide, including the UK, and the TARN dataset covers patients within the UK only. Thus, whilst the data appears applicable to our practise in the NHS, it is unknown if the use of TXA varies more widely across the globe dependent on sex. 
  • The inclusion/exclusion criteria are in keeping with clinical standards used to assess patients presenting with suspected bleeding after major trauma (i.e. systolic BP <90, HR >100) or TBI (GCS score and/or CT scan results).
  • Given the evidence supporting earlier TXA administration, it is interesting that this study selected the primary end point as 24hours. However the study does not carry out any temporal analysis despite data being available up to 28 days after injury. 
  • Moreover, this study did not address whether there was any sex dependent difference in any of the secondary outcomes analyzed in both original CRASH studies, namely vascular occlusive events, need for transfusion and dependency, after TXA. 
  • Overall, given major trauma and traumatic brain injury cost the UK billions of pounds per year and that TXA has previously been shown to be a cost-effective treatment, this study is highly relevant and based on the data available it should contribute towards a sex-neutral approach to the management of major trauma and TBI in the UK.  

Bottom Line

Administration of TXA to patients with bleeding trauma reduces mortality to a similar extent in women and men, but currently women are substantially less likely to be treated with TXA in the UK.