title: Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial.
abstract: BACKGROUND
  To investigate the mechanism of action of tranexamic acid (TXA) in bleeding trauma patients, we examined the timing of its effect on mortality. We hypothesised that if TXA reduces mortality by decreasing blood loss, its effect should be greatest on the day of the injury when bleeding is most profuse. However, if TXA reduces mortality via an anti-inflammatory mechanism its effect should be greater over the subsequent days.
  
  
  METHODS
  Exploratory analysis, including per-protocol analyses, of data from the CRASH-2 trial, a randomised placebo controlled trial of the effect of TXA on mortality in 20,211 trauma patients with, or at risk of, significant bleeding. We examined hazard ratios (HR) and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths, according to the day since injury. The CRASH-2 trial is registered as ISRCTN86750102 and ClinicalTrials.gov NCT00375258.
  
  
  RESULTS
  The effect of TXA on mortality is greatest for deaths occurring on the day of the injury (HR all-cause mortality = 0.83, 0.73 to 0.93). This survival benefit is only evident in patients in whom treatment is initiated within 3 hours of their injury (HR ≤ 3 hours = 0.78, 0.68 to 0.90; HR > 3 hours = 1.02, 0.76 to 1.36). Initiation of TXA treatment within 3 hours of injury reduced the hazard of death due to bleeding on the day of the injury by 28% (HR = 0.72, 0.60 to 0.86). TXA treatment initiated beyond 3 hours of injury appeared to increase the hazard of death due to bleeding, although the estimates were imprecise.
  
  
  CONCLUSIONS
  Early administration of tranexamic acid appears to reduce mortality primarily by preventing exsanguination on the day of the injury.
authors.affiliation: Clinical Trials Unit, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. Ian.Roberts@lshtm.ac.uk.
authors.forename: Ian
authors.initials: I
authors.lastname: Roberts
authors.affiliation: Clinical Trials Unit, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. david.prieto@lshtm.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Prieto-Merino
authors.affiliation: Clinical Trials Unit, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. Daniela.Manno@lshtm.ac.uk.
authors.forename: Daniela
authors.initials: D
authors.lastname: Manno
mesh_terms: D000933:Antifibrinolytic Agents / Q000627:therapeutic use*; D002423:Cause of Death / Q000639:trends*; D058734:Exsanguination / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality; D005260:Female; D006470:Hemorrhage / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D006801:Humans; D008297:Male; D009026:Mortality / Q000639:trends; D009104:Multiple Trauma / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D013223:Statistics as Topic / Q000379:methods; D014148:Tranexamic Acid / Q000627:therapeutic use*
chemical_list: D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid