title: Tranexamic acid in bleeding trauma patients: an exploration of benefits and harms.
abstract: The CRASH-2 trial showed that tranexamic acid (TXA) administration reduces mortality in bleeding trauma patients. However, the effect appeared to depend on how soon after injury TXA treatment was started. Treatment within 3 h reduced bleeding deaths whereas treatment after 3 h increased the risk. We examine how patient characteristics vary by time to treatment and explore whether any such variations explain the time-dependent treatment effect.
  
  
  
  Exploratory analysis were carried out, 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 examine how patient characteristics (age, type of injury, presence or absence of head injury, Glasgow coma scale (GCS), systolic blood pressure and capillary refill time) vary with time to treatment and use univariable (restriction) and multivariable methods to examine whether any such variations explain the time-dependent effect of TXA. If not explained by differences in patient characteristics, we planned to conduct separate prespecified subgroup analyses for the early benefit and late harm.
  
  
  
  There was no substantial variation in age or capillary refill by time to treatment. However, the proportion of patients with blunt trauma, the proportion with head injury and mean systolic blood pressure increased as time to treatment increased. Mean GCS decreased as time to treatment increased. Analyses restricted to patients with blunt trauma, those without head injury and those with a systolic blood pressure <100 mmHg showed that these characteristics did not explain the time-dependent treatment effect. In a multivariable analysis the interaction with time to treatment remained highly significant (p < 0.0001). Separate subgroup analyses that examine how the benefits of early TXA treatment and the harms of late TXA treatment vary by systolic blood pressure (≤75, 76-89, >89 mmHg); GCS (severe 3-8, moderate 9-12, mild 13-15); and type of injury (penetrating versus blunt) showed no significant heterogeneity.
  
  
  
  The time-dependent effect of TXA in bleeding trauma patients is not explained by the type of injury, the presence or absence of head injury or systolic blood pressure. When given within 3 h of injury, TXA reduces death due to bleeding regardless of type of injury, GCS or blood pressure.
  
  
  
  ClinicalTrials.gov, NCT00375258 . Registered on 11 September 2006.
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.
authors.forename: Phil
authors.initials: P
authors.lastname: Edwards
authors.affiliation: Clinical Trials Unit, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.|Catholic University of Murcia, Murcia, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Prieto
authors.affiliation: Clinical Trials Unit, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Miland
authors.initials: M
authors.lastname: Joshi
authors.affiliation: Clinical Trials Unit, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Abda
authors.initials: A
authors.lastname: Mahmood
authors.affiliation: Clinical Trials Unit, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Katharine
authors.initials: K
authors.lastname: Ker
authors.affiliation: Clinical Trials Unit, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Haleema
authors.initials: H
authors.lastname: Shakur
mesh_terms: D000367:Age Factors; D000933:Antifibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001794:Blood Pressure; D016009:Chi-Square Distribution; D005342:Fibrinolysis / Q000187:drug effects*; D015600:Glasgow Coma Scale; D006470:Hemorrhage / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D016015:Logistic Models; D015999:Multivariate Analysis; D016017:Odds Ratio; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D061665:Time-to-Treatment; D014148:Tranexamic Acid / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D014949:Wounds, Nonpenetrating / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D014950:Wounds, Penetrating / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid