title: CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: the effect of tranexamic acid in traumatic brain injury--a nested randomised, placebo-controlled trial.
abstract: BACKGROUND
  Tranexamic acid (TXA) has been shown to reduce blood loss in surgical patients and the risk of death in patients with traumatic bleeding, with no apparent increase in vascular occlusive events. These findings raise the possibility that it might also be effective in traumatic brain injury (TBI).
  
  
  OBJECTIVE
  The Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage Intracranial Bleeding Study (CRASH-2 IBS) was conducted to quantify the effect of an early short course of TXA on intracranial haemorrhage and new focal cerebral ischaemic lesions in patients with TBI.
  
  
  METHODS
  CRASH-2 IBS was a prospective randomised controlled trial nested within the CRASH-2 trial. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight. We used a local pack system that selected the lowest numbered treatment pack from a box containing eight numbered packs. Apart from the pack number, the treatment packs were identical. The pack number was recorded on the entry form, which was sent to the international trial co-ordinating centre in London, UK. Once the treatment pack number was recorded, the patient was included in the trial whether or not the treatment pack was opened or the allocated treatment started. All site investigators and trial co-ordinating centre staff were masked to treatment allocation.
  
  
  METHODS
  Ten hospitals: (India) Aditya Neuroscience Centre, Sanjivani Hospital, CARE Hospital, Christian Medical College, Medical Trust Hospital, Jeevan Jyoti Hospital and (Colombia) Hospital Universitario San Vicente de Paul, Hospital Pablo Tobón Uribe, Hospital Universitario San José de Popayán and Fundación Valle del Lili.
  
  
  METHODS
  The trial was conducted in a subset of 270 CRASH-2 trial participants. Patients eligible for inclusion in the CRASH-2 IBS fulfilled the inclusion criteria for the CRASH-2 trial, and also had TBI [Glasgow Coma Scale score of ≤ 14 and a brain computerised tomography (CT) scan compatible with TBI]. Pregnant women and patients for whom a second brain CT scan was not possible were excluded.
  
  
  METHODS
  Participants were randomly allocated to receive either a loading dose of 1 g of TXA infused over 10 minutes followed by an intravenous infusion of 1 g over 8 hours or matching placebo.
  
  
  METHODS
  The primary outcome was the increase in size of intracranial haemorrhage growth between a CT scan at hospital admission and a second scan 24-48 hours later.
  
  
  RESULTS
  One hundred and thirty-three patients were allocated to TXA and 137 to placebo, of whom information on the primary (imaging) outcome was available for 123 (92%) and 126 (92%) respectively. The analysis suggested that TXA was likely to be associated with a reduction in haemorrhage growth [adjusted difference -3.8 ml, 95% credibility interval (CrI) -11.5 ml to 3.9 ml], fewer focal ischaemic lesions [adjusted odds ratio (OR) 0.54, 95% CrI 0.20 to 1.46] and fewer deaths (adjusted OR 0.49, 95% CrI 0.22 to 1.06).
  
  
  CONCLUSIONS
  This was the first randomised controlled study to evaluate the effect of TXA in TBI patients and it found that neither moderate benefits nor moderate harmful effects can be excluded. However, although uncertainty remains, our analyses suggest that TXA administration might improve outcome in TBI patients and provide grounds for evaluating this hypothesis in future research.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN86750102.
  
  
  BACKGROUND
  This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 13. See the HTA programme website for further project information.
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK. pablo.perel@lshtm.ac.uk
authors.forename: P
authors.initials: P
authors.lastname: Perel
authors.forename: R
authors.initials: R
authors.lastname: Al-Shahi Salman
authors.forename: T
authors.initials: T
authors.lastname: Kawahara
authors.forename: Z
authors.initials: Z
authors.lastname: Morris
authors.forename: D
authors.initials: D
authors.lastname: Prieto-Merino
authors.forename: I
authors.initials: I
authors.lastname: Roberts
authors.forename: P
authors.initials: P
authors.lastname: Sandercock
authors.forename: H
authors.initials: H
authors.lastname: Shakur
authors.forename: J
authors.initials: J
authors.lastname: Wardlaw
mesh_terms: D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D000933:Antifibrinolytic Agents / Q000627:therapeutic use*; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D020198:Intracranial Hemorrhage, Traumatic / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D017063:Outcome Assessment, Health Care; D011446:Prospective Studies; D011859:Radiography; D014148:Tranexamic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000889:Anti-Arrhythmia Agents; D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid