TY - JOUR
T1 - Understanding the neuroprotective effect of tranexamic acid
T2 - an exploratory analysis of the CRASH-3 randomised trial
AU - the CRASH-3 trial collaborators
AU - Brenner, Amy
AU - Belli, Antonio
AU - Chaudhri, Rizwana
AU - Coats, Timothy
AU - Frimley, Lauren
AU - Jamaluddin, Sabariah Faizah
AU - Jooma, Rashid
AU - Mansukhani, Raoul
AU - Sandercock, Peter
AU - Shakur-Still, Haleema
AU - Shokunbi, Temitayo
AU - Roberts, Ian
N1 - Funding Information:
The CRASH-3 trial was funded by the JP Moulton Charitable Foundation, the UK National Institute for Health Research Health Technology Assessment programme (NIHR HTA; 14/190/01), the Joint Global Health Trials, Medical Research Council, Department for International Development, Global Challenges Research Fund, and the Wellcome Trust (MRM0092111). The CRASH-2 trial was funded by the UK National Institute for Health Research Health Technology Assessment programme, JP Moulton Charitable Foundation, the BUPA Foundation and Pfizer (grant-in-aid for tranexamic acid and placebo). The studies were designed, conducted, analysed and interpreted by the investigators, entirely independently of all funding sources. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the funders. The funders had no role in the study design; the collection, analysis or interpretation of the data; the writing of the report; or the decision to submit the paper for publication. Acknowledgements
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - Background: The CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death. Methods: The CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis. Results: There were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58–0.94). There was no evidence of heterogeneity by severity (p = 0.64) or country income (p = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69–1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83–1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70–0.87) and death within 28 days (RR 0.88, 95% CI 0.82–0.94). Conclusions: Tranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury. Trial registration: ISRCTN15088122, registered on 19 July 2011; NCT01402882, registered on 26 July 2011.
AB - Background: The CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death. Methods: The CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis. Results: There were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58–0.94). There was no evidence of heterogeneity by severity (p = 0.64) or country income (p = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69–1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83–1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70–0.87) and death within 28 days (RR 0.88, 95% CI 0.82–0.94). Conclusions: Tranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury. Trial registration: ISRCTN15088122, registered on 19 July 2011; NCT01402882, registered on 26 July 2011.
KW - CRASH-3 trial
KW - Emergence care
KW - Epidemiology
KW - Intracranial haemorrhage
KW - Randomised controlled trial
KW - Tranexamic acid
KW - Traumatic brain injury
UR - http://www.scopus.com/inward/record.url?scp=85095781531&partnerID=8YFLogxK
U2 - 10.1186/s13054-020-03243-4
DO - 10.1186/s13054-020-03243-4
M3 - Article
C2 - 33172504
AN - SCOPUS:85095781531
SN - 1364-8535
VL - 24
JO - Critical Care
JF - Critical Care
IS - 1
M1 - 560
ER -