Understanding the neuroprotective effect of tranexamic acid: an exploratory analysis of the CRASH-3 randomised trial.
CRASH-3 trial
Emergence care
Epidemiology
Intracranial haemorrhage
Randomised controlled trial
Tranexamic acid
Traumatic brain injury
Journal
Critical care (London, England)
ISSN: 1466-609X
Titre abrégé: Crit Care
Pays: England
ID NLM: 9801902
Informations de publication
Date de publication:
11 11 2020
11 11 2020
Historique:
received:
02
06
2020
accepted:
12
08
2020
entrez:
11
11
2020
pubmed:
12
11
2020
medline:
15
7
2021
Statut:
epublish
Résumé
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. 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. 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). 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. ISRCTN15088122 , registered on 19 July 2011; NCT01402882 , registered on 26 July 2011.
Sections du résumé
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.
Identifiants
pubmed: 33172504
doi: 10.1186/s13054-020-03243-4
pii: 10.1186/s13054-020-03243-4
pmc: PMC7657351
doi:
Substances chimiques
Antifibrinolytic Agents
0
Neuroprotective Agents
0
Tranexamic Acid
6T84R30KC1
Banques de données
ClinicalTrials.gov
['NCT01402882']
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
560Subventions
Organisme : Medical Research Council
ID : MR/M009211/1
Pays : United Kingdom
Organisme : Department of Health
ID : 06/303/20
Pays : United Kingdom
Organisme : Department of Health
ID : 14/190/01
Pays : United Kingdom
Organisme : J P Moulton Charitable Foundation
ID : n/a
Pays : International
Organisme : Health Technology Assessment Programme
ID : 14/190/01
Pays : International
Organisme : the Joint Global Health Trials, Medical Research Council, Department for International Development, Global Challenges Research Fund, and the Wellcome Trust
ID : MRM0092111
Pays : International
Investigateurs
Ian Roberts
(I)
Haleema Shakur-Still
(H)
Amy Aeron-Thomas
(A)
Antonio Belli
(A)
Amy Brenner
(A)
Muhammad Anwar Chaudary
(MA)
Rizwana Chaudhri
(R)
Sabariah Faizah Bt Jamaluddin
(SFB)
Lauren Frimley
(L)
Kiran Javaid
(K)
Rashid Jooma
(R)
Aasia Kayani
(A)
Caroline Leech
(C)
Khalid Mahmood
(K)
Raoul Mansukhani
(R)
Julina Md Noor
(JM)
Jorge Mejia-Mantilla
(J)
Phil Moss
(P)
Jason Pott
(J)
Peter Sandercock
(P)
Temitayo Shokunbi
(T)
Liliana Vallecilla
(L)
Henry Benjamin Hartzenberg
(HB)
Manjul Joshipura
(M)
Pablo Perel
(P)
Michael J Clarke
(MJ)
Samuel C Ohaegbulam
(SC)
Anthony Rodgers
(A)
Tony Brady
(T)
Yashbir Dewan
(Y)
Phil Edwards
(P)
Edward O Komolafe
(EO)
Monica Arribas
(M)
Emma Austin
(E)
Eni Balogun
(E)
Lin Barneston
(L)
Collette Barrow
(C)
Danielle Beaumont
(D)
Myriam Benyahia
(M)
Imogen Brooks
(I)
Madeleine Cargill
(M)
Laura Carrington
(L)
Lisa Cook
(L)
Beatrice Cornu-Hewitt
(B)
Amber Geer
(A)
Daniel Gilbert
(D)
Catherine Gilliam
(C)
Julio Gil-Onandia
(J)
Daniel Hetherington
(D)
Courtenay Howe
(C)
Carolyn Hughes
(C)
David I'anson
(D)
Rob Jackson
(R)
Miland Joshi
(M)
Sneha Kansagra
(S)
Taemi Kawahara
(T)
Katharine Ker
(K)
Sergey Kostrov
(S)
Abda Mahmood
(A)
Hakim Miah
(H)
Bernard Ndungu
(B)
Kelly Needham
(K)
Cecilia Okusi
(C)
Aroudra Outtandy
(A)
Raul Pardinaz-Solis
(R)
Daniel Pearson
(D)
Tracey Pepple
(T)
Claude Pisani
(C)
David Prieto-Merino
(D)
Danielle Prowse
(D)
Nigel Quashi
(N)
Anna Quinn
(A)
Maria Ramos
(M)
Mia Reid
(M)
Chris Roukas
(C)
Giulia Scrapa
(G)
Chelci Squires
(C)
Jemma Tanner
(J)
Andrew Thayne
(A)
Lesley Vidaurre
(L)
Elizabeth Woods
(E)
Bukola Fawole
(B)
Olusade Adetayo
(O)
Olujide Okunade
(O)
Tamar Gogichaishvili
(T)
Maria de Los Angeles Munoz-Sanchez
(M)
Fatos Olldashi
(F)
Satish Krishnan
(S)
Vincent Djientcheu
(V)
Jorge Loria Castellanos
(JL)
Frank Rasulo
(F)
Qadamkhear Hama
(Q)
Yakub Mulla
(Y)
Ioan Stefan Florian
(IS)
Juan Tobar
(J)
Hussein Khamis
(H)
Conor Deasy
(C)
Bobby Wellsh
(B)
Jean Williams-Johnson
(J)
Susilo Chandra
(S)
Vincent Mutiso
(V)
Rizwan Butt
(R)
Muhammad Hammad Nasir
(MH)
Salman Ahmad
(S)
Farwah Aslam
(F)
Khurram Ishaque
(K)
Faheem Usmani
(F)
Shahrukh Rizvi
(S)
Farhad Ali
(F)
Omair Sajjad
(O)
Ali Zunair
(A)
Lal Rehman
(L)
Raza Rizvi
(R)
Farrukh Javeed
(F)
Shakeel Ahmed
(S)
Asad Abbas
(A)
Ali Afzal
(A)
Ali Mikdad
(A)
Asif Bashir
(A)
Anwar Chaudary
(A)
Tariq Salahuddin
(T)
Bashir Ahemed
(B)
Amir Aziz
(A)
Naveed Ashraf
(N)
Shahzad Hussain
(S)
Usman Ahmad
(U)
Muhammad Asif
(M)
Muhammad Adil
(M)
Adeel Rauf
(A)
Rizwan Khan
(R)
Bilal Ahmad
(B)
Umair Afzal
(U)
Hassan Raza
(H)
Quratul Ain
(Q)
Sajjad Yaqoob
(S)
Qaiser Waseem
(Q)
Muffasser Nishat
(M)
Suneel Semvel
(S)
Javed Iqbal
(J)
Samra Majeed
(S)
Sana Zulfiqar
(S)
Madeeha Iqbal
(M)
Nazia Majeed
(N)
Manzoor Ahmed
(M)
Nadeem Akhtar
(N)
Mohammad Malik
(M)
Yasir Shehzad
(Y)
Muhammad Yousaf
(M)
Abdul Wahid
(A)
Abdul Samad
(A)
Saifullah Shah
(S)
Mumtaz Ali
(M)
Jehan Zeb
(J)
Abdus Salam Khan
(AS)
Adeela Irfan
(A)
Salman Sharif
(S)
Riaz Memon
(R)
Ben Bloom
(B)
Tim Harris
(T)
Imogen Skene
(I)
Geoffrey Bellhouse
(G)
Olivia Boulton
(O)
Geraldine Ward
(G)
Catherine Jarvis
(C)
Carly Swann
(C)
Sathananathan Ratnam
(S)
Ronald Carrera
(R)
Kamal Yakoub
(K)
David Davies
(D)
Emma Fellows
(E)
Heather Jarman
(H)
Sarah Rounding
(S)
Elizabeth Johnson
(E)
Catherine Loughran
(C)
Fiona Lecky
(F)
Kate Clayton
(K)
Angiy Michael
(A)
Angela Coumbarides
(A)
Jason Kendall
(J)
Beverley Faulkner
(B)
Ruth Worner
(R)
Emma Gendall
(E)
Philip Hopkins
(P)
Paul Riozzi
(P)
Hannah Cotton
(H)
Raine Astin-Chamberlain
(R)
Mark Wilson
(M)
Jan Bodnar
(J)
Rachel Williams
(R)
Alberto Rigoni
(A)
Abdo Sattout
(A)
John Fletcher
(J)
Calum Edge
(C)
Nina Maryanji
(N)
Adrian Boyle
(A)
Susie Hardwick
(S)
Ellen Nichols
(E)
Catherine Hayhurst
(C)
Frank Coffey
(F)
Chris Gough
(C)
Philip Miller
(P)
Lucy Ryan
(L)
Melanie Darwent
(M)
Alexis Espinosa
(A)
Sally Beer
(S)
Julie Norton
(J)
Holly Maguire
(H)
Kay Finney
(K)
Anthony Kehoe
(A)
Rosalyn Squire
(R)
Alison Jeffery
(A)
Christiane Vorwerk
(C)
Denise Foord
(D)
Eliot Wilkinson
(E)
Avril Kuhrt
(A)
Shammi Ramlakhan
(S)
Stuart Reid
(S)
Andy Curran
(A)
Sean McMullan
(S)
Tajek Hassan
(T)
Stuart Nuttall
(S)
Stephen Haig
(S)
Saif Al-Nahhas
(S)
Diederik Bulters
(D)
Ardalan Zolnourian
(A)
Tamsin Ribbons
(T)
Ian Mew
(I)
Tanya de Weymarn
(T)
Victoria Hughes
(V)
Jane McVicar
(J)
Cieran McKiernan
(C)
Liza Keating
(L)
Henrik Reschreiter
(H)
Judith Wright
(J)
Louisa Chan
(L)
Himanshu Kataria
(H)
Alastair Ireland
(A)
Richard Body
(R)
Alasdair Corfield
(A)
Shindo Francis
(S)
William Townend
(W)
Timothy Coats
(T)
James Gagg
(J)
Sarah Wilson
(S)
Rowley Cottingham
(R)
Simon Tucker
(S)
Frank Sutherland
(F)
Louisa Mitchell
(L)
Lucy Parker
(L)
Ola Afolabi
(O)
Fiona Hunter
(F)
Mark Jadav
(M)
Kayode Adeboye
(K)
Mandy Grocutt
(M)
Gabrielle May
(G)
David Watson
(D)
Andrea Wootten
(A)
Sarah Robertshaw
(S)
Susan Dorrian
(S)
Rob Perry
(R)
Hyun Choi
(H)
Claire McGroarty
(C)
Paul Shone
(P)
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(D)
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(S)
Julina Noor
(J)
Norizan Rosli
(N)
Leonard Leong Sang Xian
(LLS)
Yong De Jun
(Y)
Fatahul Mohamed
(F)
Cheng Hee Song
(CH)
Arman Hawari
(A)
Leong Yuen Chin
(LY)
Hardawani Mohd Hussein
(HM)
Mohd Lotfi
(M)
Hafiq Hamid
(H)
Nujaimin Udin
(N)
Peck Lian
(P)
See Choo
(S)
Kwanhathai Wong
(K)
Fathiyah Gani
(F)
Mardhiah Jusoh
(M)
Darrsini Rajakumar
(D)
Chia Boon Yang
(CB)
Nur Shahidah Binti Dzulkiflee
(NSB)
Wong Chok Ky
(WC)
Muhaimin Azwan Bin Mohd Azman
(MABM)
Adi Bin Osman
(AB)
Azma Haryaty Ahmad
(AH)
Ramzuzaman Ismail
(R)
Si Qi Lai
(SQ)
Mohd Amin Bin Mohidin
(MAB)
Norwani Binti Deraman
(NB)
Salliza Binti Selamat
(SB)
Ida Abidin
(I)
Nurkhairulnizam Halim
(N)
Zuraini Bakar
(Z)
Zainalabidin Mohamed Ismail
(ZM)
Badrul Hisham
(B)
Ruhaida Kamal
(R)
Zainal Effendy
(Z)
Mashitah Ismail
(M)
Noor Azleen
(N)
Liu Yeo Seng
(LY)
Kamarul Aryffin Baharuddin
(KA)
Regunath Kandasamy
(R)
Azlan Kamalludin
(A)
Shamsul Asmee
(S)
Mohd Fadzil
(M)
Ahmad Basitz
(A)
Norhaya Abdullah
(N)
Giorgi Ingorokva
(G)
Shota Ingorokva
(S)
Iamze Agdgomelashvili
(I)
Kote Mumladze
(K)
Ioseb Maisuradze
(I)
Iulia Kugusheva
(I)
Buba Shalamberidze
(B)
Gia Tomadze
(G)
Juan Fernandez-Ortega
(J)
Raimundo Seara-Valero
(R)
Guillermo Ibañez-Botella
(G)
Victoria Garcia-Martinez
(V)
Melida Garcia Martul
(MG)
Santiago Freita Ramos
(SF)
Guillermo Lago Preciado
(GL)
Claudio Garcia-Alfaro
(C)
Angeles Munoz-Sanchez
(A)
Rafael Bellido-Alba
(R)
Carmen Corcobado
(C)
Ana Bueno
(A)
Alfonso Ambros
(A)
Juan Tihista Jimenez
(JT)
Jose Roldan Ramirez
(JR)
José Martín
(J)
Laura Inés Rodríguez
(LI)
Jaime Fontanals
(J)
José Manuel Jiménez-Moragas
(JM)
Joaquín Paya Berbegal
(JP)
Olaomi Oluwole
(O)
Raji Mahmud
(R)
Nancy Ukwu
(N)
Femi Bankole
(F)
Abidemi Oseni
(A)
Bamidele Adebayo
(B)
Adefolarin Malomo
(A)
Liadi Tiamiyu
(L)
Adefisayo Adekanmbi
(A)
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(L)
Ayodeji Olubodun
(A)
Fidelis Ojeblenu
(F)
Michael Uwaezuoke
(M)
Edward Komolafe
(E)
Oluwafemi Owagbemi
(O)
Fatai Ishola
(F)
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(A)
Ukpong Udoffa
(U)
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(A)
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(A)
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(S)
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(N)
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(D)
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(A)
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(O)
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(AC)
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Sebastian Betancur Londoño
(SB)
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(VM)
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(C)
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(S)
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(J)
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(S)
Yidhira Fajardo-Gaviria
(Y)
Yam Roka
(Y)
Ushma Ghising
(U)
Narayani Roka
(N)
Manzil Shrestha
(M)
Upendra Devkota
(U)
Bivek Vaidya
(B)
Pankaj Nepal
(P)
Amit Thapa
(A)
Bidur Kc
(B)
Ajit Shrestha
(A)
Rajiv Jha
(R)
Prabin Shrestha
(P)
Irgen Hodaj
(I)
Erion Spaho
(E)
Asllan Selaj
(A)
Nirian Bendo
(N)
Tomohisa Shoko
(T)
Hideki Endo
(H)
Atsushi Senda
(A)
Yasushi Hagihara
(Y)
Takashi Fuse
(T)
Naohisa Masunaga
(N)
Yasuhiro Otomo
(Y)
Ryuichiro Egashira
(R)
Takahiro Ohnuki
(T)
Alya AlMazmi
(A)
Subrata Saha
(S)
Alexander Suvarov
(A)
Than Latt Aung
(TL)
Kaung Myat Tun
(KM)
Tint Tint Khaing
(TT)
Thinzar Maw
(T)
Orlane Ndome
(O)
Mireille Moumi
(M)
André Mbida
(A)
Joseph Fondop
(J)
Mba Sebastien
(M)
Abdul Azim
(A)
Jan Adil
(J)
Zabiullah Amiry
(Z)
Jorge Loría-Castellanos
(J)
Nancy Guevara Rubio
(NG)
Patricia Ortega Leon
(PO)
Francisco Estrada
(F)
Erandy Montes de Oca-García
(EM)
Hafid Sanchez
(H)
Angélica Soria
(A)
Paola Bonucci
(P)
Federico Franchi
(F)
Alan Girardini
(A)
Himdad Hameed
(H)
Muhammad Basim
(M)
Simon Stock
(S)
Eap Hourt
(E)
Ali Ilunga
(A)
Jonathan Mulenga
(J)
Horia Ples
(H)
Adam Danil
(A)
Mircea Gorgan
(M)
Ioan Florian
(I)
Dusan Vlahovic
(D)
James French
(J)
Jeffrey East
(J)
Antonius Kurniawan
(A)
Julius Kiboi
(J)
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