{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T20:07:52Z","timestamp":1770754072892,"version":"3.50.0"},"reference-count":17,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T00:00:00Z","timestamp":1605052800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T00:00:00Z","timestamp":1605052800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment Programme","doi-asserted-by":"publisher","award":["14\/190\/01"],"award-info":[{"award-number":["14\/190\/01"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Joint Global Health Trials, Medical Research Council, Department for International Development, Global Challenges Research Fund, and the Wellcome Trust","award":["MRM0092111"],"award-info":[{"award-number":["MRM0092111"]}]},{"name":"J P Moulton Charitable Foundation","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Crit Care"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n<jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>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.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>The CRASH-3 trial randomised 9202 patients within 3\u2009h of injury with a GCS score\u2009\u2264\u200912 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\u2009h of injury and within 28\u2009days, 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.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>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\u2009h 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\u20130.94). There was no evidence of heterogeneity by severity (<jats:italic>p<\/jats:italic>\u00a0=\u20090.64) or country income (<jats:italic>p<\/jats:italic>\u00a0=\u20090.68). The risk of death beyond 24\u2009h 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\u20131.12). The risk of death at 28\u2009days 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\u20131.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70\u20130.87) and death within 28\u2009days (RR 0.88, 95% CI 0.82\u20130.94).<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>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.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Trial registration<\/jats:title>\n<jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.isrctn.com\/ISRCTN15088122\">ISRCTN15088122<\/jats:ext-link>, registered on 19 July 2011; <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01402882\">NCT01402882<\/jats:ext-link>, registered on 26 July 2011.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13054-020-03243-4","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T00:08:16Z","timestamp":1605053296000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Understanding the neuroprotective effect of tranexamic acid: an exploratory analysis of the CRASH-3 randomised trial"],"prefix":"10.1186","volume":"24","author":[{"name":"On behalf of the CRASH-3 trial collaborators","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2017-5994","authenticated-orcid":false,"given":"Amy","family":"Brenner","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Belli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rizwana","family":"Chaudhri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Coats","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Frimley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabariah Faizah","family":"Jamaluddin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rashid","family":"Jooma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raoul","family":"Mansukhani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Sandercock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haleema","family":"Shakur-Still","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Temitayo","family":"Shokunbi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,11,11]]},"reference":[{"key":"3243_CR1","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1016\/S1474-4422(17)30118-7","volume":"16","author":"N Stocchetti","year":"2017","unstructured":"Stocchetti N, Carbonara M, Citerio G, et al. Severe traumatic brain injury: targeted management in the intensive care unit. Lancet Neurol. 2017;16:452\u201364.","journal-title":"Lancet Neurol"},{"key":"3243_CR2","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1016\/S0140-6736(19)32233-0","volume":"394","author":"CRASH-3 Collaborators","year":"2019","unstructured":"CRASH-3 Collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019;394:1713\u201323.","journal-title":"Lancet"},{"key":"3243_CR3","doi-asserted-by":"publisher","first-page":"109","DOI":"10.3171\/jns.2002.96.1.0109","volume":"96","author":"M Oertel","year":"2002","unstructured":"Oertel M, Kelly DF, McArthur D, et al. Progressive hemorrhage after head trauma: predictors and consequences of the evolving injury. J Neurosurg. 2002;96:109\u201316.","journal-title":"J Neurosurg"},{"key":"3243_CR4","doi-asserted-by":"publisher","unstructured":"Collaborators C-3 IBMS. Tranexamic acid in traumatic brain injury: an explanatory study nested within the CRASH-3 trial. Eur J Trauma Emerg Surg. 2020. https:\/\/doi.org\/10.1007\/s00068-020-01316-1.","DOI":"10.1007\/s00068-020-01316-1"},{"key":"3243_CR5","doi-asserted-by":"publisher","first-page":"g4934","DOI":"10.1136\/bmj.g4934","volume":"349","author":"K Ker","year":"2014","unstructured":"Ker K, Roberts I. Tranexamic acid for surgical bleeding. BMJ. 2014;349:g4934.","journal-title":"BMJ"},{"key":"3243_CR6","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/S0140-6736(10)60835-5","volume":"376","author":"H Shakur","year":"2010","unstructured":"CRASH-2 trial collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet (London, England). 2010;376:23\u201332.","journal-title":"Lancet (London, England)"},{"key":"3243_CR7","doi-asserted-by":"publisher","first-page":"2105","DOI":"10.1016\/S0140-6736(17)30638-4","volume":"389","author":"WOMAN Trial Collaborators","year":"2017","unstructured":"WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389:2105\u201316.","journal-title":"Lancet"},{"key":"3243_CR8","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1038\/d41586-019-00857-9","volume":"567","author":"V Amrhein","year":"2019","unstructured":"Amrhein V, Greenland S, McShane B. Scientists rise up against statistical significance. Nature. 2019;567:305\u20137.","journal-title":"Nature"},{"key":"3243_CR9","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1136\/bmj.292.6522.746","volume":"292","author":"MJ Gardner","year":"1986","unstructured":"Gardner MJ, Altman DG. Confidence intervals rather than P values: estimation rather than hypothesis testing. Br Med J (Clin Res Ed). 1986;292:746\u201350.","journal-title":"Br Med J (Clin Res Ed)"},{"key":"3243_CR10","doi-asserted-by":"crossref","unstructured":"Heidet M. Tranexamic acid for acute traumatic hemorrhage in emergency medicine. Eur J Emerg Med. 2020;1:85\u201386.","DOI":"10.1097\/MEJ.0000000000000671"},{"key":"3243_CR11","doi-asserted-by":"publisher","unstructured":"Taccone FS, Citerio G, Stocchetti N. Is tranexamic acid going to CRASH the management of traumatic brain injury? Intensive Care Med. 2019. https:\/\/doi.org\/10.1007\/s00134-019-05879-5.","DOI":"10.1007\/s00134-019-05879-5"},{"key":"3243_CR12","doi-asserted-by":"publisher","unstructured":"Heymann EP. Tranexamic acid in traumatic intracranial bleeding: recognizing the limit of results (of the CRASH-3 trial). Eur J Emerg Med. 2019; published online Dec 18. https:\/\/doi.org\/10.1097\/MEJ.0000000000000657.","DOI":"10.1097\/MEJ.0000000000000657"},{"key":"3243_CR13","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.1016\/S0140-6736(19)32312-8","volume":"394","author":"AP Cap","year":"2019","unstructured":"Cap AP. CRASH-3: a win for patients with traumatic brain injury. Lancet. 2019;394:1687\u20138.","journal-title":"Lancet"},{"key":"3243_CR14","doi-asserted-by":"publisher","first-page":"86","DOI":"10.12688\/wellcomeopenres.14700.2","volume":"3","author":"I Roberts","year":"2018","unstructured":"Roberts I, Belli A, Brenner A, et al. Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial. Wellcome Open Res. 2018;3:86.","journal-title":"Wellcome Open Res"},{"key":"3243_CR15","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1186\/s13054-014-0685-8","volume":"18","author":"I Roberts","year":"2014","unstructured":"Roberts I, Prieto-Merino D, Manno D. Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial. Crit Care. 2014;18:685.","journal-title":"Crit Care"},{"key":"3243_CR16","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1186\/s13063-018-2900-4","volume":"19","author":"A Brenner","year":"2018","unstructured":"Brenner A, Arribas M, Cuzick J, et al. Outcome measures in clinical trials of treatments for acute severe haemorrhage. Trials. 2018;19:533.","journal-title":"Trials"},{"key":"3243_CR17","volume-title":"Tranexamic acid for patients with traumatic brain injury: a randomized, double-blinded, placebo-controlled trial","author":"S Yutthakasemsunt","year":"2013","unstructured":"Yutthakasemsunt S, Kittiwatanagul W, Piyavechvirat P, Phuenpathom N, Lumbiganon P. Tranexamic acid for patients with traumatic brain injury: a randomized, double-blinded, placebo-controlled trial. 2013 http:\/\/www.biomedcentral.com\/1471-227X\/13\/20 (accessed 1 July 2019)."}],"container-title":["Critical Care"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13054-020-03243-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13054-020-03243-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13054-020-03243-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T00:38:17Z","timestamp":1605055097000},"score":1,"resource":{"primary":{"URL":"https:\/\/ccforum.biomedcentral.com\/articles\/10.1186\/s13054-020-03243-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,11]]},"references-count":17,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["3243"],"URL":"https:\/\/doi.org\/10.1186\/s13054-020-03243-4","relation":{},"ISSN":["1364-8535"],"issn-type":[{"value":"1364-8535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,11]]},"assertion":[{"value":"2 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 November 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Most patients with TBI are unable to provide informed consent to participate in a clinical trial due to the nature of their injury. As per the Declaration of Helsinki, patients who are incapable of giving consent are an exception to the general rule of informed consent in clinical trials. In the CRASH-3 trial, consent was sought from the patient\u2019s relative or a legal representative unless no such representative was available, in which case the study proceeded with the agreement of two clinicians. If the patient regained capacity, they were told about the trial and written consent was sought to continue participation. If either the patient or their representative declined consent, participation was stopped. If patients were included in the trial but did not regain capacity, consent was sought from a relative or legal representative. We adhered to the requirements of the local and national ethics committees.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"560"}}