{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T04:27:02Z","timestamp":1772166422940,"version":"3.50.1"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,7,30]],"date-time":"2019-07-30T00:00:00Z","timestamp":1564444800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,7,30]],"date-time":"2019-07-30T00:00:00Z","timestamp":1564444800000},"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":["11\/01\/04"],"award-info":[{"award-number":["11\/01\/04"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2019,12]]},"DOI":"10.1186\/s13063-019-3561-7","type":"journal-article","created":{"date-parts":[[2019,7,30]],"date-time":"2019-07-30T09:02:53Z","timestamp":1564477373000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Tranexamic acid for acute gastrointestinal bleeding (the HALT-IT trial): statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial"],"prefix":"10.1186","volume":"20","author":[{"name":"HALT-IT 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":"Adefemi","family":"Afolabi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syed Masroor","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Arribas","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":"Jack","family":"Cuzick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Gilmore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Hawkey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vipul","family":"Jairath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiran","family":"Javaid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aasia","family":"Kayani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muttiullah","family":"Mutti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Arif","family":"Nadeem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haleema","family":"Shakur-Still","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Stanworth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Veitch","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":[[2019,7,30]]},"reference":[{"key":"3561_CR1","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1111\/j.1365-2036.2010.04495.x","volume":"33","author":"LA Button","year":"2011","unstructured":"Button LA, Roberts SE, Evans PA, Goldacre MJ, Akbari A, Dsilva R, et al. Hospitalized incidence and case fatality for upper gastrointestinal bleeding from 1999 to 2007: a record linkage study. Aliment Pharmacol Ther. 2011;33:64\u201376.","journal-title":"Aliment Pharmacol Ther"},{"key":"3561_CR2","doi-asserted-by":"publisher","first-page":"g4606","DOI":"10.1136\/bmj.g4606","volume":"349","author":"J Hippisley-Cox","year":"2014","unstructured":"Hippisley-Cox J, Coupland C. Predicting risk of upper gastrointestinal bleed and intracranial bleed with anticoagulants: cohort study to derive and validate the QBleed scores. BMJ. 2014;349:g4606.","journal-title":"BMJ"},{"issue":"2","key":"3561_CR3","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1097\/01.mcg.0000248004.73075.ad","volume":"42","author":"George J. Theocharis","year":"2008","unstructured":"Theocharis GJ, Thomopoulos KC, Sakellaropoulos G, Katsakoulis E, Nikolopoulou V. Changing trends in the epidemiology and clinical outcome of acute upper gastrointestinal bleeding in a defined geographical area in Greece. J Clin Gastroenterol. 2008;42:128\u201333.","journal-title":"Journal of Clinical Gastroenterology"},{"key":"3561_CR4","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1097\/00042737-200012020-00007","volume":"12","author":"P Czernichow","year":"2000","unstructured":"Czernichow P, Hochain P, Nousbaum JB, Raymond JM, Rudelli A, Dupas JL, et al. Epidemiology and course of acute upper gastro-intestinal haemorrhage in four French geographical areas. Eur J Gastroenterol Hepatol. 2000;12:175\u201381.","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"3561_CR5","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1111\/j.1572-0241.2003.07517.x","volume":"98","author":"M van Leerdam","year":"2003","unstructured":"van Leerdam M, Vreeburg E, Rauws EA, Geraedts AA, Tijssen JG, Reitsma J, et al. Acute upper GI bleeding: did anything change?: time trend analysis of incidence and outcome of acute upper GI bleeding between 1993\/1994 and 2000. Am J Gastroenterol. 2003;98:1494\u20139.","journal-title":"Am J Gastroenterol"},{"key":"3561_CR6","doi-asserted-by":"publisher","first-page":"439","DOI":"10.3109\/00365521.2012.763174","volume":"48","author":"JP Hreinsson","year":"2013","unstructured":"Hreinsson JP, Kalaitzakis E, Gudmundsson S, Bj\u00f6rnsson ES. Upper gastrointestinal bleeding: incidence, etiology and outcomes in a population-based setting. Scand J Gastroenterol. 2013;48:439\u201347.","journal-title":"Scand J Gastroenterol"},{"key":"3561_CR7","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1038\/ajg.2012.168","volume":"107","author":"L Laine","year":"2012","unstructured":"Laine L, Yang H, Chang S-C, Datto C. Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009. Am J Gastroenterol. 2012;107:1190\u20135.","journal-title":"Am J Gastroenterol"},{"key":"3561_CR8","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1007\/s10620-017-4882-6","volume":"63","author":"BA Wuerth","year":"2018","unstructured":"Wuerth BA, Rockey DC. Changing epidemiology of upper gastrointestinal hemorrhage in the last decade: a nationwide asnalysis. Dig Dis Sci. 2018;63:1286\u201393.","journal-title":"Dig Dis Sci"},{"key":"3561_CR9","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1016\/j.gie.2014.09.027","volume":"81","author":"MS Abougergi","year":"2015","unstructured":"Abougergi MS, Travis AC, Saltzman JR. The in-hospital mortality rate for upper GI hemorrhage has decreased over 2 decades in the United States: a nationwide analysis. Gastrointest Endosc. 2015;81:882\u20138 e1.","journal-title":"Gastrointest Endosc"},{"key":"3561_CR10","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1136\/gut.2010.228437","volume":"60","author":"SA Hearnshaw","year":"2011","unstructured":"Hearnshaw SA, Logan RFA, Lowe D, Travis SPL, Murphy MF, Palmer KR. Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 UK audit. Gut. 2011;60:1327\u201335.","journal-title":"Gut"},{"key":"3561_CR11","volume-title":"Acute lower GI bleeding in the UK: patient characteristics, interventions and outcomes in the first nationwide audit","author":"K Oakland","year":"2016","unstructured":"Oakland K, Guy R, Uberoi R, Hogg R, Mortensen N, Murphy MF, et al. Acute lower GI bleeding in the UK: patient characteristics, interventions and outcomes in the first nationwide audit. 2016."},{"key":"3561_CR12","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1097\/00042737-200506000-00008","volume":"17","author":"F Di Fiore","year":"2005","unstructured":"Di Fiore F, Lecleire S, Merle V, Herv\u00e9 S, Duhamel C, Dupas J-L, et al. Changes in characteristics and outcome of acute upper gastrointestinal haemorrhage: a comparison of epidemiology and practices between 1996 and 2000 in a multicentre French study. Eur J Gastroenterol Hepatol. 2005;17:641\u20137.","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"3561_CR13","doi-asserted-by":"publisher","first-page":"3566","DOI":"10.1111\/j.1572-0241.2000.03376.x","volume":"95","author":"HB El-Serag","year":"2000","unstructured":"El-Serag HB, Everhart JE. Improved survival after variceal hemorrhage over an 11-year period in the Department of Veterans Affairs. Am J Gastroenterol. 2000;95:3566\u201373.","journal-title":"Am J Gastroenterol"},{"key":"3561_CR14","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1002\/hep.20339","volume":"40","author":"N Carbonell","year":"2004","unstructured":"Carbonell N, Pauwels A, Serfaty L, Fourdan O, L\u00e9vy VG, Poupon R. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology. 2004;40:652\u20139.","journal-title":"Hepatology."},{"key":"3561_CR15","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1136\/gut.49.5.682","volume":"49","author":"PA McCormick","year":"2001","unstructured":"McCormick PA, O\u2019Keefe C. Improving prognosis following a first variceal haemorrhage over four decades. Gut. 2001;49:682\u20135.","journal-title":"Gut."},{"key":"3561_CR16","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1111\/j.1365-2036.2011.04651.x","volume":"33","author":"A Lanas","year":"2011","unstructured":"Lanas A, Aabakken L, Fonseca J, Mungan ZA, Papatheodoridis GV, Piessevaux H, et al. Clinical predictors of poor outcomes among patients with nonvariceal upper gastrointestinal bleeding in Europe. Aliment Pharmacol Ther. 2011;33:1225\u201333.","journal-title":"Aliment Pharmacol Ther"},{"key":"3561_CR17","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1136\/gut.38.3.316","volume":"38","author":"TA Rockall","year":"1996","unstructured":"Rockall TA, Logan RF, Devlin HB, Northfield TC. Risk assessment after acute upper gastrointestinal haemorrhage. Gut. 1996;38:316\u201321.","journal-title":"Gut"},{"key":"3561_CR18","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.bpg.2007.10.011","volume":"22","author":"ME Van Leerdam","year":"2008","unstructured":"Van Leerdam ME. Epidemiology of acute upper gastrointestinal bleeding. Best Pract Res Clin Gastroenterol. 2008;22:209\u201324.","journal-title":"Best Pract Res Clin Gastroenterol"},{"issue":"12","key":"3561_CR19","doi-asserted-by":"publisher","first-page":"e49507","DOI":"10.1371\/journal.pone.0049507","volume":"7","author":"Stephen E. Roberts","year":"2012","unstructured":"Roberts SE, Button LA, Williams JG. Prognosis following upper gastrointestinal bleeding. PLoS One. 2012;7(12):e49507. \n                              https:\/\/doi.org\/10.1371\/journal.pone.0049507\n                              \n                           .","journal-title":"PLoS ONE"},{"key":"3561_CR20","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.1038\/ajg.2014.263","volume":"109","author":"V Jairath","year":"2014","unstructured":"Jairath V, Thompson J, Kahan BC, Daniel R, Hearnshaw SA, Travis SPL, et al. Poor outcomes in hospitalized patients with gastrointestinal bleeding: impact of baseline risk, bleeding severity and process of care. Am J Gastroenterol. 2014;109:1603\u201312.","journal-title":"Am J Gastroenterol"},{"key":"3561_CR21","doi-asserted-by":"publisher","first-page":"253","DOI":"10.4103\/1319-3767.70608","volume":"16","author":"MJ Kaviani","year":"2010","unstructured":"Kaviani MJ, Pirastehfar M, Azari A, Saberifiroozi M. Etiology and outcome of patients with upper gastrointestinal bleeding: a study from South of Iran. Saudi J Gastroenterol. 2010;16:253\u20139.","journal-title":"Saudi J Gastroenterol"},{"key":"3561_CR22","doi-asserted-by":"publisher","first-page":"29","DOI":"10.4103\/njss.njss_7_15","volume":"26","author":"R Ugiagbe","year":"2016","unstructured":"Ugiagbe R, Omuemu C. Etiology of upper gastrointestinal bleeding in the University of Benin Teaching Hospital, South-Southern Nigeria. Niger J Surg Sci. 2016;26:29.","journal-title":"Niger J Surg Sci"},{"key":"3561_CR23","first-page":"425","volume":"20","author":"J Wang","year":"2017","unstructured":"Wang J, Cui Y, Wang J, Chen B, He Y, Chen M. Clinical epidemiological characteristics and change trend of upper gastrointestinal bleeding over the past 15 years. Zhonghua Wei Chang Wai Ke Za Zhi. 2017;20:425\u201331.","journal-title":"Zhonghua Wei Chang Wai Ke Za Zhi"},{"key":"3561_CR24","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1111\/jgh.13617","volume":"32","author":"M Minakari","year":"2017","unstructured":"Minakari M, Badihian S, Jalalpour P, Sebghatollahi V. Etiology and outcome in patients with upper gastrointestinal bleeding: study on 4747 patients in the central region of Iran. J Gastroenterol Hepatol. 2017;32:789\u201396.","journal-title":"J Gastroenterol Hepatol"},{"key":"3561_CR25","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1097\/MCG.0b013e318297fb40","volume":"48","author":"JJ Kim","year":"2014","unstructured":"Kim JJ, Sheibani S, Park S, Buxbaum J, Laine L. Causes of bleeding and outcomes in patients hospitalized with upper gastrointestinal bleeding. J Clin Gastroenterol. 2014;48:113\u20138.","journal-title":"J Clin Gastroenterol"},{"key":"3561_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4172\/2161-069X.1000235","volume":"04","author":"MHH Hassan Al-Dholea","year":"2014","unstructured":"Hassan Al-Dholea MHH, Mohsen Mohammed Al-Makdad ASM, Mohammed Al-Haimi MA, Makky MTA, Abdellah hassan Balfaqih OS, Ahmed WAM, et al. Determinants and outcome of acute upper gastrointestinal bleeding in Yemen. J Gastrointest Dig Syst. 2014;04:1\u20134.","journal-title":"J Gastrointest Dig Syst"},{"key":"3561_CR27","first-page":"455","volume":"41","author":"R Elwakil","year":"2011","unstructured":"Elwakil R, Reda MA, Abdelhakam SM, Ghoraba DM, Ibrahim WA. Causes and outcome of upper gastrointestinal bleeding in Emergency Endoscopy Unit of Ain Shams University Hospital. J Egypt Soc Parasitol. 2011;41:455\u201367.","journal-title":"J Egypt Soc Parasitol"},{"key":"3561_CR28","first-page":"518","volume":"12","author":"ON Alema","year":"2012","unstructured":"Alema ON, Martin DO, Okello TR. Endoscopic findings in upper gastrointestinal bleeding patients at Lacor Hospital, northern Uganda. Afr Health Sci. 2012;12:518\u201321.","journal-title":"Afr Health Sci"},{"key":"3561_CR29","unstructured":"Jiang Y, Li Y, Xu H, Shi Y, Song Y, Li Y. Risk factors for upper gastrointestinal bleeding requiring hospitalization. Int J Clin Exp Med. 2016;9(2):4539\u201344."},{"key":"3561_CR30","doi-asserted-by":"publisher","first-page":"34","DOI":"10.4103\/1319-3767.91737","volume":"18","author":"A Gado","year":"2012","unstructured":"Gado A, Abdelmohsen A, Ebeid B, Axon A. Clinical outcome of acute upper gastrointestinal hemorrhage among patients admitted to a government hospital in Egypt. Saudi J Gastroenterol. 2012;18:34.","journal-title":"Saudi J Gastroenterol"},{"issue":"2","key":"3561_CR31","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1590\/S0004-28032002000200002","volume":"39","author":"Cyrla ZALTMAN","year":"2002","unstructured":"Zaltman C, Souza HS, Castro ME, Sobral, Mde F, Dias PC, Lemos V Jr. Upper gastrointestinal bleeding in a Brazilian hospital: a retrospective study of endoscopic records. Arq Gastroenterol. 2002;39:74\u201380.","journal-title":"Arquivos de Gastroenterologia"},{"key":"3561_CR32","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1186\/s12876-015-0353-8","volume":"15","author":"V Kayamba","year":"2015","unstructured":"Kayamba V, Sinkala E, Mwanamakondo S, Soko R, Kawimbe B, Amadi B, et al. Trends in upper gastrointestinal diagnosis over four decades in Lusaka, Zambia: a retrospective analysis of endoscopic findings. BMC Gastroenterol. 2015;15:127.","journal-title":"BMC Gastroenterol"},{"key":"3561_CR33","unstructured":"Sher F, Ullah RS, Khan J, Mansoor SN, Ahmed N. Frequency of different causes of upper gastrointestinal bleeding using endoscopic procedure at a tertiary care hostpital. Pak Armed Forces Med J. 2014."},{"key":"3561_CR34","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.3346\/jkms.2016.31.10.1611","volume":"31","author":"MS Kwak","year":"2016","unstructured":"Kwak MS, Cha JM, Han YJ, Yoon JY, Jeon JW, Shin HP, et al. The clinical outcomes of lower gastrointestinal bleeding are not better than those of upper gastrointestinal bleeding. J Korean Med Sci. 2016;31:1611\u20136.","journal-title":"J Korean Med Sci"},{"key":"3561_CR35","first-page":"746","volume":"35","author":"P-I Hsu","year":"1994","unstructured":"Hsu P-I, Lin X-Z, Chan S-H, Lin C-Y, Chang T-T, Shin J-S, et al. Bleeding peptic ulcer-risk factors for rebleeding and sequential changes in endoscopic findings. Gtut. 1994;35:746\u20139.","journal-title":"Gtut."},{"key":"3561_CR36","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1136\/bmj.1.5739.26","volume":"1","author":"TC Northfield","year":"1971","unstructured":"Northfield TC. Factors predisposing to recurrent haemorrhage after acute gastrointestinal bleeding. Br Med J. 1971;1:26\u20138.","journal-title":"Br Med J"},{"key":"3561_CR37","first-page":"968","volume":"82","author":"JL Smith","year":"1982","unstructured":"Smith JL, Graham DY. Variceal hemorrhage: a critical evaluation of survival analysis. Gastroenterol Am Gastroenterol Assoc. 1982;82:968\u201373.","journal-title":"Gastroenterol Am Gastroenterol Assoc"},{"key":"3561_CR38","doi-asserted-by":"publisher","first-page":"e3054","DOI":"10.1136\/bmj.e3054","volume":"344","author":"K Ker","year":"2012","unstructured":"Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ. 2012;344:e3054.","journal-title":"BMJ"},{"key":"3561_CR39","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":"3561_CR40","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, Bautista R, Caballero J, Coats T, 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":"3561_CR41","first-page":"CD006640","volume":"11","author":"C Bennett","year":"2014","unstructured":"Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding. Cochrane database Syst Rev. 2014;11:CD006640.","journal-title":"Cochrane database Syst Rev"},{"key":"3561_CR42","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1186\/1745-6215-15-450","volume":"15","author":"I Roberts","year":"2014","unstructured":"Roberts I, Coats T, Edwards P, Gilmore I, Jairath V, Ker K, et al. HALT-IT\u2014tranexamic acid for the treatment of gastrointestinal bleeding: study protocol for a randomised controlled trial. Trials. 2014;15:450.","journal-title":"Trials"},{"key":"3561_CR43","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, Jairath V, Stanworth S, Ker K, et al. Outcome measures in clinical trials of treatments for acute severe haemorrhage. Trials. 2018;19:533.","journal-title":"Trials"},{"key":"3561_CR44","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1136\/jcp.33.Suppl_14.63","volume":"33","author":"L Poller","year":"1980","unstructured":"Poller L. Fibrinolysis and gastrointestinal haemorrhage. J Clin Pathol Roy Coll Path. 1980;33:63\u20137.","journal-title":"J Clin Pathol Roy Coll Path"},{"key":"3561_CR45","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/0140-6736(93)90278-O","volume":"341","author":"JM al-Mohana","year":"1993","unstructured":"al-Mohana JM, Lowe GD, Murray GD, Burns HG. Association of fibrinolytic tests with outcome of acute upper-gastrointestinal-tract bleeding. Lancet (London, England). 1993;341:518\u201321.","journal-title":"Lancet (London, England)"},{"key":"3561_CR46","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1016\/j.dld.2008.01.010","volume":"40","author":"M Primignani","year":"2008","unstructured":"Primignani M, Dell\u2019Era A, Bucciarelli P, Bottasso B, Bajetta MT, de Franchis R, et al. High-d-dimer plasma levels predict poor outcome in esophageal variceal bleeding. Dig Liver Dis. 2008;40:874\u201381.","journal-title":"Dig Liver Dis"},{"key":"3561_CR47","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/BF00554669","volume":"20","author":"A Pilbrant","year":"1981","unstructured":"Pilbrant A, Schannong M, Vessman J. Pharmacokinetics and bioavailability of tranexamic acid. Eur J Clin Pharmacol. 1981;20:65\u201372.","journal-title":"Eur J Clin Pharmacol"},{"key":"3561_CR48","unstructured":"Rowland M, Tozer TN, Derendorf H, Hochhaus G. Clinical pharmacokinetics and pharmacodynamics. 2011. \n                              https:\/\/www.ncbi.nlm.nih.gov\/nlmcatalog\/101510735\n                              \n                           ."},{"key":"3561_CR49","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1016\/S0140-6736(02)08594-X","volume":"359","author":"SJ Pocock","year":"2002","unstructured":"Pocock SJ, Clayton TC, Altman DG. Survival plots of time-to-event outcomes in clinical trials: good practice and pitfalls. Lancet. 2002;359:1686\u20139.","journal-title":"Lancet"},{"key":"3561_CR50","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/j.dld.2013.12.010","volume":"46","author":"V Jairath","year":"2014","unstructured":"Jairath V, Rehal S, Logan R, Kahan B, Hearnshaw S, Stanworth S, et al. Acute variceal haemorrhage in the United Kingdom: patient characteristics, management and outcomes in a nationwide audit. Dig Liver Dis. 2014;46:419\u201326.","journal-title":"Dig Liver Dis"},{"key":"3561_CR51","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1038\/ajg.2009.702","volume":"105","author":"L Laine","year":"2010","unstructured":"Laine L, Spiegel B, Rostom A, Moayyedi P, Kuipers EJ, Bardou M, et al. Methodology for randomized trials of patients with nonvariceal upper gastrointestinal bleeding: Recommendations from an international consensus conference. Am J Gastroenterol. 2010;105:540\u201350.","journal-title":"Am J Gastroenterol"},{"issue":"1","key":"3561_CR52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/MBC.0000000000000789","volume":"30","author":"Roberto Picetti","year":"2019","unstructured":"Picetti R, Shakur-Still H, Medcalf RL, Standing JF, Roberts I. What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies. Blood Coagul Fibrinolysis. 2019;30:1\u201310.","journal-title":"Blood Coagulation & Fibrinolysis"},{"key":"3561_CR53","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/S0140-6736(17)32455-8","volume":"391","author":"A Gayet-Ageron","year":"2017","unstructured":"Gayet-Ageron A, Prieto-Merino D, Ker K, Shakur H, Ageron F-X, Roberts I, et al. Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients. Lancet. 2017;391:125\u201332.","journal-title":"Lancet"},{"key":"3561_CR54","first-page":"1842","volume":"132","author":"CK Ward-Caviness","year":"2018","unstructured":"Ward-Caviness CK, Huffman JE, Everett K, Germain M, van Dongen J, Hill WD, et al. DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis. Blood Am Soc Hematol. 2018;132:1842\u201350.","journal-title":"Blood Am Soc Hematol"},{"key":"3561_CR55","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.critrevonc.2006.06.004","volume":"60","author":"M Franchini","year":"2006","unstructured":"Franchini M. Hemostasis and aging. Crit Rev Oncol Hematol. 2006;60:144\u201351.","journal-title":"Crit Rev Oncol Hematol"},{"key":"3561_CR56","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1046\/j.1365-2141.1997.1222936.x","volume":"97","author":"GD Lowe","year":"1997","unstructured":"Lowe GD, Rumley A, Woodward M, Morrison CE, Philippou H, Lane DA, et al. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey. I. Illustrative reference ranges by age, sex and hormone use. Br J Haematol. 1997;97:775\u201384.","journal-title":"Br J Haematol"},{"key":"3561_CR57","doi-asserted-by":"publisher","first-page":"8","DOI":"10.3928\/0098-9134-19990301-05","volume":"25","author":"M Shelkey","year":"1999","unstructured":"Shelkey M, Wallace M. Katz Index of Independence in Activities of Daily Living. J Gerontol Nurs. 1999;25:8\u20139.","journal-title":"J Gerontol Nurs"},{"key":"3561_CR58","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1093\/aje\/kwh090","volume":"159","author":"G Zou","year":"2004","unstructured":"Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol Narnia. 2004;159:702\u20136.","journal-title":"Am J Epidemiol Narnia"},{"key":"3561_CR59","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1016\/S0140-6736(05)61026-4","volume":"365","author":"J Cuzick","year":"2005","unstructured":"Cuzick J. Forest plots and the interpretation of subgroups. Lancet (London, England). 2005;365:1308.","journal-title":"Lancet (London, England)"},{"key":"3561_CR60","doi-asserted-by":"publisher","first-page":"680","DOI":"10.7326\/0003-4819-154-10-201105170-00008","volume":"154","author":"TJ VanderWeele","year":"2011","unstructured":"VanderWeele TJ, Knol MJ. Interpretation of subgroup analyses in randomized trials: heterogeneity versus secondary interventions. Ann Intern Med. 2011;154:680\u20133.","journal-title":"Ann Intern Med"},{"key":"3561_CR61","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1016\/S0140-6736(11)60278-X","volume":"377","author":"I Roberts","year":"2011","unstructured":"CRASH-2 collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377:1096\u2013101 e2.","journal-title":"Lancet"},{"key":"3561_CR62","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1002\/rth2.12028","volume":"1","author":"T Lisman","year":"2017","unstructured":"Lisman T, Porte RJ. Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases. Res Pract Thromb Haemost. 2017;1:150\u201361.","journal-title":"Res Pract Thromb Haemost"},{"key":"3561_CR63","doi-asserted-by":"publisher","first-page":"10062","DOI":"10.3748\/wjg.v21.i35.10062","volume":"21","author":"A Blasi","year":"2015","unstructured":"Blasi A. Coagulopathy in liver disease: lack of an assessment tool. World J Gastroenterol. 2015;21:10062\u201371.","journal-title":"World J Gastroenterol"},{"key":"3561_CR64","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1055\/s-0035-1550437","volume":"41","author":"F Leebeek","year":"2015","unstructured":"Leebeek F, Rijken D. The fibrinolytic status in liver diseases. Semin Thromb Hemost. 2015;41:474\u201380.","journal-title":"Semin Thromb Hemost"},{"key":"3561_CR65","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s12874-016-0110-x","volume":"16","author":"P Royston","year":"2016","unstructured":"Royston P, Parmar MKB. Augmenting the logrank test in the design of clinical trials in which non-proportional hazards of the treatment effect may be anticipated. BMC Med Res Methodol. 2016;16:16.","journal-title":"BMC Med Res Methodol"},{"key":"3561_CR66","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1097\/EDE.0b013e3181c1ea43","volume":"21","author":"MA Hern\u00e1n","year":"2010","unstructured":"Hern\u00e1n MA. The hazards of hazard ratios. Epidemiology. 2010;21:13\u20135.","journal-title":"Epidemiology"},{"key":"3561_CR67","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1016\/j.jclinepi.2012.09.017","volume":"66","author":"A Latouche","year":"2013","unstructured":"Latouche A, Allignol A, Beyersmann J, Labopin M, Fine JP. A competing risks analysis should report results on all cause-specific hazards and cumulative incidence functions. J Clin Epidemiol. 2013;66:648\u201353.","journal-title":"J Clin Epidemiol"},{"key":"3561_CR68","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1161\/CIRCULATIONAHA.115.017719","volume":"133","author":"PC Austin","year":"2016","unstructured":"Austin PC, Lee DS, Fine JP. Introduction to the analysis of survival data in the presence of competing risks. Circulation. 2016;133:601\u20139.","journal-title":"Circulation."},{"key":"3561_CR69","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1214\/aos\/1176350951","volume":"16","author":"RJ Gray","year":"1988","unstructured":"Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141\u201354.","journal-title":"Ann Stat"},{"key":"3561_CR70","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1080\/01621459.1999.10474144","volume":"94","author":"JP Fine","year":"1999","unstructured":"Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496\u2013509.","journal-title":"J Am Stat Assoc"},{"key":"3561_CR71","doi-asserted-by":"publisher","first-page":"e222","DOI":"10.1016\/S2214-109X(17)30467-9","volume":"6","author":"B Li","year":"2018","unstructured":"Li B, Miners A, Shakur H, Roberts I. WOMAN Trial Collaborators. Tranexamic acid for treatment of women with post-partum haemorrhage in Nigeria and Pakistan: a cost-effectiveness analysis of data from the WOMAN trial. Lancet Glob Heal. 2018;6:e222\u20138.","journal-title":"Lancet Glob Heal"}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-019-3561-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13063-019-3561-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-019-3561-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T19:09:05Z","timestamp":1595963345000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-019-3561-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,30]]},"references-count":71,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["3561"],"URL":"https:\/\/doi.org\/10.1186\/s13063-019-3561-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.2.276\/v4","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.276\/v2","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.276\/v3","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.276\/v1","asserted-by":"object"}]},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,30]]},"assertion":[{"value":"1 February 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The trial was approved by the UK NRES Committee East of England (reference number 12\/EE\/0038), as well as national and local research ethics committees of participating countries outside the UK. Informed consent will be obtained from all study participants.","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":"467"}}