A high-dose 24-hour tranexamic acid infusion for the treatment of significant gastrointestinal bleeding: HALT-IT RCT

Ian Roberts, Haleema Shakur-Still, Adefemi Afolabi, Adegboyega Akere, Monica Arribas, Emma Austin, Kiran Bal, Nuha Bazeer, Danielle Beaumont, Amy Brenner, Laura Carrington, Rizwana Chaudhri, Timothy Coats, Ian Gilmore, Kenneth Halligan, Irshad Hussain, Vipul Jairath, Kiran Javaid, Aasia Kayani, Ton Lisman, Raoul Mansukhani, Alec Miners, Muttiullah Mutti, Muhammad Arif Nadeem, Richard Pollok, Danielle Prowse, Jonathan Simmons, Simon Stanworth, Andrew Veitch, Jack Williams, Ian Roberts, Haleema Shakur-Still, Adefemi Afolabi, Adegboyega Akere, Monica Arribas, Emma Austin, Kiran Bal, Nuha Bazeer, Danielle Beaumont, Amy Brenner, Laura Carrington, Rizwana Chaudhri, Timothy Coats, Ian Gilmore, Kenneth Halligan, Irshad Hussain, Vipul Jairath, Kiran Javaid, Aasia Kayani, Ton Lisman, Raoul Mansukhani, Alec Miners, Muttiullah Mutti, Muhammad Arif Nadeem, Richard Pollok, Danielle Prowse, Jonathan Simmons, Simon Stanworth, Andrew Veitch, Jack Williams

Abstract

Background: Tranexamic acid reduces blood loss in surgery and the risk of death in trauma patients. Meta-analyses of small trials suggest that tranexamic acid decreases the number of deaths from gastrointestinal bleeding, but these meta-analyses are prone to selection bias.

Objective: The trial provides reliable evidence of the effect of tranexamic acid on mortality, rebleeding and complications in significant acute gastrointestinal bleeding.

Design: A multicentre, randomised, placebo-controlled trial and economic analysis. Patients were assigned by selecting one treatment pack from a box of eight, which were identical apart from the pack number. Patients, caregivers and outcome assessors were masked to allocation. The main analyses were by intention to treat.

Setting: The setting was 164 hospitals in 15 countries, co-ordinated from the London School of Hygiene & Tropical Medicine.

Participants: Adults with significant upper or lower gastrointestinal bleeding (n = 12,009) were eligible if the responsible clinician was substantially uncertain about whether or not to use tranexamic acid. The clinical diagnosis of significant bleeding implied a risk of bleeding to death, including hypotension, tachycardia or signs of shock, or urgent transfusion, endoscopy or surgery.

Intervention: Tranexamic acid (a 1-g loading dose over 10 minutes, then a 3-g maintenance dose over 24 hours) or matching placebo.

Main outcome measures: The primary outcome was death due to bleeding within 5 days of randomisation. Secondary outcomes were all-cause and cause-specific mortality; rebleeding; need for endoscopy, surgery or radiological intervention; blood product transfusion; complications; disability; and days spent in intensive care or a high-dependency unit.

Results: A total of 12,009 patients were allocated to receive tranexamic acid (n = 5994, 49.9%) or the matching placebo (n = 6015, 50.1%), of whom 11,952 (99.5%) received the first dose. Death due to bleeding within 5 days of randomisation occurred in 222 (3.7%) patients in the tranexamic acid group and in 226 (3.8%) patients in the placebo group (risk ratio 0.99, 95% confidence interval 0.82 to 1.18). Thromboembolic events occurred in 86 (1.4%) patients in the tranexamic acid group and 72 (1.2%) patients in the placebo group (risk ratio 1.20, 95% confidence interval 0.88 to 1.64). The risk of arterial thromboembolic events (myocardial infarction or stroke) was similar in both groups (0.7% in the tranexamic acid group vs. 0.8% in the placebo group; risk ratio 0.92, 95% confidence interval 0.60 to 1.39), but the risk of venous thromboembolic events (deep-vein thrombosis or pulmonary embolism) was higher in tranexamic acid-treated patients than in placebo-treated patients (0.8% vs. 0.4%; risk ratio 1.85, 95% confidence interval 1.15 to 2.98). Seizures occurred in 38 patients who received tranexamic acid and in 22 patients who received placebo (0.6% vs. 0.4%, respectively; risk ratio 1.73, 95% confidence interval 1.03 to 2.93). In the base-case economic analysis, tranexamic acid was not cost-effective and resulted in slightly poorer health outcomes than no tranexamic acid.

Conclusions: Tranexamic acid did not reduce death from gastrointestinal bleeding and, although inexpensive, it is not cost-effective in adults with acute gastrointestinal bleeding.

Future work: These results caution against a uniform approach to the management of patients with major haemorrhage and highlight the need for randomised trials targeted at specific pathophysiological processes.

Limitations: Although this is one of the largest randomised trials in gastrointestinal bleeding, we cannot rule out a modest increase or decrease in death due to bleeding with tranexamic acid.

Trial registration: Current Controlled Trials ISRCTN11225767, ClinicalTrials.gov NCT01658124 and EudraCT 2012-003192-19.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 58. See the NIHR Journals Library website for further project information.

Keywords: BLOOD LOSS; BLOOD TRANSFUSION; COST-BENEFIT ANALYSIS; GASTROINTESTINAL HAEMORRHAGE; PULMONARY EMBOLISM; STROKE; TRANEXAMIC ACID; VENOUS THROMBOSIS.

References

    1. Roberts I, Coats T, Edwards P, Gilmore I, Jairath V, Ker K, et al. HALT-IT – tranexamic acid for the treatment of gastrointestinal bleeding: study protocol for a randomised controlled trial. Trials 2014;15:450.
    1. Brenner A, Afolabi A, Ahmad SM, Arribas M, Chaudhri R, Coats T, et al. Tranexamic acid for acute gastrointestinal bleeding (the HALT-IT trial): statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial. Trials 2019;20:467.
    1. HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet 2020;395:1927–36.
    1. van Leerdam ME. Epidemiology of acute upper gastrointestinal bleeding. Best Pract Res Clin Gastroenterol 2008;22:209–24.
    1. Hearnshaw SA, Logan RF, Lowe D, Travis SP, Murphy MF, Palmer KR. Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 UK audit. Gut 2011;60:1327–35.
    1. Oakland K, Guy R, Uberoi R, Hogg R, Mortensen N, Murphy MF, Jairath V, UK Lower GI Bleeding Collaborative. Acute lower GI bleeding in the UK: patient characteristics, interventions and outcomes in the first nationwide audit. Gut 2018;67:654–62.
    1. Farrell JJ, Friedman LS. Review article: the management of lower gastrointestinal bleeding. Aliment Pharmacol Ther 2005;21:1281–98.
    1. Williams JG, Roberts SE, Ali MF, Cheung WY, Cohen DR, Demery G, et al. Gastroenterology services in the UK. The burden of disease, and the organisation and delivery of services for gastrointestinal and liver disorders: a review of the evidence. Gut 2007;56(Suppl. 1):1–113.
    1. Longstreth GF. Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 1997;92:419–24.
    1. 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;33:64–76.
    1. 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.
    1. 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;42:128–33.
    1. 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;12:175–81.
    1. van Leerdam ME, Vreeburg EM, Rauws EA, Geraedts AA, Tijssen JG, Reitsma JB, Tytgat GN. 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;98:1494–9.
    1. Hreinsson JP, Kalaitzakis E, Gudmundsson S, Björnsson ES. Upper gastrointestinal bleeding: incidence, etiology and outcomes in a population-based setting. Scand J Gastroenterol 2013;48:439–47.
    1. Laine L, Yang H, Chang SC, 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;107:1190–5.
    1. Wuerth BA, Rockey DC. Changing Epidemiology of upper gastrointestinal hemorrhage in the last decade: a nationwide analysis. Dig Dis Sci 2018;63:1286–93.
    1. 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;81:882–8.e1.
    1. Di Fiore F, Lecleire S, Merle V, Hervé S, Duhamel C, Dupas JL, 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;17:641–7.
    1. 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;16:253–9.
    1. Ugiagbe R, Omuemu C. Etiology of upper gastrointestinal bleeding in the University of Benin Teaching Hospital, South-Southern Nigeria. Niger J Surg Sci 2016;26:29–32.
    1. 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;20:425–31.
    1. 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;32:789–96.
    1. 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;48:113–18.
    1. Barnert J, Messmann H. Diagnosis and management of lower gastrointestinal bleeding. Nat Rev Gastroenterol Hepatol 2009;6:637–46.
    1. Hassan Al-Dholea MHH, Mohsen Mohammed Al-Makdad ASM, Mohammed Al-Haimi MA. Determinants and outcome of acute upper gastrointestinal bleeding in Yemen. J Gastrointest Dig Syst 2014;4.
    1. 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;41:455–67.
    1. Alema ON, Martin DO, Okello TR. Endoscopic findings in upper gastrointestinal bleeding patients at Lacor hospital, northern Uganda. Afr Health Sci 2012;12:518–21.
    1. 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;9:4539–44.
    1. Gado AS, Ebeid BA, Abdelmohsen AM, Axon AT. Clinical outcome of acute upper gastrointestinal hemorrhage among patients admitted to a government hospital in Egypt. Saudi J Gastroenterol 2012;18:34–9.
    1. Zaltman C, Souza HS, Castro ME, Sobral Mde F, Dias PC, Lemos V. Upper gastrointestinal bleeding in a Brazilian hospital: a retrospective study of endoscopic records. Arq Gastroenterol 2002;39:74–80.
    1. 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.
    1. 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 hospital. Pak Armed Forces Med J 2014;64:410–3.
    1. van der Werf MJ, de Vlas SJ, Brooker S, Looman CW, Nagelkerke NJ, Habbema JD, Engels D. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 2003;86:125–39.
    1. British Society of Gastroenterology. UK Comparative Audit of Upper Gastrointestinal Bleeding and the Use of Blood. 2007. URL: www.bsg.org.ukpdf_word_docsblood_audit_report_07.pdf (accessed 13 October 2020).
    1. 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;33:1225–33.
    1. Rockall TA, Logan RF, Devlin HB, Northfield TC. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996;38:316–21.
    1. Roberts SE, Button LA, Williams JG. Prognosis following upper gastrointestinal bleeding. PLOS ONE 2012;7:e49507.
    1. Jairath V, Thompson J, Kahan BC, Daniel R, Hearnshaw SA, Travis SP, et al. Poor outcomes in hospitalized patients with gastrointestinal bleeding: impact of baseline risk, bleeding severity, and process of care. Am J Gastroenterol 2014;109:1603–12.
    1. 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;31:1611–6.
    1. Hsu PI, Lin XZ, Chan SH, Lin CY, Chang TT, Shin JS, et al. Bleeding peptic ulcer – risk factors for rebleeding and sequential changes in endoscopic findings. Gut 1994;35:746–9.
    1. Northfield TC. Factors predisposing to recurrent haemorrhage after acute gastrointestinal bleeding. Br Med J 1971;1:26–8.
    1. Smith JL, Graham DY. Variceal hemorrhage: a critical evaluation of survival analysis. Gastroenterology 1982;82:968–73.
    1. Lau JY, Sung JJ, Lee KK, Yung MY, Wong SK, Wu JC, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000;343:310–16.
    1. Jairath V, Barkun AN. Improving outcomes from acute upper gastrointestinal bleeding. Gut 2012;61:1246–9.
    1. Rockall TA, Logan RF, Devlin HB, Northfield TC. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage. BMJ 1995;311:222–6.
    1. National Institute for Health and Care Excellence (NICE) (UK). Acute Upper Gastrointestinal Bleeding in Over 16s: Management. London: NICE; 2016. URL: (accessed 13 October 2020).
    1. National Comparative Audit of Blood Transfusion. Results from a National Audit National Comparative Audit of Lower Gastrointestinal Bleeding and the Use of Blood. 2016. URL: (accessed 13 October 2020).
    1. Oakland K, Chadwick G, East JE, Guy R, Humphries A, Jairath V, et al. Diagnosis and management of acute lower gastrointestinal bleeding: guidelines from the British Society of Gastroenterology. Gut 2019;68:776–89.
    1. Prentice CR. Basis of antifibrinolytic therapy. J Clin Pathol Suppl 1980;14:35–40.
    1. al-Mohana JM, Lowe GD, Murray GD, Burns HG. Association of fibrinolytic tests with outcome of acute upper-gastrointestinal-tract bleeding. Lancet 1993;341:518–21.
    1. Poller L and Thomson J. Evidence for a relationship between fibrinolysis and haematemesis. Br J Haematol 1973;24:664.
    1. 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.
    1. The CRASH-2 Trial Collaborators. 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 2010;376:23–32.
    1. The 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.
    1. Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, et al. Tranexamic acid in patients undergoing coronary-artery surgery. N Engl J Med 2017;376:136–48.
    1. The CRASH-3 Trial 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;394:1713–23.
    1. The CRASH-2 Trial 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;377:1096–101.
    1. Guerriero C, Cairns J, Perel P, Shakur H, Roberts I, CRASH 2 trial collaborators. Cost-effectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 trial. PLOS ONE 2011;6:e18987.
    1. Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev 2014;11:CD006640.
    1. Straube S, Tramèr MR, Moore RA, Derry S, McQuay HJ. Mortality with upper gastrointestinal bleeding and perforation: effects of time and NSAID use. BMC Gastroenterol 2009;9:41.
    1. Electronic medicines compendium (emc). Cyklokapron Tablets – Summary of Product Characteristics (SmPC). URL: (accessed 15 May 2020).
    1. Committee for Human Medicinal Products. Guideline for Good Clinical Practice E6(R2). 2016. URL: (accessed 1 September 2021).
    1. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013;310:2191–4.
    1. Henry DA, Carless PA, Moxey AJ, O’Connell D, Stokes BJ, Fergusson DA, Ker K. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2011;1:CD001886.
    1. Horrow JC, Van Riper DF, Strong MD, Grunewald KE, Parmet JL. The dose-response relationship of tranexamic acid. Anesthesiology 1995;82:383–92.
    1. 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.
    1. National Institute for Health and Care Excellence. Guide to the Methods of Technology Appraisal 2013. URL: (accessed 2 October 2020).
    1. Williams J, Roberts I, Shakur-Still H, Lecky FE, Chaudhri R, Miners A. Cost-effectiveness analysis of tranexamic acid for the treatment of traumatic brain injury, based on the results of the CRASH-3 randomised trial: a decision modelling approach. BMJ Glob Health 2020;5:e002716.
    1. Morgan E. National Life Tables, UK: 2016 to 2018. Newport: Office for National Statistics; 2019.
    1. Crooks CJ, Card TR, West J. Excess long-term mortality following non-variceal upper gastrointestinal bleeding: a population-based cohort study. PLOS Med 2013;10:e1001437.
    1. Jairath V, Kahan BC, Gray A, Doré CJ, Mora A, James MW, et al. Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. Lancet 2015;386:137–44.
    1. The EuroQol Group. EuroQol – a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199–208.
    1. Campbell HE, Stokes EA, Bargo D, Logan RF, Mora A, Hodge R, et al. Costs and quality of life associated with acute upper gastrointestinal bleeding in the UK: cohort analysis of patients in a cluster randomised trial. BMJ Open 2015;5:e007230.
    1. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychosocial function. JAMA 1963;185:914–19.
    1. Kind P, Dolan P, Gudex C, Williams A. Variations in population health status: results from a United Kingdom national questionnaire survey. BMJ 1998;316:736–41.
    1. Joint Formulary Committee. British National Formulary. 76th ed. London: BMJ Group and Pharmaceutical Press; 2019.
    1. Curtis L, Burns A. Unit Costs of Health and Social Care 2018. Canterbury: Personal Social Services Research Unit, University of Kent; 2018. URL: (accessed 2 October 2020).
    1. 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 Health 2018;6:e222–e228.
    1. NHS Improvement. National Schedule of Reference Costs 2017/18. URL: (accessed 2 October 2020).
    1. NHS Blood and Transplant. NHS Blood and Transplant Price List 2018/2019. URL: (accessed 2 October 2020).
    1. Ramagopalan SV, Samnaliev M, Weir S, Sammon CJ, Carroll R, Alikhan R. Costs of gastrointestinal bleeding events in atrial fibrillation: a UK Clinical Practice Research Datalink study. Future Cardiol 2019;15:367–75.
    1. Coats TJ, Morsy M. Biological mechanisms and individual variation in fibrinolysis after major trauma. Emerg Med J 2020;37:135–40.
    1. Roberts I, Shakur H, Fawole B, Kuti M, Olayemi O, Bello A, et al. Haematological and fibrinolytic status of Nigerian women with post-partum haemorrhage. BMC Pregnancy Childbirth 2018;18:143.
    1. Blasi A, Patel VC, Adelmeijer J, Azarian S, Hernandez Tejero M, Calvo A, et al. Mixed fibrinolytic phenotypes in decompensated cirrhosis and acute-on-chronic liver failure with hypofibrinolysis in those with complications and poor survival. Hepatology 2020;71:1381–90.
    1. Lisman T. Decreased plasma fibrinolytic potential as a risk for venous and arterial thrombosis. Semin Thromb Hemost 2017;43:178–84.
    1. Gluud LL, Klingenberg SL, Langholz E. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev 2012;1:CD006640.
    1. Lecker I, Wang DS, Whissell PD, Avramescu S, Mazer CD, Orser BA. Tranexamic acid-associated seizures: causes and treatment. Ann Neurol 2016;79:18–26.
    1. Stanley AJ, Laine L, Dalton HR, Ngu JH, Schultz M, Abazi R, et al. Comparison of risk scoring systems for patients presenting with upper gastrointestinal bleeding: international multicentre prospective study. BMJ 2017;356:i6432.
    1. Roberts I, Ker K. How systematic reviews cause research waste. Lancet 2015;386:1536.
    1. Mallett S, Clarke M. The typical Cochrane review: how many trials? How many participants? Int J Technol Asses Health Care 2002;18:820–3.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner