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

Abstract

Background Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding.

Methods We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.

Findings Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).

Interpretation We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial.

Metadata

Item Type:	Article
Authors/Creators:	Roberts, I Shakur-Still, H Afolabi, A Akere, A Arribas, M Brenner, A Chaudhri, R Gilmore, I Halligan, K Hussain, I Jairath, V Javaid, K Kayani, A Lisman, T Mansukhani, R Mutti, M Arif Nadeem, M Pollok, R Simmons, J Soomro, M Stanworth, S Veitch, A Hawkey, C Afolabi, A Cuzick, J Halligan, K Henry, D Metcalfe, C Roberts, I Gray, R Barkun, A David, S Devereaux, P Brady, T Roberts, I Shakur-Still, H Coats, T Edwards, P Gilmore, I Jairath, V Ker, K Manno, D Stanworth, S Veitch, A Arribas, M Austin, E Bal, K Balogun, E Barrow, C Beaumont, D Benyahia, M Brenner, A Brooks, I Cargill, M Carrington, L Edwards, P Frimley, L Geer, A Gilbert, D Gilliam, C Gil Onandia, J Golfi, N Hetherington, D Howe, C Hughes, C I'anson, D Jackson, R Joshi, M Kansagra, S Kawahara, T Ker, K Kostrov, S Manno, D Mansukhani, R Miah, H Ndungu, B Needham, K Outtandy, A Pearson, D Pepple, T Prowse, D Quashi, N Quinn, A Ramos, M Ranopa, L Reid, M Roberts, I Roukas, C Shakur-Still, H Squires, C Tanner, J Thayne, A Uddin, R Chaudhri, R Mutti, M Javaid, K Kayani, A Fawole, B Bello, FA Olayemi, O Afolabi, A Okunade, O Adetayo, O Chaudhri, R Mutti, M Afolabi, A Bello, FA Fawole, B Olayemi, O Khamis, H Shukri Bin Jahit, M Gogichaishvili, T Mateescu, RB Adhikaree, A Abdo, AE Zaher, M Deasy, C Alvarez Gregori, J Wellsh, B Lawton, L Kamath, R Barry, A Carpio, R Finney, K Maguire, H James, M Coffey, F Gough, C Sawers, L Thi, A-A Simmons, J Burnett, C Jacques, N Murray, V Pollok, R Jarman, H Lambe, C Rounding, S Tucker, S Al-Idari, R Guest, S Stoddard, E Yeo, D Bergin, C Hardy, E Thunder, J Jhalli, P Hartley, E Jarvis, C Swann, C Reed, M Gallagher, B Grahamslaw, J O'Brien, R Harris, T Bellhouse, G Boulton, O Skene, I Stanley, A Johnstone, J Maguire, D Thornton, S Banks, M Bercades, G Marks, D Ryu, J Harris, T Dowty, C Pott, J Skene, I East, J Bailey, A Beer, S Davies, S Appelboam, A Mackle, D Small, J Vorwerk, C Atkins, R Bradbury, I Coats, T Bryceland, C McClelland, L Thomas, M Clayton, K Michael, A Haig, S Al-Nahhas, S Godfrey, T Boger, P Comer, R Watkins, B Afolabi, O Afzal, S Cowton, A Everett, S Fazakerley, R Onoviran, F Snook, J Berry, J Simpson, D Keep, J Cotton, H Helyar, S Rutter, M Johnston, T O'Rourke, L Chan, L Tambellini, J Trodd, D Shutt, J Moreton, S Oglesby, A Boyle, A Haeger, N Hardwick, S Kendall, J Faulkner, B Worner, R Hearnshaw, S Doona, M Price, M Hunter, L Bell, M Loureiro, V Kehoe, A Jefferey, A Squire, R Hartin, D Bell, S Newman, A Gagg, J Foot, J Wakeford, S May, G Bartram, T Cumpstay, P Parker, L Das, R Pahary, S Wright, G Butt, G Christmas, N Wilson, S Ashfaq, M Chandler, L Al-Nahhas, S Demetriou, C Kaye, P Carley, S Brown, A Jones, L Whileman, A Greenaway, J Tregonning, J Harris, T Bellhouse, G Kuhrt, A Goodacre, S https://orcid.org/0000-0003-0803-8444 Jones, J Owen, C Mitra, A Harper-Payne, A Trudgill, N Hayes, A Butt, F Clifford, G Kinnon, A Fowler, S Pillay, K Gidwani, S McNair, A Omer, O de Weymarn, T Amin, A Chan, L Martin, J Mathieu, N Barnes, S Turvill, J Sweeting, H Draegebo, M McNaught, M Grocutt, M Margalef, J Humphrey, J Jackson, R Bellis, F Hunt, J Mitra, A Stevenson, A Watson, N Barden, S Paterson, S Veitch, A Macdonald, C Hobday, D Orugun, O Allison, A Dyer, T McBride, S Sawicki, W Rayner, B Flowerdew, L Barbour, J Klein, J Hood, S Palmer, N de Wolff, J Shenoy, A Trudgill, N Swallow, P Srirajaskanthan, R Hussain, I Arshad, H Aslam, N Bangash, A Qamar, M Zahoor, H Mutti, M Arshad, S ain Ghalib, Q Hameed, T Saif, T Shafi, W Arif Nadeem, M Ali, A Khan, S Muaaz, M Taj, A Ghafoor, A Afridi, A Ahmad, M Aslam, M Kumar, S Soomro, M Ali, M Bughio, U Chang, A Shaikh, S Ahmad, S Ali, Z Waqar, M Mushir, A Sattar, S Goraya, S Aslam, S Fatima, N Noreen, S Saleem, S Rahman, F Iqbal, N Khalid, M Riaz, U Umar, M Akhter, T Khan, J Misbah, N Afzal, M Kayani, M Shah, S Tarar, S Khan, S Iqbal, Y Khan, E Reki, M Hussain, T Iqbal, S Khurram, M Shafi, M Shaikh, A Ahmed, A Kumar, A Sachdev, P Nasir, KM Chaudhry, ZI Zubair, M Tayyab, G Mushtaq, J Nasir, M Khan, A Ali, A Ali, S Uddin, W Ahmed, S Kazmi, T Channa, S Aman, A Shaikh, M Rizvi, T Hussain, A Baqai, HZ Rasheed, Z Khan, A Irfan, A Husain, A Aslam, A Yahya, K Azhar, S Ul Haq, M Afzal, A Imran, M Saeed, I Yusuf, A Hassan, M Marwat, M Ishfaq, M Bashir, T Kumar, S Yaqoob, S Wahid, A Akere, A Fakoya, T Oke, T Tejan, E Olaomi, O Badejo, O Nnaemaka, O Ukwu, N Arowolo, O Aderounmu, A Wuraola, F Ugiagbe, R Atiri, A Eghaghe, E Adekoya, A Tade, AO Shonoiki, O Olatoke, S Raji, T Ekwunife, C Onyekpere, C Ahmed, A Muhammad, D Odeghe, E Lesi, O Osueni, A Samaila, A Nahuche, A Ajayi, A Dongo, A Ijoma, U Adebanjo, AT Igetei, R Yilkudi, M Osisanya, K Okeke, EN Enwere, OO Esmat, S Ashoush, O Naga, M Nagy, F Saiid, M Shaker, A Khamis, H Helmy, A Saafan, S Abdel Monem, M Din, J Azis, K Brukan, M Singh, S Zakaria, A Farid, S Hashim, N Mafauzy, M Najmi, W Amri, N Yi, X Hisyam, M Ng, E Ramli, Z Yee Lim, S Voon, K Young Yam, S Jahit, M Joon, L Melikidze, B Kazaishvili, D Gogichaishvili, T Grubelashvili, N Mosidze, B Tomadze, G Megreladze, A Oprita, R Pestroiu Calescu, D Chioncel, C Ragea, A Mateescu, B Busuioc, B Voiosu, A Cotirlet, A Pintilie, I Jinga, M Balaban, D Tanău, M Negreanu, L Bataga, S Priya, K Baral, S K.C., A Sah, V Yadav, V Adhikaree, A Abdo, A Ahmed, D Al Anazi, M Al Balkhi, A Deasy, C Álvarez Gregori, J Fornieles Pérez, H Beqiri, A Wellsh, B Lawton, L
Copyright, Publisher and Additional Information:	© 2020 The Authors. Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. https://creativecommons.org/licenses/by/4.0/
Dates:	Published: 18 June 2020
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Health and Related Research (Sheffield) > ScHARR - Sheffield Centre for Health and Related Research The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	06 Jul 2020 09:23
Last Modified:	06 Jul 2020 09:23
Status:	Published
Publisher:	Elsevier
Refereed:	Yes
Identification Number:	10.1016/s0140-6736(20)30848-5
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:162834

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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

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