The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial

Fatos Olldashi*, Mihal Kerçi, Tefik Zhurda, Klotilda Ruçi, Arben Banushi, Mario Sardón Traverso, Juan Jiménez, Jorge Balbi, Christian Dellera, Silvana Svampa, Gustavo Quintana, Gustavo Piñero, Jorge Teves, Ian Seppelt, David Mountain, Zsolt Balogh, Maniruz Zaman, Patrick Druwé, Robert Rutsaert, Guy MazairacFogang Pascal, Zognou Yvette, Djeuchon Chancellin, Patrick Okwen, Jules Djokam-Liapoe, Ernest Jangwa, Lawrence Mbuagbaw, Ninying Fointama, Frank Baillie, Ji Yao Jiang, Guo Yi Gao, Yin Hui Bao, Carlos Morales, Juan Sierra, Santiago Naranjo, Camilo Correa, Carolina Gómez, Jorge Herrera, Liliana Caicedo, Alexei Rojas, Henry Pastas, Hugo Miranda, Alfredo Constaín, Mayla Perdomo, Diego Muñoz, Álvaro Duarte, Edwin Vásquez, Camilo Ortiz, Bernardo Ayala, Hernán Delgado, Gloria Benavides, Lorena Rosero, Jorge Mejía-Mantilla, Ana Varela, Maríaisabel Calle, José Castillo, Alberto García, Juan Ciro, Clara Villa, Roberto Panesso, Luz Flórez, Argemiro Gallego, Fabián Puentes-Manosalva, Leonor Medina, Kelly Márquez, Adalgiza Reyes Romero, Ricardo Hernández, Julio Martínez, Wilson Gualteros, Zulma Urbina, Julio Velandia, Federico Benítez, Adolfo Trochez, Andrés Villarreal, Pamela Pabón, Héctor López, Laureano Quintero, Andrés Rubiano, Juan Tamayo, Marjoris Piñera, Daimi Martínez, Heriberto Martínez, Eugenio Casola, Mario Domínguez, Carlos Herrera, Marcos Iraola, Omar Rojas, Irene Pastrana, Daniel Rodríguez, Sergio Álvarez De La Campa, Thorvald Fortún, Martha Larrea, Lensky Aragón, Aida Madrazo, Petr Svoboda, Mario Izurieta, Alberto Daccach, Mónica Altamirano, Antonio Ortega, Bolívar Cárdenas, Luis González, Marcelo Ochoa, Fernando Ortega, Fausto Quichimbo, Jenny Guiñanzaca, Ines Zavala, Sayra Segura, Johnny Jerez, Daniel Acosta, Fabián Yánez, Rubén Camacho, Hussein Khamis, Hossam Shafei, Ali Kheidr, Hani Nasr, Moetaz Mosaad, Safwat Rizk, Hesham El Sayed, Taha Moati, Emad Hokkam, Mamdouh Amin, Hany Lowis, Medhat Fawzy, Nabil Bedir, Mohamed Aldars, Virginia Rodríguez, Juan Tobar, Jorge Alvarenga, Budu Shalamberidze, Elza Demuria, Nikoloz Rtveliashvili, Gocha Chutkerashvili, David Dotiashvili, Tamar Gogichaishvili, George Ingorokva, David Kazaishvili, Besik Melikidze, Natia Iashvili, Gia Tomadze, Manana Chkhikvadze, Leri Khurtsidze, Zviad Lomidze, Diana Dzagania, Nikoloz Kvachadze, Giorgi Gotsadze, Vakhtang Kaloiani, Nino Kajaia, Jonathan Dakubo, Simon Naaeder, Priscilla Sowah, Adamu Yusuf, Alhaji Ishak, Paul Selasi-Sefenu, Ballu Sibiri, Sampson Sarpong-Peprah, Theodore Boro, Kanjithanda Bopaiah, Kishore Shetty, Raja Subbiah, Lukman Mulla, Anand Doshi, Yashbir Dewan, Sarvpreet Grewal, Pradipta Tripathy, Jacob Mathew, Bharat Gupta, Anil Lal, Majulie Choudhury, Sanjay Gupta, Smita Gupta, Arun Chug, Venkataramana Pamidimukkala, Palaniappan Jagannath, Mohan Maharaj, Ramaraju Vommi, Naresh Gudipati, W. H. Chhang, Pankaj Patel, Nilay Suthar, Deepa Banker, Jyotish Patel, Satish Dharap, Ranjeet Kamble, Shraddha Patkar, Sushil Lohiya, Rakesh Saraf, Dinesh Kumar, Satish Parihar, Rahul Gupta, Rasananda Mangual, Alagumuthu, Don Kooper, Chinmaya Mohapatra, Suresh David, Wesley Rajaleelan, Appas, Ashok Pangi, Vivek Saraf, Santhosh Chikareddy, Sushil Mankar, Anil Golhar, Rahul Sakhare, Nilesh Wagh, Dhiman Hazarika, Pratyush Chaudhuri, Prakash Ketan, Govindbhai Purohit, Yogesh Purohit, Mandakini Pandya, Rakesh Gupta, Shashi Kiran, Saurab Walia, Sonam Goyal, Sidhant Goyal, Satish Goyal, Ashok Attri, Rajeev Sharma, Ashok Oberai, Mahesh Oberai, Supriya Oberoi, Gajendra Kant Tripathi, Vijayan Peettakkandy, Premkumar Karuthillath, Pavithran Vadakammuriyil, Jalindar Pol, Sunita Pol, Manisha Saste, Subrat Raul, Shashi Tiwari, Neileino Nelly, M. Chidambaram, Viswanathan Kollengode, Sam Thampan, Sunder Rajan, Sushrut Rajan, Subodh Raju, Renuka Sharma, Subbiah Venkatesh Babu, Chellappa Sumathi, Protyush Chatterjee, Alok Agarwal, Hemant Magar, Meera Magar, Manmohan Singh, Deepak Gupta, Kamal Haloi, Varsha Sagdeo, Pramod Giri, Nimesh Verma, Ravi Jariwala, Ashish Goti, Aman Prabhu-Gaonkar, Sagar Utagi, Mahesh Joshi, Ruchit Agrawal, Gopal Sharma, Gurvinder Saini, Vinod Tewari, Yad Yadav, Vijay Parihar, Neelam Venkataramana, Shailesh Rao, Narayana Reddy, Virsing Hathila, Vithal Das, Kantibhai Agaja, Aniruddh Purohit, Akilesh Lahari, Rajesh Bhagchandani, Bala Vidyasagar, P. K. Sachan, Tanmoy Das, Sharad Vyas, Sujoy Bhattacharjee, Parag Sancheti, T. Manoj, Mubarak Moideen, Kailash Pansey, V. P. Chandrasekaran, Kabul Saikia, Hoshedar Tata, Sanjay Vhora, Aniket Shah, Gordon Rangad, S. Rajasekaran, S. T. Shankarlal, Sathish Devadoss, M. Saleem, Haroon Pillay, Zulfiquer Hazarika, Parikshit Deshmukh, S. P. Murugappan, Amit Jaiswal, Deepak Vangani, Prakash Modha, Chawngrolien Chonzik, Megha Praveen, Vijaya Sethurayar, Sojan Ipe, Naresh Shetty, R. P. Gupta, Vinod Jain, Ketan Shah, Moch Dwikoryanto, Nyoman Golden, Kuning Atmadjaya, Ketut Wiargitha, Ketut Sudiasa, Gede Suwedagatha, Farhad Bal'Afif, Vicky Budipramana, Tabrani, Agung Lemuel, Susilo Chandra, Faisol Ama, Ehsan Sherafatkazemzadeh, Ehsan Moradi, Alireza Sheikhi, Ali Ziaee, Ahmad Fanaei, Esmaeil Hajinasrollah, Kamran Heidari, Bassim Mohammad, Najah Hadi, Giovanna Perone, Elena De Peri, Annalisa Volpi, Jean Johnson, Masayoshi Abe, Vincent Mutiso, Benjamin Okanga, Daniel Ojuka, Baharudin Abdullah, Hishamuddin Rahman, Yazid Noh, Sabariah Jamaluddin, Hasnah Dawal, April Roslani, Chee Wei Law, P. Devashanti, Yusof Wahab, Shanta Velaiutham, Ridzuan Dato, Jorge Loría, Erandy Montes, Eduardo Gómez, Víctor Cazales, Paúl Bautista, Raúl Bautista, David Ahumada, Edwin Hernández, Germahin Velásquez, Patricia Ortega, Gabriel Lira, Francisco Estrada, Jorge Martínez, Juan Martínez, Julio Casasola, Oluwole Olaomi, Yari Abubakar, Kanati Apollo, Olawale Badejo, Ogemdi Ihekire, Pius Iribhogbe, Olugbenga Oludiran, Emmanuel Obeta, Collins Okojie, Ernest Udefiagbon, Edward Komolafe, Patrick Olaleye, Tochukwu Uzochukwu, Uvie Onakpoya, Andrew Dongo, Lateef Thanni, Adefemi Afolabi, Titilade Akinola, Adeyinka Ademola, Olusola Akute, Lawal Khalid, Lawal Abubakar, Muhammad Aminu, Mike Ogirima, Ambrose Attansey, Durodola Michael, Olaniran Aremu, Odebode Olugbenga, Udoffa Ukpong, Yusuf Salman, Nene Obianyo, Chinenye Ani, Roderick Ezeadawi, Oluwadiya Kehinde, Agodirin Olaide, Andrea Jogo, Terna Bitto, Stanley Anyanwu, Okechukwu Mbonu, Mobolaji Oludara, Michael Somoye, Bello Shehu, Nasir Ismail, Amechi Katchy, Rowland Ndoma-Egba, Ngim Grace-Inah, Zumnan Songden, Abdulrahman Abdulraheem, Akpan Otu, Timothy Nottidge, Domingo Inyang, David Idiapho, Herb Giebel, Ramatu Hassan, Adeyinka Adisa, Akinbolaji Akinkuolie, Kalu Okam, Abubakar Musa, Ignatius Falope, John Eze, José Caballero, Wenceslao Azabache, Oscar Salirrosas, Alonso Soto, Elfi Torres, Gloria Ramírez, Mónica Pérez, Cesar Malca, Juan Velez, Raul Yepez, Hernan Yupanqui, Pedro Lagos, Diana Rodriguez, Jorge Flores, Anselmo Moya, Alejandro Barrionuevo, Marco Gonzales-Portillo, Edgar Núñez, Abdelazeem Eldawlatly, Mohammed Al Naami, Bilal Delvi, Walid Alyafi, Branko Djurovic, Ivan Ng, Aktham Yaghi, Anton Laincz, Stefan Trenkler, Jozef Valky, Mphako Modiba, Peter Legodi, Thomas Rangaka, Lee Wallis, Ángeles Muñoz, Ana Serrano, Pilar Marcos, Martin Rubi, Victoria De La Torre, Ranjith Ellawala, Samitha Wijeratna, Lukshrini Gunaratna, Crishantha Wijayanayaka, Kitugi Nungu, Billy Haonga, Grenda Mtapa, Surakrant Yutthakasemsunt, Warawut Kittiwattanagul, Parnumas Piyavechvirat, Tawatcahi Impool, Santipong Thummaraj, Rusta Salaeh, Sakchai Tangchitvittaya, Kamol Wattanakrai, Teerasak Jiravongbunrod, Chatchai Soonthornthum, Surasak Meephant, Pusit Subsompon, Phaiboon Pensuwan, Wicheanrat Chamnongwit, Zouheir Jerbi, Abderraouef Cherif, Mark Nash, Tim Harris, Jay Banerjee, Ramzi Freij, Jason Kendall, Stephen Moore, William Townend, Rowland Cottingham, Dan Becker, Stuart Lloyd, Peter Burdett-Smith, Kazim Mirza, Andrew Webster, Suzanne Brady, Amanda Grocutt, John Thurston, Fiona Lecky, Steve Goodacre, Yakub Mulla, Dennis Sakala, Charles Chengo

*Corresponding author for this work

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654 Citations (Scopus)

Abstract

Background The aim of the CRASH-2 trial was to assess the effects of early administration of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage. Tranexamic acid significantly reduced all-cause mortality. Because tranexamic acid is thought to exert its effect through inhibition of fibrinolysis, we undertook exploratory analyses of its effect on death due to bleeding.

Methods The CRASH-2 trial was undertaken in 274 hospitals in 40 countries. 20 211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min followed by infusion of 1 g over 8 h) or placebo. Patients were randomly assigned by selection of the lowest numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Both participants and study staff (site investigators and trial coordinating centre staff) were masked to treatment allocation. We examined the effect of tranexamic acid on death due to bleeding according to time to treatment, severity of haemorrhage as assessed by systolic blood pressure, Glasgow coma score (GCS), and type of injury. All analyses were by intention to treat. The trial is registered as ISRCTN86750102, ClinicalTrials.gov NCT00375258, and South African Clinical Trial Register/Department of Health DOH-27-0607-1919.

Findings 10 096 patients were allocated to tranexamic acid and 10 115 to placebo, of whom 10 060 and 10 067, respectively, were analysed. 1063 deaths (35) were due to bleeding. We recorded strong evidence that the effect of tranexamic acid on death due to bleeding varied according to the time from injury to treatment (test for interaction p<0·0001). Early treatment (≤1 h from injury) significantly reduced the risk of death due to bleeding (198/3747 [5·3] events in tranexamic acid group vs 286/3704 [7·7] in placebo group; relative risk [RR] 0·68, 95 CI 0·57-0·82; p<0·0001). Treatment given between 1 and 3 h also reduced the risk of death due to bleeding (147/3037 [4·8] vs 184/2996 [6·1]; RR 0·79, 0·64-0·97; p=0·03). Treatment given after 3 h seemed to increase the risk of death due to bleeding (144/3272 [4·4] vs 103/3362 [3·1]; RR 1·44, 1·12-1·84; p=0·004). We recorded no evidence that the effect of tranexamic acid on death due to bleeding varied by systolic blood pressure, Glasgow coma score, or type of injury.

Interpretation Tranexamic acid should be given as early as possible to bleeding trauma patients. For trauma patients admitted late after injury, tranexamic acid is less effective and could be harmful.

Funding UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation.

Original languageEnglish
Pages (from-to)1096-1101
Number of pages8
JournalThe Lancet
Volume377
Issue number9771
DOIs
Publication statusPublished - Mar 2011
Externally publishedYes

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