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1. The effect of statins on muscle symptoms in primary care: the StatinWISE series of 200 N-of-1 RCTs

Author

Michael Moore, Jane Armitage, Ian Roberts, Andrew Thayne, Emily Herrett, Alexander Perkins, Haleema Shakur-Still, Elizabeth A. Williamson, Danielle Beaumont, Thomas M. MacDonald, Tjeerd van Staa, Danielle Prowse, Kieran Brack, Ben Goldacre, Zahra Jamal, Maurice Hoffman, and Liam Smeeth

Subjects
N of 1 trial, Weakness, medicine.medical_specialty, Technology Assessment, Biomedical, lcsh:Medical technology, Statin, Visual analogue scale, medicine.drug_class, Cost-Benefit Analysis, Atorvastatin, 030204 cardiovascular system & hematology, Placebo, visual analogue scale, 03 medical and health sciences, 0302 clinical medicine, general practitioners, Internal medicine, muscle pain, Humans, Medicine, 030212 general & internal medicine, Adverse effect, Myositis, business.industry, Muscles, Health Policy, cholesterol, atorvastatin, medicine.disease, cardiovascular diseases, primary health care, England, lcsh:R855-855.5, medication adherence, Hydroxymethylglutaryl-CoA Reductase Inhibitors, medicine.symptom, business, secondary prevention, Research Article, medicine.drug
Abstract

Background Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis. Objectives To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related. Design A series of 200 double-blinded N-of-1 trials. Setting Participants were recruited from 50 general practices in England and Wales. Participants Patients who were considering discontinuing statin use and those who had discontinued statin use in the last 3 years because of perceived muscle symptoms. Interventions Participants were randomised to a sequence of six 2-month treatment periods during which they received 20 mg of atorvastatin daily or a matched placebo. Main outcome measures The primary outcome was self-reported muscle symptoms rated using a visual analogue scale on the last week of each treatment period. Secondary outcomes included the participant’s belief about the cause of their muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant, any other symptoms they experienced, adherence to medication, the participant’s decision about statin treatment following the trial, and whether or not they found their own trial result helpful. Results A total of 151 out of 200 (75.5%) randomised participants provided one or more visual analogue scale measurements in a placebo period and one or more measurements in a statin period, and were included in the primary analysis. There was no evidence of a difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo –0.11, 95% confidence interval –0.36 to 0.14; p = 0.398). Withdrawals, adherence and missing data were similar during the statin periods and the placebo periods. Conclusions Among people who previously reported severe muscle symptoms while taking statins, this series of randomised N-of-1 trials found no overall effect of statins on muscle symptoms compared with the placebo. The slight difference in withdrawals due to muscle symptoms suggests that statins may contribute to symptoms in a small number of patients. The results are generalisable to patients who are considering discontinuing or have already discontinued statins because of muscle symptoms, and who are willing to re-challenge or participate in their own N-of-1 trial. Future work We recommend that additional statins and doses are explored using N-of-1 trials. More broadly, N-of-1 trials present a useful tool for exploring transient symptoms with other medications. Limitations This study used 20-mg doses of atorvastatin only. Furthermore, a dropout rate of 43% was observed, but this was accounted for in the power calculations. Trial registration Current Controlled Trials ISRCTN30952488 and EudraCT 2016-000141-31. 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. 16. See the NIHR Journals Library website for further project information.

Published
2021
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2. WOMAN-PharmacoTXA trial: Study protocol for a randomised controlled trial to assess the pharmacokinetics and pharmacodynamics of intramuscular, intravenous and oral administration of tranexamic acid in women giving birth by caesarean section [version 1; peer review: 2 approved]

Author

Mwansa Ketty Lubeya, Danielle Prowse, Haleema Shakur-Still, Aasia Kayani, Rizwana Chaudhri, Ian Roberts, Amber Geer, Monica Arribas, Stanislas Grassin-Delyle, and Kiran Javaid

Subjects
Tranexamic acid, Antifibrinolytic, medicine.drug_class, viruses, medicine.medical_treatment, Science, Medicine (miscellaneous), General Biochemistry, Genetics and Molecular Biology, law.invention, Study Protocol, oral, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Randomized controlled trial, law, Medicine, Caesarean section, 030212 general & internal medicine, Adverse effect, intramuscular, business.industry, virus diseases, clinical trial, Articles, biochemical phenomena, metabolism, and nutrition, digestive system diseases, Pharmacodynamics, caesarean section, 030220 oncology & carcinogenesis, Anesthesia, PPH, business, Intramuscular injection, medicine.drug
Abstract

Background: Intravenous tranexamic acid (TXA) within 3 hours of birth significantly reduces death due to bleeding in women with postpartum haemorrhage (PPH). Most PPH deaths occur in the first hours after giving birth and treatment delay decreases survival. One barrier to rapid TXA treatment is the need for intravenous injection. Intramuscular injection and oral solution of TXA would be easier and faster to administer and would require less training. However, the pharmacokinetics (PK), pharmacodynamics and safety of TXA administered by different routes in pregnant women have not been established. The main aim of this study is to ascertain whether IM and oral solution of TXA will be absorbed at levels sufficient to inhibit fibrinolysis in pregnant women. Methods: WOMAN-PharmacoTXA is a prospective, randomised, open label trial to be conducted in Zambia and Pakistan. Adult women undergoing caesarean section with at least one risk factor for PPH will be included. Women will be randomised to receive one of the following about 1 hour prior to caesarean section: 1-gram TXA IV, 1-gram TXA IM, 4-grams TXA oral solution or no TXA. Randomisation will continue until 120 participants with at least six post randomisation PK samples are included. TXA concentration in maternal blood samples will be measured at baseline and at different time points during 24 hours after receipt of intervention. Blood TXA concentration will be measured from the umbilical cord and neonate. The primary endpoint is maternal blood TXA concentrations over time. Secondary outcomes include umbilical cord and neonate TXA concentration D-dimer concentration, blood loss and clinical diagnosis of PPH, injection site reactions and maternal and neonate adverse events. Discussion: The WOMAN-PharmacoTXA trial will provide important data on pharmacokinetics, pharmacodynamics and safety of TXA after IV, intramuscular and oral administration in women giving birth by caesarean section. Trial registration: ClincalTrials.gov, NCT04274335 (18/02/2020).

Published
2021

3. 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

Author

Ian Roberts, Haleema Shakur-Still, Adefemi Afolabi, Adegboyega Akere, Monica Arribas, Amy Brenner, Rizwana Chaudhri, Ian Gilmore, Kenneth Halligan, Irshad Hussain, Vipul Jairath, Kiran Javaid, Aasia Kayani, Ton Lisman, Raoul Mansukhani, Muttiullah Mutti, Muhammad Arif Nadeem, Richard Pollok, Jonathan Simmons, Majid Soomro, Simon Stanworth, Andrew Veitch, Christopher Hawkey, Jack Cuzick, David Henry, Chris Metcalfe, Richard Gray, Alan Barkun, Suresh David, Philip Devereaux, Tony Brady, Timothy Coats, Phil Edwards, Katharine Ker, Daniela Manno, Emma Austin, Kiran Bal, Eni Balogun, Collette Barrow, Danielle Beaumont, Myriam Benyahia, Imogen Brooks, Madeleine Cargill, Laura Carrington, Lauren Frimley, Amber Geer, Daniel Gilbert, Catherine Gilliam, Julio Gil Onandia, Nayia Golfi, Daniel Hetherington, Courtenay Howe, Carolyn Hughes, David I'anson, Rob Jackson, Miland Joshi, Sneha Kansagra, Taemi Kawahara, Sergey Kostrov, Hakim Miah, Bernard Ndungu, Kelly Needham, Aroudra Outtandy, Daniel Pearson, Tracey Pepple, Danielle Prowse, Nigel Quashi, Anna Quinn, Maria Ramos, Laura Ranopa, Mia Reid, Chris Roukas, Chelci Squires, Jemma Tanner, Andrew Thayne, Ruhama Uddin, Bukola Fawole, Folasade Adenike Bello, Oladapo Olayemi, Olujide Okunade, Olusade Adetayo, Hussein Khamis, Mohammad Shukri Bin Jahit, Tamar Gogichaishvili, Radu Bogdan Mateescu, Ajay Adhikaree, Abdelmounem Eltayeib Abdo, Mohammad Zaher, Conor Deasy, Joaquin Alvarez Gregori, Bobby Wellsh, Luke Lawton, Raghavendra Kamath, Adrian Barry, Racquel Carpio, Kay Finney, Holly Maguire, Martin James, Frank Coffey, Chris Gough, Lisa Sawers, Aye-Aye Thi, Claire Burnett, Nicola Jacques, Victoria Murray, Heather Jarman, Christine Lambe, Sarah Rounding, Simon Tucker, Romaih Al-Idari, Samuel Guest, Emma Stoddard, David Yeo, Colin Bergin, Elaine Hardy, Joanne Thunder, Paul Jhalli, Edward Hartley, Catherine Jarvis, Carly Swann, Matthew Reed, Bernadette Gallagher, Julia Grahamslaw, Rachel O'Brien, Timothy Harris, Geoffrey Bellhouse, Olivia Boulton, Imogen Skene, Adrian Stanley, Janet Johnstone, Donogh Maguire, Susan Thornton, Matthew Banks, Georgia Bercades, Daniel Marks, Jung Ryu, Claire Dowty, Jason Pott, James East, Adam Bailey, Sally Beer, Sian Davies, Andrew Appelboam, Daisy Mackle, Jennifer Small, Christiane Vorwerk, Rachel Atkins, Isobel Bradbury, Catriona Bryceland, Lisa McClelland, Martin Thomas, Kate Clayton, Angiy Michael, Stephen Haig, Saif Al-Nahhas, Tim Godfrey, Philip Boger, Rachel Comer, Barbara Watkins, Ola Afolabi, Shazad Afzal, Amanda Cowton, Simon Everett, Ruth Fazakerley, Felicia Onoviran, Jonathon Snook, Jackie Berry, Diane Simpson, Jeff Keep, Hannah Cotton, Sinead Helyar, Matthew Rutter, Tracey Johnston, Laura O'Rourke, Louisa Chan, Joanna Tambellini, Dawn Trodd, James Shutt, Sarah Moreton, Abby Oglesby, Adrian Boyle, Nicola Haeger, Susie Hardwick, Jason Kendall, Beverley Faulkner, Ruth Worner, Sarah Hearnshaw, Mary Doona, Maria Price, Laura Hunter, Maggie Bell, Vania Loureiro, Anthony Kehoe, Alison Jefferey, Rosalyn Squire, David Hartin, Stephanie Bell, Alexandra Newman, James Gagg, Jayne Foot, Sue Wakeford, Gabrielle May, Thomas Bartram, Paul Cumpstay, Lucy Parker, Rita Das, Sheik Pahary, Gavin Wright, Georgina Butt, Natasha Christmas, Sarah Wilson, Mohammed Ashfaq, Louise Chandler, Carrie Demetriou, Philip Kaye, Simon Carley, Andrew Brown, Lucy Jones, Amanda Whileman, John Greenaway, Julie Tregonning, Avril Kuhrt, Steve Goodacre, John Jones, Charlotte Owen, Anu Mitra, Abby Harper-Payne, Nigel Trudgill, Anne Hayes, Faheem Butt, Gayle Clifford, Andrew Kinnon, Susan Fowler, Kris Pillay, Shweta Gidwani, Alistair McNair, Omer Omer, Tanya de Weymarn, Adnan Amin, Jane Martin, Nick Mathieu, Simon Barnes, James Turvill, Helen Sweeting, Morten Draegebo, Marion McNaught, Mandy Grocutt, Jordi Margalef, Julian Humphrey, Richard Jackson, Fionn Bellis, Jane Hunt, Alastair Stevenson, Nicholas Watson, Steven Barden, Stuart Paterson, Chris Macdonald, David Hobday, Olu Orugun, Andrew Allison, Tristan Dyer, Samuel McBride, Wojciech Sawicki, Ben Rayner, Lynsey Flowerdew, Jamie Barbour, Jason Klein, Stephen Hood, Nicola Palmer, Jacob de Wolff, Achuth Shenoy, Peter Swallow, Rajaventhan Srirajaskanthan, Hamza Arshad, Naeem Aslam, Anam Bangash, Muhammad Qamar, Haroon Zahoor, Saba Arshad, Quratul ain Ghalib, Tehseen Hameed, Tayyaba Saif, Wajahat Shafi, Abid Ali, Shehroze Khan, Muhammad Muaaz, Ahmad Taj, Aamir Ghafoor, Aamir Afridi, Mansoor Ahmad, Mujahid Aslam, Sandeep Kumar, Mohsin Ali, Ubedullah Bughio, Adil Chang, Sana Shaikh, Syed Ahmad, Zeeshan Ali, Marium Waqar, Aiman Mushir, Sadaf Sattar, Saifullah Goraya, Sharmeen Aslam, Nighat Fatima, Saadia Noreen, Sheraz Saleem, Fazal Rahman, Nadeem Iqbal, Mohammad Khalid, Umar Riaz, Muhammad Umar, Tayyab Akhter, Javaria Khan, Noureen Misbah, Muhammad Afzal, Mobeen Kayani, Syed Shah, Shahida Tarar, Sherbat Khan, Yasir Iqbal, Essa Khan, Maqbool Reki, Tanveer Hussain, Shafqat Iqbal, Muhammad Khurram, Muhammad Shafi, Abrar Shaikh, Aijaz Ahmed, Ameet Kumar, Pinkey Sachdev, Khalid Mahmood Nasir, Zafar Iqbal Chaudhry, Muhammad Zubair, Ghias Tayyab, Junaid Mushtaq, Muhammad Nasir, Amir Khan, Amjad Ali, Sajjad Ali, Wasim Uddin, Sohaib Ahmed, Tazaeen Kazmi, Saleh Channa, Adeeqa Aman, Mouzam Shaikh, Tahir Rizvi, Amjad Hussain, Haider Zaigham Baqai, Zakawat Rasheed, Abdus Khan, Adeela Irfan, Aamir Husain, Asifa Aslam, Khalid Yahya, Salman Azhar, Mansoor Ul Haq, Adeel Afzal, Muhammad Imran, Iram Saeed, Aasim Yusuf, Mariam Hassan, Mumtaz Marwat, Muhammad Ishfaq, Tahir Bashir, Santosh Kumar, Sajjad Yaqoob, Abdul Wahid, Tinuola Fakoya, Temitope Oke, Edries Tejan, Oluwole Olaomi, Olawale Badejo, Okafor Nnaemaka, Nancy Ukwu, Olukayode Arowolo, Adewale Aderounmu, Funmilola Wuraola, Rose Ugiagbe, Alexander Atiri, Enadeghe Eghaghe, Adeleke Adekoya, Adedayo Oluyomi Tade, Olatunji Shonoiki, Samuel Olatoke, Toafiq Raji, Christopher Ekwunife, Chigozirim Onyekpere, Adamu Ahmed, Daniyan Muhammad, Emuobor Odeghe, Olufunmilayo Lesi, Azeberoje Osueni, Adamu Samaila, Aminu Nahuche, Akande Ajayi, Andrew Dongo, Uchenna Ijoma, Ademola Tolulope Adebanjo, Rufina Igetei, Monday Yilkudi, Kehinde Osisanya, Edith Nonyelum Okeke, Oguamanam Okezie Enwere, Serag Esmat, Omar Ashoush, Mazen Naga, Fady Nagy, Mostafa Saiid, Ahmed Shaker, Ashraf Helmy, Saafan Saafan, Mohammed Abdel Monem, Jiffre Din, Khairul Azis, Muhyuddin Brukan, Sanjay Singh, Andee Zakaria, Shaik Farid, Nizam Hashim, Masykurin Mafauzy, Wan Najmi, Nil Amri, Xin Yi, Mohammad Hisyam, Elaine Ng, Zuhrirahimi Ramli, Shyang Yee Lim, Kelvin Voon, Sir Young Yam, Mohammad Jahit, Lee Joon, Besik Melikidze, Davit Kazaishvili, Nino Grubelashvili, Baadur Mosidze, Gia Tomadze, Avto Megreladze, Ruxandra Oprita, Dorina Pestroiu Calescu, Camelia Chioncel, Andrei Ragea, Bogdan Mateescu, Bogdan Busuioc, Andrei Voiosu, Adrian Cotirlet, Iulia Pintilie, Mariana Jinga, Daniel Balaban, Marcel Tanău, Lucian Negreanu, Simona Bataga, Khushboo Priya, Shankar Baral, Anuj K.C., Vijay Sah, Vijay Yadav, Abdelmounem Abdo, Dalia Ahmed, Marzouqah Al Anazi, Areej Al Balkhi, Joaquín Álvarez Gregori, Helio Fornieles Pérez, and Arben Beqiri

Subjects
Gastrointestinal bleeding, Lower gastrointestinal bleeding, business.industry, Maintenance dose, Placebo-controlled study, General Medicine, 030204 cardiovascular system & hematology, A300, medicine.disease, Placebo, Loading dose, 03 medical and health sciences, 0302 clinical medicine, Anesthesia, Medicine, 030212 general & internal medicine, business, Stroke, Tranexamic acid, medicine.drug
Abstract

Summary 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. Funding UK National Institute for Health Research Health Technology Assessment Programme.

Published
2020
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4. Effect of tranexamic acid by baseline risk of death in acute bleeding patients: a meta-analysis of individual patient-level data from 28 333 patients

Author

Francois-Xavier Ageron, Angele Gayet-Ageron, Katharine Ker, Timothy J. Coats, Haleema Shakur-Still, Ian Roberts, Aasia Kayani, Amber Geer, Bernard Ndungu, Bukola Fawole, Catherine Gilliam, Cecelia Adetayo, Collette Barrow, Danielle Beaumont, Danielle Prowse, David I'Anson, Eni Balogun, Hakim Miah, Imogen Brooks, Julio Onandia, Kiran Javaid, Laura Suncuan, Lauren Frimley, Mia Reid, Monica Arribas, Myriam Benyahia, Olujide Okunade, Phil Edwards, Rizwana Chaudhri, Sergey Kostrov, Sneha Kansagra, Tracey Pepple, Antifibrinolytics Trials Collaboration, Kayani, A., Geer, A., Ndungu, B., Fawole, B., Gilliam, C., Adetayo, C., Barrow, C., Beaumont, D., Prowse, D., I'Anson, D., Balogun, E., Miah, H., Shakur-Still, H., Roberts, I., Brooks, I., Onandia, J., Ker, K., Javaid, K., Suncuan, L., Frimley, L., Reid, M., Arribas, M., Benyahia, M., Okunade, O., Edwards, P., Chaudhri, R., Kostrov, S., Kansagra, S., and Pepple, T.

Subjects
Adult, Male, Risk, medicine.medical_specialty, Antifibrinolytic, medicine.drug_class, Baseline risk, Hemorrhage, Antifibrinolytic Agents/therapeutic use, 03 medical and health sciences, Young Adult, 0302 clinical medicine, 030202 anesthesiology, Internal medicine, medicine, Coagulopathy, Humans, ddc:613, Randomized Controlled Trials as Topic, ddc:618, business.industry, Acute bleeding, medicine.disease, Postpartum haemorrhage, Antifibrinolytic Agents, 3. Good health, Anesthesiology and Pain Medicine, Tranexamic Acid, Patient level data, Acute Disease, Female, Hemorrhage/drug therapy, Tranexamic Acid/therapeutic use, antifibrinolytics, bleeding, coagulopathy, mortality, postpartum haemorrhage, trauma, Meta-analysis, business, Tranexamic acid, medicine.drug
Abstract

Background Early administration of the antifibrinolytic drug tranexamic acid reduces death from bleeding in trauma and postpartum haemorrhage. We examined how the effectiveness and safety of antifibrinolytic drugs varies by the baseline risk of death as a result of bleeding. Methods We performed an individual patient-level data meta-analysis of randomised trials including more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials performed between January 1, 1946 and July 5, 2018 (PROSPERO, number 42016052155). Results Two randomised trials were selected where 28 333 patients received tranexamic acid treatment within 3 h after the onset of acute bleeding. Baseline characteristics to estimate the risk of death as a result of bleeding were divided into four categories: Low (0–5%), intermediate (6–10%), high (11–20%), and very high (>20%). Most patients had a low baseline risk of death as a result of bleeding (23 008 [81%]). Deaths as a result of bleeding occurred in all baseline risk categories with 240 (1%), 202 (8%), 232 (14%), and 357 (30%) deaths in the low-, intermediate-, high-, and very high-risk categories, respectively. The effectiveness of tranexamic acid did not vary by baseline risk when given within 3 h after bleeding onset (P=0.51 for interaction term). There was no increased risk of vascular occlusive events with tranexamic acid and it did not vary by baseline risk categories (P=0.25). Conclusions Tranexamic acid appears to be safe and effective regardless of baseline risk of death. Because many deaths are in patients at low and intermediate risk, tranexamic acid use should not be restricted to the most severely injured or bleeding patients.

Published
2020

5. 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

Author

Haleema Shakur, Ian Roberts, Bukola Fawole, Rizwana Chaudhri, Mohamed El-Sheikh, Adesina Akintan, Zahida Qureshi, Hussein Kidanto, Bellington Vwalika, Abdulfetah Abdulkadir, Saturday Etuk, Shehla Noor, Etienne Asonganyi, Zarko Alfirevic, Danielle Beaumont, Carine Ronsmans, Sabaratnam Arulkumaran, Adrian Grant, Kaosar Afsana, Metin Gülmezoglu, Beverley Hunt, Oladapo Olayemi, Iain Chalmers, Pisake Lumbiganon, Gilda Piaggio, Tony Brady, Diana Elbourne, Eni Balogun, Tracey Pepple, Danielle Prowse, Nigel Quashi, Lin Barneston, Collette Barrow, Lisa Cook, Lauren Frimley, Daniel Gilbert, Catherine Gilliam, Rob Jackson, Taemi Kawahara, Hakim Miah, Sergey Kostrov, Maria Ramos, Phil Edwards, Tom Godec, Sumaya Huque, Olujide Okunade, Olusade Adetayo, Aasia Kayani, Kiran Javaid, Chrstine Biryabarema, Robert Tchounzou, Mohan Regmi, Kastriot Dallaku, Mateus Sahani, Sayeba Akhter, Nicolas Meda, Anthony Kwame Dah, Olufemi Odekunle, Oluwabusola Monehin, Austin Ojo, Grace Akinbinu, Ifeoma Offiah, Ubong Akpan, Uduak Udofia, Useneno Okon, Ezukwa Omoronyia, Okpe James, Nike Bello, Blessed Adeyemi, Chris Aimakhu, Olufemi Akinsanya, Bamidele Adeleye, Oluwaseun Adeyemi, Kayode Oluwatosin, Abiodun Aboyeji, Abiodun Adeniran, Adebayo Adewale, Noah Olaomo, Lawrence Omo-Aghoja, Emmanuel Okpako, Lucky Oyeye, Francis Alu, John Ogudu, Ezekiel Ladan, Ibrahim Habib, Babasola Okusanya, Olatunde Onafowokan, David Isah, Abalaka Aye, Felix Okogbo, Egbaname Aigere, Mark Ogbiti, Temitope Onile, Olaide Salau, Yinka Amode, Kamil Shoretire, Adebola Owodunni, Kehinde Ologunde, Akintunde Ayinde, Moses Alao, Olalekan Awonuga, Babatunde Awolaja, Omololu Adegbola, Fatimah Habeebu-Adeyemi, Adeyemi Okunowo, Hadiza Idris, Ola Okike, Nneka Madueke, Josiah Mutihir, Nankat Joseph, Babatunde Adebudo, Adeniyi Fasanu, Olugbenga Akintunde, Olufemi Abidoye, Owigho Opreh, Sophia Udonwa, Gladys Dibia, Simeon Bazuaye, Arafat Ifemeje, Aniefiok Umoiyoho, Emmanuel Inyang-Etoh, Sununu Yusuf, Kayode Olayinka, Babalola Adeyemi, Olusegun Ajenifuja, Umar Ibrahim, Yusuf Baffah Adamu, Oluwarotimi Akinola, Grace Adekola-Oni, Paul Kua, Roseline Iheagwam, Audu Idrisa, Ado Geidam, Andrea Jogo, Joseph Agulebe, Joseph Ikechebelu, Onyebuchi Udegbunam, Jacob Awoleke, Oluseyi Adelekan, Hajaratu Sulayman, Nkeiruka Ameh, Nurudeen Onaolapo, Affiss Adelodun, William Golit, Dachollom Audu, Adetunji Adeniji, Folasade Oyelade, Lamaran Dattijo, Palmer Henry, Olabisi Loto, Odidika Umeora, Abraham Onwe, Emily Nzeribe, Bartthy Okorochukwu, Augustine Adeniyi, Emmanuel Gbejegbe, Akpojaro Ikpen, Ikemefuna Nwosu, Abdulrasaq Sambo, Olubunmi Ladipo, Sola Abubakar, Ola Nene Okike, Enyinnaya Chikwendu Nduka, Eziamaka Pauline Ezenkwele, Daniel Onwusulu, Theresa Azonima Irinyenikan, Swati Singh, Amaitari Bariweni, Hadiza Galadanci, Peter Achara, Osagie Osayande, Mohammed Gana, Kiran Jabeen, Ayesha Mobeen, Sadaf Mufti, Maliha Zafar, Basharat Ahmad, Maimoona Munawar, Jeharat Gul, Naseema Usman, Fehmida Shaheen, Mariam Tariq, Nadia Sadiq, Rabia Batool, Habiba Sharaf Ali, Manahil Jaffer, Asma Baloch, Noonari Mukhtiar, Tasneem Ashraf, Raheela Asmat, Salma Khudaidad, Ghazala Taj, Roshan Qazi, Saira Dars, Faryal Sardar, Sanobar Ashfaq, Saeeda Majeed, Sadaqat Jabeen, Rukhsana Karim, Farzana Burki, Syeda Rabia Bukhari, Fouzia Gul, Musarrat Jabeen, Akhtar Sherin, Qurratul Ain, Shahid Rao, Uzma Shaheen, Samina Manzoor, Shabween Masood, Shabana Rizvi, Anita Ali, Abida Sajid, Aisha Iftikhar, Shazia Batool, Lubna Dar, Shahenzad Sohail, Shazia Rasul, Shamsa Humayun, Rashida Sultana, Sofia Manzoor, Syeda Mazhar, Afshan Batool, Asia Nazir, Nasira Tasnim, Hajira Masood, Razia Khero, Neelam Surhio, Samana Aleem, Naila Israr, Saba Javed, Lubna Bashir, Samina Iqbal, Faiza Aleem, Rubina Sohail, Saima Iqbal, Samina Dojki, Alia Bano, Naseem Saba, Maimoona Hafeez, Nishat Akram, Riffat Shaheen, Haleema Hashmi, Sharmeen Arshad, Rubina Hussain, Sadia Khan, Nighat Shaheen, Safia Khalil, Pushpa Sachdev, Gulfareen Arain, Amtullah Zarreen, Sara Saeed, Shamayela Hanif, Nabia Tariq, Mahwish Jamil, Shama Chaudhry, Hina Rajani, Tayyiba Wasim, Summera Aslam, Nilofar Mustafa, Huma Quddusi, Sajila Karim, Shazia Sultana, Misbah Harim, Mohd Chohan, Nabila Salman, Fareesa Waqar, Shamsunnisa Sadia, Lubna Kahloon, Shehla Manzoor, Samar Amin, Umbreen Akram, Ambreen Ikram, Samina Kausar, Tahira Batool, Brigadier Naila, Tahir Kyani, Christine Biryabarema, Ruth Bulime, Regina Akello, Bernadette Nakawooya Lwasa, Joselyn Ayikoru, Christine Namulwasira, Patrick Komagum, Isabirye Rebecca, Nayiga Annet, Nakirigya Nuulu, Elizabeth Nionzima, Rose Bwotya, Margret Nankya, Sarah Babirye, Joseph Ngonzi, Cesar Sanchez, Nkonwa Innocent, Kusasira Anitah, Ayiko Jackson, Elizabeth Ndagire, Christine Nanyongo, Dominic Drametu, Grace Meregurwa, Francis Banya, Rita Atim, Emmanuel Byaruhanga, Lema Felix, Hussein Iman, Vincent Oyiengo, Peninah Waigi, Rose Wangui, Faiza Nassir, Musimbi Soita, Rophina Msengeti, Zeinab Zubier, Hillary Mabeya, Antony Wanjala, Henry Mwangi, Brian Liyayi, Evelyn Muthoka, Alfred Osoti, Amos Otara, Veronicah Ongwae, Victor Wanjohi, Bonface Musila, Kubasu Wekesa, Alex Nyakundi Bosire, Alice Ntem, Angeline Njoache, Alice Ashu, André Simo, Dorothy Keka, Kenfack Bruno, Amadou Ndouoya, Martin Saadio, Mesack Tchana, Odel Gwan, Pauline Assomo, Venantius Mutsu, Nji Eric, Pascal Foumane, Philemon Nsem, Jeanne Fouedjio, Ymele Fouelifack, Pierre Marie Tebeu, Georges Nko'ayissi, Eta Ngole Mbong, Wisal Nabag, Riham Desougi, Hadia Mustafa, Huida Eltaib, Taha Umbeli, Khalid Elfadl, Murwan Ibrahim, Abdalla Mohammed, Awadia Ali, Somia Abdelrahiem, Mohammed Musa, Khidir Awadalla, Samirra Ahmed, Mahdi Bushra, Omer Babiker, Hala Abdullahi, Mohamed Ahmed, Elhassan Safa, Huida Almardi, Duria Rayis, Saeed Abdelrahman Abdelgabar, Gillian Houghton, Andrew Sharpe, Jim Thornton, Nick Grace, Carys Smith, Kim Hinshaw, Dawn Edmundson, Paul Ayuk, Alison Bates, George Bugg, Joanne Wilkins, Clare Tower, Alysha Allibone, Eugene Oteng-Ntim, Ahmad Kazumari, Anna Danford, Matilda Ngarina, Muzdalifat Abeid, Khadija Mayumba, Magreth Zacharia, George Mtove, Leonard Madame, Anthony Massinde, Berno Mwambe, Rwakyendela Onesmo, Sebastian Kitengile Ganyaka, Shyam Gupta, Rabindra Bhatt, Ajay Agrawal, Pramila Pradhan, Nikita Dhakal, Punita Yadav, Gyanendra Karki, Bhola Ram Shrestha, Mwansa Lubeya, Jane Mumba, Willies Silwimba, Isaiah Hansingo, Noojiri Bopili, Ziche Makukula, Alexander Kawimbe, Mwansa Ketty Lubeya, Willard Mtambo, Mathew Ng'ambi, Saimir Cenameri, Ilir Tasha, Aferdita Kruja, Besnik Brahimaj, Armida Tola, Leon Kaza, Desire Tshombe, Elizabeth Buligho, Roger Paluku-Hamuli, Charles Kacha, Kato Faida, Badibanga Musau, Herman Kalyana, Phanny Simisi, Serge Mulyumba, Nzanzu Kikuhe Jason, Jean Robert Lubamba, Willis Missumba, Ferdousi Islam, Nazneen Begum, Ferdousi Chowdhury, Rokeya Begum, Farjana Basher, Nazlima Nargis, Abu Kholdun, Shahela Jesmin, Shrodha Paul, Hailemariam Segni, Getachew Ayana, William Haleke, Hassen Hussien, Fikre Geremew, Moussa Bambara, Adolphe Somé, Amadou Ly, Roamba Pabakba, Horace Fletcher, Leslie Samuels, Henry Opare-Addo, Roderick Larsen-Reindorf, Kwadwo Nyarko-Jectey, Glen Mola, Malts Wai, Magdy El Rahman, Wafaa Basta, Hussein Khamis, Maria Fernanda Escobar, Liliana Vallecilla, and Gabriel Essetchi Faye

Subjects
medicine.medical_specialty, Hysterectomy, business.industry, medicine.medical_treatment, Placebo-controlled study, General Medicine, 030204 cardiovascular system & hematology, Placebo, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Relative risk, Anesthesia, Clinical endpoint, medicine, Caesarean section, Maternal death, 030212 general & internal medicine, business, Tranexamic acid, medicine.drug
Abstract

Background\ud Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage.\ud \ud Methods\ud In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283.\ud \ud Findings\ud Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group.\ud \ud Interpretation\ud Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset.\ud \ud Funding\ud London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.

Published
2017
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6. 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

Author

Angèle Gayet-Ageron, David Prieto-Merino, Katharine Ker, Haleema Shakur, François-Xavier Ageron, Ian Roberts, Aasia Kayani, Amber Geer, Bernard Ndungu, Bukola Fawole, Catherine Gilliam, Cecelia Adetayo, Collette Barrow, Danielle Beaumont, Danielle Prowse, David I'Anson, Eni Balogun, Hakim Miah, Imogen Brooks, Julio Onandia, Kiran Javaid, Laura Suncuan, Lauren Frimley, Mia Reid, Monica Arribas, Myriam Benyahia, Olujide Okunade, Phil Edwards, Rizwana Chaudhri, Sergey Kostrov, Sneha Kansagra, and Tracey Pepple

Subjects
Adult, Male, medicine.medical_specialty, MEDLINE, Hemorrhage, 030204 cardiovascular system & hematology, Time-to-Treatment, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pregnancy, Internal medicine, Childbirth, Medicine, Humans, 030212 general & internal medicine, Young adult, Aged, ddc:618, business.industry, Postpartum Hemorrhage, General Medicine, Odds ratio, Middle Aged, medicine.disease, Antifibrinolytic Agents, 3. Good health, Surgery, Clinical trial, Logistic Models, Meta-analysis, Acute Disease, Wounds and Injuries, Female, business, Tranexamic acid, medicine.drug
Abstract

BACKGROUND: Antifibrinolytics reduce death from bleeding in trauma and post-partum haemorrhage. We examined the effect of treatment delay on the effectiveness of antifibrinolytics. METHODS: We did an individual patient-level data meta-analysis of randomised trials done with more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials done between Jan 1, 1946, and April 7, 2017, from MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, PubMed, Popline, and the WHO International Clinical Trials Registry Platform. The primary measure of treatment benefit was absence of death from bleeding. We examined the effect of treatment delay on treatment effectiveness using logistic regression models. We investigated the effect of measurement error (misclassification) in sensitivity analyses. This study is registered with PROSPERO, number 42016052155. FINDINGS: We obtained data for 40 138 patients from two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Overall, there were 3558 deaths, of which 1408 (40%) were from bleeding. Most (884 [63%] of 1408) bleeding deaths occurred within 12 h of onset. Deaths from post-partum haemorrhage peaked 2-3 h after childbirth. Tranexamic acid significantly increased overall survival from bleeding (odds ratio [OR] 1·20, 95% CI 1·08-1·33; p=0·001), with no heterogeneity by site of bleeding (interaction p=0·7243). Treatment delay reduced the treatment benefit (p

Published
2017

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