Brett L Houston1, Patrick R Lawler2,3,4, Ewan C Goligher3,4,5, Michael E Farkouh2, Charlotte Bradbury6, Marc Carrier7, Vlad Dzavik2, Dean A Fergusson7, Robert A Fowler8, Jean-Phillippe Galanaud8, Peter L Gross9, Emily G McDonald10, Mansoor Husain2, Susan R Kahn11, Anand Kumar1, John Marshall12, Srinivas Murthy13, Arthur S Slutsky14, Alexis F Turgeon15,16, Scott M Berry17, Robert S Rosenson18, Jorge Escobedo19, Jose C Nicolau20, Lindsay Bond21, Bridget-Anne Kirwan22,23, Sophie de Brouwer22, Ryan Zarychanski1,24. 1. Max Rady Faculty of Health Sciences, Max Rady College of Medicine, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada. 2. Peter Munk Cardiac Centre, University Health Network and University of Toronto, Toronto, ON, Canada. 3. Toronto General Hospital Research Institute, Toronto, ON, Canada. 4. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada. 5. Department of Medicine, Division of Respirology, University Health Network, Toronto, ON, Canada. 6. Faculty of Health Sciences, University of Bristol, Bristol, UK. 7. Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. 8. Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada. 9. Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University & Hamilton Health Sciences, Hamilton, ON, Canada. 10. Clinical Practice Assessment Unit, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada. 11. Center for Clinical Epidemiology, Jewish General Hospital/Lady Davis Institute, Division of Internal Medicine, Department of Medicine, McGill University, Montreal, QC, Canada. 12. Department of Surgery, St Michael's Hospital and the University of Toronto, Toronto, ON, Canada. 13. The University of British Columbia, Vancouver, BC, Canada. 14. Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital and Departments of Medicine, Surgery, and Biomedical Engineering, University of Toronto, Toronto, ON, Canada. 15. Department of Anesthesiology and Critical Care Medicine, Division of Critical Care Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada. 16. CHU de Québec - Université Laval Research Centre, Population Health and Optimal Health Practices Research Unit, Trauma-Emergency-Critical Care Medicine, Université Laval, Québec, QC, Canada. 17. Berry Consultants, LLC, Austin, TX, USA. 18. The Zena and Michael A. Wiener Cardiovascular Institute, Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 19. Medical Research Unit on Clinical Epidemiology, Mexican Social Security Institute, Mexico City, Mexico. 20. Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil. 21. Ozmosis Research Inc., Toronto, ON, Canada. 22. Department of Clinical Research, SOCAR Research SA, Nyon, Switzerland. 23. Faculty of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, London, England. 24. Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada.
Abstract
BACKGROUND:Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. METHODS: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. CONCLUSION: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.
RCT Entities:
BACKGROUND:Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. METHODS: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. CONCLUSION: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.
Authors: Ronald Lg Flumignan; Vinicius T Civile; Jéssica Dantas de Sá Tinôco; Patricia If Pascoal; Libnah L Areias; Charbel F Matar; Britta Tendal; Virginia Fm Trevisani; Álvaro N Atallah; Luis Cu Nakano Journal: Cochrane Database Syst Rev Date: 2022-03-04
Authors: Azita H Talasaz; Parham Sadeghipour; Hessam Kakavand; Maryam Aghakouchakzadeh; Elaheh Kordzadeh-Kermani; Benjamin W Van Tassell; Azin Gheymati; Hamid Ariannejad; Seyed Hossein Hosseini; Sepehr Jamalkhani; Michelle Sholzberg; Manuel Monreal; David Jimenez; Gregory Piazza; Sahil A Parikh; Ajay J Kirtane; John W Eikelboom; Jean M Connors; Beverley J Hunt; Stavros V Konstantinides; Mary Cushman; Jeffrey I Weitz; Gregg W Stone; Harlan M Krumholz; Gregory Y H Lip; Samuel Z Goldhaber; Behnood Bikdeli Journal: J Am Coll Cardiol Date: 2021-03-11 Impact factor: 24.094
Authors: Michelle Sholzberg; Bruno R da Costa; Grace H Tang; Hassan Rahhal; Musaad AlHamzah; Lisa Baumann Kreuziger; Fionnuala Ní Áinle; Mozah Obaid Almarshoodi; Paula D James; David Lillicrap; Marc Carrier; Andrew Beckett; Michael Fralick; Saskia Middeldorp; Agnes Y Y Lee; Kevin E Thorpe; Elnara Márcia Negri; Mary Cushman; Peter Jüni Journal: Res Pract Thromb Haemost Date: 2021-12-17
Authors: Michelle Sholzberg; Grace H Tang; Hassan Rahhal; Musaad AlHamzah; Lisa Baumann Kreuziger; Fionnuala Ní Áinle; Faris Alomran; Khalid Alayed; Mohammed Alsheef; Fahad AlSumait; Carlos Eduardo Pompilio; Catherine Sperlich; Sabrena Tangri; Terence Tang; Peter Jaksa; Deepa Suryanarayan; Mozah Almarshoodi; Lana A Castellucci; Paula D James; David Lillicrap; Marc Carrier; Andrew Beckett; Christos Colovos; Jai Jayakar; Marie-Pier Arsenault; Cynthia Wu; Karine Doyon; E Roseann Andreou; Vera Dounaevskaia; Eric K Tseng; Gloria Lim; Michael Fralick; Saskia Middeldorp; Agnes Y Y Lee; Fei Zuo; Bruno R da Costa; Kevin E Thorpe; Elnara Márcia Negri; Mary Cushman; Peter Jüni Journal: BMJ Date: 2021-10-14