John B Holcomb1, Ernest E Moore2, Jason L Sperry3, Jan O Jansen4, Martin A Schreiber5, Deborah J Del Junco6, Philip C Spinella7, Angela Sauaia8, Karim Brohi9, Eileen M Bulger10, Andrew P Cap11, John R Hess12, Donald Jenkins13, Roger J Lewis14, Matthew D Neal3, Craig Newgard15, Shibani Pati16, Anthony E Pusateri17, Sandro Rizoli18, Robert T Russell19, Stacy A Shackelford20, Deborah M Stein21, Marie E Steiner22, Henry Wang23, Kevin R Ward24, Pampee Young25. 1. Center for Injury Science, Division of Acute Care Surgery, University of Alabama at Birmingham, Birmingham, AL. 2. Ernest E. Moore Shock Trauma Center at Denver Health, Distinguished Professor, Ernest E Moore Shock Trauma Center at Denver Health, University of Colorado Denver, Denver, CO. 3. Pittsburgh Trauma Research Center and the Department of Surgery, University of Pittsburgh, Pittsburgh, PA. 4. Division of Acute Care Surgery, Center for Injury Science, University of Alabama at Birmingham, Birmingham, AL. 5. Oregon Health & Science University, Portland, OR. 6. Joint Trauma System, DoD Center of Excellence for Trauma, San Antonio, TX. 7. Division of Critical Care, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO. 8. Department of Public Health and Surgery, University of Colorado Denver, School of Public health, University of Colorado, Denver, CO. 9. Centre for Trauma Sciences, Queen Mary University of London, London, UK. 10. Department of Surgery, University of Washington, Seattle WA. 11. US Army Institute of Surgical Research, Uniformed Services University, Ft Sam Houston, TX. 12. Department of Laboratory Medicine and Hematology, University of Washington School of Medicine, Seattle, WA. 13. Department of Surgery, Division of Trauma and Emergency Surgery, UT Health, San Antonio, TX. 14. Berry Consultants LLC, Austin, TX; Department of Emergency Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA. 15. Center for Policy and Research in Emergency Medicine, Oregon Health & Science University, Portland, OR. 16. Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA. 17. US Army Institute of Surgical Research, JBSA-Fort Sam Houston, San Antonio, TX. 18. Department of Surgery, Hamad General Hospital, Doha, Qatar. 19. Children's Hospital of Alabama, University of Alabama at Birmingham, Birmingham, AL. 20. Joint Trauma System, Defense Health Agency, San Antonio, TX. 21. Zuckerberg San Francisco General Hospital and Trauma Center, UCSF, San Francisco, CA. 22. Department of Pediatrics, Division of Pediatric Hematology and Oncology, Division of Pediatric Critical Care Medicine, University of Minnesota Medical School, Minneapolis, MN. 23. Department of Emergency Medicine, University of Texas Health Science Center at Houston, Houston TX. 24. Emergency Medicine and Biomedical Engineering, Executive Director, Michigan Center for Integrative Research in Critical Care, University of Michigan, Ann Arbor, MI. 25. American Red Cross, Biomedical Division, Washington, D.C., Vanderbilt University Medical Center, Nashville, TN.
Abstract
OBJECTIVE: To address the clinical and regulatory challenges of optimal primary endpoints for bleeding patients by developing consensus-based recommendations for primary clinical outcomes for pivotal trials in patients within 6 categories of significant bleeding, (1) traumatic injury, (2) intracranial hemorrhage, (3) cardiac surgery, (4) gastrointestinal hemorrhage, (5) inherited bleeding disorders, and (6) hypoproliferative thrombocytopenia. BACKGROUND: A standardized primary outcome in clinical trials evaluating hemostatic products and strategies for the treatment of clinically significant bleeding will facilitate the conduct, interpretation, and translation into clinical practice of hemostasis research and support alignment among funders, investigators, clinicians, and regulators. METHODS: An international panel of experts was convened by the National Heart Lung and Blood Institute and the United States Department of Defense on September 23 and 24, 2019. For patients suffering hemorrhagic shock, the 26 trauma working-group members met for almost a year, utilizing biweekly phone conferences and then an in-person meeting, evaluating the strengths and weaknesses of previous high quality studies. The selection of the recommended primary outcome was guided by goals of patient-centeredness, expected or demonstrated sensitivity to beneficial treatment effects, biologic plausibility, clinical and logistical feasibility, and broad applicability. CONCLUSIONS: For patients suffering hemorrhagic shock, and especially from truncal hemorrhage, the recommended primary outcome was 3 to 6-hour all-cause mortality, chosen to coincide with the physiology of hemorrhagic death and to avoid bias from competing risks. Particular attention was recommended to injury and treatment time, as well as robust assessments of multiple safety related outcomes.
OBJECTIVE: To address the clinical and regulatory challenges of optimal primary endpoints for bleedingpatients by developing consensus-based recommendations for primary clinical outcomes for pivotal trials in patients within 6 categories of significant bleeding, (1) traumatic injury, (2) intracranial hemorrhage, (3) cardiac surgery, (4) gastrointestinal hemorrhage, (5) inherited bleeding disorders, and (6) hypoproliferative thrombocytopenia. BACKGROUND: A standardized primary outcome in clinical trials evaluating hemostatic products and strategies for the treatment of clinically significant bleeding will facilitate the conduct, interpretation, and translation into clinical practice of hemostasis research and support alignment among funders, investigators, clinicians, and regulators. METHODS: An international panel of experts was convened by the National Heart Lung and Blood Institute and the United States Department of Defense on September 23 and 24, 2019. For patients suffering hemorrhagic shock, the 26 trauma working-group members met for almost a year, utilizing biweekly phone conferences and then an in-person meeting, evaluating the strengths and weaknesses of previous high quality studies. The selection of the recommended primary outcome was guided by goals of patient-centeredness, expected or demonstrated sensitivity to beneficial treatment effects, biologic plausibility, clinical and logistical feasibility, and broad applicability. CONCLUSIONS: For patients suffering hemorrhagic shock, and especially from truncal hemorrhage, the recommended primary outcome was 3 to 6-hour all-cause mortality, chosen to coincide with the physiology of hemorrhagic death and to avoid bias from competing risks. Particular attention was recommended to injury and treatment time, as well as robust assessments of multiple safety related outcomes.
Authors: Marco Tartaglione; Luca Carenzo; Lorenzo Gamberini; Cristian Lupi; Aimone Giugni; Carlo Alberto Mazzoli; Valentina Chiarini; Silvia Cavagna; Davide Allegri; John B Holcomb; David Lockey; Giovanni Sbrana; Giovanni Gordini; Carlo Coniglio Journal: BMJ Open Date: 2022-05-30 Impact factor: 3.006
Authors: Philip C Spinella; Nahed El Kassar; Andrew P Cap; Andrei L Kindzelski; Christopher S Almond; Alan Barkun; Terry B Gernsheimer; Joshua N Goldstein; John B Holcomb; Alfonso Iorio; Dennis M Jensen; Nigel S Key; Jerrold H Levy; Stephan A Mayer; Ernest E Moore; Simon J Stanworth; Roger J Lewis; Marie E Steiner Journal: J Trauma Acute Care Surg Date: 2021-08-01 Impact factor: 3.697
Authors: Ernest E Moore; Hunter B Moore; Lucy Z Kornblith; Matthew D Neal; Maureane Hoffman; Nicola J Mutch; Herbert Schöchl; Beverley J Hunt; Angela Sauaia Journal: Nat Rev Dis Primers Date: 2021-04-29 Impact factor: 65.038
Authors: Krithika Suresh; Julia M Dixon; Chandni Patel; Brenda Beaty; Deborah J Del Junco; Shaheem de Vries; Hendrick J Lategan; Elmin Steyn; Janette Verster; Steven G Schauer; Tyson E Becker; Cord Cunningham; Sean Keenan; Ernest E Moore; Lee A Wallis; Navneet Baidwan; Bailey K Fosdick; Adit A Ginde; Vikhyat S Bebarta; Nee-Kofi Mould-Millman Journal: Scand J Trauma Resusc Emerg Med Date: 2022-10-17 Impact factor: 3.803