Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Patrick R. Lawler; Ewan C. Golighe; Jeffrey S. Berge; Matthew D. Neal; Bryan J. McVerry; Jose C. Nicolau; Michelle N. Gong; Marc Carrier; Robert S. Rosenson; Harmony R. Reynolds; Alexis F. Turgeon; Jorge Escobedo; David T. Huang; Charlotte A. Bradbury; Brett L. Houston; Lucy Z. Kornblith; Anand Kumar; Susan R. n Kah; Mary Cushman; Zoe McQuilten; Arthur S. Slutsky; Keri S. Kim; Anthony C. Gordon; Bridget-Anne Kirwan; Maria M. Brooks; Alisa M. Higgins; Roger J. Lewis; Elizabeth Lorenzi; Scott M. Berry; Lindsay R. Berry; Derek C. Angus; Colin J. McArthur; Steven A. Webb; Michael E. Farkouh; Judith S. Hochman; Ryan Zarychanski; Aaron W. Aday; Farah Al-Beidh; Djillali Annane; Yaseen M. Arabi; Diptesh Aryal; Lisa Baumann Kreuziger; Abi Beane; Zahra Bhimani; Shailesh Bihari; Henny H. Billett; Lindsay Bond; Marc Bonten; Frank Brunkhorst; Meredith Buxton; Adrian Buzgau; Lana A. Castellucci; Sweta Chekuri; Jen-Ting Chen; Allen C. Cheng; Tamta Chkhikvadzw; Benjamin Coiffard; Todd W. Costantini; Sophie de Brouwer; Lennie P. G. Derde; Michelle A. Detry; Abhijit Duggal; Vladimir Dzavik; Mark B. Effron; Lise J. Estcourt; Brendan M. Everett; Dean A. Fergusson; Mark Fitzgerald; Robert A. Fowler; Jean P. Galanaud; Benjamin T. Galen; Sheetal Gandotra; Sebastian Garcia-Madrona; Timothy D. Girard; Lucas C. Godoy; Andrew L. Goodman; Herman Goossens; Cameron Green; Yonatan Y. Greenstein; Peter L. Gross; Naomi M. Hamburg; Rashan Haniffa; George Hanna; Nicholas Hanna; Sheila M. Hegde; Carolyn M. Hendrickson; R. Duncan Hite; Alexander A. Hindenburg; Aluko A. Hope; James M. Horowitz; Christopher M. Horvat; Kristin Hudock; Beverley J. Hunt; Mansoor Husain; Robert C. Hyzy; Vivek N. Iyer; Jeffrey R. Jacobson; Devachandran Jayakumar; Norma M. Keller; Akram Khan; Yuri Kim; Andrei L. Kindzelski; Andrew J. Kin; M. Margaret Knudson; Aaron E. Kornblith; Vidya Krishnan; Matthew E. Kutcher; Michael A. Laffan; Francois Lamontagne; Gregoire Le Gal; Christine M. Leeper; Eric S. Leifer; George Lim; Felipe Gallego Lima; Kelsey Linstrum; Edward Litton; Jose Lopez-Sendon; Jose L. Lopez-Sendon Moreno; Sylvain A. Lother; Saurabh Malhotra; Miguel Marcos; Andrea Saud Marinez; John C. Marshall; Nicole Marten; Michael A. Matthay; Daniel F. McAuley; Emily G. McDonald; Anna McGlothlin; Shay P. McGuinness; Saskia Middeldorp; Stephanie K. Montgomery; Steven C. Moore; Raquel Morillo Guerreor; Paul R. Mouncey; Srinivas Murthy; Girish B. Nair; Rahul Nair; Alistair D. Nichol; Brenda Nunez-Garcia; Ambarish Pandey; Pauline K. Park; Rachael L. Parke; Jane C. Parker; Sam Parnia; Jonathan D. Paul; Yessica S. Perez Gonzalez; Mauricio Pompilio; Matthew E. Prekker; John G. Quigley; Natalia S. Rost; Kathryn Rowan; Fernanda O. Santos; Marlene Santos; Mayler Olombrada Santos; Lewis Satterwhite; Christina T. Saunders; Roger E. G. Schutgens; Christopher W. Seymour; Deborah M. Siegal; Delcio G. Silva; Manu Shankar-Hari; John P. Sheehan; Aneesh B. Singhal; Dayna Solvaso; Simon J. Stanworth; Tobias Tritschler; Anne M. Turner; Wilma Van Bentum-Puijk; Frank L. van de Veerdonk; Sean van Diepen; Gloria Vazquez-Grande; Lana Wahid; Vanessa Wareham; Bryan J. Wells; R. Jay Widmer; Jennifer G. Wilson; Eugene Yuriditsky; Fernando G. Zampieri; ACTIV-4a Investigators

doi:10.1056/NEJMoa2105911

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Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Journal article

Peer reviewed

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Patrick R. Lawler, Ewan C. Golighe, Jeffrey S. Berge, Matthew D. Neal, Bryan J. McVerry, Jose C. Nicolau, Michelle N. Gong, Marc Carrier, Robert S. Rosenson, Harmony R. Reynolds, …

The New England journal of medicine, Vol.385(9), pp.790-802

26/08/2021

DOI: https://doi.org/10.1056/NEJMoa2105911

PMID: 34351721

Abstract

General & Internal Medicine

Life Sciences & Biomedicine

Medicine, General & Internal

Science & Technology

BACKGROUND Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline D-dimer level. RESULTS The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high D-dimer cohort, 92.9% in the low D-dimer cohort, and 97.3% in the unknown D-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.

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Title: Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19
Creators - without role: Patrick R. Lawler - University Health Network
Ewan C. Golighe - University of Toronto
Jeffrey S. Berge - Supreme Council Of Health
Matthew D. Neal - University Health Network
Bryan J. McVerry - University Health Network
Jose C. Nicolau - University Health Network
Michelle N. Gong - University Health Network
Marc Carrier - University Health Network
Robert S. Rosenson - University Health Network
Harmony R. Reynolds - University Health Network
Alexis F. Turgeon - University Health Network
Jorge Escobedo - University Health Network
David T. Huang - University Health Network
Charlotte A. Bradbury - University Health Network
Brett L. Houston - University Health Network
Lucy Z. Kornblith - University Health Network
Anand Kumar - University of Manitoba
Susan R. n Kah - McGill University
Mary Cushman - University Health Network
Zoe McQuilten - University Health Network
Arthur S. Slutsky - St. Michael's Hospital
Keri S. Kim - University Health Network
Anthony C. Gordon - University Health Network
Bridget-Anne Kirwan - University Health Network
Maria M. Brooks - University Health Network
Alisa M. Higgins - University Health Network
Roger J. Lewis - University Health Network
Elizabeth Lorenzi - University Health Network
Scott M. Berry - University Health Network
Lindsay R. Berry - University Health Network
Derek C. Angus - University of Pittsburgh
Colin J. McArthur - Monash University
Steven A. Webb - Monash University
Michael E. Farkouh - Univ Hlth Network, Peter Munk Cardiac Ctr, Toronto, ON, Canada
Judith S. Hochman - Supreme Council Of Health
Ryan Zarychanski - University of Manitoba
Aaron W. Aday - University Health Network
Farah Al-Beidh - University Health Network
Djillali Annane - University Health Network
Yaseen M. Arabi - University Health Network
Diptesh Aryal - University Health Network
Lisa Baumann Kreuziger - University Health Network
Abi Beane - University Health Network
Zahra Bhimani - St. Michael's Hospital
Shailesh Bihari - University Health Network
Henny H. Billett - University Health Network
Lindsay Bond - University Health Network
Marc Bonten - Utrecht University
Frank Brunkhorst - University Health Network
Meredith Buxton - University Health Network
Adrian Buzgau - University Health Network
Lana A. Castellucci - University Health Network
Sweta Chekuri - University Health Network
Jen-Ting Chen - University Health Network
Allen C. Cheng - University Health Network
Tamta Chkhikvadzw - Supreme Council Of Health
Benjamin Coiffard - University Health Network
Todd W. Costantini - University Health Network
Sophie de Brouwer - University Health Network
Lennie P. G. Derde - University Health Network
Michelle A. Detry - University Health Network
Abhijit Duggal - University Health Network
Vladimir Dzavik - University Health Network
Mark B. Effron - University Health Network
Lise J. Estcourt - University Health Network
Brendan M. Everett - University Health Network
Dean A. Fergusson - University Health Network
Mark Fitzgerald - University Health Network
Robert A. Fowler - University Health Network
Jean P. Galanaud - University Health Network
Benjamin T. Galen - University Health Network
Sheetal Gandotra - University Health Network
Sebastian Garcia-Madrona - University Health Network
Timothy D. Girard - University Health Network
Lucas C. Godoy - University Health Network
Andrew L. Goodman - University Health Network
Herman Goossens - University Health Network
Cameron Green - University Health Network
Yonatan Y. Greenstein - University Health Network
Peter L. Gross - University Health Network
Naomi M. Hamburg - University Health Network
Rashan Haniffa - University Health Network
George Hanna - University Health Network
Nicholas Hanna - University Health Network
Sheila M. Hegde - University Health Network
Carolyn M. Hendrickson - University Health Network
R. Duncan Hite - University Health Network
Alexander A. Hindenburg - University Health Network
Aluko A. Hope - University Health Network
James M. Horowitz - University Health Network
Christopher M. Horvat - University Health Network
Kristin Hudock - University Health Network
Beverley J. Hunt - University Health Network
Mansoor Husain - University Health Network
Robert C. Hyzy - University Health Network
Vivek N. Iyer - University Health Network
Jeffrey R. Jacobson - University Health Network
Devachandran Jayakumar - University Health Network
Norma M. Keller - University Health Network
Akram Khan - University Health Network
Yuri Kim - University Health Network
Andrei L. Kindzelski - University Health Network
Andrew J. Kin - University of Pittsburgh
M. Margaret Knudson - University Health Network
Aaron E. Kornblith - University Health Network
Vidya Krishnan - University Health Network
Matthew E. Kutcher - University of Mississippi
Michael A. Laffan - Imperial Coll London, London, England
Francois Lamontagne - Univ Sherbrooke, Sherbrooke, PQ, Canada
Gregoire Le Gal - Ottawa Hosp Res Inst, Ottawa, ON, Canada
Christine M. Leeper - University of Pittsburgh
Eric S. Leifer - University of Portland
George Lim - Univ Calif Los Angeles, Los Angeles, CA USA
Felipe Gallego Lima - MED Institute
Kelsey Linstrum - University of Pittsburgh
Edward Litton - St John God Subiaco Hosp, Perth, WA, Australia
Jose Lopez-Sendon - Univ Autonoma, IdiPaz Res Inst, Madrid, Spain
Jose L. Lopez-Sendon Moreno - Hosp Ramon & Cajal, Madrid, Spain
Sylvain A. Lother - University of Manitoba
Saurabh Malhotra - Cook Cty Hlth, Chicago, IL USA
Miguel Marcos - Universidad de Salamanca
Andrea Saud Marinez - Avanti
John C. Marshall - St Michaels Hosp Unity Hlth, Toronto, ON, Canada
Nicole Marten - St Boniface Gen Hosp, Winnipeg, MB, Canada
Michael A. Matthay - Univ Calif San Francisco, Zuckerberg San Francisco Gen Hosp, San Francisco, CA 94143 USA
Daniel F. McAuley - Queens University
Emily G. McDonald - McGill University
Anna McGlothlin - Berry
Shay P. McGuinness - Monash University
Saskia Middeldorp - Radboud University Nijmegen
Stephanie K. Montgomery - University of Pittsburgh
Steven C. Moore - Pennsylvania State University
Raquel Morillo Guerreor - Hosp Ramon & Cajal, Madrid, Spain
Paul R. Mouncey - Intens
Srinivas Murthy - University of British Columbia
Girish B. Nair - Beaumont Hlth, Royal Oak, MI USA
Rahul Nair - The Bronx Defenders
Alistair D. Nichol - Monash University
Brenda Nunez-Garcia - Univ Calif San Francisco, Zuckerberg San Francisco Gen Hosp, San Francisco, CA 94143 USA
Ambarish Pandey - College Station Medical Center
Pauline K. Park - University of Michigan–Ann Arbor
Rachael L. Parke - Auckland City Hosp, Auckland, New Zealand
Jane C. Parker - Monash University
Sam Parnia - Supreme Council Of Health
Jonathan D. Paul - University of Chicago
Yessica S. Perez Gonzalez - Inst Mexicano Seguro Social, Mexico City, DF, Mexico
Mauricio Pompilio - Hosp Cora Mato Grosso do Sul, Campo Grande, MS, Brazil
Matthew E. Prekker - College Station Medical Center
John G. Quigley - University of Illinois Urbana-Champaign
Natalia S. Rost - Supreme Council Of Health
Kathryn Rowan - University of British Columbia
Fernanda O. Santos - Hosp Julho, Sao Paulo, Brazil
Marlene Santos - St Michaels Hosp Unity Hlth, Toronto, ON, Canada
Mayler Olombrada Santos - Clin Res Ctr, INGOH, Goiania, Go, Brazil
Lewis Satterwhite - Berry Consultants, Austin, TX USA
Christina T. Saunders - College Station Medical Center
Roger E. G. Schutgens - Utrecht University
Christopher W. Seymour - University of Pittsburgh
Deborah M. Siegal - Ottawa Hosp Res Inst, Ottawa, ON, Canada
Delcio G. Silva - Hosp Univ Maria Aparecida Pedrossia, Campo Grande, MS, Brazil
Manu Shankar-Hari - Guys & St Thomas NHS Fdn Trust, London, England
John P. Sheehan - Supreme Council Of Health
Aneesh B. Singhal - Supreme Council Of Health
Dayna Solvaso - University of Manitoba
Simon J. Stanworth - University of Oxford
Tobias Tritschler - University of Bern
Anne M. Turner - College Station Medical Center
Wilma Van Bentum-Puijk - Utrecht University
Frank L. van de Veerdonk - Radboud University Nijmegen
Sean van Diepen - University of Alberta
Gloria Vazquez-Grande - University of Manitoba
Lana Wahid - Duke University
Vanessa Wareham - Ozmosis Research
Bryan J. Wells - Emory University
R. Jay Widmer - Baylor Medical Center at Garland
Jennifer G. Wilson - Stanford University
Eugene Yuriditsky - NYU Langone Hosp, New York, NY USA
Fernando G. Zampieri - Hosp Coracao, Sao Paulo, Brazil
ACTIV-4a Investigators
Publication Details: The New England journal of medicine, Vol.385(9), pp.790-802
Publisher: Massachusetts Medical Soc
Number of pages: 13
Grant note: Victoria General Hospital Foundation APP1101719; APP1116530 / Australian National Health and Medical Research Council; National Health and Medical Research Council (NHMRC) of Australia CTN 2014-012 / Health Research Board of Ireland; Health Research Board - Ireland AR7-162822 / Canadian Institutes of Health Research; Canadian Institutes of Health Research (CIHR) OTA-20-011; 1OT2HL156812-01; UL1TR001445 / National Heart, Lung, and Blood Institute, National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) CancerCare Manitoba Foundation 602525 / European Union through FP7HEALTH-2013-INNOVATION: the Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) consortium Lyonel G. Israels Research Chair in Hematology (University of Manitoba) Amgen National Center for Advancing Translational Sciences of the NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) U.K. National Institute for Health Research (NIHR); National Institute for Health Research (NIHR) Minderoo Foundation RP-2015-06-18 / NIHR Research Professorship New York University Clinical and Translational Science Award program 215522 / Wellcome Trust NIHR Imperial Biomedical Research Centre 158584; 447335 / Canadian Institutes of Health Research (Strategy for Patient-Oriented Research Innovative Clinical Trials Program); Canadian Institutes of Health Research (CIHR) CS-2016-16-011 / NIHR Clinician Scientist Fellowship PHRC-20-0147 / French Ministry of Health Breast Cancer Research Foundation 101003589 / Horizon 2020 research and innovation program: the Rapid European Covid-19 Emergency Research response (RECOVER) consortium LifeArc Foundation, Thistledown Foundation, Research Manitoba Ontario Ministry of Health, Peter Munk Cardiac Centre Global Coalition for Adaptive Research 16/631 / Health Research Council of New Zealand
Identifiers: 9921377008331
Academic Unit: King Abdulaziz University; King Saud Bin Abdulaziz University for Health Sciences
Language: English
Resource Type: Journal article