N Engl J Med . Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

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N Engl J Med


. 2021 Aug 4.
doi: 10.1056/NEJMoa2103417. Online ahead of print.
Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19


REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators; Ewan C Goligher ¹ , Charlotte A Bradbury ¹ , Bryan J McVerry ¹ , Patrick R Lawler ¹ , Jeffrey S Berger ¹ , Michelle N Gong ¹ , Marc Carrier ¹ , Harmony R Reynolds ¹ , Anand Kumar ¹ , Alexis F Turgeon ¹ , Lucy Z Kornblith ¹ , Susan R Kahn ¹ , John C Marshall ¹ , Keri S Kim ¹ , Brett L Houston ¹ , Lennie P G Derde ¹ , Mary Cushman ¹ , Tobias Tritschler ¹ , Derek C Angus ¹ , Lucas C Godoy ¹ , Zoe McQuilten ¹ , Bridget-Anne Kirwan ¹ , Michael E Farkouh ¹ , Maria M Brooks ¹ , Roger J Lewis ¹ , Lindsay R Berry ¹ , Elizabeth Lorenzi ¹ , Anthony C Gordon ¹ , Scott M Berry ¹ , Colin J McArthur ¹ , Matthew D Neal ¹ , Judith S Hochman ¹ , Steven A Webb ¹ , Ryan Zarychanski ¹ , Tania Ahuja ¹ , Farah Al-Beidh ¹ , Djillali Annane ¹ , Yaseen M Arabi ¹ , Diptesh Aryal ¹ , Lisa Baumann Kreuziger ¹ , Abi Beane ¹ , Zahra Bhimani ¹ , Shailesh Bihari ¹ , Henny H Billett ¹ , Lindsay Bond ¹ , Marc Bonten ¹ , Frank Brunkhorst ¹ , Meredith Buxton ¹ , Adrian Buzgau ¹ , Lana A Castellucci ¹ , Sweta Chekuri ¹ , Jen-Ting Chen ¹ , Allen C Cheng ¹ , Tamta Chkhikvadze ¹ , Benjamin Coiffard ¹ , Aira Contreras ¹ , Todd W Costantini ¹ , Sophie de Brouwer ¹ , Michelle A Detry ¹ , Abhijit Duggal ¹ , Vladimír Džavík ¹ , Mark B Effron ¹ , Heather F Eng ¹ , Jorge Escobedo ¹ , Lise J Estcourt ¹ , Brendan M Everett ¹ , Dean A Fergusson ¹ , Mark Fitzgerald ¹ , Robert A Fowler ¹ , Joshua D Froess ¹ , Zhuxuan Fu ¹ , Jean P Galanaud ¹ , Benjamin T Galen ¹ , Sheetal Gandotra ¹ , Timothy D Girard ¹ , Andrew L Goodman ¹ , Herman Goossens ¹ , Cameron Green ¹ , Yonatan Y Greenstein ¹ , Peter L Gross ¹ , Rashan Haniffa ¹ , Sheila M Hegde ¹ , Carolyn M Hendrickson ¹ , Alisa M Higgins ¹ , Alexander A Hindenburg ¹ , Aluko A Hope ¹ , James M Horowitz ¹ , Christopher M Horvat ¹ , David T Huang ¹ , Kristin Hudock ¹ , Beverley J Hunt ¹ , Mansoor Husain ¹ , Robert C Hyzy ¹ , Jeffrey R Jacobson ¹ , Devachandran Jayakumar ¹ , Norma M Keller ¹ , Akram Khan ¹ , Yuri Kim ¹ , Andrei Kindzelski ¹ , Andrew J King ¹ , M Margaret Knudson ¹ , Aaron E Kornblith ¹ , Matthew E Kutcher ¹ , Michael A Laffan ¹ , Francois Lamontagne ¹ , Grégoire Le Gal ¹ , Christine M Leeper ¹ , Eric S Leifer ¹ , George Lim ¹ , Felipe Gallego Lima ¹ , Kelsey Linstrum ¹ , Edward Litton ¹ , Jose Lopez-Sendon ¹ , Sylvain A Lother ¹ , Nicole Marten ¹ , Andréa Saud Marinez ¹ , Mary Martinez ¹ , Eduardo Mateos Garcia ¹ , Stavroula Mavromichalis ¹ , Daniel F McAuley ¹ , Emily G McDonald ¹ , Anna McGlothlin ¹ , Shay P McGuinness ¹ , Saskia Middeldorp ¹ , Stephanie K Montgomery ¹ , Paul R Mouncey ¹ , Srinivas Murthy ¹ , Girish B Nair ¹ , Rahul Nair ¹ , Alistair D Nichol ¹ , Jose C Nicolau ¹ , Brenda Nunez-Garcia ¹ , John J Park ¹ , Pauline K Park ¹ , Rachael L Parke ¹ , Jane C Parker ¹ , Sam Parnia ¹ , Jonathan D Paul ¹ , Mauricio Pompilio ¹ , John G Quigley ¹ , Robert S Rosenson ¹ , Natalia S Rost ¹ , Kathryn Rowan ¹ , Fernanda O Santos ¹ , Marlene Santos ¹ , Mayler O Santos ¹ , Lewis Satterwhite ¹ , Christina T Saunders ¹ , Jake Schreiber ¹ , Roger E G Schutgens ¹ , Christopher W Seymour ¹ , Deborah M Siegal ¹ , Delcio G Silva Jr ¹ , Aneesh B Singhal ¹ , Arthur S Slutsky ¹ , Dayna Solvason ¹ , Simon J Stanworth ¹ , Anne M Turner ¹ , Wilma van Bentum-Puijk ¹ , Frank L van de Veerdonk ¹ , Sean van Diepen ¹ , Gloria Vazquez-Grande ¹ , Lana Wahid ¹ , Vanessa Wareham ¹ , R Jay Widmer ¹ , Jennifer G Wilson ¹ , Eugene Yuriditsky ¹ , Yongqi Zhong ¹



Collaborators, Affiliations

• PMID: 34351722
• DOI: 10.1056/NEJMoa2103417

Abstract

Background: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.
Methods: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. 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.
Results: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.
Conclusions: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).