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

Abstract

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. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

• Authors: ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Patrick R Lawler, Ewan C Goligher, Jeffrey S Berger, 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 Kahn, 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, 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 Chkhikvadze, Benjamin Coiffard, Todd W Costantini, Sophie de Brouwer, Lennie P G Derde, Michelle A Detry, Abhijit Duggal, Vladimír Džavík, 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 García-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 King, M Margaret Knudson, Aaron E Kornblith, Vidya Krishnan, Matthew E Kutcher, Michael A Laffan, Francois Lamontagne, Grégoire 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, Andréa 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 Guerrero, 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 Pérez González, 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 Jr, Manu Shankar-Hari, John P Sheehan, Aneesh B Singhal, Dayna Solvason, 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, Derek C Angus, Colin J McArthur, Steven A Webb, Michael E Farkouh, Judith S Hochman, Ryan Zarychanski
• Journal: The New England journal of medicine (N Engl J Med) Vol. 385 Issue 9 Pg. 790-802 (Aug 26 2021) ISSN: 1533-4406 [Electronic] United States
• PMID: 34351721 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Pragmatic Clinical Trial, Randomized Controlled Trial)
• Copyright: Copyright © 2021 Massachusetts Medical Society.

Chemical References

• Anticoagulants
• Heparin, Low-Molecular-Weight
• Heparin

Topics

• Adult
• Aged
• Anticoagulants (administration & dosage, adverse effects, therapeutic use)
• COVID-19 (mortality)
• Female
• Hemorrhage (chemically induced)
• Heparin (administration & dosage, adverse effects, therapeutic use)
• Heparin, Low-Molecular-Weight (therapeutic use)
• Hospital Mortality
• Humans
• Male
• Middle Aged
• Survival Analysis
• Thrombosis (prevention & control)
• COVID-19 Drug Treatment