Therapeutic anticoagulation with heparin in critically Ill patients with Covid-19
File(s)
Published version
Author(s)
The REMAP-CAP, ACTIV-4a, and ATTACC Investigators
Type
Journal Article
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. opens in new tab, NCT04505774. opens in new tab, NCT04359277. opens in new tab, and NCT04372589. opens in new tab.)
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. opens in new tab, NCT04505774. opens in new tab, NCT04359277. opens in new tab, and NCT04372589. opens in new tab.)
Date Issued
2021-08-26
Date Acceptance
2021-08-01
Citation
New England Journal of Medicine, 2021, 385, pp.777-789
ISSN
0028-4793
Publisher
Massachusetts Medical Society
Start Page
777
End Page
789
Journal / Book Title
New England Journal of Medicine
Volume
385
Copyright Statement
© 2021 Massachusetts Medical Society. All rights reserved.
Sponsor
NIHR
National Institute for Health Research
Identifier
https://www.nejm.org/doi/10.1056/NEJMoa2103417
Grant Number
COVID-19-REMAP-CAP
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
Aged
Anticoagulants
COVID-19
Critical Illness
Female
Hemorrhage
Heparin
Hospital Mortality
Humans
Logistic Models
Male
Middle Aged
Odds Ratio
Respiration, Artificial
Thrombosis
Treatment Failure
REMAP-CAP Investigators
ACTIV-4a Investigators
ATTACC Investigators
Humans
Thrombosis
Critical Illness
Hemorrhage
Heparin
Anticoagulants
Treatment Failure
Respiration, Artificial
Hospital Mortality
Logistic Models
Odds Ratio
Aged
Middle Aged
Female
Male
COVID-19
11 Medical and Health Sciences
General & Internal Medicine
Publication Status
Published
Article Number
NEJMoa2103417
Date Publish Online
2021-08-26