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

N Engl J Med. 2021 Aug 26;385(9):777-789. doi: 10.1056/NEJMoa2103417. Epub 2021 Aug 4.

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.).

Publication types

  • Comparative Study
  • Multicenter Study
  • Pragmatic Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Anticoagulants / administration & dosage*
  • Anticoagulants / adverse effects
  • Anticoagulants / therapeutic use
  • COVID-19 / mortality
  • COVID-19 Drug Treatment*
  • Critical Illness
  • Female
  • Hemorrhage / chemically induced
  • Heparin / administration & dosage*
  • Heparin / adverse effects
  • Heparin / therapeutic use
  • Hospital Mortality
  • Humans
  • Logistic Models
  • Male
  • Middle Aged
  • Odds Ratio
  • Respiration, Artificial
  • Thrombosis / prevention & control*
  • Treatment Failure

Substances

  • Anticoagulants
  • Heparin

Associated data

  • ClinicalTrials.gov/NCT02735707
  • ClinicalTrials.gov/NCT04505774
  • ClinicalTrials.gov/NCT04359277
  • ClinicalTrials.gov/NCT04372589