Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19

Ann Intern Med. 2021 May;174(5):622-632. doi: 10.7326/M20-6739. Epub 2021 Jan 26.


Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19).

Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival.

Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used.

Setting: 67 hospitals in the United States.

Participants: Adults with COVID-19 admitted to a participating ICU.

Measurements: Time to death, censored at hospital discharge, or date of last follow-up.

Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]).

Limitation: Observational design.

Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation.

Primary funding source: None.

Publication types

  • Multicenter Study
  • Observational Study

MeSH terms

  • Aged
  • Anticoagulants / administration & dosage*
  • Anticoagulants / adverse effects
  • Blood Coagulation Disorders / drug therapy*
  • Blood Coagulation Disorders / mortality
  • Blood Coagulation Disorders / virology*
  • COVID-19 / complications*
  • COVID-19 / mortality
  • Critical Illness
  • Female
  • Hemorrhage / chemically induced
  • Hemorrhage / mortality
  • Hemorrhage / virology
  • Humans
  • Intensive Care Units
  • Male
  • Middle Aged
  • SARS-CoV-2
  • Survival Rate
  • United States / epidemiology
  • Venous Thromboembolism / drug therapy
  • Venous Thromboembolism / mortality
  • Venous Thromboembolism / virology


  • Anticoagulants