Thrombosis, Bleeding, and the Effect of Anticoagulation on Survival in Critically Ill Patients with COVID-19 in the United States

Introduction: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19), yet data on thrombosis, bleeding, and therapeutic anticoagulation in this population are limited. The primary objectives of this study were to evaluate coagulation-associated complications in critically ill patients with COVID-19, and to assess whether therapeutic anticoagulation affects survival.

Methods: In a nationally-representative multicenter cohort study of 3239 critically ill adults with COVID-19 at 67 hospitals across the United States, we examined the incidence of VTE, major bleeding, and other coagulation-associated complications within 14 days following intensive care unit (ICU) admission. We used multivariable logistic regression employing complete case analysis to identify independent predictors of VTE at the time of ICU admission. In the primary analysis, we estimated the effect of therapeutic anticoagulation on 28-day survival by emulating a target trial in which critically ill patients with COVID-19 were assigned to receive or not receive therapeutic anticoagulation in the first two days of ICU admission. Patients with confirmed or suspected VTE on ICU days 1 or 2 and those with contraindications to therapeutic anticoagulation (major bleeding, thrombocytopenia) were excluded from this target trial emulation. We adjusted for confounding (22 baseline characteristic and severity of illness covariates in total) using a Cox model with inverse probability weighting.

Results:

Patients. Patients’ median age was 61 years (interquartile range, 53-71) and 2088 (64.5%) were male; 36% were White, 31% were Black, 6% were Asian, and 26% were another race. 66% were intubated and 42% were on vasopressors on ICU day 1. 1273 patients (39.3%) died and 1404 (43.4%) were discharged alive from the hospital within 28 days, while 562 (17.4%) remained hospitalized at 28 days.

Anticoagulation. All centers used, at minimum, standard prophylactic doses of anticoagulation for critically ill patients with COVID-19; 8 centers (12%) used higher than standard doses in some or all COVID-19 patients during the study period. 1412 patients (43.6%) initiated therapeutic anticoagulation within 14 days following ICU admission.

Events. During the first 14 days of ICU admission, a total of 204 patients (6.3%) developed radiographically-confirmed VTE, 90 (2.8%) had a major bleeding event (of which 66.7% occurred while receiving therapeutic anticoagulation), 48 (1.5%) developed disseminated intravascular coagulation, and 18 (0.6%) developed heparin-induced thrombocytopenia. While mortality in patients with VTE (38.2%) was similar to the cohort overall, 71.1% of patients with major bleeding died within 28 days.

Predictors of VTE. In a multivariable logistic model (Figure 1), independent predictors of VTE were male sex (odds ratio [OR], 1.70; 95% CI, 1.05-2.77), severe obesity (OR 2.08; 95% CI, 1.17-3.70 for body mass index ≥40.0 versus <30 kg/m²), and higher D-dimer (OR 4.20; 95% CI, 2.17-8.14 for >10,000 versus ≤1000 ng/ml).

Impact of Therapeutic Anticoagulation on Survival. Among 2809 patients included in the target trial emulation (Figure 2), 384 (11.9%) received therapeutic anticoagulation in the first two days of ICU admission. Groups were well-balanced following inverse probability weighting, with post-weighting absolute standardized differences of <0.1 for all 22 covariates (Figure 3). In the primary analysis, during a median follow-up of 27 days, patients who received therapeutic anticoagulation had a similar risk of death as those who did not (hazard ratio, 1.12; 95% CI, 0.92 to 1.35), Figure 4A. Results were similar in an unweighted Cox model (hazard ratio, 1.14; 95% CI, 0.96 to 1.35) and with pooling the data from nested trials on ICU days 1 and 2 (hazard ratio, 1.16; 95% CI, 0.96 to 1.39). Results were also similar across subgroups (Figure 4B).

Conclusions: Among critically ill adults with COVID-19 in the United States, the 14-day rates of radiographically-confirmed VTE and major bleeding were 6.3% and 2.8%, respectively. Major bleeding was highly morbid. Male sex, severe obesity, and elevated D-dimer on ICU admission were independent predictors of VTE. In a target trial emulation controlling for 22 baseline characteristic and severity-of-illness covariates, receipt of therapeutic anticoagulation early after ICU admission did not appear to affect survival.