From the early days of the COVID-19 pandemic, a distinct coagulation disturbance of SARS-CoV-2 infection has been recognized. This thrombo-inflammatory phenotype, characterized by endotheliopathy, hypercoagulability, and coagulation activation, results in an increased risk of thromboembolic events. Initial observational cohort studies described high rates of venous thromboembolism (VTE) in critically ill patients with COVID-19, despite consistent use of standard prophylactic doses of heparin-based anticoagulants. Additionally, published autopsy series described microthrombosis in multiple organs. These reports led to the rapid publication of expert guidance statements that advocated consideration of escalated thromboprophylaxis doses in critically ill patients with COVID-19, pending the results of randomized clinical trials evaluating different doses. Escalated thromboprophylaxis can take the form of empirical therapeutic-dose anticoagulation or, alternatively, intermediate-dose anticoagulation (generally 0.5 mg/kg of enoxaparin twice daily or 1 mg/kg of enoxaparin once daily [or an equivalent]) in an attempt to better balance thrombotic and bleeding risks. Although major bleeding is less common in patients with COVID-19, it has been associated with substantial morbidity.

In a JAMA paper, have been reported the results of a multicenter randomized clinical trial of intermediate-dose vs standard-dose heparin-based thromboprophylaxis in critically ill patients with COVID-19. Among 562 patients included in the primary analysis, the authors found no significant difference in the primary efficacy outcome (a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days of enrollment) or in the main safety outcomes (major bleeding and severe thrombocytopenia) between the 2 groups. The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group, death occurred in 43.1% of patients vs 40.9% of patients, VTE occurred in 3.3% of patients vs 3.5% of patients, and major bleeding occurred in 2.5% of patients vs 1.4% of patients. Severe thrombocytopenia, defined as a platelet count less than 20 ×10³/µL, occurred in 6 patients in the intermediate-dose group vs 0 patients in the standard-dose group. In addition, there was no benefit of intermediate-dose thromboprophylaxis in any of the prespecified subgroups.

The findings of this trial add to the growing body of evidence against dose-escalated thromboprophylaxis in critically ill patients with COVID-19. A 2021 large observational cohort study of 2809 critically ill patients with COVID-19 from 67 centers in the US found no benefit of therapeutic-dose anticoagulation initiated within 2 days of intensive care unit (ICU) admission compared with standard-dose thromboprophylaxis.