Early anticoagulation does not improve survival in critically ill COVID-19 patients

Early therapeutic anticoagulation among critically ill adults with the coronavirus disease 2019 (COVID-19) appears to have no significant impact on survival in the target trial emulation, suggests a study.

“Our findings do not support early empirical use of therapeutic anticoagulation in critically ill patients with COVID-19,” the researchers said, noting the need for well-designed, adequately powered randomized clinical trials of therapeutic anticoagulation in this population.

This multicentre cohort study assessed the incidence of venous thromboembolism (VTE) and major bleeding within 14 days after intensive care unit (ICU) admission among 3,239 critically ill adults with COVID-19 (median age, 61 years; 64.5 percent men) in 67 hospitals in the US.

The researchers conducted a target trial emulation in which patients were categorized based on receipt or non-receipt of therapeutic anticoagulation in the first 2 days of ICU admission to examine the observation effect of early treatment on survival. They used a Cox model with inverse probability weighting to adjust for confounding.

Of the patients included, 204 (6.3 percent) developed VTE and 90 (2.8 percent) had a major bleeding event. Male sex and higher D-dimer level on ICU admission independently correlated with VTE risk. [Ann Intern Med 2021;doi:10.7326/M20-6739]

“Both of these factors have been associated with adverse outcomes in COVID-19 but have not been rigorously studied in the context of VTE,” the researchers said. [Obesity 2020;28:1195-1199; Clin Infect Dis 2020;doi:10.1093/cid/ciaa270; Clin Infect Dis 2020;71:896-897]

“Elevated D-dimer on ICU day 1 may be indicative of elevated coagulation activation and therefore truly predictive of elevated VTE risk or may be representative of an existing thrombus,” they added.

Moreover, the associated 28-day mortality was much higher in patients with major bleeding (62.2 percent vs 38.2 percent), even though the rate was about half as frequent as VTE. In addition, two-thirds of major bleeding events occurred in those receiving therapeutic anticoagulation.

A total of 2,809 patients were then included in the target trial emulation, of whom 384 (11.9 percent) received early therapeutic anticoagulation. Over a median follow-up of 27 days, the primary analysis revealed that those who received early treatment had a similar risk of death as those who did not (hazard ratio, 1.12, 95 percent confidence interval, 0.92–1.35).

Previous studies, mostly from Europe, reported VTE rates ranging from 5–42 percent in critically ill COVID-19 patients. A recent meta-analysis also reported a rate of 23.9 percent. [Blood 2020;136:489-500; J Clin Med 2020;doi:10.3390/jcm9082489; Thromb Res 2020;193:1-4; Thromb Res 2020;191:9-14; Intensive Care Med 2020;46:1089-1098; Thromb Res 2020;191:145-147]

“Our findings are also consistent with prior reports in critically ill patients without COVID-19 receiving standard doses of heparin-based thromboprophylaxis,” the researchers said. [Medicine 2019;98:e15833]

The current study was limited by its observational design. Moreover, the data obtained were only on VTE and major bleeding events for the first 14 days after ICU admission, thus likely underestimating incidence in this population. Finally, VTE events were possibly underdiagnosed due to the logistic challenges of imaging in critically ill COVID-19 patients. [Ann Intern Med 2020;173:268-277]