In patients hospitalized with moderate COVID-19 with increased D-dimer concentrations, treatment with therapeutic heparin was found to decrease the risk of death at 28 days. These findings, from a randomized controlled, adaptive, open label clinical trial, were published in The BMJ.

The Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID) trial was an investigator initiated, parallel, pragmatic, adaptive study conducted at 28 sites in 6 countries. Patients (N=465) hospitalized with SARS-CoV-2 infection and who had increased D-dimer concentrations within 5 days of admission were stratified by site and age and randomly assigned in a 1:1 fashion to receive either therapeutic (n=228) or prophylactic (n=237) heparin. The primary composite outcome was admission to the intensive care unit (ICU), non-invasive mechanical ventilation, invasive mechanical ventilation, or death up to 28 days.

Among patients included in the study, the mean age was 60 years, 56.8% were men, and the mean BMI was 30.3 kg/m2. In addition, patients were admitted to the hospital within a mean of 7.1 days after symptom onset, the mean D-dimer concentration was 2.3-fold above the reference range, and the mean creatinine concentration was 85.2 mmol/L.


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Among patients in the therapeutic and prophylactic heparin groups, the mean duration of treatment was 6.5 and 6.3 days, respectively. Of note, most patients in the therapeutic (98.2%) and prophylactic (93.7%) heparin groups received low-molecular-weight heparin.

The composite primary outcome occurred among 16.2% and 21.9% of patients in the therapeutic and prophylactic heparin groups, respectively (odds ratio [OR], 0.69; 95% CI, 0.43-1.10; P =.12).

The researchers found that death from any cause occurred less frequently among patients in the therapeutic heparin group vs those in the prophylactic heparin group (1.8% vs 7.6%; OR, 0.22; 95% CI, 0.07-0.65; P =.006). The most common cause of death was hypoxemic respiratory failure.

A total of 9.2% and 11.0% of patients in the therapeutic and prophylactic heparin groups required invasive or non-invasive mechanical ventilation, respectively (OR, 0.82; 95% CI, 0.45-1.51; P =.53).

The researchers noted that ICU admission rates were not significantly different between patients in the therapeutic heparin vs those in the prophylactic heparin groups (14.5% vs 17.7%; OR, 0.79; 95% CI, 0.48-1.29; P =.34).

The mean number of ventilator-free days was significantly increased among patients in the therapeutic heparin group vs those in the prophylactic heparin group (26.5 vs 24.7 days; OR, 1.77; 95% CI, 1.02-3.08; P =.042).

Although no fatal thromboembolic events occurred among patients included in the study, the incidence of venous thromboembolism was increased among those in the therapeutic heparin group vs those in the prophylactic heparin group (0.9% vs 2.5%; OR, 0.34; 95% CI, 0.07-1.71; P =.19). In addition, D-dimer concentrations were significantly decreased among patients who received therapeutic heparin (geometric mean ratio, 0.88; 95% CI, 0.78-0.99; P =.03).

Major bleeding events occurred among 0.9% and 1.7% of patients in the therapeutic and prophylactic heparin groups, respectively (OR, 0.52; 95% CI, 0.09-2.85; P =.69). No fatal bleeding events or intracranial hemorrhage occurred among patients in either treatment group.

This study was underpowered for the analysis of the primary outcome.

According to the researchers, these findings “suggest that therapeutic heparin is beneficial in…patients [hospitalized with moderate] COVID-19.”

Disclosure: Multiple authors declared affiliations with industry. Please see the original reference for a full list of disclosures.

Reference

Sholzberg M, Tang GH, Rahhal H, et al. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400. doi:10.1136/bmj.n2400