Supporting the Use of Therapeutic Heparin for Moderate COVID-19

A therapeutic dose of heparin reduced the risk of all-cause death in moderately ill patients with COVID-19, a new study found.

The study, published in the BMJ, was designed to evaluate whether therapeutic heparin is superior to prophylactic heparin for moderately ill patients with COVID-19 and increased D-dimer levels.

“Randomized trials suggest that therapeutic heparin is beneficial in moderately ill patients with COVID-19 admitted to hospital, but of no benefit and potential harm when provided to critically ill patients,” the study authors, led by Michelle Sholzberg, MDCM, assistant professor at the University of Toronto, wrote. “Given the disparate findings in these two patient populations, there is hesitancy to adopt therapeutic heparin as standard of care in moderately ill patients with COVID-19.”

Dubbed the RAPID trial, it included 465 adults with COVID-19 admitted to 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, the United Arab Emirates and the United States between May 29, 2020, and April 12, 2021.

One group of 228 patients received therapeutic dose heparin and another group of 237 patients received prophylactic dose heparin until hospital discharge, Day 28 or death.

“The RAPID trial did not find a significant reduction in the primary composite outcome of death, mechanical ventilation, or ICU admission with therapeutic heparin,” the study authors wrote. “However, therapeutic heparin was associated with substantially decreased odds of all-cause death and low risk of major bleeding. In conjunction with the recently published multi-platform trial, the RAPID trial therefore suggests that therapeutic heparin is beneficial in moderately ill patients with COVID-19 admitted to hospital wards.”

Treatment was initiated within 24 hours of randomization, and the mean treatment duration was 6.5 days in the therapeutic heparin group and 6.3 days in the prophylactic heparin group.

The primary outcome—a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission—occurred in 37 (16.2%) of patients in the therapeutic group and 52 (21.9%) in the prophylactic group (odds ratio 0.69, 95% confidence interval 0.43-1.10; P=0.12) within the 28-day observation period.

Four patients in the therapeutic heparin group (1.8%) died, a 78% reduction compared with 18 (7.6%) in the prophylactic heparin group (0.22, 0.07-0.65; P=0.006).

Two patients in the therapeutic heparin group (0.9%) experienced venous thromboembolism, compared with six (2.5%) in the prophylactic heparin group (0.34, 0.07-1.71; P=0.19).

Two patients in the therapeutic heparin group (0.9%) experienced major bleeding, compared with four (1.7%) in the prophylactic heparin group (0.52, 0.09-2.85; P=0.69).

Among limitations of the study, the authors noted that the trial was underpowered for the analysis of the primary outcome, which may explain the difference in significance of findings between the primary outcome and the secondary outcome of all-cause death.

Compared with other recent trials, the RAPID trial showed more pronounced mortality reduction.

Combined data from three international trials found that therapeutic, antithrombotic doses of heparin benefits patients hospitalized for moderate symptoms of COVID-19 but was not better than thromboprophylaxis for patients with severe symptoms. Those studies involved data integrated into one multiplatform on more than 1000 critically ill patients and more than 2,000 with non-critical illness.

An earlier study showed promising results of the use of heparin as a “viral decoy” in the treatment of COVID-19. In that study, variants of heparin and compounds derived from edible seaweeds significantly outperformed remdesivir as a treatment for COVID-19.