Therapeutic heparin may reduce death, bleeding risks in moderate COVID-19

Use of therapeutic heparin does not appear to significantly reduce the death, mechanical ventilation, or intensive care unit (ICU) admission in hospitalized patients with moderate COVID-19 and increased D-dimer levels, reveals a study. However, it is associated with a significantly lower chances of all-cause death and reduced risk of major bleeding.

“In this randomized trial of moderately ill patients with COVID-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not associated with a significantly lower incidence of the primary composite of death, mechanical ventilation, or ICU admission compared with prophylactic heparin,” the researchers said.

Twenty-eight hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US participated in this randomized controlled, adaptive, open-label clinical trial. A total of 465 adults hospitalized with moderate COVID-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomized to therapeutic (n=228) or prophylactic heparin (n=237).

The study treatments (low molecular weight or unfractionated heparin) were given until hospital discharge, day 28, or death of the patient. Majority of the participants (mean age 60 years, mean body mass index 30.3 kg/m²) were men (n=264, 56.8 percent).

The primary outcome of a composite of death, invasive mechanical ventilation, noninvasive mechanical ventilation, or ICU admission at 28 days had occurred in 37 of 228 patients (16.2 percent) on therapeutic heparin group and in 52 of 237 (21.9 percent) of those on prophylactic heparin (odds ratio [OR], 0.69, 95 percent confidence interval [CI], 0.43–1.10; p=0.12). [BMJ 2021;375:n2400]

Four patients given therapeutic heparin and 18 assigned to prophylactic heparin succumbed to COVID-19 (1.8 percent vs 7.6 percent; OR, 0.22, 95 percent CI, 0.07–0.65; p=0.006). The composite of all-cause death or any mechanical ventilation occurred in 23 and 38 patients on therapeutic and prophylactic heparin, respectively (10.1 percent vs 16.0 percent; OR, 0.59, 95 percent CI, 0.34–1.02; p=0.06).

Two patients assigned to therapeutic heparin and six to prophylactic heparin had experienced venous thromboembolism (0.9 percent vs 2.5 percent; OR, 0.34, 95 percent CI, 0.07–1.71; p=0.19). Finally, major bleeding occurred in two and four patients, respectively (0.9 percent vs 1.7 percent; OR, 0.52, 95 percent CI, 0.09–2.85; p=0.69).

“A numerical increase in bleeding risk with prophylactic heparin in this trial is most probably a chance finding; 95 percent CIs are wide and compatible with the increased risk of bleeding associated with therapeutic heparin in the multiplatform trial by Lawler [and colleagues],” the researchers said. [N Engl J Med 2021;385:790-802]

On the other hand, the reason for low venous thromboembolic events in the current trial remains unclear. However, this could reflect eligibility criteria or improvements in therapies addressing inflammatory and thrombotic processes compared with previous studies. [N Engl J Med 2021;385:790-802; Res Pract Thromb Haemost 2020;4:1178-1191; Lancet 2021;397:2253-2263]

“The [current] trial was conducted during a 12-month period between May 2020 and May 2021. During this time, management strategies for COVID-19 have evolved, which in turn could have influenced the effect of therapeutic heparin on clinical outcomes. However, we found no time-by-treatment interaction in a sensitivity analysis,” the researchers said.