Therapeutic Heparin May Benefit Moderately Ill, Hospitalized Patients With COVID-19

The use of therapeutic heparin in hospitalized patients with moderately severe COVID-19 and increased D-dimer did not reduce the risk of a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to the intensive care unit (ICU). However, treatment with heparin was associated with lower odds of death at 28 days in these patients. This is according to a study recently published in The BMJ.

Heparin has been posited as a potential therapeutic to reduce the thrombo-inflammatory process associated with COVID-19 and subsequently mitigate the risk of severe disease or death, particularly in moderately ill patients.

In the Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID) trial, researchers led by Michelle Sholzberg, MD, of the University of Toronto in Canada, assessed value of therapeutic heparin versus prophylactic heparin in 465 moderately ill, hospitalized patients with COVID-19 and increased levels of D-dimer, a potential marker of poor COVID-19–related prognosis.

The investigators compared reductions in the rate of a composite endpoint comprising admission to the ICU, mechanical ventilation, or death by 28 days in both groups. Additional secondary outcomes were all-cause motality, ventilator-free days alive, organ support-free days alive, ICU-free days alive, hospital-free days alive, renal replacement therapy, venous thromboembolism (VTE), arterial thromboembolism, and D-dimer levels.

Patients were randomized to receive either therapeutic heparin (n=228; average age = 60.4 years) or prophylactic heparin (n=237; average age = 59.6 years). More than half of the overall population was male (56.8%), and the average body mass index was 30.3. Mean time from symptom onset to hospitalization was 7.1 days, while the average time between admission and randomization was 1.4 days. In the therapeutic and prophylactic heparin groups, the mean treatment durations were 6.5 and 6.3 days, respectively.

At a median of 1.5 days following randomization, the D-dimer levels were lower in the therapeutic heparin group (geometric mean ratio 0.88, 95% CI 0.78-0.99; p=0.03).

The 28-day primary composite outcome occurred in 16.2% of patients treated with therapeutic heparin versus 21.9% of patients who were randomly assigned to prophylactic heparin (odds ratio [OR] = 0.69; 95% CI 0.43-1.10; p=0.12). A significantly greater proportion of deaths were reported in the prophylactic heparin group versus therapeutic heparin group (1.8% vs. 7.6%; OR=0.22; 95% CI 0.07-0.65; p=0.006).

In addition, the incidence rates of a composite endpoint comprising all-cause death or any mechanical ventilation was 10.1% in the therapeutic heparin arm and 16.0% in the prophylactic heparin group (OR=0.59; 95% CI 0.34-1.02; p=0.06). The incidence rates of VTE were 0.9% in the therapeutic heparin group and 2.5% in the prophylactic heparin arm (OR=0.34; 95% CI 0.07-1.71; p=0.19).

Overall, 9.2% and 11.0% of the prophylactic heparin groups required mechanical ventilation (OR=0.82; 95% CI 0.45-1.51; p=0.53). The average number of ventilator-free days was significantly higher for the therapeutic heparin group (26.5 days) versus the prophylactic heparin group (24.7 days; OR from ordinal logistic regression 1.77; 95% CI 1.02-3.08; p=0.042).

Approximately 14.5% of patients in the therapeutic heparin group and 17.7% in the prophylactic heparin group were admitted to the ICU (OR=0.79; 95% CI 0.48-1.29; p=0.34). No significant difference was found in the average number of ICU-free days (26.0 vs. 24.2 days; OR=1.51; 95% CI 0.94-2.41; p=0.087).

The researchers observed no fatal thromboembolic events. Fewer patients in the therapeutic heparin group experienced major bleeding events (0.9% vs. 1.7%), but there was no statistically significant difference between the two groups (OR=0.52; 95% CI 0.09-2.85; p=0.69).

Study authors report no relevant conflicts of interest.


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.