In patients hospitalized with moderate COVID-19, treatment with therapeutic-dose heparin increased the likelihood of survival at hospital discharge and decreased the risk for cardiovascular or respiratory organ support compared with standard care thromboprophylaxis, according to results of an open-label, multiplatform, randomized controlled trial published in the New England Journal of Medicine.

The investigators integrated patient data from 3 platforms trials to compare the effects of therapeutic-dose heparin with standard care thromboprophylaxis for the treatment of patients hospitalized with moderate COVID-19. They specifically evaluated patients who did not require respiratory or cardiovascular support. They also stratified patients according to baseline D-dimer concentration (high, low, and unknown).

Between April 2020 and January 2021, investigators randomly assigned patients in a 1:1 fashion to receive regimens of either a therapeutic-dose of unfractionated or low-molecular-weight heparin, or standard care thromboprophylaxis. In 2 of the 3 platform trials, there was a possibility for response-adaptive randomization if a treatment group exhibited increased therapeutic benefit. Therapeutic-dose heparin was administered according to local acute venous thromboembolism treatment protocols for up to 14 days or until recovery. Recovery was defined as discharge from the hospital or discontinuation of supplemental oxygen for at least 24 hours. Thromboprophylaxis was administered by the treating physician per local practice protocol.

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The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and the number of days without cardiovascular or respiratory support up to day 21 in patients who survived until hospital discharge. They assumed that patients discharged before day 21 were alive and free of organ support through day 21. In addition, patients who died within 90 days of initial hospitalization were given the lowest score on the outcome scale (–1).

A total of 2219 patients were included in the final analysis. Baseline characteristics were similar between the 2 groups, including after stratification by D-dimer concentration. Patients with increased and unknown D-dimer concentrations tended to be older and had more comorbidities compared with those with decreased D-dimer concentrations. Overall, treatment effect did not vary significantly by patient age, level of respiratory support at enrollment, or the dose of thromboprophylactic agent administered.

The majority of patients in both groups survived until hospital discharge without organ support, and the median number of organ support-free days was 22 in both groups.

Compared with standard care thromboprophylaxis, the posterior probability that therapeutic-dose heparin increased organ support-free days was 98.6% (adjusted odds ratio [aOR], 1.27; 95% CI, 1.03-1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support was 4 percentage points higher among patients treated with therapeutic-dose heparin (95% CI, 0.5-7.2). The posterior probability that therapeutic-dose heparin increased survival until hospital discharge vs stand care thromboprophylaxis was 87.1% (mean aOR, 1.21; 95% CI, 0.87-1.68), with a median adjusted between-group difference of 1.3 percentage points (95% CI, –1.1 to 3.2).

The final posterior probability that treatment with therapeutic-dose heparin was superior to standard care thromboprophylaxis was 97.3% in patients with increased D-dimer concentrations, 92.9% in those with decreased D-dimer concentrations, and 97.3% in those with unknown D-dimer concentrations.

Major bleeding occurred in 1.9% of patients who received therapeutic-dose heparin compared with 0.9% of those who received standard care thromboprophylaxis. Fatal bleeding occurred in 3 patients in the anticoagulation group and 1 in the thromboprophylaxis group.

The study limitations included possible ascertainment bias, the absence of protocol-specified screening for deep vein thrombosis, and the exclusion of patients at increased risk for major bleeding. The investigators noted that the generalizability of the study results were difficult to fully assess because of these limitations.

The investigators concluded that for every 1000 patients hospitalized with moderate COVID-19 treated with therapeutic-dose heparin, 40 additional patients would survive until hospital discharge without organ support, and 7 would develop major bleeding.


The ATTACC, ACTIV-4a, and REMAP-CAP Investigators. Therapeutic anticoagulation with heparin in non-critically ill patients with Covid-19. N Engl J Med. Published online August 4, 2021. DOI:10.1056/NEJMoa2105911