Early treatment with therapeutic doses of low-molecular-weight heparin significantly reduced major thromboembolism and death without increasing major bleeding in hospitalized COVID-19 patients with elevated D-dimer levels in the Hep-COVID trial.

“This was an investigator-initiated trial and we did it because we saw patients getting blood clots and dying in front of us while on standard doses of preventative heparin,” Dr. Alex C. Spyropoulos, principal investigator and professor at the Feinstein Institutes for Medical Research in New York, told Reuters Health by phone.

“We were able to prove in this prospective trial that D-dimer levels more than four times the upper limit of normal are able to predict a very high-risk group of hospitalized COVID-19 patients – and giving therapeutic doses of heparin in these patients works. This is practice changing now,” Dr. Spyropoulos said.

The findings are based on 253 adults hospitalized with COVID-19 with D-dimer levels more than four times the upper limit of normal or a sepsis-induced coagulopathy score of four or higher.

They were randomly allocated to a standard prophylactic or intermediate-dose low-molecular-weight heparin (LMWH) or unfractionated heparin or therapeutic-dose LMWH throughout hospitalization. Patients were stratified at the time of randomization based on intensive-care unit (ICU) or non-ICU care status.

The incidence of major thromboembolism or death (the primary outcome) was significantly lower in the therapeutic-dose group (28.7 percent vs. 41.9 percent; relative risk: 0.68; 95 percent confidence interval, 0.49 to 0.96), according to the JAMA Internal Medicine report.

The benefit was driven by a reduction in thromboembolism (10.9 percent vs. 29.0 percent; RR 0.37; 95 percent CI, 0.21 to 0.66).

The incidence of major bleeding was 1.6 percent with standard-dose heparin and 4.7 percent with therapeutic-dose heparin (RR, 2.88; 95 percent CI, 0.59 to 14.02). “There were numerically more major bleeds in the therapeutic-dose group, consistent with other studies in critically ill patients with COVID-19,” the authors note in their paper.

The benefit of therapeutic-dose heparin was restricted to the non-ICU population, suggesting the need to start treatment early in the course of disease before the hyperinflammatory state and cytokine storm sets in, Dr. Spyropoulos told Reuters Health.

“It’s what I call a just-in-time paradigm,” he noted. “By assessing patient risk early and giving therapeutic-dose heparin very early on in their hospitalization, you actually probably alter the whole course of disease and decrease the potential for getting blood clots and dying from that.”

“In the non-ICU population, the number needed to treat is 5 to prevent one major thrombosis and death and the number needed to harm is 2,000. These are numbers that as a researcher I’ve never seen in my lifetime and I’ve been doing this for quarter century,” Dr. Spyropoulos told Reuters Health.

The co-authors of an editorial say the HEP-COVID study “confirms and builds” on other studies, leading to three important conclusions concerning the efficacy and safety of anticoagulant therapy in hospitalized patients with COVID-19.

“First, the data support that therapeutic anticoagulation with LMWH or unfractionated heparin is associated with improved outcomes in hospitalized patients with COVID-19 who are not critically ill or in the ICU setting, particularly those patients with elevated D-dimer levels,” write Dr. Lana Wahid and Dr. Thomas Ortel with Duke University Medical Center, in Durham, North Carolina.

“Second, the data also indicate that patients who are critically ill and/or in the ICU do not benefit from therapeutic anticoagulation and manifest an increased risk for bleeding compared with patients receiving prophylactic-dose anticoagulation. The beneficial effect of therapeutic anticoagulation is diminished and the risk of hemorrhage is increased in patients with progressively more severe disease, potentially related to hyperinflammation, endothelial disruption, platelet activation, and coagulopathy,” they say.

“Third, none of the studies would support the use of an anticoagulant administered at a dose between prophylactic and therapeutic, whether for ICU or non-ICU patients,” they note.

The Hep-COVID study was supported by the Feinstein Institutes for Medical Research, the Broxmeyer Fellowship in Clinical Thrombosis, and a grant from the National Institute on Aging. Dr. Spyropoulos has received grants from Janssen and personal fees from Bayer, Bristol Myers Squibb, Boehringer Ingelheim, and The ATLAS Group.

Editor’s note: Please refer to our recent article on COVID Management for more tips.