Two trials show no differences between patients who received enoxaparin vs standard of care

The routine use of antithrombotic therapies to prevent thromboembolic complications provided no benefit for symptomatic outpatients with COVID-19, according to the results of two randomized trials.

In the OVID trial, the 30-day risk of hospitalization and death was similar among patients who received the anticoagulant enoxaparin (Lovenox) 40 mg daily for 14 days and those who received standard of care (3% in each group, adjusted relative risk 0.98, 95% CI 0.38-2.56, P=0.96), reported Stefano Barco, MD, of University Hospital Zurich in Switzerland, and colleagues.

Furthermore, in the ETHIC trial, there was no difference in the composite of all-cause mortality and hospitalization at 21 days between patients who received enoxaparin 40 mg once or twice daily on the basis of body weight and a standard-of-care group (11% in each group, unadjusted HR 1.09, 95% CI 0.49-2.43, P=0.83), said Ajay K. Kakkar, MBBS, of the Thrombosis Research Institute in London, England, and colleagues.

The results from the OVID and ETHIC trials were published in The Lancet Haematology, and were in line with those from a previous study — the North American ACTIV-4B trial — which showed that antithrombotic therapy with either aspirin or apixaban (Eliquis) did not reduce the rate of a composite clinical outcome of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization as a result of cardiovascular or pulmonary causes compared with placebo.

COVID-19 has emerged as a highly prothrombotic viral disease, causing arterial and venous thromboembolic events, both sets of researchers noted. However, it was unclear whether antithrombotic therapy would prevent thromboembolic complications and slow disease progression in newly diagnosed patients with COVID-19.

“Investigations of the utility of antithrombotic treatments to prevent respiratory failure and mortality in any patient population with SARS-CoV-2 infection have generally shown little if any role for antithrombotics,” wrote Jean M. Connors, MD, and Paul M. Ridker, MD, MPH, both of Brigham and Women’s Hospital in Boston, in an accompanying commentary. “Thus, in the absence of new data, the bottom line for a global clinical community that continues to deal with a frustrating ongoing pandemic, less consistently appears to be more with regard to antithrombotic therapy for outpatients with COVID-19.”


The phase III randomized open-label OVID trial was conducted across eight centers in Germany and Switzerland. From August 2020 to January 2022, 472 outpatients ages 50 and older with acute COVID-19 were randomly assigned 1:1 to either enoxaparin 40 mg for 14 days or standard of care. The primary outcome was a composite of any hospitalization and all-cause death within 30 days of randomization.

No deaths or major bleeding events were reported during the study. Eight serious adverse events were recorded in the enoxaparin group versus nine in the control group.

Barco and colleagues noted that the overall risk of COVID-19-related hospitalization was lower than expected, and could probably be explained by the fact that the highest-risk group — patients over the age of 70 — was underrepresented in the study. “As a consequence, the results of OVID must be carefully translated to elderly patients, for whom more evidence from randomized controlled trials is needed,” they wrote.


The phase IIIb randomized controlled ETHIC trial was conducted across 15 centers in Belgium, Brazil, India, South Africa, Spain, and the U.K., and included 219 participants ages 30 and older who had not received a COVID-19 vaccine and had confirmed symptomatic COVID-19 in the outpatient setting, plus at least one risk factor for severe disease.

Participants were randomly assigned 1:1 to either subcutaneous enoxaparin for 21 days (40 mg once daily if they weighed <100 kg and 40 mg twice daily if they weighed ≥100 kg) or standard of care (without enoxaparin).

At 21 days, bleeding events had occurred in two patients in the enoxaparin group (one minor bleed and one bleed of unknown severity) and one patient in the standard-of-care group (major abnormal uterine bleeding). The most common adverse event among both groups was COVID-19-related pneumonia (6% of the enoxaparin group and 4% of the standard-of-care group). One patient in the enoxaparin group died, with cause of death unknown.

Although the study was terminated early due to a lower-than-expected enrollment rate and a lower-than-expected event rate, the results suggested “early anticoagulation for the prevention of thromboembolic complications in non-critical outpatients with COVID-19 might have no clinical benefit and should not be used routinely in this clinical setting,” Kakkar and colleagues concluded. “Combined with the data from other studies, our results will inform guidelines and guide clinical practice.”

The OVID study was primarily funded by the Swiss National Science Foundation. Funding for the ETHIC trial was provided by the Thrombosis Research Institute and Sanofi.

Primary Source

The Lancet Haematology

Source Reference: Barco S, et al “Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, phase 3 trial” Lancet Haematol 2022; DOI: 10.1016/S2352-3026(22)00175-2.

Secondary Source

The Lancet Haematology

Source Reference: Cools F, et al “Thromboprophylactic low-molecular-weight heparin versus standard of care in unvaccinated, at-risk outpatients with COVID-19 (ETHIC): an open-label, multicentre, randomised, controlled, phase 3b trial” Lancet Haematol 2022; DOI: 10.1016/S2352-3026(22)00173-9.

Additional Source

The Lancet Haematology

Source Reference: Connors JM, Ridker PM “Antithrombotic prophylaxis for symptomatic outpatients with COVID-19: less is consistently more” Lancet Haematol 2022; DOI: 10.1016/S2352-3026(22)00205-8.

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