Can higher dose of blood thinners improve outcomes in patients hospitalized for COVID-19?

USA: A higher dose of blood-thinning medication than usual in noncritically ill patients hospitalized for COVID-19 did not significantly reduce death risk, a treatment need in an ICU, a confirmed stroke or blood clot at 30 days, results from the FREEDOM-COVID trial have shown. 

The study, however, showed that 30% fewer patients treated with the higher dose died within 30 days, and significantly fewer patients became seriously ill enough to need a breathing tube.

The findings from the large, randomized international trial were presented at the American College of Cardiology's Annual Scientific Session Together With the World Congress of Cardiology. 

"Although our study did not reach its primary endpoint, it has shown that patients admitted to the hospital for COVID-19 who are not yet critically ill but who have early signs of lung damage caused by the virus substantially benefit from a higher dose of blood-thinning medication to stop disease progression, prevent the need for lung intubation and prevent death, without a significant increase in the risk of bleeding," said Valentin Fuster, MD, PhD, president of Mount Sinai Heart, physician-in-chief of The Mount Sinai Hospital in New York City and the study's principal investigator.

COVID-19 infection can cause severe inflammation of blood vessels throughout the body, which increases risk for blood clots in the lungs, kidneys, brain and elsewhere. For this reason, the current standard of care is to treat patients hospitalized for COVID-19 with a prophylactic dose (a low preventive dose) of a blood thinner to prevent blood clots from forming, Fuster said. A 2020 study by Fuster and colleagues showed a 50% higher likelihood of survival for hospitalized patients with COVID-19 who received a blood thinner than for those who did not. While subsequent studies have suggested that patients with COVID-19 who are not yet ill enough to need intensive care might benefit from a higher therapeutic versus prophylactic dose of a blood thinner, this approach has not been tested in a large-scale trial until now.

The FREEDOM-COVID trial enrolled 3,398 patients in 10 countries around the world (average age 53 years, 60% male) who had confirmed COVID-19 and were hospitalized but not critically ill or requiring ICU care. Patients were randomly assigned to receive a low preventive dose of the heparin-based blood thinner enoxaparin, a higher (treatment strength) dose of enoxaparin (with both doses given by injection under the skin) or a treatment-strength dose of a direct oral anticoagulant, apixaban (given by mouth). Most patients received their assigned medication within 24 hours of admission.

For their analysis, researchers combined the two groups receiving treatment-strength blood thinners and compared this combined group with the group receiving the lower preventive dose. At 30 days, occurrence of the primary endpoint (the combined risk of death from any cause, need for treatment in an intensive-care unit, a confirmed blood clot or a stroke) was not significantly different across the two treatment strengths, occurring in 13.2% of patients receiving the lower preventive blood-thinner dose and in 11.3% of patients in the combined group receiving a treatment-strength dose.

However, when each element of the primary endpoint was assessed individually, treatment-strength blood thinners were significantly better at preventing death or the need for a breathing tube, which is a marker of worsening illness requiring intensive care. Overall, 4.9% of patients receiving a treatment-strength dose died of any cause within 30 days compared with 7% of those receiving the lower preventive dose. The difference between the two groups in the number of patients needing a breathing tube (6.4% in the combined treatment-strength group compared with 8.4% in the preventive-dose group) was also statistically significant.

The primary safety endpoint was the rate of major bleeding during hospitalization, which occurred in 0.1% of patients in the lower preventive dose group and 0.4% of those in the combined treatment-strength dose group. No significant differences in bleeding were seen between the group receiving treatment-strength enoxaparin and the group receiving treatment-strength apixaban.

An important observation from subgroup analyses was that patients who showed early signs of COVID-19 related lung damage such as pulmonary infiltrates (known as acute respiratory distress syndrome) in an admission X-ray or CT scan were less likely to die or experience another primary endpoint event if treated with the treatment-strength dose of blood thinners.

"This finding suggests that patients who are hospitalized for COVID-19 and have early signs of lung damage who are not yet critically ill will substantially benefit from receiving a treatment-strength dose of a blood thinner to stop disease progression in the lungs and prevent the need for a breathing tube," said Gregg W. Stone, MD, professor of medicine (cardiology) at the Icahn School of Medicine at Mount Sinai in New York City and co-author of the study. "For patients already critically ill with COVID-19 and on a breathing tube, the use of a treatment-strength blood thinner is unlikely to be beneficial, but for patients with less advanced lung damage or other high-risk features, this treatment may be lifesaving."