The FREEDOM trial was initiated and led by Valentin Fuster, MD, PhD, President of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital.
An international trial led by Mount Sinai found that high-dose anticoagulation can reduce deaths by 30 percent and intubations by 25 percent in hospitalized COVID-19 patients who are not critically ill, when compared to the standard treatment, which is low-dose anticoagulation. The innovative FREEDOM trial was initiated and led by Valentin Fuster, MD, PhD, President of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital.
The study results were announced Monday, March 6, in a late-breaking clinical trial presentation at the scientific sessions of the American College of Cardiology Together With World Congress of Cardiology (ACC.23/WCC) in New Orleans and simultaneously published in the Journal of the American College of Cardiology.
“What we learned from this trial is that many patients hospitalized with COVID-19 with pulmonary involvement, but not yet in the intensive care unit (ICU), will benefit from high-dose subcutaneous enoxaparin or oral apixaban to inhibit thrombosis and the progression of the disease,” Dr. Fuster says. “This is the first study to show that high-dose anticoagulation may improve survival in this patient population—a major finding since COVID-19 deaths are still prevalent.”
Clinical Insights, Early in the Pandemic
This work was prompted by the discovery early in the pandemic that many patients hospitalized with COVID-19 developed high levels of life-threatening blood clots. In March 2020, during the early days of the pandemic, Dr. Fuster observed patients with blood clots in their legs who had been admitted with COVID-19. After hearing from colleagues abroad of other cases of small, pervasive, and unusual clotting that had triggered myocardial infarctions, strokes, and pulmonary embolisms, he initiated decisive action.
“We became one of the first medical centers in the world to treat all COVID-19 patients with anticoagulant medications,” says Dr. Fuster, a pioneer in the study of atherothrombotic disease. “It was a decision that we believe saved many lives.”
This early protocol led to groundbreaking research and insights by Mount Sinai into the role of anticoagulation in the management of COVID-19-infected patients. Mount Sinai research showed that treatment with prophylactic (low-dose) anticoagulation was associated with improved outcomes both in and out of the intensive care unit among hospitalized COVID-19 patients. Researchers further observed that therapeutic (high-dose) anticoagulation might lead to better results. Then, they designed the FREEDOM COVID Anticoagulation Strategy Randomized Trial to look further into the most effective regimen and dosage for improving outcomes of hospitalized COVID-19 patients who are not critically ill.
Researchers enrolled 3,398 hospitalized adult patients with confirmed COVID-19 (median age 53) from 76 urban and rural hospitals across 10 countries—including hospitals within the Mount Sinai Health System—between August 26, 2020, and September 19, 2022. Patients were not in the ICU or intubated, and about half of them had signs of COVID-19 impacting their lungs with acute respiratory distress syndrome (ARDS). Patients were randomized to receive doses of three different types of anticoagulants within 24 to 48 hours of being admitted to the hospital and followed for 30 days. Equal numbers of patients were treated with one of three different drug regimens: low-dose injections of enoxaparin, high-dose injections of enoxaparin, and high-dose, oral doses of apixaban. They compared the combined therapeutic groups to the prophylactic group.
Informing Future Care
The primary endpoint was a combination of death, requirement for ICU care, systemic thromboembolism (blood clots traveling through the arteries), or ischemic stroke at 30 days. This endpoint was not significantly reduced among the groups. However, 30-day mortality was lower for those treated with high-dose anticoagulation compared with those on the low-dose regimen. Seven percent of patients treated with the low-dose anticoagulation died within 30 days, compared with 4.9 percent of patients treated with high-dose anticoagulation—an overall reduction of 30 percent. The need for intubations was also reduced in the high-dose group: 6.4 percent of patients on the high-dose regimen were intubated within 30 days compared with 8.4 percent in the low-dose group—a 25 percent reduction. The study showed high-dose anticoagulation to be especially beneficial for patients with ARDS, a condition where COVID-19 damages the lungs. Among patients with ARDS at the time of hospital admission, 12.3 percent in the low-dose anticoagulation group died within 30 days, compared with 7.9 in the high-dose group.
All groups had low bleeding rates, and there were no differences between the two therapeutic blood thinners for safety and efficacy.
“This is an important study for patients with COVID-19 who are sick enough to require hospitalization but not so ill as to require ICU management. In this group of patients with radiologic evidence of ARDS, therapeutic dose anticoagulation prevents disease progression, especially the need for intubation, and saves lives,” says co-Principal Investigator Gregg W. Stone, MD, Professor of Medicine (Cardiology), and Population Health Science and Policy, at the Icahn School of Medicine at Mount Sinai. “This is especially important as COVID-19 is not going away. Even in the United States, the current number of daily deaths, although much lower than at the peak of the pandemic, is twice that compared with just one year ago. And in other countries COVID-19 is raging”
The FREEDOM trial was coordinated by the Mount Sinai Heart Health System. Dr. Fuster raised all funding for the trial.