FREEDOM COVID: Therapeutic dose anticoagulation does not reduce MACE in non-critically ill COVID-19 patients

By Leah Kosyakovsky on

Key Points:

  • There have been conflicting data on the role and recommended dosage of anticoagulation in non-critically-ill patients with COVID-19.
  • In the open-label FREEDOM COVID study, therapeutic anticoagulation was compared with prophylactic doses of enoxaparin in patients hospitalized for COVID-19. The primary endpoint was a 30-day composite of all-cause mortality, requirement For ICU level-of-care, systemic thromboembolism, or ischemic stroke.
  • Therapeutic anticoagulation did not result in any significant differences in the composite endpoint, but it did result in lower 30-day mortality and endotracheal intubation compared with prophylaxis.

COVID-19 infection results in microvascular and macrovascular disease and subsequent venous and arterial thrombosis. However, there have been conflicting data regarding the utility and required dosage of anticoagulation in hospitalized, non-ICU COVID patients. In a breaking presentation at the 2023 ACC Conference today, Dr. Valentin Fuster (Mount Sinai, NYC) and his team presented their study: “The FREEDOM COVID Anticoagulation Strategy Randomized Trial.”

The FREEDOM COVID trial (NCT04512079) was an open-label multiplatform trial of hospitalized COVID-19 pts not requiring critical care who were randomized to different regimens of therapeutic dose anticoagulation with heparin vs. usual-care pharmacologic thromboprophylaxis. The inclusion criteria comprised any adults who were hospitalized for COVID within the prior 48 hours for either confirmed (based on PCR or antigen positive test for SARS-CoV-2) or suspected COVID-19 with associated hypoxia, fever, and at least one abnormal biomarker associated with COVID-19 infection. Key exclusion criteria included ICU requirement, anticipated hospital stay <72 hours, and treatment with therapeutic anticoagulation within 7 days. The primary outcome was a 30-day composite of all-cause mortality, requirement for ICU level-of-care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group. All analyses were performed in the modified intention-to-treat population.

A total of 3452 patients were randomized at 76 hospitals across 10 countries between August 26, 2020, and September 19, 2022; 1141 were randomized to prophylactic enoxaparin, 1136 to therapeutic enoxaparin, and 1121 to therapeutic apixaban.  The average age was 52, and 40% were women. 20% had diabetes and 54% had an ARDS appearance by imaging. The primary endpoint was not significantly different between the therapeutic and both prophylactic enoxaparin arms, 13,2% vs 11,3% respectively (HR 0.85; 95% CI 0.69 to 1.04; p=0.11). .On individual secondary component analysis, all-cause mortality was reduced in the therapeutic enoxaparin arm (HR 0.70 (95%CI 0.5-0.9), p=0.01). Intubation was also less common in the therapeutic arm (HR 0.75 (95%CI 0.5-0.9), p=0.03). On subgroup analysis, patients with ARDS or abnormal CXRs without ARDS benefited most from the therapeutic strategy; consistent effects were observed across all other pre-specified subgroups. India was observed to have a markedly lower event rate than the remaining participating countries. Safety outcomes with therapeutic-dose enoxaparin and apixaban were similar, and bleeding was infrequent with all three regimens (0.1-0.5% rate of BARC Major types 3, 5 across the three arms).

When discussing the clinical implications of the study at ACC, Dr. Fuster stated: “Among non-critically ill patients hospitalized with COVID-19, at 30 days the lower incidence of the primary outcome for therapeutic dose compared with prophylactic dose did not reach statistical significance; however, significantly fewer pts treated with therapeutic-dose died or required endotracheal intubation within 30 days…based on these findings, the use of therapeutic-dose anticoagulation may improve outcomes in non-critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU level-of care.”