FREEDOM COVID Anticoagulation Strategy Randomized Trial
Overview
- Phase
- Phase 4
- Intervention
- Enoxaparin
- Conditions
- COVID-19
- Sponsor
- Valentin Fuster
- Enrollment
- 3460
- Locations
- 21
- Primary Endpoint
- Time to first event
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
Coronavirus Disease (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has led to unprecedented morbidity and mortality in the modern era. To date, nearly 13 million people have contracted COVID-19, leading to more than 550,000 deaths worldwide. As the number of affected individuals continues to climb, effective strategies for treatment and prevention of the disease are of paramount importance. SARS-CoV-2 is understood to directly invade cells via the human angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed predominantly in the lungs but also throughout the cardiovascular system. Thus, while acute respiratory distress syndrome remains a feared complication, new thromboembolic disease has emerged as a common and potentially catastrophic manifestation of COVID-19.
Detailed Description
This is a Prospective, multi-center, open label, randomized controlled comparative safety and effectiveness trial with objectives: 1. To determine the effectiveness of enoxaparin and apixaban in patients hospitalized (but not yet intubated) with confirmed COVID-19 and 2. To determine the safety of enoxaparin and apixaban in patients hospitalized (but not yet intubated) with confirmed COVID-19. Observational analyses have suggested potential benefit for in-hospital use of anticoagulation. Yet, due to a lack of rigorous evidence for optimal anticoagulation regimens, practice patterns among hospitalized patients with COVID-19 vary significantly. Specifically, the choice of anticoagulant, dosing, and duration of treatment are not well understood. A preliminary analysis of approximately 2700 patients admitted to the Mount Sinai Health System (MSHS) in New York, demonstrated an association between in-hospital administration of therapeutic Anticoagulation (AC) and improved survival compared to no or prophylactic dose AC. A subsequent analysis under review of a larger 4400 patient cohort with longer follow up demonstrated similar associations with reduction in the risk of mortality and risk of intubation. Further analyses suggest more pronounced benefit with therapeutic as opposed to prophylactic doses. Bleeding rates were generally low overall, but higher among patients on therapeutic anticoagulation. Finally, though exploratory in nature, a potential signal for benefit was observed for patients on novel oral anticoagulant therapy (primarily apixaban) at therapeutic doses compared to low molecular weight heparin. Ultimately, randomized controlled trials are needed to elucidate the optimal anticoagulation regimen to improve outcomes in patients hospitalized with COVID-19.
Investigators
Valentin Fuster
Principal Investigator
Icahn School of Medicine at Mount Sinai
Eligibility Criteria
Inclusion Criteria
- •Hospitalization within the prior 24 hours for either confirmed (based on PCR or antigen positive test for SARS-CoV-2) or suspected COVID-19 based on 3 criteria (all 3 must be present for suspected cases):
- •Fever \>38 degrees Celsius
- •O2 saturation ≤94
- •Abnormal laboratory marker (at least 1):
- •i. d-dimer ≥1.0 μg /mL ii. CRP \>2 mg/L iii. Ferritin \>300 μg /L iv. Lymphopenia \<1500 cells /m3
- •Patient or legal guardian provides written informed consent
Exclusion Criteria
- •Age \<18 years
- •Mechanical ventilation on admission or high likelihood for the need for invasive mechanical ventilation within 24 hours of admission
- •Anticipated duration of hospital stay \<72 hours
- •Treatment with therapeutic dose UFH or LMWH, vitamin K antagonists, or NOACs within seven days
- •Active bleeding
- •Risk factors for bleeding, including:
- •intracranial surgery or stroke within 3 months
- •history of intracerebral arteriovenous malformation
- •cerebral aneurysm or mass lesions of the central nervous system
- •intracranial malignancy
Arms & Interventions
Prophylactic Enoxaparin
Prophylactic enoxaparin (40 mg SC QD; 30 mg SC QD for CrCl \<30 mL/min)
Intervention: Enoxaparin
Full Dose Enoxaparin
Full-dose enoxaparin (1 mg/kg SC Q12h; 1 mg/kg SC QD for CrCl \<30 mL/min)
Intervention: Enoxaparin
Apixaban
Apixaban (5 mg Q12h; 2.5 mg Q12h for patients with at least two of three of age ≥80 years, weight ≤60 kg or serum creatinine ≥1.5 mg/dL)
Intervention: Apixaban
Outcomes
Primary Outcomes
Time to first event
Time Frame: 30 days
The time to first event rate within 30 days of randomization of the composite of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism (including pulmonary emboli) confirmed by imaging or requiring surgical intervention OR ischemic stroke confirmed by imaging.
Number of in-hospital rate of BARC 3 or 5
Time Frame: 30 days
Number of in-hospital rate of BARC 3 or 5 bleeding (binary). BARC Type 3: a. Overt bleeding plus hemoglobin drop of 3 to \< 5 g/dL (provided hemoglobin drop is related to bleed); transfusion with overt bleeding b. Overt bleeding plus hemoglobin drop \< 5 g/dL (provided hemoglobin drop is related to bleed); cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring IV vasoactive agents c. Intracranial hemorrhage confirmed by autopsy, imaging, or lumbar puncture; intraocular bleed compromising vision. BARC Type 5: 1. Probable fatal bleeding 2. Definite fatal bleeding (overt or autopsy or imaging confirmation)
Secondary Outcomes
- Number of participants with Myocardial infarction(90 days after randomization)
- Number of participants with Pulmonary Emboli(90 days after randomization)
- Number of All Death(90 days after randomization)
- Number of participants with Deep Vein Thrombosis(90 days after randomization)
- Number of participants requiring Ventilation(90 days after randomization)
- Number of participants with Systemic Thromboembolism(90 days after randomization)
- Cause of Death(90 days after randomization)
- Number of participants with Stroke(90 days after randomization)