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.
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.
Drug: Enoxaparin
Prophylactic enoxaparin (40 mg SC QD; 30 mg SC QD for CrCl <30 mL/min) Full-dose enoxaparin (1 mg/kg SC Q12h; 1 mg/kg SC QD for CrCl <30 mL/min)
Drug: 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)
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):
1. Fever >38 degrees Celsius
2. O2 saturation ≤94
3. 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:
1. intracranial surgery or stroke within 3 months
2. history of intracerebral arteriovenous malformation
3. cerebral aneurysm or mass lesions of the central nervous system
4. intracranial malignancy
5. history of intracranial bleeding
6. history of bleeding diatheses (e.g., hemophilia)
7. history of gastrointestinal bleeding within previous 3 months
8. thrombolysis within the previous 7 days
9. presence of an epidural or spinal catheter
10. recent major surgery <14 days
11. uncontrolled hypertension (sBP > 200 mmHg or dBP > 120 mmHg)
12. other physician-perceived contraindications to anticoagulation
13. Platelet count <50 x109/L, INR >2.0, or baseline aPTT >50 seconds
14. Hemoglobin <80 g/L (to minimize the likelihood of requiring red blood cell
transfusion if potential bleeding were to occur)
15. current treatment with antithrombotics or antiplatelet agents including but not
limited to ticagrelor, prasugrel, and aspirin> 100mg, or non-steroidal
anti-inflammatory drugs (e.g. ibuprofen, naproxen, etc.) due to increased risk of
bleeding, unless such agents can be permanently discontinued (aspirin <= 100mg
and clopidogrel <=75mg is permitted)
- Acute or subacute bacterial endocarditis
- History of heparin induced thrombocytopenia (HIT) or other heparin allergy including
hypersensitivity
- Patients with non-COVID-19 related clinical condition for which life expectancy is <6
months
- Pregnancy (women of childbearing potential are required to have a negative pregnancy
test prior to enrollment)
- Active enrollment in other trials related to anticoagulation
- Patients has end stage kidney disease (ESKD) on chronic dialysis
- Patient is a member of a vulnerable population: In the judgment of the investigator
the patient is unable to give Informed Consent for reasons of incapacity, immaturity,
adverse personal circumstances or lack of autonomy. This may include: Individuals with
mental disability, persons in nursing homes, children, impoverished persons, persons
in emergency situations, homeless persons, nomads, refugees, and those incapable of
giving informed consent. Vulnerable populations also may include members of a group
with a hierarchical structure such as university students, subordinate hospital and
laboratory personnel, employees of the Sponsor, members of the armed forces, and
persons kept in detention.
Icahn School of Medicine at Mount Sinai
New York, New York, United States
Instituto do Coração - INCOR
São Paulo, Brazil
Instituto Prevent Senior - IPS
São Paulo, Brazil
Clínica de la Costa
Barranquilla, Colombia
Clínica Shaio
Bogotá, Colombia
Fundación Cardioinfantil
Bogotá, Colombia
Fundacion Oftalmológica de Santander - Foscal
Bucaramanga, Colombia
Centro Médico Imbanaco
Cali, Colombia
CardioVid
Medellín, Colombia
Eternal Heart Care Centre and Research Ins Pvt Ltd.
Jaipur, India
Jaipur National University
Jaipur, India
Sawai Mann Singh Hospital
Jaipur, India
Jaslok Hospital & Research Center
Mumbai, India
Saifee Hospital
Mumbai, India
Sengupta Hospital & Research Institute
Nagpur, India
D Y Patil University School of Medicine & D Y Patil Hospital
Navi Mumbai, India
Hospital Cardiológica Aguascalientes
Aguascalientes, Mexico
Centro Médico Nacional 20 de Noviembre
Mexico City, Mexico
Christus Muguerza Hospital Alta Especialidad
Monterrey, Mexico
Centro de Estudios Clinicos de Querétaro S.C.
Santiago de Querétaro, Mexico
Centro Medico Hospital del Prado
Tijuana, Mexico