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.

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.

Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).

Beginning 9 months and ending 36 months following article publication.

Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose. The type of analysis that will be conducted is for individual participant data meta-analysis. Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata.