This study is being conducted to assess the effectiveness of intermediate versus prophylactic doses of anticoagulation (blood thinners) in patients critically ill with COVID-19 in the intensive care units (ICUs) throughout the hospital. Anticoagulation is part of the patient's usual standard of care but determining the dose of anticoagulation is based on physician preference. The investigators are conducting this study (a randomized trial with adaptive design employing cluster randomization) with the support of all of the ICUs to collect data in order to determine what should be the standard of care in terms of anticoagulation in these critically ill patients. The patients care will not be altered other than the choice of anticoagulation (both approved and used throughout the hospital as standard of care) based on the ICU bed they are assigned. Patient data will be collected until discharge.
Hemostatic, biomarker, and inflammatory changes are common in severe manifestations of
coronavirus disease 2019 (COVID-19).Such factors, as well as the bedridden status and
critical illness may constitute a prothrombotic milieu, predisposing to venous and arterial
thrombosis. However, the optimal antithrombotic regimen for patients with COVID-19,
especially those with severe disease, remains uncertain and is currently an area of active
clinical interest. Prophylactic-dose anticoagulation is generally recommended for acutely ill
hospitalized patients. However, given the hemostatic abnormalities of severe COVID-19
illness, it is unknown whether more intensive anticoagulation is preferred to reduce the risk
of thrombotic events, potentially mitigating microvascular and macrovascular thrombi and even
disseminated intravascular coagulation (DIC). Further, the risks of therapeutic dose
anticoagulation must be weighed against the bleeding risks inherent to this approach. To
address this critical gap in knowledge in an area of clinical equipoise, the investigators
plan to conduct a cluster-randomized trial in patients admitted to intensive care units
(ICUs) in a large volume academic medical center to select the best anticoagulation
intervention.
Drug: Enoxaparin Prophylactic Dose
Prophylactic dose anticoagulation (per Columbia University Irving Medical Center (CUIMC) Guidelines):
If eGFR ≥30 mL/min (stable kidney function):
BMI < 40 kg/m2: Enoxaparin 40 mg SC daily
BMI 40 - 50 kg/m2: Enoxaparin 40 mg SC q12h
BMI > 50 kg/m2: Enoxaparin 60 mg SC q12h
Other Name: Lovenox
Drug: Heparin Infusion
Unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1 -0.3U/mL.
Other Name: Heparin
Drug: Heparin SC
Unfractionated heparin at 5000-7500 units subcutaneous (SC) every 8 hours.
Other Name: Heparin
Drug: Enoxaparin/Lovenox Intermediate Dose
If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily.
Other Name: Lovenox
Inclusion Criteria:
- Confirmed diagnosis of COVID-19 by reverse transcription polymerase chain reaction
(RT-PCR)
- New admission to eligible CUIMC ICUs within 5 days
- Transfer from nonparticipating to participating ICU is eligible if otherwise
meets eligibility criteria.
- Patients transferred between participating ICUs will maintain initial treatment
assignment.
- Patients not on therapeutic anticoagulation and who were already admitted to
participating ICU within 5 days of trial initiation are additionally eligible.
Exclusion Criteria:
- Weight under 50kg
- Contraindication to anticoagulation in the opinion of the treating clinician including
- overt bleeding
- platelet count <50,000
- Bleeding Academic Research Consortium (BARC) major bleeding in the past 30 days
- Gastrointestinal (GI) bleeding within 3 months
- history of intracranial hemorrhage
- Ischemic stroke within the past 2 weeks
- craniotomy/major neurosurgery within the past 30 days
- cardiothoracic surgery within the past 30 days
- intra-abdominal surgery within 30 days prior to enrollment
- Head or spinal trauma in the last months
- History of uncorrected cerebral aneurysm or arteriovenous malformation (AVM)
- Intracranial malignancy
- Presence of an epidural or spinal catheter
- Recent major surgery within the last 14 days
- Decrease in hemoglobin >3 g/dL over the last 24 hours
- Allergic reaction to anticoagulants (e.g. Heparin Induced Thrombocytopenia) as
documented in the electronic health records. Extracorporeal membrane oxygenation
(ECMO) support or other mechanical circulatory support.
- Severe chronic liver dysfunction (history of portosystemic hypertension (HTN),
esophageal varices, or Child-Pugh class C or above or similar Model For End-Stage
Liver Disease (MELD) scores), abnormality in liver function tests (aspartate
aminotransferase (AST), alanine aminotransferase (ALT), bilirubin) 5 times greater
than upper normal limit.
- A history of congenital bleeding diatheses or anatomical anomaly that predisposes to
hemorrhage (e.g. hemophilia, hereditary hemorrhagic telangiectasia)
- Treating physician preference for therapeutic anticoagulation
- Enrollment in other concurrent trials related to anticoagulant or antiplatelet therapy
- Existing treatment with therapeutic anticoagulation during the previous 7 days of
hospitalization prior to ICU admission (e.g. for venous thromboembolism (VTE), atrial
fibrillation, mechanical valve, etc).
- Do-not-resuscitate (DNR) /do-not-intubate (DNI) or comfort measures only (CMO) orders
prior to randomization.
Columbia University Medical Center
New York, New York, United States
Ajay Kirtane, MD, Study Chair
Columbia University