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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intervention arm: intermediate-dose anticoagulation | Experimental | If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily or unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1-0.3 U/mL. If eGFR <30 mL/min or acute kidney injury or CRRT: Unfractionated heparin infusion at 10 units/kg/hour (minimum 500 units/hour if CRRT) with goal anti-Xa 0.1-0.3 U/mL |
|
| Control arm: prophylaxis | Active Comparator | Prophylactic dose anticoagulation (per Columbia University Irving Medical Center (CUIMC) Guidelines): If eGFR ≥30 mL/min (stable kidney function):
If eGFR < 30 mL/min or acute kidney injury:
If CRRT: Unfractionated heparin infusion pre-filter at 500 units/hour |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Enoxaparin Prophylactic Dose | Drug | Prophylactic dose anticoagulation (per Columbia University Irving Medical Center (CUIMC) Guidelines): If eGFR ≥30 mL/min (stable kidney function):
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| Measure | Description | Time Frame |
|---|---|---|
| Total Number of Patients Who Were Alive and Without Venous/Thrombotic Events in ICU | Composite of being alive and without clinically-relevant venous or arterial thrombotic events at discharge from ICU (without transfer to another ICU or palliative care unit/hospice) or at 30 days (if ICU duration lasted 30 days or longer). | Discharge from ICU or 30 days |
| Measure | Description | Time Frame |
|---|---|---|
| Total Number of Patients With Clinically Relevant Venous or Arterial Thrombotic Events in ICU | Composite of being alive and with clinically relevant venous or arterial thrombotic events at discharge from ICU (without transfer to another ICU or palliative care unit/hospice) or at 30 days (if ICU duration lasted 30 days or longer). | Discharge from hospital or 30 days |
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Inclusion Criteria:
Confirmed diagnosis of COVID-19 by reverse transcription polymerase chain reaction (RT-PCR)
New admission to eligible CUIMC ICUs within 5 days
Exclusion Criteria:
Weight under 50kg
Contraindication to anticoagulation in the opinion of the treating clinician including
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.
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| Name | Affiliation | Role |
|---|---|---|
| Ajay Kirtane, MD | Columbia University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Columbia University Medical Center | New York | New York | 10032 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35244208 | Derived | Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19: a rapid review. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2. | |
| 33502773 | Derived | Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Intervention Arm: Intermediate-dose Anticoagulation | If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily or unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1-0.3 U/mL. If eGFR <30 mL/min or acute kidney injury or CRRT: Unfractionated heparin infusion at 10 units/kg/hour (minimum 500 units/hour if CRRT) with goal anti-Xa 0.1-0.3 U/mL Heparin Infusion: Unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1 -0.3U/mL. Enoxaparin/Lovenox Intermediate Dose: If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 30, 2020 |
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| Heparin Infusion | Drug | Unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1 -0.3U/mL. |
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| Heparin SC | Drug | Unfractionated heparin at 5000-7500 units subcutaneous (SC) every 8 hours. |
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| Enoxaparin/Lovenox Intermediate Dose | Drug | If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily. |
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| ICU Length of Stay | Length of stay measured in days. | Discharge from ICU, up to 36 days |
| Total Number of Patients With the Need for Renal Replacement Therapy in the ICU | The impact of intermediate-dose anti-coagulation compared with prophylactic anti-coagulation on rates of acute kidney injury and renal recovery in the ICU will be measured with the total number of patients who need of renal replacement therapy in the ICU. | Discharge from ICU or 30 days |
| Total Number of Patients With Major Bleeding in the ICU | Major bleeding will be assessed by BARC criteria (> BARC 3), also explored by International Society on Thrombosis and Haemostasis (ISTH) and Thrombolysis in Myocardial Infarction (TIMI) criteria. | Discharge from ICU or 30 days |
| Hospital Length of Stay | Length of stay measured in days. | Discharge from ICU, up to 36 days |
| 32407672 | Derived | Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020 Jun;7(6):e438-e440. doi: 10.1016/S2352-3026(20)30145-9. Epub 2020 May 11. No abstract available. |
| FG001 | Control Arm: Prophylaxis | Prophylactic dose anticoagulation (per Columbia University Irving Medical Center (CUIMC) Guidelines): If eGFR ≥30 mL/min (stable kidney function):
If eGFR < 30 mL/min or acute kidney injury:
If CRRT: Unfractionated heparin infusion pre-filter at 500 units/hour Enoxaparin Prophylactic Dose: Prophylactic dose anticoagulation (per Columbia University Irving Medical Center (CUIMC) Guidelines): If eGFR ≥30 mL/min (stable kidney function):
Heparin SC: Unfractionated heparin at 5000-7500 units subcutaneous (SC) every 8 hours. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Intervention Arm: Intermediate-dose Anticoagulation | If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily or unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1-0.3 U/mL. If eGFR <30 mL/min or acute kidney injury or CRRT: Unfractionated heparin infusion at 10 units/kg/hour (minimum 500 units/hour if CRRT) with goal anti-Xa 0.1-0.3 U/mL Heparin Infusion: Unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1 -0.3U/mL. Enoxaparin/Lovenox Intermediate Dose: If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily. |
| BG001 | Control Arm: Prophylaxis | Prophylactic dose anticoagulation (per Columbia University Irving Medical Center (CUIMC) Guidelines): If eGFR ≥30 mL/min (stable kidney function):
If eGFR < 30 mL/min or acute kidney injury:
If CRRT: Unfractionated heparin infusion pre-filter at 500 units/hour Enoxaparin Prophylactic Dose: Prophylactic dose anticoagulation (per Columbia University Irving Medical Center (CUIMC) Guidelines): If eGFR ≥30 mL/min (stable kidney function):
Heparin SC: Unfractionated heparin at 5000-7500 units subcutaneous (SC) every 8 hours. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Total Number of Patients Who Were Alive and Without Venous/Thrombotic Events in ICU | Composite of being alive and without clinically-relevant venous or arterial thrombotic events at discharge from ICU (without transfer to another ICU or palliative care unit/hospice) or at 30 days (if ICU duration lasted 30 days or longer). | Posted | Count of Participants | Participants | Discharge from ICU or 30 days |
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| ||||||||||||||||||||||||||||||
| Secondary | Total Number of Patients With Clinically Relevant Venous or Arterial Thrombotic Events in ICU | Composite of being alive and with clinically relevant venous or arterial thrombotic events at discharge from ICU (without transfer to another ICU or palliative care unit/hospice) or at 30 days (if ICU duration lasted 30 days or longer). | Posted | Count of Participants | Participants | Discharge from hospital or 30 days |
| ||||||||||||||||||||||||||||||||
| Secondary | ICU Length of Stay | Length of stay measured in days. | Posted | Mean | Full Range | days | Discharge from ICU, up to 36 days |
| |||||||||||||||||||||||||||||||
| Secondary | Total Number of Patients With the Need for Renal Replacement Therapy in the ICU | The impact of intermediate-dose anti-coagulation compared with prophylactic anti-coagulation on rates of acute kidney injury and renal recovery in the ICU will be measured with the total number of patients who need of renal replacement therapy in the ICU. | Posted | Count of Participants | Participants | Discharge from ICU or 30 days |
| ||||||||||||||||||||||||||||||||
| Secondary | Total Number of Patients With Major Bleeding in the ICU | Major bleeding will be assessed by BARC criteria (> BARC 3), also explored by International Society on Thrombosis and Haemostasis (ISTH) and Thrombolysis in Myocardial Infarction (TIMI) criteria. | Posted | Count of Participants | Participants | Discharge from ICU or 30 days |
| ||||||||||||||||||||||||||||||||
| Secondary | Hospital Length of Stay | Length of stay measured in days. | Posted | Mean | Full Range | days | Discharge from ICU, up to 36 days |
|
Up to 30 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Intervention Arm: Intermediate-dose Anticoagulation | If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily or unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1-0.3 U/mL. If eGFR <30 mL/min or acute kidney injury or CRRT: Unfractionated heparin infusion at 10 units/kg/hour (minimum 500 units/hour if CRRT) with goal anti-Xa 0.1-0.3 U/mL Heparin Infusion: Unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1 -0.3U/mL. Enoxaparin/Lovenox Intermediate Dose: If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily. | 10 | 46 | 0 | 46 | 15 | 46 |
| EG001 | Control Arm: Prophylaxis | Prophylactic dose anticoagulation (per Columbia University Irving Medical Center (CUIMC) Guidelines): If eGFR ≥30 mL/min (stable kidney function):
If eGFR < 30 mL/min or acute kidney injury:
If CRRT: Unfractionated heparin infusion pre-filter at 500 units/hour Enoxaparin Prophylactic Dose: Prophylactic dose anticoagulation (per Columbia University Irving Medical Center (CUIMC) Guidelines): If eGFR ≥30 mL/min (stable kidney function):
Heparin SC: Unfractionated heparin at 5000-7500 units subcutaneous (SC) every 8 hours. | 11 | 48 | 0 | 48 | 12 | 48 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Venous Thromboembolism | Vascular disorders | Non-systematic Assessment |
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| Actionable Line Thrombosis | Vascular disorders | Non-systematic Assessment |
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| CVVH Filter Thrombosis | Vascular disorders | Non-systematic Assessment |
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| Acute Kidney Injury | Renal and urinary disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Sahil A. Parikh, MD | Columbia University | 212-305-3617 | sap2196@cumc.columbia.edu |
| May 4, 2022 |
| Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D020246 | Venous Thrombosis |
| D018352 | Coronavirus Infections |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D014777 | Virus Diseases |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D013927 | Thrombosis |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D017984 | Enoxaparin |
| D006493 | Heparin |
| ID | Term |
|---|---|
| D006495 | Heparin, Low-Molecular-Weight |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
| D002241 | Carbohydrates |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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