Arterial Thrombosis, COVID-19, Venous Thromboses
Conditions
Keywords
COVID-19, coronavirus, anticoagulation
Brief summary
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.
Detailed description
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.
Interventions
DRUGEnoxaparin Prophylactic Dose
Prophylactic dose anticoagulation (per Columbia University Irving Medical Center (CUIMC) Guidelines): If eGFR ≥30 mL/min (stable kidney function): 1. BMI \< 40 kg/m2: Enoxaparin 40 mg SC daily 2. BMI 40 - 50 kg/m2: Enoxaparin 40 mg SC q12h 3. BMI \> 50 kg/m2: Enoxaparin 60 mg SC q12h
DRUGHeparin Infusion
Unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1 -0.3U/mL.
DRUGHeparin SC
Unfractionated heparin at 5000-7500 units subcutaneous (SC) every 8 hours.
DRUGEnoxaparin/Lovenox Intermediate Dose
If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily.
Sponsors
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Patients Who Were Alive and Without Venous/Thrombotic Events in ICU | Discharge from ICU or 30 days | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Patients With Clinically Relevant Venous or Arterial Thrombotic Events in ICU | Discharge from hospital or 30 days | 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). |
| ICU Length of Stay | Discharge from ICU, up to 36 days | Length of stay measured in days. |
| Total Number of Patients With the Need for Renal Replacement Therapy in the ICU | Discharge from ICU or 30 days | 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. |
| Total Number of Patients With Major Bleeding in the ICU | Discharge from ICU or 30 days | 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. |
| Hospital Length of Stay | Discharge from ICU, up to 36 days | Length of stay measured in days. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 46 |
| Control Arm: Prophylaxis Prophylactic dose anticoagulation (per Columbia University Irving Medical Center (CUIMC) Guidelines):
If eGFR ≥30 mL/min (stable kidney function):
1. BMI \< 40 kg/m2: Enoxaparin 40 mg SC daily
2. BMI 40 - 50 kg/m2: Enoxaparin 40 mg SC q12h
3. BMI \> 50 kg/m2: Enoxaparin 60 mg SC q12h
If eGFR \< 30 mL/min or acute kidney injury:
1. 50-120 kg: Unfractionated heparin 5000 units SC q8h
2. \>120 kg: Unfractionated heparin 7500 units SC q8h
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):
1. BMI \< 40 kg/m2: Enoxaparin 40 mg SC daily
2. BMI 40 - 50 kg/m2: Enoxaparin 40 mg SC q12h
3. BMI \> 50 kg/m2: Enoxaparin 60 mg SC q12h
Heparin SC: Unfractionated heparin at 5000-7500 units subcutaneous (SC) every 8 hours. | 48 |
| Total | 94 |
Baseline characteristics
| Characteristic | Intervention Arm: Intermediate-dose Anticoagulation | Total | Control Arm: Prophylaxis |
|---|---|---|---|
| Age, Continuous | 62.6 years STANDARD_DEVIATION 12.2 | 62.9 years STANDARD_DEVIATION 11.8 | 63.2 years STANDARD_DEVIATION 11.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 67 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 27 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 33 Participants | 66 Participants | 33 Participants |
| Race (NIH/OMB) White | 8 Participants | 18 Participants | 10 Participants |
| Region of Enrollment United States | 46 participants | 94 participants | 48 participants |
| Sex: Female, Male Female | 21 Participants | 44 Participants | 23 Participants |
| Sex: Female, Male Male | 25 Participants | 50 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 46 | 11 / 48 |
| other Total, other adverse events | 15 / 46 | 12 / 48 |
| serious Total, serious adverse events | 0 / 46 | 0 / 48 |
Outcome results
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).
Time frame: Discharge from ICU or 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Arm: Intermediate-dose Anticoagulation | Total Number of Patients Who Were Alive and Without Venous/Thrombotic Events in ICU | 28 Participants |
| Control Arm: Prophylaxis | Total Number of Patients Who Were Alive and Without Venous/Thrombotic Events in ICU | 31 Participants |
Secondary
Hospital Length of Stay
Length of stay measured in days.
Time frame: Discharge from ICU, up to 36 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intervention Arm: Intermediate-dose Anticoagulation | Hospital Length of Stay | 17.78 days |
| Control Arm: Prophylaxis | Hospital Length of Stay | 17.73 days |
Secondary
ICU Length of Stay
Length of stay measured in days.
Time frame: Discharge from ICU, up to 36 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intervention Arm: Intermediate-dose Anticoagulation | ICU Length of Stay | 23 days |
| Control Arm: Prophylaxis | ICU Length of Stay | 26 days |
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).
Time frame: Discharge from hospital or 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Arm: Intermediate-dose Anticoagulation | Total Number of Patients With Clinically Relevant Venous or Arterial Thrombotic Events in ICU | 15 Participants |
| Control Arm: Prophylaxis | Total Number of Patients With Clinically Relevant Venous or Arterial Thrombotic Events in ICU | 18 Participants |
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.
Time frame: Discharge from ICU or 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Arm: Intermediate-dose Anticoagulation | Total Number of Patients With Major Bleeding in the ICU | 5 Participants |
| Control Arm: Prophylaxis | Total Number of Patients With Major Bleeding in the ICU | 5 Participants |
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.
Time frame: Discharge from ICU or 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Arm: Intermediate-dose Anticoagulation | Total Number of Patients With the Need for Renal Replacement Therapy in the ICU | 11 Participants |
| Control Arm: Prophylaxis | Total Number of Patients With the Need for Renal Replacement Therapy in the ICU | 15 Participants |