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Intermediate or Prophylactic-Dose Anticoagulation for Venous or Arterial Thromboembolism in Severe COVID-19 (IMPROVE)

Primary Purpose

COVID-19, Venous Thromboses, Arterial Thrombosis

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Enoxaparin Prophylactic Dose
Heparin Infusion
Heparin SC
Enoxaparin/Lovenox Intermediate Dose
Sponsored by
Columbia University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19 focused on measuring COVID-19, coronavirus, anticoagulation

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Columbia University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Intervention arm: intermediate-dose anticoagulation

Control arm: prophylaxis

Arm Description

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

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 If eGFR < 30 mL/min or acute kidney injury: 50-120 kg: Unfractionated heparin 5000 units SC q8h >120 kg: Unfractionated heparin 7500 units SC q8h If CRRT: Unfractionated heparin infusion pre-filter at 500 units/hour

Outcomes

Primary Outcome Measures

Total Number of Patients with Clinically Relevant Venous or Arterial 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).

Secondary Outcome Measures

Total Number of Patients with In hospital Clinically Relevant Venous or Arterial Thrombotic Events
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).
ICU Length of Stay
Length of stay measured in 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.
Total Number of Patients with Major bleeding in the ICU
Major bleeding will be assessed by BARC criteria, also explored by International Society on Thrombosis and Haemostasis (ISTH) and Thrombolysis in Myocardial Infarction (TIMI) criteria.
Hospital Length of Stay
Length of stay measured in days.

Full Information

First Posted
April 27, 2020
Last Updated
September 27, 2021
Sponsor
Columbia University
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1. Study Identification

Unique Protocol Identification Number
NCT04367831
Brief Title
Intermediate or Prophylactic-Dose Anticoagulation for Venous or Arterial Thromboembolism in Severe COVID-19
Acronym
IMPROVE
Official Title
Intermediate or Prophylactic-Dose Anticoagulation for Venous or Arterial Thromboembolism in Severe COVID-19: A Cluster Based Randomized Selection Trial (IMPROVE-COVID)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
May 2, 2020 (Actual)
Primary Completion Date
May 12, 2021 (Actual)
Study Completion Date
May 12, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Columbia University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19, Venous Thromboses, Arterial Thrombosis
Keywords
COVID-19, coronavirus, anticoagulation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
94 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intervention arm: intermediate-dose anticoagulation
Arm Type
Experimental
Arm Description
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
Arm Title
Control arm: prophylaxis
Arm Type
Active Comparator
Arm Description
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 If eGFR < 30 mL/min or acute kidney injury: 50-120 kg: Unfractionated heparin 5000 units SC q8h >120 kg: Unfractionated heparin 7500 units SC q8h If CRRT: Unfractionated heparin infusion pre-filter at 500 units/hour
Intervention Type
Drug
Intervention Name(s)
Enoxaparin Prophylactic Dose
Other Intervention Name(s)
Lovenox
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Heparin Infusion
Other Intervention Name(s)
Heparin
Intervention Description
Unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1 -0.3U/mL.
Intervention Type
Drug
Intervention Name(s)
Heparin SC
Other Intervention Name(s)
Heparin
Intervention Description
Unfractionated heparin at 5000-7500 units subcutaneous (SC) every 8 hours.
Intervention Type
Drug
Intervention Name(s)
Enoxaparin/Lovenox Intermediate Dose
Other Intervention Name(s)
Lovenox
Intervention Description
If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily.
Primary Outcome Measure Information:
Title
Total Number of Patients with Clinically Relevant Venous or Arterial Thrombotic Events in ICU
Description
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
Secondary Outcome Measure Information:
Title
Total Number of Patients with In hospital Clinically Relevant Venous or Arterial Thrombotic Events
Description
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 hospital or 30 days
Title
ICU Length of Stay
Description
Length of stay measured in days.
Time Frame
Discharge from ICU or 30 days
Title
Total Number of Patients with the Need for Renal Replacement Therapy in the ICU
Description
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 hospital or 30 days
Title
Total Number of Patients with Major bleeding in the ICU
Description
Major bleeding will be assessed by BARC criteria, also explored by International Society on Thrombosis and Haemostasis (ISTH) and Thrombolysis in Myocardial Infarction (TIMI) criteria.
Time Frame
Discharge from hospital or 30 days
Title
Hospital Length of Stay
Description
Length of stay measured in days.
Time Frame
Discharge from hospital or 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ajay Kirtane, MD
Organizational Affiliation
Columbia University
Official's Role
Study Chair
Facility Information:
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35244208
Citation
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. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
Results Reference
derived
PubMed Identifier
33502773
Citation
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.
Results Reference
derived
PubMed Identifier
32407672
Citation
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.
Results Reference
derived

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Intermediate or Prophylactic-Dose Anticoagulation for Venous or Arterial Thromboembolism in Severe COVID-19

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