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

• ClinicalTrials.gov Identifier: NCT04367831
• Recruitment Status: Completed
• First Posted: April 29, 2020
• Last Update Posted: September 29, 2021
• Sponsor: Columbia University
• Information provided by (Responsible Party): Sahil A. Parikh, Columbia University

Tracking Information

• First Submitted Date: April 27, 2020
• First Posted Date: April 29, 2020
• Last Update Posted Date: September 29, 2021
• Actual Study Start Date: May 2, 2020
• Actual Primary Completion Date: May 12, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 27, 2020)

Total Number of Patients with Clinically Relevant Venous or Arterial Thrombotic Events in ICU [ Time Frame: 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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 28, 2020)

• Total Number of Patients with In hospital Clinically Relevant Venous or Arterial Thrombotic Events [ Time Frame: Discharge from hospital 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).
• ICU Length of Stay [ Time Frame: Discharge from ICU or 30 days ]
  Length of stay measured in days.
• Total Number of Patients with the Need for Renal Replacement Therapy in the ICU [ Time Frame: Discharge from hospital 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 [ Time Frame: Discharge from hospital or 30 days ]
  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 [ Time Frame: Discharge from hospital or 30 days ]
  Length of stay measured in days.

Original Secondary Outcome Measures (submitted: April 27, 2020)

• Total Number of Patients with In hospital Clinically Relevant Venous or Arterial Thrombotic Events [ Time Frame: Discharge from hospital 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).
• ICU Length of Stay [ Time Frame: Discharge from ICU or 30 days ]
  Length of stay measured in days.
• Total Number of Patients with the Need for Renal Replacement Therapy in the ICU [ Time Frame: Discharge from hospital or 30 days ]
  To determine the impact of intermediate-dose anti-coagulation compared with prophylactic anti-coagulation on rates of acute kidney injury and renal recovery in the ICU.
• Total Number of Patients with Major bleeding in the ICU [ Time Frame: Discharge from hospital or 30 days ]
  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 [ Time Frame: Discharge from hospital or 30 days ]
  Length of stay measured in days.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Intermediate or Prophylactic-Dose Anticoagulation for Venous or Arterial Thromboembolism in Severe COVID-19
• Official Title: Intermediate or Prophylactic-Dose Anticoagulation for Venous or Arterial Thromboembolism in Severe COVID-19: A Cluster Based Randomized Selection Trial (IMPROVE-COVID)
• 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.
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment

Condition

• COVID-19
• Venous Thromboses
• Arterial Thrombosis

Intervention

• Drug: 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
  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

Study Arms

• Experimental: 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

  Interventions:

  • Drug: Heparin Infusion
  • Drug: Enoxaparin/Lovenox Intermediate Dose
• Active Comparator: 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

  Interventions:

  • Drug: Enoxaparin Prophylactic Dose
  • Drug: Heparin SC

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 27, 2021): 94
• Original Estimated Enrollment (submitted: April 27, 2020): 100
• Actual Study Completion Date: May 12, 2021
• Actual Primary Completion Date: May 12, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04367831
• Other Study ID Numbers: AAAS8980
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Sahil A. Parikh, Columbia University
• Original Responsible Party: Same as current
• Current Study Sponsor: Columbia University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Ajay Kirtane, MD; Columbia University

• PRS Account: Columbia University
• Verification Date: September 2021