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

Intermediate or Prophylactic-Dose Anticoagulation for Venous or Arterial Thromboembolism in Severe COVID-19: A Cluster Based Randomized Selection Trial (IMPROVE-COVID)

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.

Study Overview

• Status: Completed
• Conditions: COVID-19; Venous Thromboses; Arterial Thrombosis
• Intervention / Treatment: Drug: Heparin Infusion; Drug: Enoxaparin/Lovenox Intermediate Dose; Drug: Enoxaparin Prophylactic Dose; Drug: Heparin SC

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
• Enrollment (Actual): 94
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: Heparin Infusion; Unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1 -0.3U/mL.; Other Names: Heparin; Drug: Enoxaparin/Lovenox Intermediate Dose; If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily.; Other Names: Lovenox
Active Comparator: Control arm: prophylaxis; 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	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 Names: Lovenox; Drug: Heparin SC; Unfractionated heparin at 5000-7500 units subcutaneous (SC) every 8 hours.; Other Names: Heparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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
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

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Study Chair: Ajay Kirtane, MD, Columbia University

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2020
• Primary Completion (Actual): May 12, 2021
• Study Completion (Actual): May 12, 2021

Study Registration Dates

• First Submitted: April 27, 2020
• First Submitted That Met QC Criteria: April 27, 2020
• First Posted (Actual): April 29, 2020

Study Record Updates

• Last Update Posted (Estimated): December 10, 2024
• Last Update Submitted That Met QC Criteria: November 15, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: COVID-19; coronavirus; anticoagulation
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19; Thrombosis; Venous Thrombosis; Thromboembolism; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Fibrinolytic Agents; Anticoagulants; Enoxaparin sodium; Enoxaparin; Heparin; Calcium heparin
• Other Study ID Numbers: AAAS8980

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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