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

NCT ID: NCT04367831

Last Updated: 2024-12-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 94 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-02
• Study Completion Date: 2021-05-12

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.

Conditions

COVID-19; Venous Thromboses; Arterial Thrombosis

Keywords

COVID-19; coronavirus; anticoagulation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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

Group Type: EXPERIMENTAL

Heparin Infusion

Intervention Type: DRUG

Unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1 -0.3U/mL.

Enoxaparin/Lovenox Intermediate Dose

Intervention Type: DRUG

If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily.

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

Group Type: ACTIVE_COMPARATOR

Enoxaparin Prophylactic Dose

Intervention Type: DRUG

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

Intervention Type: DRUG

Unfractionated heparin at 5000-7500 units subcutaneous (SC) every 8 hours.

Interventions

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

Intervention Type: DRUG

Heparin Infusion

Unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 0.1 -0.3U/mL.

Intervention Type: DRUG

Heparin SC

Unfractionated heparin at 5000-7500 units subcutaneous (SC) every 8 hours.

Intervention Type: DRUG

Enoxaparin/Lovenox Intermediate Dose

If estimated glomerular filtration rate (eGFR) ≥ 30 mL/min: enoxaparin 1mg/kg subcutaneous (SC) daily.

Intervention Type: DRUG

Other Intervention Names

Lovenox; Heparin; Heparin; Lovenox

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Columbia University

OTHER

Sponsor Role: lead

Responsible Party

Sahil A. Parikh

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ajay Kirtane, MD

Role: STUDY_CHAIR

Columbia University

Locations

Columbia University Medical Center

New York, New York, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 35244208 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33502773 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32407672 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

AAAS8980

Identifier Type: -

Identifier Source: org_study_id