Clinical trial NCT04367831: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: COVID-19
Venous Thromboses
Arterial Thrombosis
Keywords: COVID-19
coronavirus
anticoagulation
Lead sponsor: Columbia University
Sponsor class: OTHER
First posted: 2020-04-29
Enrollment: 94
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Total Number of Patients Who Were Alive and Without Venous/Thrombotic Events in ICU
timeFrame: Discharge from ICU or 30 days
Secondary outcomes:
measure: Total Number of Patients With Clinically Relevant Venous or Arterial Thrombotic Events in ICU
timeFrame: Discharge from hospital or 30 days
measure: ICU Length of Stay
timeFrame: Discharge from ICU, up to 36 days
measure: Total Number of Patients With the Need for Renal Replacement Therapy in the ICU
timeFrame: Discharge from ICU or 30 days
measure: Total Number of Patients With Major Bleeding in the ICU
timeFrame: Discharge from ICU or 30 days
measure: Hospital Length of Stay
timeFrame: Discharge from ICU, up to 36 days
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
Study officials:
affiliation: Columbia University
name: Ajay Kirtane, MD
role: STUDY_CHAIR
References:
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.
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.
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.