A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care as a Rapid Response to (SARS-CoV-2) COVID-19 Pandemic
- Conditions
- Severe Acute Respiratory SyndromeCOVIDAnticoagulants and Bleeding DisordersCoronavirus InfectionThromboembolism, Venous
- Interventions
- Drug: Therapeutic anticoagulation
- Registration Number
- NCT04444700
- Lead Sponsor
- University of Sao Paulo General Hospital
- Brief Summary
Coagulopathy of COVID-19 afflicts approximately 20% of patients with severe COVID-19 and is associated with need for critical care and death. COVID-19 coagulopathy is characterized by elevated D-dimer, an indicator of fibrin formation and clot lysis, and a mildly prolonged prothrombin time, suggestive of coagulation consumption. To date, it seems that COVID-19 coagulopathy manifests with thromboembolism, thus anticoagulation may be of benefit. We propose to conduct a parallel pragmatic multi-centre open-label randomized controlled trial to determine the effect of therapeutic anticoagulation compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer.
- Detailed Description
2-arm, parallel, pragmatic, multi-centre, open-label randomized controlled trial to determine the effect of therapeutic anticoagulation, with low molecular weight heparin or unfractionated heparin (high dose nomogram), compared to standard care in hospitalized patients with COVID-19 and an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Eligible participants will be randomized to one of two treatment regimens, receiving either therapeutic anticoagulation or standard care until discharged from hospital, death or day 28.
The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death up to 28 days.
Key secondary outcomes between study arms up to day 28 include:
1. All-cause death
2. Composite outcome of ICU admission or all-cause death
3. Composite outcome of mechanical ventilation or all-cause death
4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation
5. Number of participants who received red blood cell transfusion (≥1 unit)
6. Number of participants with transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate
7. Renal replacement therapy;
8. Number of hospital-free days alive
9. Number of ICU-free days alive
10. Number of ventilator-free days alive
11. Number of organ support-free days alive
12. Number of participants with venous thromboembolism
13. Number of participants with arterial thromboembolism
14. Number of participants with heparin induced thrombocytopenia
15. Changes in D-dimer up to day 3
The treatment arm is therapeutic anticoagulation with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram). The choice of LMWH versus UFH will be at the clinician's discretion. LMWH options include: Tinzaparin, Enoxaparin, or Dalteparin. UFH will be administered using a weight-based nomogram with titration according to the center-specific protocol. Therapeutic anticoagulation will be administered until discharged from hospital, 28 days or death. If the patient is admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician is in agreement. The standard care arm is the administration of LMWH, UFH or fondaparinux at thromboprophylactic doses in the absence of contraindication.
No study specific bloodwork will be ordered aside from a single D-dimer test (if not collected through standard of care) up to and including day 3 after randomization for all participants in both study arms. In those on the active treatment arm who are receiving UFH, the aPTT or UFH anti-Xa will be drawn according to local institutional UFH nomogram protocol guidance. All laboratory results will be collected from standard of care from admission to hospital discharge, death or 28 days, where available. An optional biobanking component will collect blood at baseline and 2 follow up time points.
This study will immediately impact the clinical care of patients with severe COVID-19 internationally, whether the findings are positive or negative, as COVID-19 coagulopathy is a highly prevalent complication of severe COVID-19 and may precede the respiratory manifestations that characterize it.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 465
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Therapeutic anticoagulation Therapeutic anticoagulation Therapeutic anticoagulation with LMWH or UFH (high dose nomogram). The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Therapeutic anticoagulation will be administered until discharged from hospital, 28 days or death. If the patient is admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician is in agreement.
- Primary Outcome Measures
Name Time Method Composite outcome of ICU admission (yes/no), non-invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all-cause death (yes/no) up to 28 days. up to 28 days Composite outcome of ICU admission (yes/no), non-invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all-cause death (yes/no) up to 28 days.
- Secondary Outcome Measures
Name Time Method Composite outcome of ICU admission or all-cause death Up to 28 days Composite outcome of ICU admission or all-cause death
Major bleeding Up to 28 days Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation
ICU-free days alive up to day 28 Up to 28 days ICU-free days alive up to day 28
Organ support-free days alive up to day 28 Up to 28 days Organ support-free days alive up to day 28
Arterial thromboembolism Up to 28 days Arterial thromboembolism
All-cause death Up to 28 days All-cause death
Composite outcome of mechanical ventilation or all-cause death Up to 28 days Composite outcome of mechanical ventilation or all-cause death
Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate Up to 28 days Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate
Renal replacement therapy Up to 28 days Renal replacement therapy defined as continuous renal replacement therapy or intermittent hemodialysis
Ventilator-free days alive up to day 28 Up to 28 days Ventilator-free days alive up to day 28
Heparin induced thrombocytopenia Up to 28 days Heparin induced thrombocytopenia
Changes in D-dimer up to day 3 Up to day 3 D-dimer
Red blood cell transfusion Up to 28 days Red Blood Cell transfusion (greater than or equal to 1 unit)
Hospital-free days alive up to day 28 Up to 28 days Hospital-free days alive up to day 28
Venous thromboembolism Up to 28 days Venous thromboembolism
Trial Locations
- Locations (1)
Hospital das Clínicas da FMUSP
🇧🇷São Paulo, SP, Brazil