ANTIcoagulation in Severe COVID-19 Patients
- Conditions
- Severe COVID-19 Pneumonia
- Interventions
- Drug: Tinzaparin, Low dose prophylactic anticoagulationDrug: Tinzaparin, High dose prophylactic anticoagulationDrug: Tinzaparin,Therapeutic anticoagulation
- Registration Number
- NCT04808882
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
Coronavirus disease 2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may predispose patients to thrombotic disease due to a state of profound inflammation, platelet activation, and endothelial dysfunction leading to respiratory distress and increased mortality. The incidence of macrovascular thrombotic events varies from 10 to 30% in COVID-19 hospitalized patients depending on the type of arterial or vein thrombosis captured and severity of illness . Observational results in patients receiving routine low-dose prophylactic anticoagulation (LD-PA), several institutions have recently released guidance statement to prevent macrovascular thrombotic events with dose escalation anticoagulation. In these recommendations, high-dose prophylactic anticoagulation (HD-PA) and therapeutic anticoagulation (TA) can be employed either empirically or based on the body mass index and increased D-dimer values. No randomized trial has validated this approach, and other recent recommendations challenge this approach. Microvascular thrombotic events are also of major concern in critically ill patients with COVID-19, even in the absence of obvious macrovascular thrombotic events. A large review of autopsy findings in COVID-19-related deaths reported micro thrombi in small pulmonary vessels. More generally, COVID-19-induced endothelitis and coagulopathy across vascular beds of different organs lead to widespread microvascular thrombosis with microangiopathy and occlusion of capillaries. Thus, in severe COVID-19 patients requiring oxygen therapy without initial macrovascular thrombotic event, a HD-PA or a TA could be beneficial by limiting the extension of microvascular thrombosis and the evolution of the lung and multi-organ microcirculatory dysfunction. In a large observational cohort of 2,773 COVID-19 patients, a lower in-hospital mortality in ventilated patients receiving TA as compared to those receiving PA (29.1% vs. 62.7%). Our hypothesis is dual: i) first, that TA and HD-PA strategies mitigate microthrombosis and each limit the progression of COVID-19, including respiratory failure and multi-organ dysfunction, with in fine a decreased mortality and duration of disease, as compared to a low-dose PA; ii) second, that TA outperforms HD-PA in this setting.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 353
-
Age ≥ 18 years ;
-
Severe COVID-19 pneumonia, defined by:
- A newly-appeared pulmonary parenchymal infiltrate; AND
- a positive RT-PCR (either upper or lower respiratory tract) for COVID-19 (SARS-CoV-2); AND
- WHO progression scale ≥ 5 (on The Who ordinal scale)
-
Written informed consent (patient, next of skin or emergency situation).
-
In view of the exceptional and urgent situation, affiliation to a social security scheme will not be a criterion for inclusion.
- Pregnancy and breast feeding woman;
- Postpartum (6 weeks);
- Extreme weights (<40 kg or >100 kg);
- Patients admitted since more than 72 hours to the hospital (if the WHO ordinal scale is 5 at time of inclusion) or since more than 72 hours to the intensive care unit (if the WHO ordinal scale is 6 or more at time of inclusion);
- Need for therapeutic anticoagulation (except for COVID-related pulmonary thrombosis);
- Bleeding event related to hemostasis disorders, acute clinically significant bleed, current gastrointestinal ulcer or any organic lesion with high risk for bleeding
- Platelet count < 50 G/L;
- Within 15 days of recent surgery, within 24 hours of spinal or epidural anesthesia;
- Any prior intracranial hemorrhage, enlarged acute ischemic stroke, known intracranial malformation or neoplasm, acute infectious endocarditis;
- Severe renal failure (creatinine clearance <30 mL/min);
- Iodine allergy;
- Hypersensitivity to heparin or its derivatives including low-molecular-weight heparin;
- History of type II heparin-induced thrombocytopenia;
- Chronic oxygen supplementation;
- Moribund patient or death expected from underlying disease during the current admission;
- Patient deprived of liberty and persons subject to institutional psychiatric care;
- Patients under guardianship or curatorship;
- Participation to another interventional research on anticoagulation.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Low dose prophylactic anticoagulation Tinzaparin, Low dose prophylactic anticoagulation LD-PA High dose prophylactic anticoagulation Tinzaparin, High dose prophylactic anticoagulation HD-PA Therapeutic anticoagulation Tinzaparin,Therapeutic anticoagulation TA
- Primary Outcome Measures
Name Time Method All-cause mortality Day-28 Number of days to clinical improvement Day-28 Clinical improvement will be assessed through a seven-category ordinal scale derived from the WHO scale, using the following categories: 1. not hospitalized with resumption of normal activities; 2. not hospitalized, but unable to resume normal activities; 3. hospitalized, not requiring supplemental oxygen; 4. hospitalized, requiring supplemental oxygen; 5. hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6. hospitalized, requiring ECMO, invasive mechanical ventilation, or both; and 7. death. As all included patients will at least require oxygen supplementation, live discharge from hospital will represent a minimal 2-points decrease in the 7-points scale, thus a clinical improvement.
- Secondary Outcome Measures
Name Time Method Proportion of patients with at least one thrombotic event at Day-28 Day-28 Proportion of patients with any bleeding event at Day-28 Day-28 Number of days to clinical improvement assessed through a seven-category ordinal scale derived from the WHO scale Day-28 Number of days alive and free from supplemental oxygen at Day-28 Day-28 Length of hospital stay Day-28 Quality of life and disability at assessed using a quality of life questionnaire Day-90 Proportion of patients with at least one major bleeding event (MBE) at Day-28 Day-28 Score on the seven-category ordinal scale derived from the WHO Ordinal scale Day-28 Net clinical benefit of anticoagulation assessed by the absence of thrombotic event, major bleeding event, Heparin Induced Thrombocytopenia and all-cause death Day-28 All-cause deaths Day-28 and Day-90 Proportion of patients with at least one life-threatening bleeding event at Day-28 Day-28 Proportion of patients with Heparin Induced Thrombocytopenia at Day-28 Day-28 Proportion of patients needing intubation at Day-28 Day-28 Number of days alive and free from vasopressors at Day-28 Day-28 D-dimers levels Day-7 Sepsis-Induced Coagulopathy Score (SCS) Day-7 Score on WHO Ordinal Scale Day-28 Number of days alive and free from invasive mechanical ventilation at Day-28 Day-28 Length of intensive care unit stay Day-28
Trial Locations
- Locations (1)
Henri Mondor Hospital
🇫🇷Créteil, France