ANTIcoagulation in Severe COVID-19 Patients: a Multicenter, Parallel-group, Open-label, Randomized Controlled Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 353
- 试验地点
- 1
- 主要终点
- All-cause mortality
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Low dose prophylactic anticoagulation
LD-PA
干预措施: Tinzaparin, Low dose prophylactic anticoagulation (Drug)
High dose prophylactic anticoagulation
HD-PA
干预措施: Tinzaparin, High dose prophylactic anticoagulation (Drug)
Therapeutic anticoagulation
TA
干预措施: Tinzaparin,Therapeutic anticoagulation (Drug)
结局指标
主要结局
All-cause mortality
时间窗: Day-28
Number of days to clinical improvement
时间窗: 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.
次要结局
- 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)