NCT04808882

ANTIcoagulation in Severe COVID-19 Patients

ANTIcoagulation in Severe COVID-19 Patients: a Multicenter, Parallel-group, Open-label, Randomized Controlled Trial

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 353 (actual)
• Sponsor: Assistance Publique - Hôpitaux de Paris · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Severe COVID-19 Pneumonia

Interventions

Type	Name	Description
DRUG	Tinzaparin, Low dose prophylactic anticoagulation	Participants randomized to the LD-PA strategie will receive the low weight molecular heparin (LMWH) tinzaparin, considering its contraindications, recommended dose ranges and monitoring if applicable, as follows: LD-PA : 3500 IU/24h. Depending on the type of tinzaparin pre-filled syringe available in the participating center, the dose of 4000 IU/24h will be allowed in place of 3500 IU/24h. If tinzaparin is not punctually available, the use of enoxaparin will be allowed as follows: LD-PA: 4000 IU/24h. After day-14, or hospital discharge, or in case of an indication for TA, or of serious adverse event related to anticoagulation, the investigational anticoagulation strategy will be discontinued and anticoagulation treatment will be left at the discretion of attending physicians. Recommendations for the management of COVID-19 pneumonia will be followed, including the use of dexamethasone. These recommendations will be subject to modifications based on the new literature data.
DRUG	Tinzaparin, High dose prophylactic anticoagulation	Participants randomized to the HD-PA strategie will receive the low weight molecular heparin (LMWH) tinzaparin, considering its contraindications, recommended dose ranges and monitoring if applicable, as follows: HD-PA : 7000 IU/24h. If tinzaparin is not punctually available, the use of enoxaparin will be allowed as follows: HD-PA: 4000 IU/12h. After day-14, or hospital discharge, or in case of an indication for TA, or of serious adverse event related to anticoagulation, the investigational anticoagulation strategy will be discontinued and anticoagulation treatment will be left at the discretion of attending physicians. Recommendations for the management of COVID-19 pneumonia will be followed, including the use of dexamethasone. These recommendations will be subject to modifications based on the new literature data.
DRUG	Tinzaparin,Therapeutic anticoagulation	Participants randomized to the TA strategie will receive the low weight molecular heparin (LMWH) tinzaparin, considering its contraindications, recommended dose ranges and monitoring if applicable, as follows: TA : 175 IU/kg/24h. If tinzaparin is not punctually available, the use of enoxaparin will be allowed as follows: TA: 100 IU/kg/12h. After day-14, or hospital discharge, or in case of an indication for TA, or of serious adverse event related to anticoagulation, the investigational anticoagulation strategy will be discontinued and anticoagulation treatment will be left at the discretion of attending physicians. Recommendations for the management of COVID-19 pneumonia will be followed, including the use of dexamethasone. These recommendations will be subject to modifications based on the new literature data.

Timeline

• Start date: 2021-04-14
• Primary completion: 2022-01-10
• Completion: 2022-03-13
• First posted: 2021-03-22
• Last updated: 2022-09-08

Locations

1 site across 1 country: France