ANTIcoagulation in Severe COVID-19 Patients

NCT ID: NCT04808882

Last Updated: 2022-09-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 353 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-14
• Study Completion Date: 2022-03-13

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.

Conditions

Severe COVID-19 Pneumonia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Low dose prophylactic anticoagulation

LD-PA

Group Type: EXPERIMENTAL

Tinzaparin, Low dose prophylactic anticoagulation

Intervention Type: DRUG

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.

High dose prophylactic anticoagulation

HD-PA

Group Type: EXPERIMENTAL

Tinzaparin, High dose prophylactic anticoagulation

Intervention Type: DRUG

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.

Therapeutic anticoagulation

TA

Group Type: EXPERIMENTAL

Tinzaparin,Therapeutic anticoagulation

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

LD-PA; HD-PA; TA

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Vincent LABBE, MD

Role: STUDY_DIRECTOR

Assistance Publique Hopitaux de Paris (AP-HP)

Locations

Henri Mondor Hospital

Créteil, , France

Countries

France

References

Labbe V, Contou D, Heming N, Megarbane B, Razazi K, Boissier F, Ait-Oufella H, Turpin M, Carreira S, Robert A, Monchi M, Souweine B, Preau S, Doyen D, Vivier E, Zucman N, Dres M, Fejjal M, Noel-Savina E, Bachir M, Jaffal K, Timsit JF, Picos SA, Mariotte E, Martis N, Juguet W, Melica G, Rondeau P, Audureau E, Mekontso Dessap A; ANTICOVID Investigators. Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia: The ANTICOVID Randomized Clinical Trial. JAMA Intern Med. 2023 Jun 1;183(6):520-531. doi: 10.1001/jamainternmed.2023.0456.

Reference Type: DERIVED

PMID: 36946232 (View on PubMed)

Labbe V, Contou D, Heming N, Megarbane B, Ait-Oufella H, Boissier F, Carreira S, Robert A, Vivier E, Fejjal M, Doyen D, Monchi M, Preau S, Noel-Savina E, Souweine B, Zucman N, Picos SA, Dres M, Juguet W, Mariotte E, Timsit JF, Turpin M, Razazi K, Gendreau S, Baloul S, Voiriot G, Fartoukh M, Audureau E, Mekontso Dessap A. Comparison of standard prophylactic, intermediate prophylactic and therapeutic anticoagulation in patients with severe COVID-19: protocol for the ANTICOVID multicentre, parallel-group, open-label, randomised controlled trial. BMJ Open. 2022 Apr 26;12(4):e059383. doi: 10.1136/bmjopen-2021-059383.

Reference Type: DERIVED

PMID: 35473740 (View on PubMed)

Other Identifiers

2020-A03531-38

Identifier Type: REGISTRY

Identifier Source: secondary_id

APHP201624

Identifier Type: -

Identifier Source: org_study_id