Anticoagulation in Patients Suffering From COVID-19 Disease The ANTI-CO Trial

Study Overview
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Brief Summary
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Patients with COVID-19 associated ARDS and mechanical ventilation have a high mortality. Part of the disease is an activation of the coagulation system which seems to contribute to clotformation in the pulmonary bloodstream. Recently we implemented an algorithm applying higher doses of heparins (LMWH). However, this approach could not inhibit clotformation enough. Bivalirudin could prevent clotformation better and support dissolving existing clots. Therefore, we want to compare 50 patients with the standard treatment with 50 patients under bivalirudin treatment which we normally apply in patients with a HIT-syndrome. Our primary outcome measure is oxygenation reflected as P/F ratio.

Detailed Description
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The pandemic of COVID-19, a newly upcoming viral disease caused by SARS-CoV-2, puts the whole worlds health system under pressure. Patients suffering from this disease mainly develop respiratory symptoms, which can lead to severe acute respiratory distress syndrome (ARDS) necessitating ICU admission in 10-20% of the cases admitted to hospital. In addition to these symptoms, patients show lymphopenia, cardiac symptoms and altered coagulation profiles. Although those patients are treated in the ICU the mortality there is more than 20% due to multiorgan failure. One of the recent insights in this disease is its effect on the coagulation system. Meanwhile we know that the coagulation system gets activated. Furthermore, it seems that clot formation takes place in the pulmonary micro-vasculature which could contribute to the widely observed gas-exchange impairment. Therefore, many centers apply empiric anticoagulation for their COVID-patients. At the moment, we at HMC, also apply an empirical anticoagulation protocol as our standard approach. However, this is a symptomatic treatment without good proof. Bivalirudin is a well-known agent which is used in HMC for cases in which anticoagulation is needed, but a contraindication for heparin exists (i.e. HIT syndrome). This drug has an interesting pharmacologic profile. It acts independent of antithrombin (AT), the physiological compound which enhances heparin effects under normal circumstances. This lack of dependence on AT, makes Bivalirudin an attractive choice in light of the contradictory reports on the levels of AT during COVID infection. If AT levels are decreased during the infection, heparin (as well as LMWH) cannot work efficiently, which would render our treatment less effective. Luckily, bivalirudin acts without the support of AT, so we could bypass this problem. In addition, bivalirudin has some fibrinolytic activities. It inhibits clot-bound thrombin which as a result destabilizes the clot rendering it more susceptible to thrombolysis. This property partially supports the dissolving of clots and could support re-opening the pulmonary microcirculation. Objectives: To prove the positive effect of anticoagulation with bivalirudin intravenously on gas-exchange in patients with COVID-19 and respiratory failure on invasive mechanical ventilation.

Official Title
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Anticoagulation in Patients Suffering From COVID-19 Disease-The Anti-Co Trial

Conditions
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Anticoagulation in COVID-19 ARDS

Intervention / Treatment
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* Drug: Bivalirudin Injection
* Drug: Standard treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient (≥ 18 years of age) Positive COVID-test Under mechanical ventilation D-Dimers>1.2 mg/L Exclusion Criteria: Pregnancy Allergy to the drug (bivalirudin) Inherited coagulation abnormalities No informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized controlled trial.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard treatment<br>In this arm the patients will be treated according to our standard anticoagulation protocol. The patients will not be treated with Bivalirudin (the investigational drug). | Drug: Standard treatment<br>* This group will receive standard anticoagulation with LMWH/UFH<br>|
| Experimental: Bivalirudin arm<br>The patients will be anticoagulated according to the institutional HIT-protocol which uses Bivalirudin as anticoagulant. | Drug: Bivalirudin Injection<br>* The patients will receive iv Bivalirudin according to the institutional HIT protocol.<br>* Other names: anticoagulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P/F ratio | the P/F ratio is a surrogate parameter for oxygenation in ARDS. | three days of intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kidney function | The kidney function frequently is deteriorated in COVID-19 patients | three days of intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARDS, COVID-19, Anticoagulation