Concentration-effect Relationship of Enoxaparin for Thromboembolic Prevention

NCT ID: NCT04520620

Last Updated: 2020-08-20

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-02
• Study Completion Date: 2020-07-10

Brief Summary

Patients with COVID-19 have special demographic characteristics including thromboembolic risk factors .

The pharmacokinetics of enoxaparin administered subcutaneously in the intensive care unit patient are not described.

Finally, given the lack of knowledge on the pharmacokinetic/pharmacodynamic properties of enoxaparin in intensive care unit patients infected with SARS-CoV-2, we propose to conduct a prospective multicenter cohort study to collect the biological data necessary for its study.

Detailed Description

D-dimers greater than 1 μg/mL are a prognostic factor for 28-day mortality (odds ratio=18, 2-128). The use of preventive doses of enoxaparin (4,000 to 6,000 anti-Xa per day) or unfractionated heparin (10,000 to 15,000 IU per day) has been associated with a reduction in mortality of approximately one-third in patients with D-dimer levels greater than 3 μg/mL or those with sepsis-induced coagulopathy (SIC (sepsis-induced coagulopathy) score > 4)

For the intensive care unit patient, the preventive enoxaparin dosages were increased to 4,000 anti-Xa IU twice daily and to 6,000 anti-Xa IU twice daily if the patient weighs more than 120 kg. Curative treatment is even proposed in cases of marked inflammatory syndrome and/or hypercoagulability (e.g. fibrinogen > 8 g/L or D-Dimer > 3 μg/mL or 3000 ng/mL) even without symptomatic thrombosis.

Given the lack of data on the use of these high "prophylactic" doses of enoxaparin, it is proposed that anti-Xa activity be monitored after the 3rd injection, and then regularly in the event of renal failure (because LMWHs are renally eliminated), to look for overdosage exposing a higher risk of bleeding. It is also proposed to regularly monitor (at least every 48 hours) the hemostasis of patients in search of multivisceral failure, or of coagulopathy of consumption which will require a re-evaluation of the heparin therapy dosage, these events being associated with an increased risk of haemorrhage.

Conditions

Sars-CoV2

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

enoxaparin treatment

Patients infected by SARS-CoV-2 in intensive care unit with enoxaparin treatment will be included.

They will have enoxaparin pharmacokinetic and ultrasound of the lower limbs at 7, 14 and 21 days after inclusion.

Group Type: EXPERIMENTAL

Lovenox 40 MG in 0.4 mL Prefilled Syringe

Intervention Type: DRUG

Patients with a high thrombotic risk:

In patients with a BMI included between < 30 kg/m² and > 30 kg/m² without added thrombotic risk factor:

• Enoxaparin 40 milligrams, (4,000 IU) twice daily subcutaneously (SC) for the entire duration of the intensive care hospitalization
• if weight > 120 kg, enoxaparin 60 milligrams (6000 IU) twice daily subcutaneously for the entire duration of the intensive care hospitalization

Patients with a very high thrombotic risk:

In patients with a BMI > 30 kg/m2 with added thrombotic risk factor (active cancer, recent personal history of thromboembolic event), or if iterative or unusual catheter thromboses, or if marked inflammatory syndrome and/or hypercoagulability (e.g. fibrinogen > 8 g/L or D-Dimer > 3 μg/ml or 3000 ng/ml)

• Enoxaparin sodium curative at a dose of 100 IU/kg/12h subcutaneously (SC) not to exceed a dose of 100 mg/12 hours

Ultrasound of the lower limbs

Intervention Type: DEVICE

A 4-point compression ultrasound will be performed. In case of suspicion, an angiologist will perform to check the absence of legs thrombosis.

Interventions

Lovenox 40 MG in 0.4 mL Prefilled Syringe

Patients with a high thrombotic risk:

In patients with a BMI included between < 30 kg/m² and > 30 kg/m² without added thrombotic risk factor:

• Enoxaparin 40 milligrams, (4,000 IU) twice daily subcutaneously (SC) for the entire duration of the intensive care hospitalization
• if weight > 120 kg, enoxaparin 60 milligrams (6000 IU) twice daily subcutaneously for the entire duration of the intensive care hospitalization

Patients with a very high thrombotic risk:

In patients with a BMI > 30 kg/m2 with added thrombotic risk factor (active cancer, recent personal history of thromboembolic event), or if iterative or unusual catheter thromboses, or if marked inflammatory syndrome and/or hypercoagulability (e.g. fibrinogen > 8 g/L or D-Dimer > 3 μg/ml or 3000 ng/ml)

• Enoxaparin sodium curative at a dose of 100 IU/kg/12h subcutaneously (SC) not to exceed a dose of 100 mg/12 hours

Intervention Type: DRUG

Ultrasound of the lower limbs

A 4-point compression ultrasound will be performed. In case of suspicion, an angiologist will perform to check the absence of legs thrombosis.

Intervention Type: DEVICE

Other Intervention Names

enoxaparin

Eligibility Criteria

Inclusion Criteria

• Aged > 18 ans
• SARS-CoV-2 infected intensive care unit patients
• Diagnosis of SARS-CoV-2 respiratory infection was made with a nasopharyngeal swab or a deep respiratory specimen.
• Patient receiving enoxaparin treatment as part of care or as part of a clinical trial for the prevention or treatment of thromboembolic venous disease.
• Patient affiliated or entitled to a social security scheme

Exclusion Criteria

• Creatinine clearance according to Cockcroft and Gault <30ml/min.
• Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins (LMWHs)
• History of immune-mediated heparin-induced thrombocytopenia (HIT) in the last 100 days or in the presence of circulating antibodies
• Active clinically significant bleeding or a condition associated with a high risk of bleeding, such as a recent hemorrhagic stroke, gastrointestinal ulcer, the presence of a malignant tumour at high risk of bleeding, recent brain, spinal or ophthalmologic surgery, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysm or major intrarachidian or intracerebral vascular abnormalities.
• Spinal, epidural or locoregional anaesthesia or anaesthesia when enoxaparin sodium is used for curative treatment within the previous 24 hours

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

Sponsors

CHU Saint-Etienne - Laboratoire de Pharmacologie - Toxicologie - Gaz du sang

UNKNOWN

Sponsor Role: collaborator

Centre Hospitalier Universitaire de Saint Etienne

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Paul ZUFFEREY, MD

Role: PRINCIPAL_INVESTIGATOR

CHU SAINT-ETIENNE

Locations

Groupement Hospitalier des portes de Province

Montélimar, , France

Centre Hospitalier de Roanne

Roanne, , France

CHU de Saint-Etienne

Saint-Etienne, , France

Clinique Mutualiste

Saint-Etienne, , France

Countries

France

Other Identifiers

2020-001823-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

20CH089

Identifier Type: -

Identifier Source: org_study_id