Preventing COVID-19 Complications With Low- and High-dose Anticoagulation (COVID-HEP)

Preventing COVID-19-associated Thrombosis, Coagulopathy and Mortality With Low- and High-dose Anticoagulation: a Multicentric Randomized, Open-label Clinical Trial

The ongoing COVID-19 pandemic affects millions of humans worldwide and has led to thousands of acute medical hospitalizations. There is evidence that hospitalized cases often suffer from an important infection-related coagulopathy and from elevated risks of thrombosis. Anticoagulants may have positive effects here, to reduce the burden of thrombotic disease and the hyperactivity of coagulation, and may also hold beneficial anti-inflammatory effects against sepsis and the development of ARDS.

The investigators hypothesize that high-dose anticoagulants, compared with low-dose anticoagulants, lower the risk of venous and arterial thrombosis, disseminated intravascular coagulation (DIC) and mortality. This open-label controlled trial will randomize hospitalized adults with severe COVID-19 infection to therapeutic anticoagulation vs. thromboprophylaxis during the hospital stay.

Study Overview

• Status: Terminated
• Conditions: COVID; Sars-CoV2
• Intervention / Treatment: Drug: Enoxaparin

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 3

Contacts and Locations

Study Locations

• Switzerland
  • Geneva, Switzerland
    • Geneva University Hospitals
  • Lausanne, Switzerland
    • Centre Hospitalier Universitaire Vaudois (CHUV)
  • Locarno, Switzerland
    • Ospedale Regionale di Locarno
  • Sion, Switzerland
    • Hôpital du Valais

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria: adult patient with COVID-19 infections, admitted to:

• an acute non-critical medical ward with admission D-dimer levels >1,000ng/mL, or
• an acute critical ward (ICU, intermediate care unit)

Exclusion Criteria:

• ongoing or planned therapeutic anticoagulation for any other indication
• contra-indication to therapeutic anticoagulation
• hypersensitivity to heparin
• personal history of heparin-induced thrombocytopenia
• suspected or confirmed bacterial endocarditis
• bleeding events or tendency due to a suspected or confirmed hemostatic bleeding disorder
• organic lesion prone to bleeding
• platelet count <50G/L, Hb level <80g/L
• ongoing or recent (<30 days) major bleeding, ischemic stroke, trauma, surgery
• use of dual antiplatelet therapy
• pregnancy
• bodyweight <40kg or >150kg.
• end of life care setting
• unwillingness to consent
• ongoing participation in a COVID-19 randomized clinical trial testing another therapeutic intervention

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Therapeutic anticoagulation; Participants will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin) or intravenous unfractionated heparin, from admission until the end of hospital stay or clinical recovery.	Drug: Enoxaparin; Two different doses of anticoagulation; Other Names: Unfractionated heparin
Active Comparator: Prophylactic anticoagulation; Participants will be treated with prophylactic doses of subcutaneous low-molecular-weight heparin (enoxaparin) or unfractionated heparin, from admission until the end of hospital stay or clinical recovery. If hospitalized in the intensive care unit, they will receive an augmented thromboprophylaxis regimen as standard of care.	Drug: Enoxaparin; Two different doses of anticoagulation; Other Names: Unfractionated heparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite outcome of arterial or venous thrombosis, disseminated intravascular coagulation and all-cause mortality	Risk of arterial or venous thrombosis, disseminated intravascular coagulation and all-cause mortality	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial thrombosis	Risk of ischemic stroke, myocardial infarction and/or limb ischemia	30 days
Venous thromboembolism	Risk of symptomatic venous thromboembolism or asymptomatic proximal leg deep vein thrombosis	30 days
Disseminated intravascular coagulation	Risk of DIC	30 days
All-cause mortality	Risk of all-cause mortality	30 days
Sepsis-induced coagulopathy	Risk of SIC	30 days
Acute respiratory distress syndrome	Risk of ARDS	30 days
Durations of hospital stay, ICU stay, ventilation	Number of days with these care processes	30 days
Sequential organ failure assessment score	Highest score per participant	30 days
Clinical deterioration	Risk of clinical deterioration	30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major bleeding	Risk of ISTH-defined major bleeding	30 days
Clinically relevant non-major bleeding	Risk of ISTH-defined CRNMB	30 days
Heparin-induced thrombocytopenia	Risk of documented HIT	30 days
PaO2/FiO2 index	Measures of PaO2/FiO2 among participants with mechanical ventilation	30 days

Collaborators and Investigators

• Sponsor: University Hospital, Geneva

Publications and helpful links

General Publications

• Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
• Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739.
• Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020 Jun;7(6):e438-e440. doi: 10.1016/S2352-3026(20)30145-9. Epub 2020 May 11. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2020
• Primary Completion (Actual): June 2, 2021
• Study Completion (Actual): June 2, 2021

Study Registration Dates

• First Submitted: April 7, 2020
• First Submitted That Met QC Criteria: April 9, 2020
• First Posted (Actual): April 15, 2020

Study Record Updates

• Last Update Posted (Actual): September 14, 2021
• Last Update Submitted That Met QC Criteria: September 7, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: anticoagulation; thrombosis; heparin
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Enoxaparin; Calcium heparin
• Other Study ID Numbers: 2020-00794

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No