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Low-molecular-weight heparin for the prevention of clinical worsening in severe non-critically ill COVID-19 patients: a joint analysis of two randomized controlled trials

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Abstract

Coronavirus disease 2019 (COVID-19) carries a high risk of vascular thrombosis. However, whether a specific anticoagulation intensity strategy may prevent clinical worsening in severe COVID-19 patients is still debated. We conducted a joint analysis of two randomized controlled trials, COVID-19 HD (NCT044082359) and EMOS-COVID (NCT04646655), to assess the efficacy and safety of two anticoagulant regimens in hospitalized severe COVID-19 patients. Subjects with COVID-19-associated respiratory compromise and/or coagulopathy were randomly assigned to low (4000 IU qd) or high (70 IU Kg−1 every 12 h) enoxaparin dose. The primary efficacy endpoint was clinical worsening within 30 days, defined as the occurrence of at least one of the following events, whichever came first: in-hospital death, evidence of arterial or venous thromboembolism, acute myocardial infarction, need for either continuous positive airway pressure (CPAP) or non-invasive ventilation (NIV) in patients receiving standard oxygen therapy or none at randomization, and need for mechanical ventilation in any patient. The safety endpoint was major bleeding. We estimated the relative risk (RR) and its 95% confidence interval (CI) for the outcomes. Among 283 patients included in the study (144 in the low-dose and 139 in the high-dose group), 118 (41.7%) were on NIV or CPAP at randomization. 23/139 (16.5%) patients in the high-dose group reached the primary endpoint compared to 33/144 (22.9%) in the low-dose group (RR 0.72, 95% CI 0.45–1.17). No major bleeding was observed. No significant differences were found in the clinical worsening of hospitalized COVID-19 patients treated with high versus low doses of enoxaparin.

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Data availability

Data collected and analyzed for the current study are available upon reasonable request and approval of the ETHYCO investigators and of the Ethics Committee.

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Funding

None.

Author information

Author notes

  1. Roberto D'Amico and Marco Marietta have shared last authorship.

Authors and Affiliations

  1. Division of Internal Medicine, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy

    Maddalena Alessandra Wu, Alba Taino, Pietro Facchinetti, Lucia Trombetta, Francesca Tonelli & Chiara Cogliati

  2. Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy

    Cinzia Del GIovane & Roberto D’Amico

  3. Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland

    Cinzia Del GIovane

  4. Unità di Supporto Statistico Metodologico per la Ricerca Clinica Azienda Ospedaliero-Universitaria di Modena, Modena, Italy

    Cinzia Del GIovane, Roberto Vicini & Roberto D’Amico

  5. Division of Anesthesiology and Intensive Care, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy

    Riccardo Colombo

  6. Infectious Diseases Unit, University of Modena and Reggio Emilia, Modena, Italy

    Giovanni Dolci & Erica Franceschini

  7. Columbus Center Clinic, Milan, Italy

    Massimo Arquati

  8. Division of Haematology, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy

    Umberto Russo

  9. Division of Cardiology, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy

    Diego Ruggiero

  10. Hematology Unit, Azienda Ospedaliero-Universitaria, Modena, Italy

    Valeria Coluccio & Marco Marietta

  11. Servizio Formazione, Ricerca e Innovazione, Azienda Ospedaliero-Universitaria di Modena, Ospedale Policlinico, Modena, Italy

    Pasquale Mighali

  12. Division of Internal Medicine, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, Fatebenefratelli Hospital, University of Milan, Milan, Italy

    Claudia Gabiati

Authors
  1. Maddalena Alessandra Wu
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Consortia

the ETHYCO Study Group

  • Spinello Antinori
  • , Roberto Vicini
  • , Daniela Aschieri
  • , Antonio Brucato
  • , Lucio Brugioni
  • , Giacomo Casalini
  • , Enrico Clini
  • , Mauro Codeluppi
  • , Giovanni Dolci
  • , Alba Taino
  • , Roberto D’Amico
  • , Elena Condorelli
  • , Marco Marietta
  • , Riccardo Colombo
  • , Silvia Di Stasi
  • , Massimo Arquati
  • , Pasquale Mighali
  • , Augusto B Federici
  • , Pietro Facchinetti
  • , Cosimo Franco
  • , Marco Gemma
  • , Annita Gozzi
  • , Antonella Ielpo
  • , Davide Imberti
  • , Andrea Magnacavallo
  • , Marco Marietta
  • , Marianna Meschiari
  • , Lucia Trombetta
  • , Cristina Mussini
  • , Manuela Nebuloni
  • , Chiara Picchi
  • , Antonello Pietrangelo
  • , Giovanni Pinelli
  • , Giuliano Rizzardini
  • , Valeria Coluccio
  • , Diego Ruggiero
  • , Pierachille Santus
  • , Luca Sarti
  • , Matteo Silva
  • , Paola Vandelli
  • , Erica Franceschini
  • , Claudia Gabiati
  • , Francesca Tonelli
  • , Umberto Russo
  •  & Maddalena Alessandra Wu

Contributions

Conception of the work: MAW, MA, UR, MM, VC, RV, RD, PM; Methodology and data curation: MAW, CDG, RC, GD, MA, DR, RV, RD, URo; Data acquisition/investigation: MAW, GD, RC, AT, EF, PF, LT, FT, LB, GC, EC, DA, MC, EC, SDS, EF, CF, MG, AG, AI, DI, AM, DR, MMi, CM, C. Picchi, AP, GP, GR, LS, MS, PV, AT, CG, FT; Formal analysis: CDG, RD and RV; Supervision: MM, SA, CC, ABF, MN, GR, P.S; Project administration: MAW, MM, MA, RD; Writing—original draft: MAW; Writing—review and editing: MAW, CDG, RC, GD, MA, DR, RV, RD, UR, MM. The present study is based on an analysis of data of two trials. Underlying data were verified by the authors of the original studies. All authors contributed to interpretation of the results, critically revised the manuscript, and approved its final version.

Corresponding author

Correspondence to Maddalena Alessandra Wu.

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Conflict of interest

The authors have no conflicts of interest to disclose.

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The members of the ETHYCO Study Group are mentioned in the Appendix section.

Supplementary Information

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Supplementary file1 (DOCX 1582 KB)

Appendix

Appendix

Complete list of the participants to the ETHYCO (Enoxaparin at THerapeutic or prophYlactic dose in severe COVID) Study Group: III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy: Spinello Antinori; Department of Biomedical and Clinical Sciences, University of Milan, Italy: Spinello Antinori, Antonio Brucato, Manuela Nebuloni, Pierachille Santus; Columbus Center Clinic, Milan, Italy: Massimo Arquati; U.O.SD Cardiologia Riabilitativa, Hospital of Piacenza, Piacenza, Italy: Daniela Aschieri; Division of Internal Medicine, ASST Fatebenefratelli Sacco, Fatebenefratelli Hospital, Milan, Italy: Antonio Brucato; Medicina Interna d'Urgenza e Area Critica, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy: Lucio Brugioni, Luca Sarti; Respiratory Disease Unit, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy: Enrico Clini; Infectious Disease Unit, Hospital of Piacenza, Piacenza, Italy: Mauro Codeluppi; Division of Anesthesiology and Intensive Care, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy: Riccardo Colombo; Hematology Unit, Azienda Ospedaliero-Universitaria, Modena, Italy: Valeria Coluccio; Division of Internal Medicine, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy: Chiara Cogliati, Elena Condorelli, Pietro Facchinetti, Alba Taino, Francesca Tonelli, Maddalena Alessandra Wu; Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy: Roberto D'Amico, Cinzia Del Giovane; Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland: Cinzia Del Giovane; UOC Pneumologia e UTIR, AUSL Piacenza, Piacenza, Italy: Silvia Di Stasi, Cosimo Franco; Infectious Diseases Unit, University of Modena and Reggio Emilia, Modena, Italy: Giovanni Dolci, Erica Franceschini, Marianna Meschiari, Cristina Mussini; Division of Haematology, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy: Augusto B. Federici; Division of Anesthesiology and Intensive Care, ASST Fatebenefratelli Sacco, Fatebenefratelli Hospital, Milan, Italy: Marco Gemma; Servizio Formazione, Ricerca e Innovazione, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy: Annita Gozzi, Pasquale Mighali, Paola Vandelli; Internal Medicine Unit, Medical Department, Hospital of Piacenza, Piacenza, Italy: Davide Imberti; U.O.C. Pronto Soccorso/ Obi/ Medicina D’Urgenza, Hospital of Piacenza, Piacenza, Italy: Andrea Magnacavallo; Pathology Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy: Manuela Nebuloni; Medicina Interna, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy: Antonello Pietrangelo; I Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy: Giuliano Rizzardini; Division of Cardiology, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy: Diego Ruggiero; Division of Respiratory Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy: Pierachille Santus; U.O.SD Medicina D’Urgenza, Hospital of Piacenza, Piacenza, Italy: Matteo Silva; Unità di Supporto Statistico Metodologico per la Ricerca Clinica Azienda Ospedaliero-Universitaria di Modena, Modena, Italy: Roberto Vicini.

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Wu, M.A., Del GIovane, C., Colombo, R. et al. Low-molecular-weight heparin for the prevention of clinical worsening in severe non-critically ill COVID-19 patients: a joint analysis of two randomized controlled trials. Intern Emerg Med 19, 71–79 (2024). https://doi.org/10.1007/s11739-023-03439-w

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