Modulation of thromboinflammation in hospitalized COVID-19 patients with aprotinin, low molecular weight heparin, and anakinra: The DAWn-Antico study.

Abstract

Background:

Thromboinflammation plays a central role in severe COVID-19. The kallikrein pathway activates both inflammatory pathways and contact-mediated coagulation. We investigated if modulation of the thromboinflammatory response improves outcomes in hospitalized COVID-19 patients.

Methods:

In this multicenter open-label randomized clinical trial (EudraCT 2020-001739-28), patients hospitalized with COVID-19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low molecular weight heparin (LMWH; SC 50 IU/kg twice daily on the ward, 75 IU/kg twice daily in intensive care). Additionally, patients with predefined hyperinflammation received the interleukin-1 receptor antagonist anakinra (100 mg IV four times daily). The primary outcome was time to a sustained 2-point improvement on the 7-point World Health Organization ordinal scale for clinical status, or discharge.

Findings:

Between 24 June 2020 and 1 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N = 67 vs. SOC N = 35). Twenty-five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50-1.19], p = 0.24) or mortality (intervention n = 3 [4.6%] vs. SOC n = 2 [5.7%], HR 0.82 [CI 0.14-4.94], p = 0.83). There was one treatment-related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleeding.

Conclusions:

In hospitalized COVID-19 patients, modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID-19.

• Authors: Matthias M Engelen, Quentin Van Thillo, Albrecht Betrains, Iwein Gyselinck, Caroline P Martens, Valérie Spalart, Anna Ockerman, Caroline Devooght, Joost Wauters, Jan Gunst, Carine Wouters, Christophe Vandenbriele, Steffen Rex, Laurens Liesenborghs, Alexander Wilmer, Philippe Meersseman, Greet Van den Berghe, Dieter Dauwe, Ann Belmans, Michiel Thomeer, Tom Fivez, Dieter Mesotten, David Ruttens, Luc Heytens, Ilse Dapper, Sebastiaan Tuyls, Brecht De Tavernier, Peter Verhamme, Thomas Vanassche, DAWn Consortium Members
• Journal: Research and practice in thrombosis and haemostasis (Res Pract Thromb Haemost) Vol. 6 Issue 7 Pg. e12826 (Oct 2022) ISSN: 2475-0379 [Electronic] United States
• PMID: 36324831 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).