OC 13.5 - A Multicenter Randomized Clinical Trial of Modulation of Host Thromboinflammatory Response in Hospitalized Patients with COVID-19: The DAWn-Antico study

Sunday, July 10, 2022

11:45 AM – 12:00 PM

Location: ExCel Center, S11B

Presentation Format: In-Person

Presenting Author(s)

Matthias M Engelen, MD

MD, PhD candidate
University Hospitals Leuven, Belgium
Leuven, Vlaams-Brabant, Belgium

Co-Author(s)

JW

Joost Wauters

MD PhD
University Hospitals Leuven
Leuven, Vlaams-Brabant, Belgium
JG

Jan Gunst

MD PhD
University Hospitals Leuven
Leuven, Vlaams-Brabant, Belgium
CW

Carine Wouters

MD PhD
University Hospitals Leuven
Leuven, Vlaams-Brabant, Belgium
CV

Christophe Vandenbriele

MD PhD
University Hospitals Leuven
Leuven, Vlaams-Brabant, Belgium
SR

Steffen Rex

MD PhD
University Hospitals Leuven
Leuven, Vlaams-Brabant, Belgium
MT

Michiel Thomeer

MD PhD
Ziekenhuis Oost-Limburg (ZOL)
Genk, Limburg, Belgium
TF

Tom Fivez

MD
Ziekenhuis Oost-Limburg (ZOL)
Genk, Limburg, Belgium
DM

Dieter Mesotten

MD
Ziekenhuis Oost-Limburg (ZOL)
Genk, Limburg, Belgium
DR

David Ruttens

MD PhD
Ziekenhuis Oost-Limburg (ZOL)
Genk, Limburg, Belgium
LH

Luc Heytens

MD
Ziekenhuizen GasthuisZusters Antwerpen (GZA)
Antwerpen, Antwerpen, Belgium
PV

Peter Verhamme, MD, PhD

MD, PhD
University Hospitals Leuven, Belgium
Leuven, Vlaams-Brabant, Belgium
Thomas Vanassche, MD PhD

MD, PhD
University Hospitals Leuven, Belgium
Leuven, Vlaams-Brabant, Belgium

Background: Thromboinflammation in severe COVID-19 is associated with disease severity and inferior outcome. Evidence suggests that the kallikrein pathway potentially plays a vital role in COVID-19 associated thromboinflammation as it both activates downstream inflammatory pathways and contact-mediated coagulation.

Aims: To investigate whether modulation of this pronounced thromboinflammatory response can improve outcomes in hospitalized patients with severe COVID-19.

Methods: This multicenter randomized clinical trial was approved by the ethics committee and supported by the KU Leuven COVID-19 fund and Research Foundation Flanders (FWO). After informed consent, eligible patients were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention (figure 1). The intervention consisted of off-label - kallikrein-inhibiting - aprotinin combined with low molecular weight heparin (LMWH). Additionally, patients with predefined hyperinflammation were treated with the interleukin-1 receptor antagonist anakinra. The primary endpoint was time to sustain a 2-point improvement in the WHO ordinal scale for clinical status.

Results: Three hospitals in Belgium included 102 patients (35 SOC vs. 67 intervention). Twenty-five patients from the intervention group (37%) were treated with anakinra. Patients had elevated D-dimers (mean 1012.4 µg/L; SD 991.9 µg/L) and C-reactive protein (mean 81.4 mg/L; SD 59.6 mg/L) at admission confirming baseline activation of coagulation and inflammatory pathways. During hospitalization, 37% of patients were admitted to the ICU (29% SOC vs. 42% intervention), and 20% needed invasive ventilation (12% SOC vs. 25% intervention). The intervention did not affect the time to sustained clinical improvement or hospital discharge (figure 2), nor secondary clinical endpoints. Except for D-dimers at day 3, there was no significant C-reactive protein or D-dimer reductions. There were no differences in treatment-related adverse events.

Conclusion(s): In hospitalized COVID-19 patients, additional modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra was feasible and safe but did not improve clinical nor biochemical outcomes.