A multicenter randomized clinical trial of modulation of host thromboinflammatory response in hospitalized patients with COVID-19: The DAWn-Antico study

ABSTRACT

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. Aim(s) To investigate whether modulation of this pronounced thromboinflammatory response can improve outcomes in hospitalized patients with severe COVID-19. Method(s) 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 12 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. Result(s) 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 mug/L;SD 991.9 mug/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.