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.

Keywords: COVID‐19; anakinra; aprotinin; heparin; inflammation; low‐molecular‐weight; thrombosis.

FIGURE 1

Study overview. BID, twice daily; CrCl, creatinine clearance; CT, computed tomography; ICU, intensive care unit; IU, international units; IV, intravenous; LMWH, low molecular weight heparin; PCR, polymerase chain reaction; QD, once daily; QID, four times a day; SC, subcutaneous.

FIGURE 2

Study profile. Low molecular weight heparin, LWMH (CONSORT flowchart also in Appendix S1).

FIGURE 3

Outcomes. (A) primary outcome of time to sustained 2‐point improvement on 7‐point World Health Organization scale or hospital discharge. (B) Secondary outcome of daily clinical status. ECMO, extracorporeal membrane oxygenation; MV, mechanical ventilation.