Chest
Volume 162, Issue 2, August 2022, Pages 346-355
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Critical Care: Original Research
Defibrotide Therapy for SARS-CoV-2 ARDS

This article was presented at the American Society of Hematology (ASH) Conference, Atlanta, GA, December 11-14, 2021 (abstract 3237).
https://doi.org/10.1016/j.chest.2022.03.046Get rights and content

Background

SARS-CoV-2-related ARDS is associated with endothelial dysfunction and profound dysregulation of the thrombotic-fibrinolytic pathway. Defibrotide is a polyanionic compound with fibrinolytic, antithrombotic, and antiinflammatory properties.

Research Question

What is the safety and tolerability of defibrotide in patients with severe SARS-CoV-2 infections?

Study Design and Methods

We report a prospective, open-label, single-center safety trial of defibrotide for the management of SARS-CoV-2-related ARDS. Eligible participants were 18 years of age or older with clinical and radiographic signs of ARDS, no signs of active bleeding, a serum D-dimer of more than twice upper limit of normal, and positive polymerase chain reaction-based results for SARS-CoV-2. Defibrotide (6.25 mg/kg/dose IV q6h) was administered for a planned 7-day course, with serum D-dimer levels and respiratory function monitored daily during therapy.

Results

Twelve patients (median age, 63 years) were treated, with 10 patients receiving mechanical ventilation and 6 receiving vasopressor support at study entry. The median D-dimer was 3.25 μg/ml (range, 1.33-12.3) at study entry. The median duration of therapy was 7 days. No hemorrhagic or thrombotic complications occurred during therapy. No other adverse events attributable to defibrotide were noted. Four patients met the day 7 pulmonary response parameter, all four showing a decrease in serum D-dimer levels within the initial 72 h of defibrotide therapy. Three patients died of progressive pulmonary disease 11, 17, and 34 days after study entry. Nine patients (75%) remain alive 64 to 174 days after initiation of defibrotide. Day 30 all-cause mortality was 17% (95% CI, 0%-35%). All patients with a baseline Pao2 to Fio2 ratio of ≥ 125 mm Hg survived, whereas the three patients with a baseline Pao2 to Fio2 ratio of < 125 mm Hg died.

Interpretation

The use of defibrotide for management of SARS-CoV-2-related ARDS proved safe and tolerable. No hemorrhagic or thrombotic complications were reported during therapy, with promising outcomes in a patient population with a historically high mortality rate.

Trial Registry

ClinicalTrials.gov; No.: NCT04530604; URL: www.clinicaltrials.gov

Key Words

ARDS
COVID-19
defibrotide
SARS-CoV-2

Abbreviations

EC
endothelial cell
HCT
hematopoietic cell transplantation
NET
neutrophil extracellular trap
PAI-1
plasminogen activator inhibitor 1
tPA
tissue plasminogen activator
WHO
World Health Organization

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