Defibrotide Therapy for SARS-CoV-2 ARDS

David Frame, Gianni B Scappaticci, Thomas M Braun, Mary Maliarik, Thomas H Sisson, Steven W Pipe, Daniel A Lawrence, Paul G Richardson, Michael Holinstat, Robert C Hyzy, Daniel R Kaul, Kevin S Gregg, Vibha N Lama, Gregory A Yanik, David Frame, Gianni B Scappaticci, Thomas M Braun, Mary Maliarik, Thomas H Sisson, Steven W Pipe, Daniel A Lawrence, Paul G Richardson, Michael Holinstat, Robert C Hyzy, Daniel R Kaul, Kevin S Gregg, Vibha N Lama, Gregory A Yanik

Abstract

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.

Keywords: ARDS; COVID-19; SARS-CoV-2; defibrotide.

Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
A, B, Chest radiographs from patient 6 obtained at study entry (A) and day 3 (B). At the time of study entry, the patient was mechanically ventilated, on 50% Fio2, with positive end-expiratory pressure of 10 cm H2O. The patient subsequently was extubated by day 4, and all supplemental oxygen support was removed by day 7.
Figure 2
Figure 2
Bar graph showing WHO ordinal scores obtained at baseline, day 7, and day 14 from study entry. The day 30 score was obtained 30 days after completion of study therapy. WHO = World Health Organization.
Figure 3
Figure 3
Graph showing overall survival from time of study entry. Shaded area denotes pointwise 95% CI.

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Source: PubMed

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