Defibrotide shows therapeutic potential in SARS-CoV-2-related ARDS

The use of defibrotide therapy in critically ill patients with SARS-CoV-2 acute respiratory distress syndrome (ARDS) is well tolerated and appears to induce promising response rate, as shown in the results of a small open-label trial.

Among the 12 patients (median age 63 years) who received a median defibrotide therapy duration of 7 days, no haemorrhagic or thrombotic complications occurred during therapy. Moreover, there were no reports of adverse events that were drug-related. [Chest 2022;162:346-355]

Four patients met the day-7 pulmonary response parameter, all of whom exhibited a decrease in serum D-dimer levels within the initial 72 hours of therapy.

Three patients died of progressive pulmonary disease 11, 17, and 34 days after study entry. All of them had a baseline Pao₂ to Fio₂ ratio of <125 mm Hg. Meanwhile, the nine survivors (75 percent) remained alive in an outpatient setting, through 64–174 days after defibrotide initiation. These patients had a baseline Pao₂ to Fio₂ ratio of ≥125 mm Hg.

“Historically, the mortality for patients with SARS-CoV-2 ARDS is high, with day 28 mortality rates of 26–61.5 percent in patients requiring mechanical ventilation. The median duration from ICU care to death often is short: within 7 days in several reports,” according to researchers from Michigan Medicine, Ann Arbor, Michigan, US. [Zhonghua Jie He He Hu Xi Za Zhi 2021;44:354-359; Intensive Care Med 2021;47:60-73; JAMA 2020;323:1574-1581; Lancet 2020;395:1763-1770; Mayo Clin Proc 2020;95:1138-1147]

In a prospective cohort study of 4,643 critically ill adults with COVID-19 in northern Europe, mortality rates paralleled the severity of the ARDS at the time of ICU admission (30 percent, 34 percent, and 50 percent, respectively, for mild, moderate, and severe ARDS). In comparison, the 30-day mortality among defibrotide-treated patients in the current study was 17 percent (95 percent confidence interval, 0–35). [Intensive Care Med 2021;47:60-73]

“Although this study was not designed to assess efficacy, the day 30 and 60 survival are promising, considering the high acuity of disease in patients at study entry,” the researchers pointed out.

Specifically, 10 patients received mechanical ventilation while six received vasopressor support at study entry. The median D-dimer of all 12 patients at baseline was 3.25 μg/ml (range, 1.33–12.3).

Defibrotide is a US Food and Drug Administration-approved drug for treating adult and paediatric patients with veno-occlusive disease/sinusoidal obstruction syndrome with renal or pulmonary dysfunction after haematopoietic cell transplantation (HCT). Common toxicities reported in HCT recipients were hypotension, diarrhoea, vomiting, epistaxis, pulmonary alveolar haemorrhage, gastrointestinal haemorrhage, septicaemia, and cerebral haemorrhage. [Blood 2016;127:1656-1665]

“Although the current study followed dosing guidelines established in HCT recipients (6.25 mg/kg IV q6h), we used a much shorter course of therapy (7–14 days) than typically given to HCT recipients, in which 21 days of therapy are administered routinely,” the researchers said, adding that the use of a longer therapy course (>7 days) might not be required, because all responders did so within 7 days of study initiation.

The researchers acknowledged that the pilot study was small and could not address the role of concurrent anticoagulation, with only three of 12 patients receiving heparinization during study therapy. Nevertheless, they argued that that defibrotide therapy could be reasonably considered in patients with less acute pulmonary disease (ie, WHO ordinal scores <6), as backed by data from the current study, in which all patients with severe pulmonary disease at baseline (Pao₂ to Fio₂ ratio <125 mm Hg) died within 60 days of therapy and all patients with a baseline Pao₂ to Fio₂ ratio of >125 mm Hg survived.

“Given that SARS-CoV-2-related thromboinflammation, complement activation, and resultant endothelial damage may begin early in a patient’s clinical course, one might consider initiating defibrotide therapy in any patient hospitalized for SARS-CoV-2 in whom prophylactic heparinization is being considered. Combining an immunomodulatory and antithrombotic agent such as defibrotide with prophylactic doses of low-molecular-weight heparin may be an attractive option to consider in this clinical situation,” they added. [Expert Opin Ther Targets 2021;25:423-433; Blood 2016;127:1719-1727; J Thromb Haemost 2020;18:3113-3115]

The researchers called for additional studies examining earlier initiation of defibrotide therapy, specifically targeting those with lower WHO ordinal scores.