TOPLINE:

Inhaled nebulized unfractionated heparin (UFH) added to standard care reduced the odds of intubation or death in nonintubated patients hospitalized with COVID compared with standard care alone. It also showed a favorable safety profile, with no pulmonary or major bleeding events.

METHODOLOGY:

• A prospective meta-trial pooling six randomized clinical trials evaluated whether inhaled nebulized UFH reduces the risk for intubation or death in 478 patients hospitalized for COVID (median age, 54 years; 61.4% men) who did not immediately require invasive mechanical ventilation.
• The trials were conducted at 10 hospitals across Argentina, Brazil, Egypt, Indonesia, Ireland, and the US, with enrollment from June 2020 to December 2022.
• Patients with polymerase chain reaction-confirmed SARS-CoV-2 infection within the past 21 days were randomly assigned to receive nebulized UFH plus standard care (n = 238) or standard care alone (n = 240).
• The median total dose of nebulized UFH was 225,000 IU, and the median number of doses was 15.
• The primary outcome was intubation or death within 28 days of randomization. Secondary outcomes were hospital mortality, 28-day mortality, and COVID resolution or progression; safety outcomes were also assessed.

TAKEAWAY:

• Patients who received nebulized UFH plus standard care had 57% lower odds of intubation or death than those who received standard care alone (odds ratio [OR], 0.43; P = .001).
• In-hospital mortality was markedly lower in the UFH group than in the standard care group (OR, 0.26; P < .001); 28-day mortality was significantly lower as well (hazard ratio, 0.36; P = .004).
• The UFH group had a 30% higher likelihood of earlier discharge after accounting for death before discharge and differences between the studies (P = .018).
• Fewer patients in the UFH group than in the standard care group required high-flow nasal oxygen or noninvasive ventilation by day 7. No adverse events, including pulmonary hemorrhage or major bleeding, were reported in either group.

IN PRACTICE:

“The positive results from this study have implications for the future treatment of lung injury arising from COVID-19 and potentially from other causes,” the authors of the study wrote.

“Robust clinical trials evaluating inhaled nebulized UFH in hospitalized patients with lung injury, particularly those resulting from viral and bacterial respiratory infections, are now needed,” they added.

SOURCE:

This study was led by Frank M.P. van Haren, Australian National University, College of Health and Medicine, Canberra, Australia. It was published online on September 27, 2025, in eClinicalMedicine.

LIMITATIONS:

Most studies included in this meta-trial were unblinded and lacked placebos. The meta-trial design had drawbacks relative to a single multisite trial with a uniform protocol, as individual studies followed different protocols, delivery methods, and UFH doses. Differences in UFH source and preparation across countries may have introduced additional variability. Finally, the results do not apply to patients with COVID requiring invasive mechanical ventilation.

DISCLOSURES:

The meta-trial was sponsored by the INHALE-HEP Collaborative Research Group; no direct funding was received. The Brazilian study was funded by The J.R. Moulton Charity Trust, and the Irish study received funding through a Science Foundation Ireland (SFI) grant to Cúram, the SFI’s Centre for Research in Medical Devices. Some authors disclosed receiving research grants or honoraria, serving on several data safety monitoring boards, holding patents or stock or stock options, or having other ties with various organizations, including pharmaceutical and healthcare companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.