Inhaled heparin slashes ventilation, death in COVID patients, analysis suggests

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A meta-trial of randomized clinical studies conducted in 6 countries suggests that the use of inhaled heparin dramatically reduced the risk of intubation, death, and in-hospital death in hospitalized COVID-19 patients.

Drug has unique set of properties

For the study, published late last week in eClinicalMedicine, researchers in Argentina, Brazil, Egypt, Indonesia, Ireland, and the United States prospectively analyzed pooled data from trials involving 478 adult COVID-19 patients who were hospitalized but didn't require mechanical ventilation.

The patients had been randomly assigned to receive either inhaled nebulized unfractionated heparin (UFH) in addition to standard care or standard care alone to prevent intubation or death or in-hospital death from June 2020 to December 2022. In total, 238 patients were in the UFH group, and 240 were controls (215 of whom received standard care, and 25 of whom were given a placebo).

The median patient age was 54 years, and most were men. The dosage, duration, and delivery method differed among study protocols, and follow-up ranged from 28 to 60 days.

Previous preclinical and clinical studies of inhaled nebulised UFH in lung injury, have shown a positive effect on pulmonary coagulation, inflammation, oxygenation and other lung injury parameters.

Just under one-third of all patients received supplemental oxygen, another 25% received high-flow nasal oxygen or non-invasive ventilation, 79% received corticosteroids, and 25% were given the antiviral drug remdesivir.

A widely available, cost-effective drug used to treat and prevent blood clots, UFH is typically injected. This formulation, which targets the lungs directly, "has a strong rationale as a treatment for severe respiratory infections, including COVID-19, due to its antiviral, anti-inflammatory, and anti-coagulant properties, which may prevent viral entry, lung injury progression, and pulmonary thrombosis," the study authors wrote.

"Previous preclinical and clinical studies of inhaled nebulised UFH in lung injury, have shown a positive effect on pulmonary coagulation, inflammation, oxygenation and other lung injury parameters," they added.

Possible application in other respiratory diseases

In-hospital death among nebulized-UFH recipients was 4.3%, compared with 14.3% in controls (odds ratio [OR], 0.26), and the hazard ratio for 28-day mortality was significantly lower in the UFH group, at 0.36.

There was no heterogeneity in treatment effect between studies, suggesting that the overall effect was consistent between studies, and no difference was observed in treatment effect between patients given supplementary oxygen at baseline and those who weren't.

An analysis using a two-stage individual patient data meta-analysis combining aggregate data confirmed significant differences between the groups in terms of intubation or death (risk ratio [RR], 0.53) or in-hospital death (RR, 0.32).

We're aiming to conduct another trial in Europe to confirm its effectiveness in fighting other common respiratory infections such as influenza and RSV [respiratory syncytial virus].

Frank van Haren, MD, PhD

After excluding data from the only controlled study, conducted in the United States, a consistent reduction in intubation or death was seen at the longest follow up in the UFH group compared with controls (OR, 0.51). UFH recipients also had a shorter median hospital length of stay than the control group (6 vs 7 days) when death before hospital release was treated as a competing event. No safety issues or pulmonary or systemic bleeding were reported among UHF recipients.

Co-senior author Clive Page, PhD, of King's College London, said in a university news release that no other drug has heparin's combination of anti-viral, anti-inflammatory, and anti-coagulant properties. "We know it’s only a matter of time until the next pandemic, and there are still COVID-19 patients who get very sick," he said. "This is a great weapon to have up our sleeve."

The drug would also be beneficial for patients with a weakened immune system, such as those with cancer, when they have a respiratory infection, the authors said, adding that further development is needed before broad adoption of inhaled UHF. The team is currently developing an improved formulation designed specifically for inhalation.

Lead author Frank van Haren, MD, PhD, of Australian National University, said that inhaled UHF could stop any respiratory pathogen from infecting patients and damaging the lungs and that even patients with non-infectious lung disease could benefit.

"We're aiming to conduct another trial in Europe to confirm its effectiveness in fighting other common respiratory infections such as influenza and RSV [respiratory syncytial virus]," he said. "And because it's inexpensive, it's much more accessible for those from low-income countries."