Several years after the first outbreak of COVID 19, scientists are still striving to find a solution in relation to therapy that will prevent severe respiratory failure and mortality in hospitals. A recent breakthrough is an investigator initiated international meta trial, published in eClinicalMedicine in The Lancet (2025), demonstrating that inhaled nebulised unfractionated heparin (UFH) could help to decrease the risk of intubation and death in hospitalised patients to a significant degree.
Such a multinational study is quite convincing and has provided a firm evidence that a drug that has been used widely as an anticoagulant before can also be extremely critical in preventing lung injury and enhancing the outcome of patients with COVID 19.
Background: Why Heparin?
Antiviral and anti inflammatory properties are also shown by heparin, which is well known as an anti-blood clotting drug. Studies in the laboratory have revealed that UFH attaches to the SARS-CoV-2 spike protein, which inhibits the virus to enter the human cells.
Besides this, it has the potential to reduce lung inflammation and microvascular thrombosis which is a good reason why it should be used in the treatment of respiratory infections.
Prior to this meta-trial, pilot studies had indicated that inhaled UFH had the potential to raise the oxygen levels of COVID 19 patients, yet there was not certain evidence of mortality or even the reduction of intubation. This was a universal struggle to bridge that gap.
Design and Participants
A prospective meta-trial that used six randomised clinical trials was carried out by researchers between June 2020 and December 2022 by pooling data on Argentina, Brazil, Egypt, Indonesia, Ireland, and the USA.
A total of 478 hospitalised COVID 19 patients who were yet to be intubated were recruited.
Participants were selected into two categories:
Treatment Group: Given inhaled nebulised unfractionated heparin in addition to usual care.
Control Group: Standard care only (one trial with placebo saline inhalation).
The dosage was slightly different between countries (between 5,000 and 25,000 IU per session), all produced based on hospital grade nebulisers and within 7- 21 days.
Key Findings
Less Intubation and Death.
The main outcome, the intubation or the death, was also much less frequent in patients receiving inhaled UFH:
11.2% of patients who underwent treatment vs. 22.4 in the control group.
Dramatic Drop in Mortality
The hospital mortality decreased to 4.3 percent in the UFH group as compared to 14.3 percent in the controls (OR 0.26, p < 0.001).
The survival curve of the 28 days indicated that there was a definite benefit in the patients taking inhaled heparin.
Shorten the time to stay and recover faster.
The median length of stay of patients who were given inhaled heparin was lower than the control group 6 vs 7 days (p = 0.018). They were also more capable of improving on the World Health Organization Modified Ordinal Clinical Scale (MOCS) of COVID 19 by day 7.
Excellent Safety Profile
The greatest risk of anticoagulant treatment is bleeding yet no pulmonary or systemic bleeding occurred in this study. Significantly, the groups did not differ in terms of blood-clotting times (aPTT) significantly.
Mechanism of action of inhaled Heparin?
UFH inhaled has several protective mechanisms in the lung:
Antiviral effect: Inhibition of the connection of the SARS-CoV-2 spike protein with the ACE2 receptor decreases the entry of the virus into the lung cells.
Anti inflammatory effect: Inhibits pulmonary inflammation by preventing neutrophil extracellular traps (NETs) which are responsible causes of tissue damage.
Anticoagulant effect: HInders microvascular thrombosis, hyaline membrane, and fibrin deposition major aspects of extreme COVID-19 pulmonary injuries.
A combination of these measures, in turn, prevents lung tissue damage, enhances the oxygenation process, and delays the development of a critical illness.
International Cooperation and Corporate Social Responsibility.
The meta trial included the data of 10 hospitals across six countries, which guaranteed the variety of patient demographics and healthcare environments. All trials were approved by the local ethics and were conducted in accordance with the international standards of research. The meta trial was not paid by any pharmaceutical company, which minimized the possibility of bias. Only independent Brazilian and Irish institutions provided funding.
Future Treatment Implication.
The outcomes of this research are not only a promising one but may change the way clinicians treat serious respiratory infections. Should these results be confirmed by large scale trials, nebulised UFH could be a cheap, ubiquitous treatment of COVID 19 and potentially of other types of lung injury like influenza related ARDS or bacterial pneumonia.
This could be easily adopted with little regulation since heparin is already approved and is relatively easy to find in most hospitals.
Limitations Accepted by Researchers.
The findings can be described as encouraging but the authors state that there are certain limitations:
The majority of the individual trials were not placebo controlled but open label.
Countries had different nebuliser devices and doses.
The recruitment was terminated earlier than the anticipated sample size of 712 patients because of the reduction of the pandemic.
In spite of these, the statistical analysis demonstrated that the benefits were similar across all of the countries, and no substantial heterogeneity was found in the results.
Conclusion
The international meta-trial conducted by the INHALE-HEP Collaborative Research Group provides strong evidence to support the idea that inhaled nebulised unfractionated heparin is effective and harmless in reducing the intubation and mortality of hospitalised patients with COVID 19.
Its antiviral, anti inflammatory and anticoagulant action makes it a unique multi mechanistic treatment approach that fulfills the fundamental pathophysiology of COVID 19 lung damage. Having no significant safety issues and high clinical effectiveness, inhaled heparin becomes a prospective, scalable intervention in the field of respiratory care in the world.
The results of this study as the authors conclude should be substantiated by future controlled clinical trials that are desperately much needed to validate these findings and investigate its potential past COVID 19 potentially offering a new era of treatment of acute lung injury.
References
Van Haren F.M.P. et al. Efficacy of inhaled nebulised unfractionated heparin to prevent intubation or death in hospitalised patients with COVID-19: An international meta-trial of randomised clinical studies. eClinicalMedicine, 2025, Elsevier https://doi.org/10.1016/j.eclinm.2025.103339