Professor Clive Page, emeritus professor of pharmacology at King’s College London, outlines how an international collaboration has shown that inhaled heparin – repurposed during the pandemic – can reduce the need for ventilation and mortality among hospitalised patients with Covid-19, highlighting its potential as a low-cost treatment for respiratory infections and future pandemics.
Early in the Covid-19 pandemic, the use of inhaled nebulised unfractionated heparin (UFH) was proposed on the basis that it could help block the entry of the SARS-CoV-2 virus into epithelial cells.
However, its primary benefit was thought to lie in its unique profile encompassing broad anti-inflammatory effects and local anticoagulant action within the lungs, which may reduce alveolar coagulation and hyaline membrane formation – key factors that impair gas exchange in patients hospitalised with active infection.
A 2022 pilot study of UFH was published as a multicentre, single-arm case series of 98 hospitalised patients with Covid-19, many of whom were already receiving systemic heparin as part of their standard of care.
Outcomes included plasma activated partial thromboplastin time (APTT) levels at baseline and at peak during treatment, and adverse events, including bleeding, to ensure there were no further anticoagulant effects from the additional inhaled anticoagulant.
Inhaled UFH was safe, with minimal effect on systemic anticoagulation and no clinically significant increase in APPT in patients receiving concomitant anticoagulation. We believe the lack of a safety signal with UFH is due to its high negative charge, which reduces bioavailability.
Inhaled UFH and the INHALEd meta-trial
Continuing on from this, a study published in July 2020, led by Professor Frank van Haren of the Australian National University (ANU), showed that patients at risk of developing Covid-19 acute respiratory distress syndrome (ARDS) benefited from the off-label use of inhaled UFH.
During the pandemic, investigators across six countries, led by a team at ANU and in collaboration with King’s College London, established the international INHALEd Unfractionated HEParin for the Treatment of Hospitalised Patients With COVID-19 (INHALE-HEP) study.
The aim was to evaluate the safety and effectiveness of inhaled UFH as a treatment for patients admitted to hospital with confirmed SARS-CoV-2 infection, with the aim of reducing the risk of intensive care unit admission and ventilation.
INHALE-HEP was conducted as a prospective, investigator-initiated international meta-trial, designed to pool individual patient data from multiple ongoing randomised clinical trials in real time.
The meta-trial approach differs from a traditional meta-analysis by prospectively harmonising protocols and combining data as studies are conducted, enabling faster generation of robust evidence.
INHALEd meta-trial findings
Eligible studies were prospective, randomised trials comparing inhaled UFH plus standard of care with standard care alone in hospitalised adults with confirmed Covid-19 who did not require immediate invasive mechanical ventilation.
While individual trials retained flexibility in dosing, frequency, delivery systems and treatment duration, all contributing studies agreed to collect a predefined core dataset and to align on key clinical outcomes.
Patients were enrolled across multiple countries and healthcare settings, improving generalisability and allowing inclusion despite regional variability in case numbers.
The primary outcome for the meta-trial was a composite of intubation or death within 28 days or the longest follow-up available, reflecting progression to severe respiratory failure. Secondary outcomes included measures of oxygenation, clinical deterioration and mortality.
A total of 478 patients from 10 hospitals across Argentina, Brazil, Egypt, Indonesia, Ireland and the US were included, and results demonstrated a statistically significant reduction in the primary outcome, with UFH associated with lower odds of intubation or death compared with standard care.
Mortality alone was also significantly reduced, and no major safety concerns or cases of pulmonary or systemic bleeding were reported in patients receiving UFH.
Overcoming practical challenges in INHALEd-HEP
A key challenge in conducting this multicentre trial was the variation in protocols across participating countries, including differences in heparin formulations, dosing regimens, delivery devices and treatment duration.
Despite this heterogeneity, inhaled UFH demonstrated a highly significant clinical benefit, with reductions in both the need for intubation and overall mortality.
To further address concerns around variability and strengthen the evidence base, journal referees recommended conducting a complementary conventional meta-analysis alongside the prospective meta-trial.
The meta-analysis incorporated all eligible studies, including a placebo-controlled trial from the US, to test the robustness of the findings and assess consistency across diverse clinical settings.
The results mirrored those of the meta-trial, again showing reduced intubation rates and mortality, thereby reinforcing confidence in the treatment effect despite differences in study design and implementation.
Other practical challenges arose during the pandemic, notably concerns that aerosolised delivery could increase viral transmission, which limited the use of placebo controls in several countries.
In addition, the viscous nature of heparin made timely and consistent inhalation administration more difficult in clinical settings.
Evidence from the Brazilian study, published separately, indicated that clinicians observed patient improvement after approximately six doses, with earlier case series also showing rapid gains in oxygenation, suggesting a relatively early therapeutic effect.
A collaborative success
The success of this study reflects an unprecedented level of international collaboration and the willingness of people in different companies to work together during a global health emergency.
By prospectively pooling data across multiple trials, we were able to recruit a larger, more diverse patient population, enabling the generation of clear, robust efficacy and safety signals.
These findings build on earlier evidence, including the Brazilian study, which had already demonstrated similar benefits in a smaller patient cohort and highlighted the potential of inhaled UFH as an effective treatment.
Importantly, we have now established a strong international research network that is well positioned to evaluate inhaled UFH – or indeed other therapeutic interventions – in larger, coordinated trials for other respiratory diseases.
Where next for heparin?
Work is underway to develop a novel heparin formulation for inhalation. One of the key challenges identified in the meta-trial was that all participating centres used territory-specific heparin products ‘off label’, which had originally been approved for systemic administration and were not optimised for delivery to the lungs.
Indeed, we are planning to undertake a platform phase 3 study of an optimal and patent protected inhalable formulation and device combination product for the treatment of the complications of respiratory infections. The aim is to reduce the risk of progression to ARDS, thereby limiting the need for intensive care admission and mechanical ventilation.
If a standardised and more efficient inhaled formulation can be developed, it may enable wider use of inhaled heparin across a range of respiratory diseases and reduce reliance on off-label prescribing, where optimal dosing strategies remain unclear.
Author
Clive Page OBE PhD FRSB FBPhS (Hon) FFPM (Hon)
Emeritus professor of pharmacology, King’s College London, UK
