Discussion
This exploratory study showed clinical benefit for nebulised UFH on top of standard of care for patients hospitalised with COVID-19. The primary endpoints showed a reduction in mortality, reaching significance in the mITT population, but no difference in duration of hospital stay. For the secondary endpoints, positive effects of nebulised UFH were observed on MOCS change and rates of mechanical ventilation. Overall, nebulised UFH appeared to be well tolerated.
The two analysis populations of key interest were the ITT and mITT. The purpose of the mITT was to exclude subjects from both treatment arms with rapid disease progression within 24 hours of admission, resulting in mechanical ventilation or death. There is limited scope for nebulised UFH to alter the disease trajectory in these subjects, as their disease trajectory implies a poor prognosis. Furthermore, these subjects received few (<4) or no UFH doses before ventilation or death; the potential benefits of nebulised UFH are unlikely to be realised after such short treatment duration is subjects with rapidly progressive disease. While the mortality benefit in this study was greatest (and significant) in the mITT population (odds ratio 0.20), a numerical (non-significant) trend was observed in the ITT population (odds ratio 0.51). A post-hoc analysis of subjects who received at least 6 nebulised UFH doses showed a greater benefit (odds ratio 0.1, p=0.0184), compatible with the concept that at least 24 hrs UFH treatment allows a greater possibility for the clinical benefit of this treatment to be realised.
The secondary endpoints for MOCS change and rates of ventilation showed evidence for nebulised UFH clinical efficacy. Taken together with the mortality efficacy signals observed, these results support larger studies of the benefits of nebulised UFH on COVID-19. Our results will also be used as part of an ongoing meta-trial involving a higher number of patients with COVID-19 [1]. The results of this study are consistent with a recently published case series of 98 patients showing that nebulised UFH administration in hospitalised patients with COVID-19 is safe and potentially beneficial [15], and earlier studies reporting a beneficial effect in patients with ARDS pre-pandemic [5].
The duration of hospital stay (co-primary endpoint) did not show any differences between groups. This outcome measure can be influenced by a variety of factors including age, co-morbidities and rate of recovery from COVID-19. It is probable that our study was too small to see any difference in this outcome measure. Additionally, this endpoint was likely influenced by hospital pressures during the peak of the pandemic to create space for newly diagnosed COVID-19 patients by the rapid (subjective) discharge of improving patients.
We had planned to recruit a sample size for this trial of 100 study subjects. However, we only managed to recruit 76 patients into the study due to changes in the prevalence of COVID-19 patients in the state of Sao Paulo between February 25th, 2021, when the study started and July 14th, 2021 when the Steering Committee decided to end recruitment and analyse the data. The smaller than anticipated study size the possibility to conduct sub-group analysis. Other limitations included the heterogeneity of the clinical status of patients on admission to hospital, the change in vaccination status through the progress of the trial and the open label status of the treatment arms.
Whilst our study is in a limited number of patients, it suggests that use of nebulised UFH is safe and may provide additional benefit in reducing mortality in patients hospitalised with COVID-19 on top of standard of care, including patients who were also receiving systemic heparin [12, 16]. Whilst a number of effective treatments have now been identified to treat hospitalised patients with COVID-19 [15], the recent emergence of new variants of SARs-CoV-2, that appear to be highly transmissible and possibly escape the impact of many of the available vaccines, shows that there is still a need to continue to seek effective treatments for this and future virally mediated pneumonias. The ability of heparin administered by inhalation to be anti-viral and prevent infection of mammalian cells with SARs-CoV [1, 11], coupled with its well-recognised ability to reduce inflammation by binding various cytokines implicated in the cytokine storm often associated with COVID-19 [1, 10], as well as the well-recognised anti-coagulant effect of this drug of benefit in dealing with the alveolar coagulation seen in such patients, suggests that further controlled, larger studies of nebulised UFH are warranted, given that this a widely available and affordable medicine.