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.