Discussion
The pooled analyses in this updated systematic review and meta-analysis
indicated no evidence of any significant association between ACEIs/ARBs
and any COVID-19 related clinical outcomes; however, the sub-group
analyses revealed evidence of a negative impact of ACEIs/ARBs use and
some COVID-19 related clinical outcomes such as higher odds of
hospitalisation, ICU admission and ventilator use. Contrastingly, a
positive impact in terms of lower odds of death/ICU admission, as a
composite outcome, and a higher rate of hospital discharge. Furthermore,
our study findings, for the first time, showed inter-class variations
between ACEIs and ARBs effects on COVID-19 clinical outcomes with low
quality evidence indicating lower risk of acquiring COVID-19, less
severe COVID-19 infection, higher rate of ICU admission and ventilator
use with ARBs but not ACEIs.
Our study findings also showed no significant association between
ACEIs/ARBs and mortality, severe COVID-19 infection, or positive tests
for COVID-19, in agreement with two previously published systematic
reviews (29, 30). This was despite the inclusion of more recently
published studies (18, 27, 37, 38, 46, 47, 50), which implies
consistency of evidence. This is encouraging given the controversies
surrounding hydroxychloroquine. Furthermore, these non-significant
associations were also observed for additional COVID-19 related outcomes
including ICU admission, hospitalisation, and hospital discharge.
However, unlike the previous two systematic reviews (29, 30), our study
found evidence of associations between ACEI/ARB use and certain COVID-19
clinical outcomes. Whilst the pooled estimate of the sub-group analyses
indicated a higher odds of ICU admission with ACEIs/ARBs among studies
conducted in the USA (23, 40, 41) and peer-reviewed studies (23, 25,
41), all these studies were of poor quality and none performed adjusted
analyses to account for potential confounders. Confounding by indication
is of particular concern with comorbidities such as CVD and diabetes
associated with more severe COVID-19 morbidity and mortality (4-6).
Similarly, the observed significant associations between ACEIs/ARBs use
and high odds of ventilator use and hospital discharge rates were from
Benelli et al (38) with crude analysis and non-peer-reviewed and
Ip et al (27) and Zeng et al (26) which were both non-peer
reviewed, of poor quality and used crude analyses. Similarly, the
studies in the pooled analyses that showed significant association of
ARBs use and ICU admission (38, 39), lower risk of acquiring COVID-19
infection (45), and severe infection (18, 19) were of poor quality, used
unadjusted/crude analyses, and/or non-peer reviewed. In terms of
duration of hospital stay, Yang et al (25) and Zeng et al(26) both reported a reduction in hospital stay with ACEIs/ARBs;
however, it was not possible to combine them in the meta-analysis as
they used different measure of effects with the former reporting the
outcome as a mean difference while the latter as a median.
On the other hand, our study findings showed high quality evidence on
the association of ACEIs/ARBs and higher odds of hospitalisation but
lower odds of death/ICU admission (as a composite endpoint). The higher
odd of hospitalisation was observed in the sub-group analyses of studies
conducted in the USA (40, 41), used adjusted analyses (44),
peer-reviewed (41) and of good quality (44); whereas the studies for
lower death/ICU admission were from Europe (37, 42), used adjusted
analyses and of good quality (37), although all of them were non-peer
reviewed.
Several hypotheses have been suggested to explain the negative and
positive effects of ACEIs/ARBs use on COVID-19 clinical outcomes. The
former is thought to be related to ACEIs/ARBs potential ability to
up-regulate ACE2, the cell entry point for COVID-19; hence facilitate
COVID-19 cell entry and its subsequent infectivity/pathogenicity (52);
however, the evidence to date demonstrates ACE2’s up-regulation
consistently in cardiac and renal tissues in response to ARBs therapy
but not ACEIs (4, 53); this observed difference between ARBs and ACEIs
has been suggested to be due to the increased level of angiotensin-II,
which occurs following ARBs treatment but not ACEIs, which in turn
imposes an increased substrate load on ACE2 enzyme requiring its
upregulation (54). Importantly, it should be emphasised that evidence of
ACEIs/ARBs induced ACE2 upregulation in the respiratory tracts, which is
the key entry system for COVID-19, is lacking (53). Furthermore, it
should be noticed that alteration in angiotensin-II level, which is only
one substrate of ACE2’s multiple substrates, is unlikely to result in
any meaningful differences in ACE2 substrate load, hence its
upregulation (53); additionally, the fact that people from various
sexes, ages, and races are all susceptible to COVID-19 infection
suggests that physiological expression of ACE2 might already be
sufficient for COVID-19 infection; thus any further ACE2 upregulation
might not have effects on the risk/severity of COVID-19 infection (25).
Together, these evidence indicate that the concerns around ACEIs/ARBs
use in COVID-19 patients might be unjustifiable. On the other hand, the
protective effect hypothesises on ACEIs/ARBs protecting against lung
injury, through blockage of the harmful angiotensin II-
AT1R axis, which gets activated by impairment of ACE2
activity as a result of ACE2’s downregulation results from ACE2’s
binding with COVID-19 virus; additionally, the corresponding increase in
angiotensin II and angiotensin I, due to ACEIs/ARBs use, would activate
the protective axis and hence reducing COVID-19 viral pathogenicity (4).
Genetic ACE2 polymorphism among some individuals has been also suggested
as potential factor explaining, at least partially, the harmful effects
on ACEIs/ARBs among COVId-19 patients (55); but this needs further
investigation.