Discussion
This umbrella review for the first time combined all the available
evidence so far from observational studies on the impact of ACEIs/ARBs
on COVID-19 clinical outcomes (47 systematic review studies which
reported 213 meta-analyses) into one pooled estimate. The collective,
combined pooled estimates indicated evidence of statistically
significant reduction in mortality, death/ICU admission and severe
COVID-19 infection in association with ACEIs/ARBs use, but significant
increase in the risk of hospitalisation (Table 1). Interestingly, there
was no evidence of any significant association between ACEIs, or ARBs
and any of the nine COVID-19 related clinical outcomes analysed in our
study.
Although the magnitude of observed impact of ACEIs/ARBs use on reducing
mortality was decreasing as the quality of studies improved (Table 2),
the evidence were overall mostly consistent across all the sub-group
analyses including a greater impact among studies that included
hypertensive patients compared with studies that did not record the
hypertension status of their study population (Table 2). In terms of
death/ICU admission, the quality of the evidence was even better because
the impact of ACEIs/ARBs use was greater and significant only among:
moderate-quality studies, peer-reviewed studies and studies with
hypertensive patients; however, the impact was significant regardless of
whether the measure of effects was crude or adjusted, even though the
impact was greater among studies with adjusted measure of effects
compared those studies with crude measure of effects (Table 2). In
contrast, the quality of the evidence for the impact of ACEIs/ARBs use
on severe COVID-19 was low since the significant reduction was only
observed among critically-low quality studies and in fact, the
significant association disappeared as the quality of the studied
enhanced from critically low quality to either low or moderate quality
(Table 2).
In terms of the impact of ACEIs/ARBs on hospitalisation, the quality of
the evidence was low because the significant association was not
apparent when the data were analysed by the quality of the studies, even
though the magnitude of the effect was almost consistent across the
various quality of the studies; besides, the significant increase in
hospitalisation was observed only among: studies that reported adjusted
measure of effects, non-peer reviewed studies and studies that did not
recorded the hypertensive status of their study population (Table 2).
The sub-group analyses demonstrated low-quality evidence regarding the
different impact of ACEIs and ARBs (as separate groups) (Table 2). This
observed difference 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 (61); hence facilitates COVID-19 virus cell
entry and its subsequent infectivity/pathogenicity (62). Furthermore,
the increase in ACE2 activity demonstrated in patients with
hypertension, either due to the pathophysiology of hypertension itself
(63) or administration of ACEIs/ARBs as antihypertensive medications
(64), could at least partially explain some of our study findings as why
ACEIs/ARBs had significant greater impact on certain COVID-19 clinical
outcomes (i.e., mortality, death/ICU admission) only among studies that
included patient with hypertension.
Several hypotheses (related to the pathophysiology of COVID-19 infection
and functions of ACE2) can explain the observed impact of ACEIs/ARBs in
our current studies. The adverse negative effects of ACEIs/ARBs could be
due to ACEIs/ARBs ability to cause upregulation of ACE2 expression
(the cell entry point for
COVID-19); hence facilitate and enhance COVID-19 viral binding and cell
entry (64); whereas the positive protective effects could be through
ACEIs/ARBs blockage of the harmful
angiotensin
II- AT1R axis and their effects on angiotensin II expression leading to
subsequent increase in the level of the protective angiotensin 1-7 and
1-9 which have anti-inflammatory and vasodilatory effects; hence
potentially attenuating the cardiac and pulmonary damages (2). Genetic
ACE2 polymorphism among some individuals has been also suggested as
potential factor explaining, at least partially, the harmful effects on
ACEIs/ARBs on COVID-19 outcomes (65).
It is worth to highlight that our study findings are still important
despite the recently published randomised clinical trial (RCT) (66)
which found insignificant differences in the mean number of days
alive/out of the hospital between those assigned to discontinue vs
continue ACEIs or ARBs. This is because of certain points that are
related to the findings from this RCT. First, this RCT was designed to
evaluate the impact of continuing ACEIs or ARBs vs. their
discontinuation after contracting COVID-19 rather than evaluating
ACEIs/ARBs use vs. non-use of these medication which was the focus of
most of the observational studies involved in our current study.
Secondly, the RCT included only patients with mild or moderate COVID-19
with more than half of the participants (57%; n=376) having mild
COVID-19, and evaluated only two COVID-19 related clinical outcomes,
namely days alive (mortality) and out of hospital days; hence leaving a
big gap in the evidence around ACEIs/ARBs’ impact on other important
COVID-19 clinical outcomes as well as limiting generalisability to
patients with severe COVID-19. Furthermore, although the RCT’s
participants were all hypertensive patients, about one-third
(~31%) and ~1% had diabetes and heart
failure, respectively, which further limits the generalisability of the
RCT’s findings to these conditions for which ACEIs/ARBs are commonly
indicated. Moreover, the RCT’s participants were all from Brazil and
hence extending the findings to other races or ethnicities will be
limited; this is particularly importantly because there are evidence
demonstrating that there are potential genetic variants of renin,
angiotensinogen, ACE, angiotensin II and ACE2 among various populations
that influence the function of the renin-angiotensin aldosterone system;
hence affecting someone’ response to the COVID-19 infection (67).
Strengths and limitations
This review presents the most comprehensive systematic overview on the
impact of RAAS inhibitors on COVID-19 related clinical outcomes, with a
wide range of sensitivity (sub-group) analyses to assess the robustness
of the evidence. None of the pooled meta-analysis estimates for the nine
studied outcomes was affected/dominated by an individual study. Although
most of the included studies were classified as ‘low’ or ‘critically
low’ quality using AMSTAR 2 tool, it is widely acknowledged that the
AMSTAR 2 tool has a high standard with most reviews rated as ‘critically
low’ (68, 69). The AMSTAR 2 tool is also prone to subjective biases (70)
, and assessment results are at the discretion of the reviewers
regarding what is a “comprehensive” literature search or
“satisfactory” explanation of heterogeneity or risk of bias assessment
(70); therefore, quality assessment was conducted fully independent in
this review. Alternatives tools to AMSTAR 2 exist such as the ROBIS
tool, however the measurement categories are found to be broadly similar
with the AMSTAR 2 tool considered more reliable (70).
Conclusion
Collective evidence so far from observational studies indicate a good
quality evidence on the significant association between ACEIs/ARBs use
and reduction in death and death/ICU admission (as a composite outcome).
Additionally, ACEIs/ARBs use was found to be associated with a
significant reduction in severe COVID-19 but a significant increase in
hospitalisation; however, the evidence for these two outcomes was of
poor quality; hence, cautious interpretation of these findings is
required. Interestingly, findings for some of the clinical outcomes were
dependent on whether the included patients had hypertension or not.
Overall, our study findings further support the current recommendations
of not discontinuing ACEIs/ARBs therapy in patients with COVID-19 due to
the lack of good quality evidence on their harm but rather it could be
beneficial to patients.