Discussion
Patients treated with RAAS blocking drugs due to cardiac and renal
diseases certainly belong to the patients with the highest risk for SARS
Cov-2 related non-fatal and fatal pneumonia. RAAS blocking drugs belong
to drug classes with the clearest proven clinical benefit to patients
with cardiac and renal diseases. Given that ACE2 is the receptor for the
SARS Cov-2 virus mediating entry to human cells, drugs that might affect
the expression of ACE2 in humans and hence potentially disease severity
are of major concern. The definitive answer whether RAAS blocking drugs
are beneficial, neutral or even harmful can only come from adequately
powered clinical trials that are currently initiated (NCT04311177
(Losartan for Patients With COVID-19 Not Requiring Hospitalization) and
NCT04312009 (Losartan for Patients With COVID-19 Requiring
Hospitalization). This will take some time. Moreover, our data (see
Figures 2 and 3) would rather suggest to study ACE inhibitors instead of
ARBs in patients with SARS Cov-2 infecion. In any case, general
practitioners and physicians in hospitals, especially on intensive care
units, treating patients with SARS CoV-2 infection ask for guidance now.
As is often the case in everyday clinical medicine, one has to
critically summarize and weigh the existing facts and then make clinical
decisions. This is, therefore, the ultimate goal of our investigation
and below the key points for decision making are summarized:
- There is currently no doubt among scientists that ACE2 is the
functional receptor of SARS-CoV mediated upper and lower respiratory
tract infections (Vaduganathan, Vardeny, Michel, McMurray, Pfeffer &
Solomon, 2020).
- Wrapp et al.(Wrapp et al., 2020) showed that the COVID-19 S protein
binds ACE2 with a much higher affinity than SARS-CoV-2. This could
partly explain the high infection rate of this virus.
- Some animal studies do suggest that treatment with either ACE
inhibitors or ARBs might increase ACE2 expression in the
cardiovascular system. Few animal data exist on the pulmonary
expression of ACE2 under RAAS blockade. It should also be emphasized
that some animal studies found no effect or even an opposite effect on
ACE2 expression (Burchill, Velkoska, Dean, Griggs, Patel & Burrell,
2012; Burrell et al., 2005; Ferrario et al., 2005; Ishiyama,
Gallagher, Averill, Tallant, Brosnihan & Ferrario, 2004; Li, Zeng,
Huang, Zhou, Zhang & Jiang, 2015; Ocaranza et al., 2006). It is worth
mentioning that one of these studies showed beneficial effects of ACE
inhibition although pulmonary ACE2 expression increased (Li, Zeng,
Huang, Zhou, Zhang & Jiang, 2015), for more details see supplementary
file Molecular Background.
- The human heart and kidney expresses ACE2, the receptor for
SARS-CoV-2. Several independent studies reported that the heart and
potentially the kidney seems to be - besides the respiratory tract -
likewise a primary target of SARS-CoV-2 infections leading to clinical
signs of myocarditis and heart failure (Chen, Li, Chen, Feng & Xiong,
2020; Chen et al., 2020; Han et al., 2020; Madjid, Safavi-Naeini,
Solomon & Vardeny, 2020) and potentially renal failure (Goicoechea et
al., 2020; Noris, Benigni & Remuzzi, 2020). The RAAS is activated in
heart failure patients and RAAS blockade is one of the clinical
mainstays in the treatment of heart failure (Bayes-Genis, 2017; de
Frutos et al., 2020; Solomon et al., 2017).
- Our meta-analysis of studies in non-COVID-19 patients clearly
indicated that patients treated with ACE inhibitors do have a lower
risk of acquiring non-fatal and fatal pneumonia regardless of the
underlying cause of pneumonia. The meta-analysis of studies
investigating the effects of ARBs, however, showed no clear beneficial
effect. In the subset of studies with the highest evidence level
(randomized placebo controlled studies) ARBs did, however, reduce the
incidence of pneumonia.
- Our meta-analysis in COVID-19 patients showed that the COVID-19
related severe adverse clinical outcomes (admission to the intensive
care unit, the use of assisted ventilation, or death) were reduced by
26% in patients treated with RAAS blocking agents. The risk of
all-cause mortality (Figure 6) was even 41 % lower in COVID-19
patients using RAAS blocking drugs.
Our findings in COVID-19 infected patients with regard to RAAS blocking
agents are thus in good agreement with findings in non-COVID-19-infected
patients with pneumonias. The smaller numbers of analysed COVID-19
positive patients and the study design of these studies do not allow a
differentiation of ACE inhibitors and ARBs effects with regard to severe
adverse clinical outcomes and all cause mortality. The findings in
COVID-19 patients are for sure less robust compared to the non-CORVID-19
studies. This is simply due to the by far lower number of analysed
COVID-19 patients so far.
Based on the data in non-COVID-19 and COVID-19 patients, we strongly
suggest that in particular ACE inhibitors should not be discontinued in
patients who need them due to cardiac and/or renal diseases. The
evidence that ACE inhibitors might affect the expression of the
molecular target in humans for the SARS CoV-2 virus (ACE2) is
controversial and comes from animal experiments. Moreover, the potential
implication of an up- or down-regulation (except for ACE2 knockout mice)
of ACE2 on the risk of infection of the lungs with SARS CoV-2 is not
established so far.
The meta-analysis of all available clinical studies in non-COVID-19
patients provides clearcut results. ACE inhibitors are beneficial for
patients with pneumonia. They reduce the odds for pneumonia and also
pneumonia related death. The limited experience so far in COVID-19
patients clearly supports this interpretation.
For ARBs the situation is less clear. The overall effect in non-COVID-19
pneumonia outcomes were neutral (Figure 3). The data in COVID-19
patients are clear: RAAS blockade – whatever drug class was used -
reduces severe adverse clinical outcomes and all-cause mortality. We do
not know for the time being wheather ACE inhibitors or ARBs or both
compound classes were the drivers of these beneficial effects. Final
conclusions can only be made when we have enough studies on this topic
separating the effects of ACE inhibiors from ARBs in COVID-19 patients.
To ensure the quality of our study, we just accepted studies in
international jounals after sussesful peer review, pre-prints were not
considered. We excluded even one COVID-19 study published in the NEJM
(Mehra, Desai, Kuy, Henry & Patel, 2020a), because the quality of the
data was questioned after publication even by the senior editor of this
journal (Mehra, Desai, Kuy, Henry & Patel, 2020b; Rubin, 2020).
It represents a study limitation that the vast majority of analysed
cases of pneumonia in our meta-analysis had not been caused by
SARS-CoV-2 infections. The somewhat high heterogeneity in our analysis -
in particular in the COVID-19 studies - is due to differences in the
design of the individual studies, different population analysed and the
way of statistical analysis of the original studies. Moreover, there was
some heterogeneity regarding the controls used in the meta-analysis due
to the definition of control group (the control group was defined as
being treated with a placebo or any other cardiovascular drug such as
calcium channel blocker or beta-blockers) used in our study. In
addition, the secondary outcome of the meta-analysis in non-COVID-19
patients was defined as pneumonia-related mortality. We accepted the
following definitions in the individual studies as pneumonia related
mortality: fatal pneumonia or in-hospital death or 30-day mortality in
patients with pneumonia. For the COVID- 19 , outcome severe adverse
clinical events, we accepted admission to the intensive care unit, the
use of assisted ventilation, or death or combinations as severe adverse
clinical event. These differences due to the particular outcome
definitions in the individual studies may likewise increase
heterogeneity. Moreover was the baseline morbitity and mortality risk of
the patients different in the individual studies furthermore increasing
heterogeneity. Finally, we had no informations on the dosages of the
used RASS blocking agents - so any analysis of dose-dependency of the
observed effects was not possible.
An investigation of this topic in a meta-analysis of all so far
available studies in non-SARS-CoV-2 pneumonia combined with an analysis
of the available studies in COVID-19 patients is the as of today best
available approach to obtain clinical evidence on this extremely
important clinical question unless adequately powered,
placebo-controlelled studies adressing this topic as primary outcome in
COVID-19 patients are available. Furthermore, it is justified to assume
that factors that determine the progression, severity and course of
pneumonia in general are factors that also determine the course of
SARS-Cov-2 pneumonia (Hendrickson & Matthay, 2013; Mizgerd, 2017;
Tsukagoshi, Ishioka, Noda, Kozawa & Kimura, 2013). This hypothesis is
supported by findings of pathological lung alterations in early disease
stages of SARS-CoV-2 infection. Early histopathological features were
non-specific and included oedema, pneumocyte hyperplasia, focal
inflammation and multinucleated giant cell formation; findings also seen
in early stages of non-SARS-Cov-2 pneumonias (Tian, Hu, Niu, Liu, Xu &
Xiao, 2020). Figure 1 illustrates the basic science and clinical points
discussed above.
In conclusion, considering the overall very weak evidence in animal
studies that the RAAS blockade related alterations of the pulmonary ACE2
expression is linked to disease severity and the clear beneficial data
of ACE inhibition in non-COVID patients on the incidence of pneumonia
and pneumonia related death, the use of ACE inhibitors in SARS-CoV-2
infected patients who need these drugs due to their cardiac and renal
diseases is justified and these compounds should not be withdrawn. Our
findings provide a stimulus for the initiation of randomized clinical
trials investigating ACE inhibitors in SARS-CoV-2 patients. The results
with regard to ARBs, however, are less clearcut. Its use is safe and the
finding that RAAS blockade (ACE inhibition and ARBs treatment was
unfortunately analysed not individually in the currently available
studies in the target population) in COVID-19 patients reduces adverse
outcomes in general and even all-cause mortality (Figure 5 and 6) asks
immeadiatly for adequately designed outcome studies with ARBs and ACE
inhibitors to disect ACE inhibitor effects from ARBs related effects in
this population.
Role of the Funding Source: There was no external funding for
this study. All authors had full access to all the data in the study and
the corresponding author had final responsibility for the decision to
submit for publication.
Disclosure Statement: The authors have no conflicts of interest
to declare.
Conflict of Interest: there is no conflict of interest for any
of the authors.