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:
  1. 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).
  2. 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.
  3. 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.
  4. 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).
  5. 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.
  6. 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.