key: cord-0993176-rbeze28b
authors: Chu, Chang; Zeng, Shufei; Hasan, Ahmed A.; Hocher, Carl‐Friedrich; Krämer, Bernhard K.; Hocher, Berthold
title: Comparison of infection risks and clinical outcomes in patients with and without SARS‐CoV‐2 lung infection under renin–angiotensin–aldosterone system blockade: Systematic review and meta‐analysis
date: 2020-12-18
journal: Br J Clin Pharmacol
DOI: 10.1111/bcp.14660
sha: 743d65fb1dfc60b08163c62ea4d1e42b6ac8856a
doc_id: 993176
cord_uid: rbeze28b

AIMS: Angiotensin‐converting enzyme‐2 (ACE2) is the receptor for SARS‐CoV‐2. Animal studies suggest that renin–angiotensin–aldosterone system (RAAS) blockers might increase the expression of ACE2 and potentially increase the risk of SARS‐CoV‐2 infection. METHODS AND RESULTS: The effect of ACE inhibitor (ACEI) treatment on the pneumonia incidence in non‐COVID‐19 patients (25 studies, 330 780 patients) was associated with a 26% reduction of pneumonia risk (odds ratio [OR]: 0.74, P < .001). Pneumonia‐related death cases in ACEI‐treated non‐COVID‐19 patients were reduced by 27% (OR: 0.73, P = .004). However, angiotensin II receptor blockers (ARB) treatment (10 studies, 275 621 non‐COVID‐19 patients) did not alter pneumonia risk in patients. Pneumonia‐related death cases in ARB‐treated non‐COVID‐19 patients was analysed only in 1 study and was significantly reduced (OR, 0.47; 95% confidence interval, 0.30 to 0.72). Results from 11 studies (8.4 million patients) showed that the risk of getting infected with the SARS‐CoV‐2 virus was reduced by 13% (OR: 0.87, P = .014) in patients treated with ACEI, whereas analysis from 10 studies (8.4 million patients) treated with ARBs showed no effect (OR, 0.92, P = .354). Results from 34 studies in 67 644 COVID‐19 patients showed that RAAS blockade reduces all‐cause mortality by 24% (OR = 0.76, P = .04). CONCLUSION: ACEIs reduce the risk of getting infected with the SARS‐CoV‐2 virus. Blocking the RAAS may decrease all‐cause mortality in COVID‐19 patients. ACEIs also reduce the risk of non‐COVID pneumonia. All‐cause mortality due to non‐COVID pneumonia is reduced by ACEI and potentially by ARBs.

Patients with cardiovascular and renal diseases are frequently treated with drugs interfering with the renin-angiotensin-aldosterone system (RAAS). The clinical benefit of angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are well established and hence became part of treatment guidelines for these patients worldwide. ACE2 is an isoenzyme of ACE1 (ACE).

Both are essential parts of the RAAS (Figure 1 ). ACE2 is involved in cardiac function, the development of hypertension and diabetes mellitus. Also, ACE2 has been identified as a functional receptor for coronaviruses, including SARS-CoV and SARS-CoV-2. SARS-CoV-2 infection is triggered by the binding of the spike protein of the virus to ACE2.

It was suggested that patients with cardiac and renal diseases, hypertension, and diabetes, who are treated with drugs potentially increasing ACE2 expression in the lungs such as ACEIs or angiotensin II receptor blockers are at higher risk for getting infected as well as having severe COVID-19 infection. 1, 2 In the current review, we summarize the molecular evidence for this hypothesis (see Figure 1 and supplementary material: Molecular Background); next, we present results of a metaanalysis of studies analysing the effects of RAAS blocking drugs (ACEIs, ARBs) on the risk of getting and dying from pneumonia in non-COVID- 19 patients and compare these findings to the so far published evidence coming from COVID-19 studies. In the COVID-19 studies, we meta-analysed the risk of getting infected with the SARS-CoV-2 virus, the risk of having severe adverse clinical outcomes and risk of all-cause mortality in COVID-19 patients treated with either ACEIs or ARBs.

F I G U R E 1 In patients with severe pneumonia, there is likewise a compensatory activation of the RAAS, resulting in tachycardia and an elevation of SVR that may be deleterious in this setting. Tachycardia, which shortens the duration of diastole, impairs the filling of the left ventricle. An elevated SVR increases left ventricular afterload (wall stress), increasing myocardial oxygen demand. These changes can lead to a further increase in left ventricular end-diastolic pressure and more edema formation. To the degree that pulmonary edema results in hypoxia, there maybe a further worsening of myocardial function. Besides these haemodynamic effects of an activated RAAS in critically ill patients with pneumonia, an activated RAAS promotes also inflammation in the lung and heart likewise contributing to impaired heart and lung function in these patients. This might explain our finding that all-cause mortality in non-COVID-19 pneumonia patients was significantly reduced when blocking the RAAS in general either with ACEI or ARBs. ACEIs do have an additional effect that might be of clinical impact. They increase levels of substance P and bradykinins which can sensitise the sensory nerves of the airways and enhance the cough reflex which may have a protective role on the tracheobronchial tree. ACE2 is expressed in human lungs and COVID-19 spike (S) protein seems to use it as a cellular entry receptor. It is still a research question whether age and the use of ACE inhibitors and/or ARBs could impact on ACE2 expression and consequently affect the infection pattern of COVID-19. Another aspect is that ARBs might stabilize the ACE2-AT1 receptor interaction and might prevent viral S protein-ACE2 interaction and internalization. Clinical data indicated that SARS-CoV-2 infection related myocarditis and heart failure may negatively influence outcome of SARS-CoV-2 pneumonia. ACE inhibitor treatment reduces the risk of pneumonia and pneumonia related mortality, whereas ARBs do not reduce the risk of pneumonia in non-COVID-19 patients. RAAS blockade reduces severe adverse clinical outcomes and all-cause mortality in COVID-19 patients. RAAS = renin-angiotensin-aldosterone system, SVR = systemic vascular resistance; Ang = angiotensin, ACE = angiotensin converting enzyme, AT1 receptors = angiotensin 1 receptors, ARBs = angiotensin receptor blockers, MCRA = mineralocorticoid receptor antagonists, COVID-19 = coronavirus disease 19 2 | METHODS

A systematic literature search was conducted to identify studies investigating the association between ACEIs or ARBs and pneumonia or COVID-19 in PubMed, Embase (searches using OVID), The

Cochrane Central Register of Controlled Trials (CENTRAL), and Clinical trial.gov. The last search was updated on 7 September 2020. The following MeSH terms were used: "angiotensin-converting enzyme inhibitors" or "angiotensin receptor antagonists" or "mineralocorticoid receptor antagonists" and "pneumonia". The key words used for the search strategy are listed in the supplementary materials. The references cited in the retrieved studies were hand-searched for the collection of missing relevant studies.

Two reviewers independently screened titles and abstracts, and further assessed the full text of each potentially relevant study to determine eligibility for inclusion. Reviews, congress reports, case reports, animal experiments and publications in languages other than English were excluded.

We considered the incidence of pneumonia in all adult patients, irrespective of risk factors at baseline, as the primary outcome. Every case of pneumonia considered in our investigation was either a new case, a recurrent case or a hospital-acquired pneumonia. Diagnosis of pneumonia was based on clinical, radiological or microbiological criteria, or International Classification of Disease codes. We did not consider undefined data or data on upper respiratory tract infections or radiation pneumonitis. The secondary outcome was pneumoniarelated mortality, including fatal pneumonia or in-hospital death or 30-day mortality. All of these secondary outcomes had to be caused primarily by pneumonia rather than other co-existing comorbid conditions. 3 All relevant clinical studies (randomized-controlled trials [RCTs] , cohort studies, case-control studies and nested case-control studies, as well as case-crossover studies) with ACEIs or ARBs as interventions and with an incidence of pneumonia were considered.

The diagnosis of COVID-19 must be proven by detection of SARS-CoV-2 RNA in the patient's upper or lower respiratory tract system. Treatment with RAAS blocking agents was defined as treatment with either an ACEI or an ARB or both (just 3 patients in 1 study).

COVID-19 related adverse severe clinical outcomes are defined as admission to the intensive care unit, the use of assisted ventilation or death. However, we only include peer-reviewed articles; considering the current situation, some observation studies are online available without careful peer review, and thus the quality might raise concerns.

To avoid considering duplicated published data, we excluded the earlier publications conducted in the same study cohort and only considered the latest publications. In our investigation, the treatment group was defined as being treated with any kind of ARBs or any kind of ACEIs. The control group was defined as being treated with a placebo or any other cardiovascular drug such as calcium-channel blockers or β-blockers. Cohort studies had to follow patients to determine pneumonia outcomes. In case-control studies, cases had to be patients with a diagnosis of pneumonia. Controls should be randomly selected to match the cases. A nested case-control study is a variation of a case-control study in which cases and controls are drawn from the population in a fully predefined cohort. In a case-crossover study, as described, 4 the study population consists of subjects who have experienced an episode of pneumonia. Similar to a crossover trial, each study subject serves as their own control.

The methodological quality of RCTs was evaluated using the Cochrane Collaboration's tool for RCTS with the following parameters: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, selective

reporting. The quality of included cohort and case control studies was assessed using the Newcastle-Ottawa scale, which has 3 aspects including 8 criteria and yield scores ranging from 0 (high risk of bias) to 9 (low risk of bias). Studies with Newcastle-Ottawa scale scores <6/9

(considered moderate-to-high risk of bias) were excluded (Table S1 ).

Overall quality of evidence was evaluated using the Grading of Recommendations, Assessment, and Evaluation (GRADE) framework. 5 

Two independent authors extracted the following data from full-text articles: study design and size, location, population characteristics, primary outcomes, data of relevant outcomes. Data were obtained irrespective of whether they had been reported as predefined outcomes or as adverse effects. We chose the odds ratio (OR) as the measurement estimate for effect because relative estimates are better comparable than absolute effects across studies with different designs, populations, and lengths of follow-up as described previously. 6 We aimed to extract the maximally adjusted OR that included the greatest number of covariates from the original publication for predescribed outcomes. Otherwise, we used the raw data to convert to crude OR through classic methods, or Peto's method if 1 arm had a zero-count cell. 7 We used the hazard ratio (HR) when OR was not available nor possible to calculate. To explore differences in estimates for outcomes, we presented the results stratified according to study design. Considering the potential risk of bias, subgroup analysis in which compare results from the adjusted and unadjusted studies was also conducted. Studies that met the inclusion criteria but could not be pooled due to insufficient data were summarized qualitatively.

Either fixed-effects model or, in the presence of heterogeneity, the random-effects method was used in the pooled results. Data were expressed as OR and 95% confidence intervals (95% CIs). Heterogeneity across studies was assessed by testing with the I 2 -statistic, considering 25%, 50% and 75% as an indication of low, moderate, and high variability, respectively. 8 Funnel-plot analysis and Begg test were performed to evaluate potential publication bias. All analyses were performed using Stata/SE in above mentioned databases. One of them was a global study, 92 however, this study was retracted on 4 June 2020 with concern about the quality of the information in the database, thus we only qualitatively summarized this study. Table S5 ).

The effect of ACEI treatment on the incidence of pneumonia was analysed in 25 studies (a total of 330 780 patients coming from 5

RCTs, [9] [10] [11] [12] [13] 7 cohort studies, 14-20 8 case-control studies, 21-28 3 nested case-control studies 29-31 and 2 case-crossover studies 32, 33 ). Overall, the use of ACEIs was associated with a significant 26% reduction in risk of pneumonia compared with controls (pooled OR, 0.74, 95% CI, 0.65 to 0.85, P < .001; I 2 = 76.9%; for further details see Table 1 ).

The effect of ARB treatment on the incidence of pneumonia was analysed in 10 studies (a total of 275 621 patients from 4 RCTs, 41-44 1 cohort study, 19 1 case-control study, 28 

We did not find any eligible studies addressing the effects of mineralocorticoid receptor antagonists on pneumonia or pneumonia-related death.

Pooled result from 11 studies, 45 Figure 4 ). T A B L E 1 Renin-angiotensin-aldosterone system inhibitors and risk of non-SARS-CoV-2 pneumonia infection 

For the primary outcome of pneumonia referring to RAAS inhibitors, funnel plots did not show apparent visual asymmetry. The Begg tests showed no evidence of publication bias (ACEI, P = .66; ARB, P = .21).

For the secondary outcome, funnel plot also did not show any visual asymmetry; testing for publication bias showed no statistic significant result (Begg's P-value for asymmetry >.999).

As for the COVID-19 studies referring to RAAS inhibitors, funnelplot showed a qualitatively asymmetrical shape for mortality, but not 

The quality/certainty of the evidence regarding the impact of RAAS blockers in patients with SARs-CoV-2 and non-SARS-CoV-2 lung This will take some time. Only 1 placebo-controlled trial with RAAS blocking agents has been reported so far. 84 However, this study is too small and had too few fatal events to allow firm conclusions.

Our data (Tables 1-4 i. There is currently no doubt among scientists that ACE2 is the functional receptor of SARS-CoV-mediated upper and lower respiratory tract infections. 94 Wrapp et al. 95 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.

ii. Some animal studies do suggest that treatment with either ACEIs 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. [96] [97] [98] [99] [100] [101] It is worth mentioning that 1 of these studies showed beneficial effects of ACE inhibition even though pulmonary ACE2 expression iii. The human heart and kidney express ACE2, the receptor for SARS-CoV-2. Several independent studies have reported that the heart and potentially the kidney seem to be-in addition to the respiratory tract-a primary target of SARS-CoV-2 infections leading to clinical signs of myocarditis and heart failure [102] [103] [104] [105] and potentially renal failure. 106 , 107 The RAAS is activated in heart failure patients and RAAS blockade is a clinical mainstay in the treatment of heart failure. [108] [109] [110] T A B L E 3 Renin-angiotensin-aldosterone system (RAAS) inhibitors and risk of COVID-19 infection have a protective role on the tracheobronchial tree. These mechanisms also improve swallowing by avoiding the exposure of the respiratory tree to oropharynx secretions. 115, 116 Taken together, the pleiotropic effects of ACEIs were suggested to reduce the incidence of pneumonia. This hypothesis is further supported by a meta-analysis indicating markedly higher pneumonia incidence in subjects with a specific polymorphism in ACE that reduces substance P and bradykinin, both of which drive the cough reflex, 117 also consistent with the notion that airway reflex sensitivity contributes to pulmonary definitions. ARBs do not increase the levels of Substance P or bradykinin and hence do not have this protective effect. This might at least be 1 reason why ACEIs do reduce the risk of getting non-COVID-19 pneumonia (Table 1) or being infected with SARS CoV-2 (Table 3) Our findings in COVID-19-infected patients with regard to RAAS To ensure the quality of our study, we just accepted studies in international journals after successful peer review, preprints were not considered. We even excluded 1 COVID-19 study published in the New England Journal of Medicine, 92 because the quality of the data was questioned after publication by the senior editor of this journal. 118, 119 T A B L E 4 Renin-angiotensin-aldosterone system (RAAS) inhibitors and COVID-19 all-cause mortality 95% confidence interval around the pooled estimate of effect includes both no effect and appreciable benefit or appreciable harm (serious level was considered for downgrading is a relative risk reduction or relative risk increase >25%, Very serious level was considered >100%); d failure to adequately control confounding. ACEIs = angiotensin-converting enzyme inhibitors; ARBs = angiotensin receptor blockers.

clinical event. These differences due to the particular outcome definitions in the individual studies may likewise increase heterogeneity. Moreover, the baseline morbidity and mortality risk of the patients was different in the individual studies furthermore increasing heterogeneity. Finally, we had no information on the dosages of the used RASS blocking agents-so any analysis of dosedependency 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 the best available approach to obtain clinical evidence on this extremely important clinical question unless adequately powered, placebo-controlled studies addressing this topic as primary outcome in COVID-19 patients are available. As of today, only 1 RCT was reported. However, this study had by far to less clinical events to be informative. 84 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. [120] [121] [122] 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. 123 Figure 1 illustrates the basic science and clinical points discussed above.

Our study provides evidence that the use of ACEIs but not ARBs reduces the risk of getting infected with the SARS CoV-2 virus. Blocking the RAAS with either ACEI or ARBs may decrease all-cause mortality in COVID-19 patients. The lack of adequately powered controlled clinical COVID-19 studies, however, limits the power of these conclusions.

ACEIs (but not ARBs) reduce the risk of non-COVID-19 pneumonia. All-cause mortality due to non-COVID-19 pneumonia is reduced by ACEI and may be reduced by ARBs (the statement for all-cause mortality for ARBs is just based on 1 study).

Considering the findings in our meta-analysis as summarized above and the overall very weak evidence in animal studies that the RAAS blockade-related alterations of the pulmonary ACE2 expression is linked to disease severity, RAAS-blocking drugs should not be withdrawn in clinical practice. Our findings provide a stimulus for the initiation of further randomized clinical trials investigating ACEIs in comparison to ARBs in COVID-19 patients to dissect ACEI effects from ARB-related effects in this population.

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China Scholarship Council supported C.C. and S.Z.Open access funding enabled and organized by Projekt DEAL.

The authors have no conflicts of interest to declare. Berthold Hocher https://orcid.org/0000-0001-8143-0579