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Different therapeutic associations of renin-angiotensin system inhibitors with coronavirus disease 2019 compared with usual pneumonia

Background/Aims Although it is near concluded that renin-angiotensin system inhibitors do not have a harmful effect on coronavirus disease 2019 (COVID-19), there is no report about whether angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) offer any protective role. This study aimed to compare the association of ARBs and ACEIs with COVID-19-related mortality. Methods All patients with COVID-19 in Korea between January 19 and April 16, 2020 were enrolled. The association of ARBs and ACEIs with mortality within 60 days were evaluated. A comparison of hazard ratio (HR) was performed between COVID-19 patients and a retrospective cohort of pneumonia patients hospitalized in 2019 in Korea. Results Among 10,448 COVID-19 patients, ARBs and ACEIs were prescribed in 1,231 (11.7%) and 57 (0.6%) patients, respectively. After adjusting for age, sex, and history of comorbidities, the ARB group showed neutral association (HR, 1.034; 95% CI, 0.765 to 1.399; p = 0.8270) and the ACEI groups showed no significant associations likely owing to the small population size (HR, 0.736; 95% CI, 0.314 to 1.726; p = 0.4810). When comparing HR between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia in 2019, the trend of ACEIs showed similar benefits, whereas the protective effect of ARBs observed in the retrospective cohort was absent in COVID-19 patients. Meta-analyses showed significant positive correlation with survival of ACEIs, whereas a neutral association between ARBs and mortality. Conclusions Although ARBs or ACEIs were not associated with fatal outcomes, potential beneficial effects of ARBs observed in pneumonia were attenuated in COVID-19.


INTRODUCTION
When coronavirus disease 2019 (COVID-19, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) emerged as a global health problem, initial epidemiologic studies reported high prevalence of hypertension, diabetes mellitus and coronary artery disease [1,2]. These chronic diseases are highly prevalent among COVID-19 patients in Korea [3]. Given that SARS-CoV-2 enters target cells via angiotensin-converting enzyme 2 (ACE2) cell surface receptors [4], the use of angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), which reportedly augment ACE2 levels [5], raise concern regarding antihypertensive agents, especially renin-angiotensin-aldosterone system (RAAS) inhibitors [6]. Although it is near concluded that ACEIs and ARBs do not increase mortality of COVID-19 patients [7][8][9], there are no reports as to whether ARBs or ACEIs have any protective role, which have been repetitively reported in pneumonia-related outcomes [10][11][12]. Given that beneficial effects have been reproducibly reported in pneumonia patients, neutral results suggest that there might be possible offset effects.
In the present study, we compared the association between the use of ARBs or ACEIs and COVID-19-related mortality in Korea. The hazard ratio (HR) was compared between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019 in Korea. Lastly, a meta-analysis was performed to compare the results of this study to those of other reports.

Study design
This was a population-based cohort study supported by the Korea Disease Control and Prevention Agency (KDCA), the National Health Insurance Service (NHIS), and the Korean Society of Hypertension, and was approved by the Institutional Review Board of Seoul National University Hospital (No. 2003(No. -102-1109. Informed consent was waived because the study was based on routinely collected administrative and claims data. All authors reviewed the manuscript for accuracy and completeness of the data.

Data collection
Data related to all 10,448 patients, who were infected with laboratory-confirmed SARS-CoV-2 until April 16, 2020, in Korea [13,14], were retrieved from compiled information available from the NHIS. Information related to medical utilization was extracted from the National Health Information Database (NHID), a public database formed by the NHIS [15].
For indirect comparative analyses, the association between the use of ARBs and/or ACEIs and the mortality of pneumonia in hospitalized Korean patients between January and June 2019 was investigated using the information retrieved from the NHID [15].

Study outcomes and definitions
The association of ARBs and ACEIs with COVID-19-related mortality within 60 days was investigated. Disease-related mortality was defined as mortality during hospitalization with the indicated disease (COVID-19 or pneumonia) as the main disease code of hospitalization. All commercially available ARBs and ACEIs in Korea were included in the analysis. Medications were classified under ARBs (candesartan, irbesartan, valsartan, losartan, telmisartan, eprosartan, fimasartan, azilsartan, and olmesartan) and ACEIs (captopril, enalapril, lisinopril, perindopril, ramipril, and zofenopril). Dichotomous variables were created to identify the use of ARBs and ACEIs defined as a filled prescription for the medication of interest with sufficient supply to overlap the date of admission, assuming 80% compliance [16].

Statistical analysis
The association of clinical characteristics with mortality within 60 days was tested using bivariate statistics. Categorical variables were analyzed with a chi-square test. Continuous variables were analyzed using an analysis of variance test. Time to occurrence of the COVID-19-related death in patients prescribed with ARBs or ACEIs was analyzed using Kaplan-Meier graphs displaying failure functions. Statistical significance was assessed using a log-rank test. Cox proportional hazard models calculated estimates of unadjusted HRs and 95% confidence intervals (CIs) for ARBs or ACEIs. The additional factors included in the models as covariates were age group, sex, and comorbidities including hypertension, type 2 diabetes mellitus, coronary heart diseases, heart failure, www.kjim.org https://doi.org/10.3904/kjim.2020.656 stroke, chronic obstructive pulmonary disorder (COPD), cancer, and chronic kidney diseases. We diagnosed the proportional hazard assumption using the Schoenfeld residuals plot. Comparisons were considered statistically significant if two-tailed p values were less than 0.05. All analyses were performed using SAS version 7.15 (SAS Institute Inc., Cary, NC, USA) and R version 4.0.0 (The R Development Core Team, Vienna, Austria).

Meta-analysis
Using PubMed searches of the MEDLINE database, we identified original papers published from 2019 to September 2020 in order to evaluate the association of ARBs or ACEIs with COVID-19 related death. The search strategy was based on the search terms "ARBs" or "ARB" or "angiotensin receptor blockers," or "ACEIs" or "ACEI" or "angiotensin converting enzyme inhibitors" or "angiotensin-converting enzyme inhibitors," and COVID-19 or COVID19 or coronavirus, and death or mortality. All available English abstracts were reviewed, and the full text was consulted as necessary to clarify eligibility status. We excluded the review articles, editorials and original papers that did not evaluate mortality (infection or hospitalization). Also, we performed an online search under the following terms: "COVID-19 and hypertension and ARBs or ACEIs." The initial search identified 259 articles. Of these, 25 articles were included for meta-analysis [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Details of the search strategy are summarized in Supplementary Fig. 1. The authors (H.Y.L. and J.A.) reviewed all abstracts independently to evaluate the eligibility criteria and appropriateness of the research topics. If the inclusion criteria were met, the article was retrieved and reviewed thoroughly. There were no discrepancies in this process.
Statistical calculations and graphs were made using Rex software version 3.3.1 (RexSoft Inc., Seoul, Korea) [34]. Two-tailed statistical significance was set at the 5% level, except for the Cochran's chi-square test for heterogeneity, which used a 10% level of significance. The pooled results for each outcome are presented as odds ratios (OR) with 95% CIs. Before applying approximate chi-square tests for heterogeneity, we clinically assessed studies for heterogeneity. Statistical heterogeneity was also examined with the I 2 statistics, where I 2 values ≥ 50% were considered to be indicators of a substantial level of heterogeneity. Forest plots were used for visual inspection. Funnel plots of effect estimates against its standard error and Copas selection model analysis were conducted to assess publication bias. We combined p values for each OR and HR from meta-analysis using Fisher and Liptak's methods [35].

RESULTS
The present study includes data related to a total of 10,448 COVID-19 patients who were hospitalized or isolated in Korea from January 19, 2020, through April 16, 2020. As of April 24, 2020, 228 of these patients (2.18%) succumbed to death. The demographic and clinical characteristics of patients are summarized in Table 1. Of the patients evaluated, 38.1% had at least one preexisting comorbid condition including hypertension (20.6%) and diabetes mellitus (17.9%). Patients prescribed with ARBs or ACEIs were more than 20 years older with a higher number of comorbidities than non-users and accounted for 11.7% and 0.6% of the overall cases, respectively. A small portion of the ACEI group corresponded to the prescription pattern reported in the Korean hypertension fact sheet [36]. Between the patients prescribed ARBs or ACEIs, the ACEI group showed a higher proportion of males (64.9% vs. 40% in overall COVID-19 patients) and more comorbidities, including diabetes mellitus and cardiovascular disease. The mean age of hypertensive patients (65.7 ± 13.0 years) was more than 20 years greater than that of the non-hypertensive patients (42.0 ± 18.8 years, p < 0.0001).
In Cox regression analysis, the ARB group showed neutral association (HR, 1.034; 95% CI, 0.765 to 1.399; p = 0.8270) and the ACEI group showed no significant associations likely owing to the small population size (HR, 0.736; 95% CI, 0.314 to 1.726; p = 0.4810) (Fig. 1B). As there is a possibility that specific ARBs have a superior impact beyond class effect [5], we evaluated the subgroup anal-  Fig. 2). The HR was compared between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019. Details related to comorbid conditions and administered medication were similarly extracted (Supplementary Table   1). Because there was no viral pneumonia epidemic in Korea, like SARS or Middle East respiratory syndrome (MERS), the 2019 pneumonia cohort was composed of bacterial and viral pneumonia patients combined. This retrospective cohort included 179,265 patients with a mean age of 39 years, of which 49.4% were females. The most common comorbid condition in the cohort was hypertension (33.3%) followed by COPD (25.1%) and diabetes mellitus (23.4%). The mortality rate at 60 days was 7.4% and sharply increased among elderly patients (≥ 60 years) to a value higher than that seen with COVID-19 ( Fig. 2A). Furthermore, the mortality was higher in patients with comorbidities, including hypertension (Supplementary Tables 2 and 3). Upon consideration of secondary factors, the results of the present study indicated a significantly lower risk of 60 days mortality with the use of ARBs (HR, 0.853; 95% CI, 0.820 to 0.887; p < 0.0001) (Supplementary Table 3  We compared HR between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia 2019 in Korea. The trend of ACEIs was similar to that in COVID-19 patients (p = 0.1319). However, the HRs of ARBs significantly differed between the retrospective cohort and the COVID-19 patients (p = 0.0040). The protective effect of ARBs observed in the retrospective cohort was lost in the COVID-19 patients (Table 3, Fig. 2B). Lastly, we performed meta-analyses of ARB and ACEI groups using the data from previous studies. The 25 eligible studies and our study included 190,135 COVID-19 patients (Supplementary Fig. 1). Meta-analysis of ACEIs showed significant decrease in relative risk by 18% to 25% (p = 0.028 [Fisher], p = 0.017 [Liptak]) (Fig. 3A). However, the ARB group showed neutral association (relative risk, 0.96 to 0.99; p = 0.915 [Fisher], p = 0.886 [Liptak]) (Fig. 3B). Combined p values for ORs and HRs are robust through Fisher and Liptak's methods. Interestingly, combined p values in ARBs have the same trend with our results, whereas those for ACEIs show a significant protective effect for all-cause mortality (Table 4). We did not detect any significant publication bias by visual inspection of the funnel plots.

DISCUSSION
In the present study, we showed that ARBs and ACEIs are not associated with COVID-19-related fatal outcomes. While the ARB group showed a neutral association, the ACEI group showed no significant results, likely due to the small cohort size.
The RAAS is activated in sepsis, and angiotensin II, the main effector of the RAAS, has been recognized as an important inflammatory agent associated with organ failure and mortality [38]. Therefore, there is a competing hypothesis that ARBs and ACEIs may provide protection against pneumonia-related fatality. Enhanced expression of ACE and angiotensin II was reported in patients with acute respiratory distress syndrome and mechanical ventilation [39][40][41]. Injurious ventilation enhances the expression of the angiotensin type 1 receptor, a potent promoter of inflammatory response [40]. Angiotensin II, a pro-inflammatory mediator, induces damage to the pulmonary and vascular endothelial cells [42,43]. ARBs and ACEIs are reported to protect the vascular endothelium [44][45][46] and to possess immunomodulatory effects [47,48]. In vivo, angiotensin II deletion and generation of anti-inflammatory Ang 1-7 revealed the potential benefits of ACE2 in H7N9 virus-induced acute lung injury [49].
In the initial reports of COVID-19, it was hypothesized that the use of ARBs or ACEIs may alter ACE2, which is a cell receptor of SARS-CoV-2, hence enhancing the infectivity of SARS-CoV-2. However, recent studies commonly reported that renin-angiotensin sys- tem inhibitors did not increase SARS-CoV-2 infectivity [23,24]. Another hypothesis is that ARBs are less effective in attenuating inflammatory response in COVID-19 than in typical pneumonia. Interestingly, ARBs showed a loss of beneficial effect on COVID-19 conflicting with previous meta-analysis results in pneumonia patients [11,16], and with data from pneumonia patients in Korea in 2019. Although several studies, which urgently reported no harm with ARBs and ACEIs in COVID-19 patients (see references for the meta-analysis), given that beneficial effects have been reproducibly reported in pneumonia patients, neutral results suggest that there might be possible offset effects. Although ARBs showed non-inferior cardiovascular protective effect to ACEIs in a large scaled randomized controlled trial [50], several meta-analyses suggested superior cardiovascular protecting effects of ACEIs over ARBs in high risk hypertensive patients [51,52]. A replenished effect of bradykinin by ACEIs, which is reduced in cardiovascular disease status, might exert a superior anti-inflammatory effect over ARBs [53]. The lack of benefit of ARBs observed in this study might be significant, because multiple clinical trials using ARBs are recruiting patients based on the initial clinical attention associated with ACE2-COVID-19 issues (14 studies, with the search terms of "COVID-19" and "ARBs," identified in ClinicalTrials.gov, accessed January 25, 2021). The current study has several limitations. Firstly, data related to drug exposure were measured based on claim data. Hence, detailed information about drug exposure, such as adherence to the medication or discontinuation during COVID-19 hospitalization, remains unknown. However, the Korean Society of Hypertension and the Korean Society of Cardiology formally recommended that doctors continue administering anti-hypertensive medication without change during COVID-19 treat-ment [54][55][56]. Therefore, we rationally assumed that the infected hypertensive patients continued the use of anti-hypertensive medications during the period of hospitalization. However, there might be a difference in the compliance of antihypertensive medications. Indeed, it was reported that about 26% of COVID-19 patients with hypertension might exhibited drug compliance below 80% [8], which potentially influenced the association between the use of ARBs or ACEIs and mortality in COVID-19 patients either directly or indirectly through the healthy adherer effect or selective prescribing [57]. Secondly, although we evaluated a total of 10,448 COVID-19 patients who were hospitalized in Korea from January 19, 2020, through April 15, 2020, the interpretation of our findings is influenced by the limited sample size. Notably, the prescription rate of ACEIs was barely 3% in hypertensive patients likely because of dry cough, a common side effect among Asians [36]. To overcome this limitation, we compared the results with a retrospective cohort of more than 170,000 pneumonia patients hospitalized from January to June in 2019 to include more than 1,000 patients with prescribed use of ACEIs, assuming that 3% of prescription rate had 40% hypertension prevalence among all pneumonia cases. The results indicated similar trends to those followed by COVID-19 and pneumonia cases. Also, we performed meta-analyses of ARBs and ACEIs using the data from previous studies merged with our study, thus evaluating 145,124 patients. The results of the meta-analysis supported the findings of our study.
In conclusion, while ARBs or ACEIs were not associated with fatal outcomes, the possible beneficial effect of ARBs observed in pneumonia patients was not observed in COVID-19 patients. The findings of this paper implicate that ARBs might have no role as a COVID-19 therapeutic.

KEY MESSAGE
1. In coronavirus disease 2019 (COVID-19) patients in Korea, angiotensin receptor blockers (ARBs) showed neutral association, whereas angiotensin converting enzyme (ACE) inhibitors showed no significant associations likely owing to the small population size. 2. When comparing a retrospective cohort of patients hospitalized with pneumonia in 2019, ACE inhibitors showed similar benef its. In contrast, the protective effect of ARBs was not reproduced in the COVID-19 cohort. 3. Meta-analysis merging the data from our and previously published studies showed significant benefit of ACE inhibitors, but a neutral association between ARBs and the mortality.