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. 2021 Mar 11;16(3):e0248058. doi: 10.1371/journal.pone.0248058

Effect of renin-angiotensin-aldosterone system inhibitors on Covid-19 patients in Korea

Jungchan Park 1,‡, Seung-Hwa Lee 2,‡,*, Seng Chan You 3, Jinseob Kim 4, Kwangmo Yang 5,*,#
Editor: Yoshihiro Fukumoto6
PMCID: PMC7951918  PMID: 33705440

Abstract

Background

The effect of renin-angiotensin-aldosterone system (RAAS) inhibitors in coronavirus disease 19 (Covid-19) patients has not been fully investigated. We evaluated the association between RAAS inhibitor use and outcomes of Covid-19.

Methods

This study was a retrospective observational cohort study that used data based on insurance benefit claims sent to the Health Insurance Review and Assessment Service of Korea by May 15, 2020. These claims comprised all Covid-19 tested cases and the history of medical service use in these patients for the past five years. The primary outcome was all-cause mortality, and the rate of ventilator care was compared between the groups.

Results

From a total of 7,590 patients diagnosed with Covid-19, two distinct cohorts were generated based on RAAS inhibitors prescribed within 6 months before Covid-19 diagnosis. A total of 1,111 patients was prescribed RAAS inhibitors, and 794 patients were prescribed antihypertensive drugs, excluding RAAS inhibitors. In propensity-score matched analysis, 666 pairs of data set were generated, and all-cause mortality of the RAAS inhibitor group showed no significant difference compared with the non-RAAS inhibitor group (14.6% vs. 11.1%; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.54–1.15; p = 0.22). The rate of ventilator care was not significantly different between the two groups (4.4% vs. 4.1%; HR, 1.04; 95%CI, 0.60–1.79; p = 0.89).

Conclusions

RAAS inhibitor treatment did not appear to increase the mortality of Covid-19 patients compared with other antihypertensive drugs, suggesting that they may be safely continued in Covid-19 patients.

Introduction

In December 2019, a major outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) was first reported in Wuhan City, China. The World Health Organization characterized the coronavirus disease 19 (Covid-19) as a pandemic on March 11, 2020, and Covid-19 has become a global threatening disease with more than 6,000,000 confirmed cases worldwide as of June 2020 [1]. In Korea, more than 11,629 cases of Covid-19 were diagnosed and 273 deaths were reported through June 2020, and the government of Korea decided to share the world’s first de-identified Covid-19 nationwide patient data collected from the Korean National Health Insurance System.

The initial epidemiologic report on Covid-19 indicated that mortality was much higher in patients with cardiovascular disease [2]. Concerns arose on use of renin-angiotensin-aldosterone system (RAAS) inhibitors, because SARS-Cov-2 is known to interact with RAAS through angiotensin-converting enzyme 2 (ACE2) as a receptor [3]. The ACE2 upregulated by RAAS inhibitors could theoretically initiate SARS-Cov-2 infection and aggravate Covid-19 virulence [3]. In contrast, mechanistic evidence from other coronaviruses suggest that downregulation of ACE2 in infected patients leads to acute lung injury, and use of RAAS inhibitors could mitigate this effect by upregulating ACE2 [4–6]. Based on these laboratory findings and considering that the indications of RAAS inhibitors include high-risk patients, it is important to define guidelines on whether to continue RAAS inhibitors in Covid-19 patients rather than switch to other antihypertensive drugs [3,7–9]. However, as the clinical data for these patients are limited, there could be serious health consequences if RAAS inhibitors are associated with Covid-19 mortality. Although a recommendation against suspension of RAAS inhibitors was made by the statement from the American and European Cardiology Societies [10], it was not based on clinical evidence, and the absence of clinical evidence supporting the safety of RAAS inhibitors in Covid-19 patients leaves clinicians with no choice but to follow the old principle of “primum non nocere (first, do no harm).” Therefore, we used de-identified Covid-19 nationwide data from Korea to evaluate the association between RAAS inhibitor use and severe Covid-19 induced outcomes. Our results may provide evidence for guidance on use of RAAS inhibitors in Covid-19 patients.

Materials and methods

Data curation

This was a retrospective observational cohort study conducted in accordance with the principles of the Declaration of Helsinki. The Institutional Review Board of Samsung Medical Center granted a waiver of approval and informed consent for this study (SMC 2020-04-009) since we used de-identified data based on the insurance benefit claims sent to the Health Insurance Review and Assessment Service of Korea (HIRA). This data set is comprised of all patients who were tested for Covid-19 in Korea until May 15, 2020, including the history of medical service used by these patients for the past five years. The data are shared in the form of the Observational Medical Outcome Partnership Common Data Model (OMOP-CDM) [11,12].

Cohort definition and outcomes

The target cohort was generated by selecting hypertensive patients with RAAS inhibitor prescriptions, including angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB), within 6 months prior to Covid-19 diagnosis. For the comparator cohort, we selected patients with antihypertensive drug prescriptions other than RAAS inhibitors within 6 months prior to Covid-19 diagnosis. The target cohort was a RAAS inhibitor group, and the comparator cohort was a non-RAAS inhibitor group. We extracted the incidence of each baseline characteristic without an exact number of patients to protect sensitive personal information and maintain a de-identified form of the data. The primary outcome was all-cause mortality. To compare the incidence of ventilator care as the secondary outcome, both cohorts were re-generated after excluding patients on ventilator care after antihypertensive drug prescriptions and before Covid-19 diagnosis.

Statistical analysis

Observational Health Data Sciences and Informatics (OHDSI) analysis tools are built into the ATLAS interactive analysis platform and the OHDSI Methods Library R packages. OHDSI’s open‐source software is publicly available on the GitHub repository (https://github.com/OHDSI/). In addition, concept sets used to define baseline characteristics and study outcomes are also available (https://github.com/OHDSI/Covid-19/). ATLAS ver. 2.7.2 was used herein. As OHDSI CDM does not provide exact numbers of patients for each covariate, we presented incidences of baseline characteristics. To minimize the effects of potential confounding factors and selection bias, we used large-scale propensity score matching and generated a matched population from the cohorts. Cox regression analysis was used to compare outcomes according to RAAS inhibitor use. Kaplan-Meier estimates were used to construct survival curves after propensity-score stratification and compared with the log-rank test. All tests were two-tailed, and p < 0.05 was considered statistically significant.

Results

Data from the insurance benefit claims sent to HIRA until May 15, 2020 indicated that a total of 7,590 patients was diagnosed with Covid-19. Among these patients, the target cohort was generated by selecting 1,111 patients prescribed RAAS inhibitors within 6 months before diagnosis, and the comparator cohort was generated by selecting 794 patients prescribed other antihypertensive drugs in the same time frame (Fig 1). Baseline characteristics are shown in Table 1. The median follow-up duration was 68 days (interquartile range 60–79) in the RAAS inhibitor group and 68 days (interquartile range 58–80) in the non-RAAS inhibitor group. A total of 666 pairs of well-balanced groups was generated after propensity score matching (Table 1 and Fig 2). In the propensity-score matched analysis, all-cause mortality of the RAAS inhibitor group showed no significant difference compared with that of the non-RAAS inhibitor group (14.6% vs. 11.1%; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.54–1.15; p = 0.22) (Table 2 and Fig 3).

Fig 1. The flowchart of patients.

Fig 1

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Table 1. Baseline characteristics.

Before propensity score adjustment After propensity score adjustment
RAAS inhibitor Non-RAAS inhibitor SMD RAAS inhibitor Non-RAAS inhibitor SMD
(N = 1,111) (N = 794) (N = 666) (N = 666)
Age group
15–19 0.1 0.6 -0.09 0.2 0.6 -0.07
20–24 0.5 2.1 -0.15 0.6 2 -0.12
25–29 0.9 3.4 -0.17 1.2 2.7 -0.11
30–34 1 2.1 -0.09 1.2 2 -0.06
35–39 1.4 1.4 0 0.9 1.1 -0.01
40–44 1.9 3.3 -0.09 2.3 2.9 -0.04
45–49 6.2 6.3 0 6.9 6.2 0.03
50–54 10.1 8.9 0.04 9.9 8.3 0.06
55–59 14.5 12 0.07 15.3 11.7 0.11
60–64 16.1 11.7 0.13 15.3 11.7 0.11
65–69 12.1 11.8 0.01 10.4 13.2 -0.09
70–74 10.1 10.5 -0.01 10.5 11 -0.01
75–79 10.8 11.2 -0.08 9.8 11.8 -0.08
80–84 7.7 6.7 0.04 7.8 6.9 0.04
85–89 4.8 5 -0.01 5.1 5 0.01
90–94 1.5 2.4 -0.06 2.1 2.3 -0.01
95–99 0.3 0.6 -0.05 0.5 0.6 -0.02
Sex: Female 55.9 55.4 0.01 55.4 54.5 0.02
Medical history
 Acute respiratory disease 74.2 70.8 0.08 71.9 70.9 0.02
 Chronic liver disease 9.6 8.6 0.04 8.7 9.8 -0.04
 Chronic obstructive lung disease 3.8 4.7 -0.04 3.8 4.5 -0.04
 Dementia 11.7 16.9 -0.15 14 16.4 -0.07
 Depressive disorder 19 27.2 -0.2 23.7 21.9 0.04
 Diabetes mellitus 41.6 28.2 0.28 30.2 32.6 -0.05
 Gastroesophageal reflux disease 44.8 44.7 0 42 45.8 -0.08
 Gastrointestinal hemorrhage 3.3 3.8 -0.02 3.5 3.9 -0.02
 Hyperlipidemia 70.7 53.7 0.36 56.5 62.5 -0.12
 Lesion of liver 4 3 0.05 3.2 3.3 -0.01
 Obesity 0.3 0.1 0.03 0.5 0.2 0.06
 Osteoarthritis 26 26.4 -0.01 24 27.5 -0.08
 Pneumonia 51.8 49.5 0.05 49.8 50.9 -0.02
 Psoriasis 1.8 0.8 0.09 1.8 0.8 0.09
 Renal impairment 6.8 4.7 0.09 5.6 5.3 0.01
 Rheumatoid arthritis 4.7 4.3 0.02 4.4 5 -0.03
 Schizophrenia 3.7 6.7 -0.14 5.1 5.4 -0.01
 Urinary tract infectious disease 7.5 9.4 -0.07 7.7 9 -0.05
 Viral hepatitis C 0.5 1 -0.05 0.3 1.1 -0.09
 Visual system disorder 49.3 49.6 -0.01 46.1 50.6 -0.09
Medical history: Cardiovascular disease
 Atrial fibrillation 3.2 3.8 -0.03 3 4.1 -0.06
 Cerebrovascular disease 9.2 6.8 0.09 8.9 8 0.03
 Coronary arteriosclerosis 0.7 1.8 -0.09 0.9 2 -0.09
 Heart disease 33.1 31.6 0.03 32 33.5 -0.03
 Ischemic heart disease 15.6 13.7 0.05 15.8 14.6 0.03
 Peripheral vascular disease 17.2 15.7 0.04 15.3 17.9 -0.07
 Pulmonary embolism 21.3 17.8 0.09 21.2 19.2 0.05
 Venous thrombosis 0.2 0.8 -0.08 0.3 0.8 -0.06
Medical history: Neoplasms
 Hematologic neoplasm 0.5 0.6 -0.03 0.3 0.5 -0.03
 Malignant lymphoma 0.1 0.3 -0.04 0.2 0.3 -0.03
 Malignant neoplastic disease 7.7 8.6 -0.03 7.2 8.7 -0.06
 Malignant tumor of breast 0.6 0.4 0.04 0.5 0.3 0.03
 Malignant tumor of colon 0.5 0.6 -0.03 0.2 0.8 -0.09
 Malignant tumor of lung 0.6 0.4 0.04 0.6 0.3 0.04
 Malignant tumor of urinary bladder 0.2 0.1 0.01 0.3 0.2 0.03
 Primary malignant neoplasm of prostate 1.2 1.5 -0.03 1.1 1.7 -0.05
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Data are presented as %.

RAAS, renin-angiotensin-aldosterone system; SMD, standardized mean difference.

Fig 2. Balance between the groups before and after propensity score matching.

Fig 2

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Table 2. Clinical outcomes.

Before propensity-score stratification After propensity-score stratification
RAAS inhibitor Non-RAAS inhibitor Unadjusted p value RAAS inhibitor Non-RAAS inhibitor Adjusted p value
(N = 1,111) (N = 794) HR (95% CI) (N = 666) (N = 666) HR (95% CI)
All-cause mortality 97 (8.7) 74 (9.3) 0.96 (0.71–1.30) 0.79 97 (14.6) 74 (11.1) 0.79 (0.54–1.15) 0.22
RAAS inhibitor Non-RAAS inhibitor Unadjusted p value RAAS inhibitor Non-RAAS inhibitor Adjusted p value
(N = 1098) (N = 787) HR (95% CI) (N = 660) (N = 660) HR (95% CI)
Ventilator care 54 (4.9) 31 (3.9) 1.23 (0.80–1.93) 0.36 29 (4.4) 27 (4.1) 1.04 (0.60–1.79) 0.89
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Data are presented as %.

RAAS, renin-angiotensin-aldosterone system; HR, hazard ratio; CI, confidence interval.

Fig 3.

Fig 3

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Kaplan-Meier curves for mortality in the (A) entire population and (B) propensity score matched population.

For ventilator care comparison, 20 patients that needed ventilator care between antihypertensive drug prescription and Covid-19 diagnosis were excluded (S1 Fig). The target cohort consisted of 1,098 patients on RAAS inhibitor treatment, and the comparator cohort consisted of 787 patients with other antihypertensive drug treatment (S1 Table). After propensity score matching, a total of 660 pairs was generated, and we found no significant imbalance between the groups (S1 Table and S2 Fig). The incidence of ventilator care also showed no difference (4.4% vs. 4.1%; HR, 1.04; 95% CI, 0.60–1.79; p = 0.89) (Table 2 and S3 Fig).

Discussion

In the current study, use of RAAS inhibitors in Covid-19 patients did not appear to be associated with higher mortality compared with that of other antihypertensive drugs. The results of our study are in agreement with recently reported studies and the current recommendations [3,7–9], and add evidence to that RAAS inhibitor treatment should be continued in Covid-19 patients.

Based on a finding from the first major outbreak of the severe acute respiratory syndrome coronavirus (SARS-Cov) in Hong Kong in 2003 that ACE2 acts as a functional receptor for coronavirus [13,14], Sommerstein and Gra¨ni presented a hypothesis that ACEi could act as a potential risk factor of Covid-19, and upregulation of ACE2 could cause fatal outcomes [15]. ACE2 was found to be the receptor-binding site for the spike protein of Covid-19 and well as in SARS-Cov, and concerns were raised on use of RAAS inhibitors in Covid-19 patients. Some authors argued that patients should discontinue RAAS inhibitors, even temporarily, given the current pandemic of Covid-19 [3,16,17]. Although the evidence for this hypothesis is insufficient and is mostly derived from in vitro studies, clinical data to refuse this hypothesis are not available. Therefore, replacing RAAS inhibitors with other antihypertensive drugs in Covid-19 patients remains controversial [18].

Some recently published commentaries have recommended against suspension or withdrawal of RAAS inhibitors [3,7–9] based on evidence from several animal and experimental models [19–21]. Several observational analysis also showed that there was no significant association between RAAS inhibitor treatment and outcomes of Covid-19 [22,23], but these studies used single-center data with a small number of patients. In this study, we reinforced the recommendation against withdrawing RAAS inhibitors by presenting real-world data of a dedicated nationwide Covid-19 patient registry. Although differences in the early stage of Covid-19 according to the use of RAAS inhibitor was unclear, we demonstrated that it was not associated with increased mortality of Covid-19 compared with other antihypertensive drugs. The previously reported effect of RAAS inhibitors on ACE2 level and activity in humans is unclear [19,20,24]. The results of studies conducted for SARS-Cov, if generalizable to Covid-19, suggest that the effect of ARB may paradoxically be protective against Covid-19 [4]. The underlying mechanism could be related to the possibility that interaction with the coronavirus may lead to ACE2 downregulation. This, in turn, causes excessive production of angiotensin by ACE, whereas lower level of ACE2 allows for conversion to angiotensin (1–7), which is a heptapeptide with vasodilator activity [5]. With ACE2 downregulation, angiotensin-II stimulates AT1 to increase pulmonary vascular permeability, thereby mediating increased lung pathology [6]. Use of RAAS inhibitors may upregulate ACE2 to compensate for this downregulation, and this could cause higher ACE2 expression to protect against acute lung injury in SARS-Cov-2 infected patients rather than to increase the risk of COVID-19.

Another issue that should be considered is the beneficial effect of RAAS inhibitors compared with other antihypertensive drugs in patients with heart disease [25]. RAAS inhibitors are antihypertensive drugs that should be used in patients with heart failure and for secondary prevention after acute myocardial infarction [25,26]. Among comorbidities of Covid-19, patients with cardiovascular disease have shown higher fatality rate [2]. With the systemic inflammatory response and immune system disorders that can occur during disease progression, Covid-19 patients can be more vulnerable to cardiovascular disorders such as myocardial injury [18]. Myocardial injury associated with SARS-CoV-2 occurred in 5 of the first 41 patients diagnosed in Wuhan [27], and Covid-19 patients with acute myocardial injury showed higher mortality than other patients [28]. Taken these together, the cardioprotective effect of RAAS inhibitors could even be helpful for outcomes of Covid-19 patients with cardiovascular disease, but this is beyond the scope of the present study and needs further investigation.

A previous report presented the difference between ACEi and ARB in the association with increased intestinal ACE messenger RNA levels and found that it was associated with ACEi but not ARB [29,30]. However, we could not conduct separate analyses based on the types of RAAS inhibitors in this study due to the enormously higher rate of ARB use. ARB has previously been reported to have a higher rate of use than ACEi in Korea [31], because the side effects of ACEi such as cough or angioedema are relatively more frequent in the Asian population. The ongoing study of “Losartan for Patients with COVID-19 Requiring Hospitalization (NCT04312009)” may provide evidence for the use of ARB, separate from ACEi.

The clinical implications of this study are that we added evidence that supports continued use of RAAS inhibitors in Covid-19 patients. RAAS inhibitors are approved for heart failure, diabetic nephropathy, and secondary prevention after acute myocardial infarction, but not all other antihypertensive drugs cover these indications [25]. Patients on RAAS inhibitor treatment are likely to be more fragile, and replacing RAAS inhibitors with other antihypertensive drugs may cause increased risk of adverse cardiovascular events. Indeed, spironolactone has been proposed as an alternative of RAAS inhibitors and even as a potential therapy for Covid-19 [32]. A number of studies on use of RAAS inhibitors in Covid-19 patients has been published and based on the data from the beginning of the outbreak, although some of them were recently retracted because of reliability and accuracy issues of the data. The result of the present study was based on reliable nationwide data from the government of Korea and supports the current recommendations that RAAS inhibitors should be continued in Covid-19 patients.

The results of this study should be interpreted with consideration of the following limitations. First, this was a retrospective study. Despite our efforts to adjust all confounding factors by propensity score matching analysis, some of the covariates were not well balanced in the propensity score matched population, and unmeasured factors might have affected the results. Second, owing to the nature of the database that retrieved the information from insurance issued claims, clinical presentation, symptoms, and hospital course could not be evaluated. Furthermore, a need for hospitalization or a radiologic evidence of lung injury represents a difference in response to the first stage, but these parameters could not be curated. Third, whether the patients actually continued or stopped taking RAAS inhibitors after diagnosis of Covid-19 could not be accurately evaluated. In addition, a comparison between the types of RAAS inhibitors (ACEi vs. ARB) was not performed. Lastly, the results of the current study are derived from a cohort of Korea; hence, the impact of ethnicity cannot be analyzed and needs further evaluation. Despite these limitations, this study provides the first real-world evidence on use of RAAS inhibitors in Covid-19 patients and valuable information for patient treatment during this pandemic.

Conclusion

In this study, RAAS inhibitor treatment did not appear to increase the mortality of Covid-19 patients compared with other antihypertensive drugs. Based on the results of the current study and previous recommendations, RAAS inhibitors may safely be continued in Covid-19 patients.

Supporting information

S1 Fig

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S2 Fig

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S3 Fig

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S1 Table. Baseline characteristics of cohorts for ventilator care comparison.

(DOCX)

Click here for additional data file. (21.7KB, docx)

Acknowledgments

The authors appreciate healthcare professionals dedicated to treating Covid-19 patients in Korea, and the Ministry of Health and Welfare and the Health Insurance Review & Assessment Service of Korea for sharing valuable national health insurance claims data in a prompt manner.

Data Availability

We used de-identified data based on the insurance benefit claims sent to the Health Insurance Review and Assessment Service of Korea (HIRA). This data set is comprised of all patients who were tested for Covid-19 in Korea until May 15, 2020, including the history of medical service used by these patients for the past five years. The data are shared in the form of the Observational Medical Outcome Partnership Common Data Model (OMOP-CDM). Observational Health Data Sciences and Informatics (OHDSI) analysis tools are built into the ATLAS interactive analysis platform and the OHDSI Methods Library R packages. OHDSI's open‐source software is publicly available on the GitHub repository (https://github.com/OHDSI/). In addition, concept sets used to define baseline characteristics and study outcomes are also available (https://github.com/OHDSI/Covid-19/).

Funding Statement

This research was funded by the Ministry of Health and Welfare, Korea (grant number: HI19C0811).

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  • 27.Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395:497–506. 10.1016/S0140-6736(20)30183-5 . [DOI] [PMC free article] [PubMed] [Google Scholar]
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  • 32.Cadegiani FA, Wambier CG, Goren A. Spironolactone: An Anti-androgenic and Anti-hypertensive Drug That May Provide Protection Against the Novel Coronavirus (SARS-CoV-2) Induced Acute Respiratory Distress Syndrome (ARDS) in COVID-19. Front Med (Lausanne). 2020; 7:453. 10.3389/fmed.2020.00453 . [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Giuseppe Vergaro

21 Oct 2020

PONE-D-20-27008

Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Covid-19 Patients in Korea

PLOS ONE

Dear Dr. Lee,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Giuseppe Vergaro, M.D..Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Park et al. performed a retrospective chart analysis on the impact of previous use of RAAS inhibitors on COVID-19 related clinical outcomes. Authors reported no difference between the group of patients treated with RAAS-inhibitors when compared to controls. The study seems very interesting and of relevant clinical interest, but probably needs language check, eventually performed by a native speakers.

1. Abstract conclusion should be more cautious since this is a retrospective analysis that may generate robust hypothesis but cannot gather general conclusion. Please tone the sentence down

2. line 170. the sentence “that use of RAAS inhibitors in Covid-19 patients was not associated with a greater incidence of mortality compared with that of other antihypertensive drugs” should be rephrased in a more proper way.

3. At line 189 the authors speculate that interaction with the coronavirus leads to ACE2 down regulation. As assessed by Michele M. Ciulla (Ciulla, M.M.; 2020). However, there are no scientific evidences that SARS-CoV-2 downregulates ACE2. Is that only authors’ speculation? Did the authors have any data about the expression regulation of ACE? Otherwise I would suggest also in this case to tone down the sentence

4. Line 195. Authors claim that RAAS inhibitors induce a higher expression level of ACE2. Again, is there any data that can support this statement?

5. Line 201. The sentence “Cardiovascular disease in Covid-19 patients showed higher fatality rates than other comorbidities such as diabetes or cardiovascular disease” is not clear. Please rephrase

6. At line 207 “Therefore, the cardioprotective effect of RAAS inhibitors may have decreased the mortality in Covid-19 patients”. This conclusion does not appear to be a result of the study. The authors so far stated that they evaluated the incidence of mortality by comparing Covid-19 positive patients treated with either RAAS inhibitors or other types of antihypertensive therapies. Do the authors have any data that can validate their statement?

7. Line 210 “A previous report presented the difference between ACEi and ARB in the association with increased intestinal messenger RNA levels and found that it was associated with ACEi but not ARB”. This sentence is of not clear understanding what type of mRNA is up regulated?.

8. Line 243 “In Covid-19 patients, RAAS inhibitor treatment was not associated with mortality”. According to the results presented by the authors this conclusion is wrong. RAAS inhibitor treatment was not associated with higher mortality compared to other antihypertensive therapies.

Reviewer #2: Introduction:

The introduction follows a logical sequence and was written concisely. This is of great importance.

Perhaps, I would recommend authors to include the statement from the American and European Cardiology Societies not recommending the suspension in early April, although this recommendation against the suspension was not based in any study confirming the safety of these classes for COVID-19.

I also highly recommend considering to bring the papers from the author below, either in the introduction or in the discussion.

This is an author that has interestingly progressed this thoughts from the perception that ACEi and ARB would lead to increased risk, and therefore proposing spironolactone as an alternative, to further studies no longer recommending to replace ACEi and ARB, and his last article, a very interesting one, where he even proposes ACEi and ARB as potential therapies for COVID-19 if acutely used. Please find the sequence below:

April/2020:

Cadegiani FA. Can spironolactone be used to prevent COVID-19-induced acute respiratory distress syndrome in patients with hypertension? Am J Physiol Endocrinol Metab. 2020 May 1;318(5):E587-E588. doi: 10.1152/ajpendo.00136.2020.

July/2020 (published online in July):

Cadegiani FA, Goren A, Wambier CG. Spironolactone may provide protection from SARS-CoV-2: Targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS). Med Hypotheses. 2020 Oct;143:110112. doi: 10.1016/j.mehy.2020.110112.

Cadegiani FA, Wambier CG, Goren A. Spironolactone: An Anti-androgenic and Anti-hypertensive Drug That May Provide Protection Against the Novel Coronavirus (SARS-CoV-2) Induced Acute Respiratory Distress Syndrome (ARDS) in COVID-19. Front Med (Lausanne). 2020 Jul 28;7:453. doi: 10.3389/fmed.2020.00453.

September/2020:

Cadegiani FA. Repurposing existing drugs for COVID-19: an endocrinology perspective. BMC Endocr Disord. 2020 Sep 29;20(1):149. doi: 10.1186/s12902-020-00626-0.

When only hospitalized patients are considered for the analysis, it is unexpected to detect differences between users and non-users of ECAi and ARB, because the potential damage caused by these drug classes is based on the enhanced viral cell entry due to increased attached ACE2 availability, which only occurs in the first stage.

Among hospitalized patients, that are in common all in the second or third stage, ECAi and ARB should no longer influence outcomes negatively.

Hence, to detect differences overall populations infected by COVID-19 would be more appropriate, and outcomes including hospitalization rate, WHO COVID Ordinal Outcomes, among others, would detect differences more accurately, if there is any.

Lines 82-83: “Therefore, we used de-identified Covid-82 19 nationwide data from Korea to evaluate the association between RAAS inhibitor use and Covid-19 outcomes.”

- If authors only considered mechanical ventilator and mortality, the objective was to detect severe COVID-19 induced outcomes, not all outcomes.

Materials and methods:

- Please specify whether the data was extracted from all patients diagnosed with COVID-19, or only those who got hospitalized. In this matter, there are two options that need to be adjusted, regardless:

1. In case all positive COVID-19 using ACEi/BRA versus other antihypertensives were considered, regardless of needing hospitalization: Inclusion of additional outcomes, including hospitalization, presence of lung injury through chest CT scan, and other parameters that better detect differences in responses to the first stage, when ACEi/BRA could theoretically play as an aggravating factor, would provide more sensitive data, and unveil early differences. However, in this case, it will be important to mention that regardless of differences in these additional parameters, disease course in terms of severity and death were not different.

2. In case only hospitalized patients were included for the analysis, this must be highlighted: “We compared patients that were hospitalized for COVID-19”.

One of the two options above should be addressed.

Results

I must congratulate the authors for the number of variables they adjusted for. Very few works have worked so well on this.

Discussion

I would bring to the discussion that whether there are differences in the early stage of COVID-19 between ACEi/ARB users and non-users is unclear, but regardless of whether these differences exist, they do not seem to impact the need of mechanical ventilation and death.

Again, please read the articles that I mentioned in the introduction. They may be helpful to increase the level of this already great paper.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: Dr. Alberto M. Marra, MD, PhD

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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PLoS One. 2021 Mar 11;16(3):e0248058. doi: 10.1371/journal.pone.0248058.r002

Author response to Decision Letter 0

24 Nov 2020

Response to the Reviewers

Reviewer #1.

Park et al. performed a retrospective chart analysis on the impact of previous use of RAAS inhibitors on COVID-19 related clinical outcomes. Authors reported no difference between the group of patients treated with RAAS-inhibitors when compared to controls. The study seems very interesting and of relevant clinical interest, but probably needs language check, eventually performed by a native speakers.

>> Response: We thank you for your kind comments. Following your recommendation, we had our script reviewed by a native professional editor.

1. Abstract conclusion should be more cautious since this is a retrospective analysis that may generate robust hypothesis but cannot gather general conclusion. Please tone the sentence down

>> Response: We understand your concern. Following your recommendation, we changed our conclusion as below.

“RAAS inhibitor treatment did not appear to increase the mortality of Covid-19 patients compared with other antihypertensive drugs, suggesting that they may be safely continued in Covid-19 patients.” (Line 55)

2. line 170. the sentence “that use of RAAS inhibitors in Covid-19 patients was not associated with a greater incidence of mortality compared with that of other antihypertensive drugs” should be rephrased in a more proper way.

>> Response: Following your recommendation, we changed it as below.

“In the current study, use of RAAS inhibitors in Covid-19 patients did not appear to be associated with higher mortality compared with that of other antihypertensive drugs.” (Line 164)

3. At line 189 the authors speculate that interaction with the coronavirus leads to ACE2 down regulation. As assessed by Michele M. Ciulla (Ciulla, M.M.; 2020). However, there are no scientific evidences that SARS-CoV-2 downregulates ACE2. Is that only authors’ speculation? Did the authors have any data about the expression regulation of ACE? Otherwise I would suggest also in this case to tone down the sentence

>> Response: Following your recommendation, we toned it down as below.

“The underlying mechanism could be related to the possibility that interaction with the coronavirus may lead to ACE2 downregulation.” (Line 192)

4. Line 195. Authors claim that RAAS inhibitors induce a higher expression level of ACE2. Again, is there any data that can support this statement?

>> Response: Following your recommendation, we toned it down as below.

“Use of RAAS inhibitors may upregulate ACE2 to compensate for this downregulation, and this could cause higher ACE2 expression to protect against acute lung injury in SARS-Cov-2 infected patients rather than to increase the risk of COVID-19.” (Line 197)

5. Line 201. The sentence “Cardiovascular disease in Covid-19 patients showed higher fatality rates than other comorbidities such as diabetes or cardiovascular disease” is not clear. Please rephrase

>> Response: Following your recommendation, we changed it as below.

“Among comorbidities of Covid-19, patients with cardiovascular disease have shown higher fatality rate [2].” (Line 204)

6. At line 207 “Therefore, the cardioprotective effect of RAAS inhibitors may have decreased the mortality in Covid-19 patients”. This conclusion does not appear to be a result of the study. The authors so far stated that they evaluated the incidence of mortality by comparing Covid-19 positive patients treated with either RAAS inhibitors or other types of antihypertensive therapies. Do the authors have any data that can validate their statement?

>> Response: Following your recommendation, we rephrased it as below.

“Taken these together, the cardioprotective effect of RAAS inhibitors could even be helpful for outcomes of Covid-19 patients with cardiovascular disease, but this is beyond the scope of the present study and needs further investigation.” (Line 210)

7. Line 210 “A previous report presented the difference between ACEi and ARB in the association with increased intestinal messenger RNA levels and found that it was associated with ACEi but not ARB”. This sentence is of not clear understanding what type of mRNA is up regulated?.

>> Response: We agree with the reviewer that this needs more explanation. So, we added a reference and clarified the type of mRNA as below.

“A previous report presented the difference between ACEi and ARB in the association with increased intestinal ACE messenger RNA levels and found that it was associated with ACEi but not ARB [29,30].” (Line 214)

8. Line 243 “In Covid-19 patients, RAAS inhibitor treatment was not associated with mortality”. According to the results presented by the authors this conclusion is wrong. RAAS inhibitor treatment was not associated with higher mortality compared to other antihypertensive therapies.

>> Response: Following your recommendation, we rephrased it as below.

“In this study, RAAS inhibitor treatment did not appear to increase the mortality of Covid-19 patients compared with other antihypertensive drugs. Based on the results of the current study and previous recommendations, RAAS inhibitors may safely be continued in Covid-19 patients.” (Line 253)

Reviewer #2.

Introduction:

The introduction follows a logical sequence and was written concisely. This is of great importance.

Perhaps, I would recommend authors to include the statement from the American and European Cardiology Societies not recommending the suspension in early April, although this recommendation against the suspension was not based in any study confirming the safety of these classes for COVID-19.

>> Response: We thank you for your kind comments. Following your recommendation, we added as below.

“Although a recommendation against suspension of RAAS inhibitors was made by the statement from the American and European Cardiology Societies [10], it was not based on clinical evidence, and the absence of clinical evidence supporting the safety of RAAS inhibitors in Covid-19 patients leaves clinicians with no choice but to follow the old principle of “primum non nocere (first, do no harm).” (Line 80)

I also highly recommend considering to bring the papers from the author below, either in the introduction or in the discussion.

This is an author that has interestingly progressed this thoughts from the perception that ACEi and ARB would lead to increased risk, and therefore proposing spironolactone as an alternative, to further studies no longer recommending to replace ACEi and ARB, and his last article, a very interesting one, where he even proposes ACEi and ARB as potential therapies for COVID-19 if acutely used. Please find the sequence below:

April/2020:

Cadegiani FA. Can spironolactone be used to prevent COVID-19-induced acute respiratory distress syndrome in patients with hypertension? Am J Physiol Endocrinol Metab. 2020 May 1;318(5):E587-E588. doi: 10.1152/ajpendo.00136.2020.

July/2020 (published online in July):

Cadegiani FA, Goren A, Wambier CG. Spironolactone may provide protection from SARS-CoV-2: Targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS). Med Hypotheses. 2020 Oct;143:110112. doi: 10.1016/j.mehy.2020.110112.

Cadegiani FA, Wambier CG, Goren A. Spironolactone: An Anti-androgenic and Anti-hypertensive Drug That May Provide Protection Against the Novel Coronavirus (SARS-CoV-2) Induced Acute Respiratory Distress Syndrome (ARDS) in COVID-19. Front Med (Lausanne). 2020 Jul 28;7:453. doi: 10.3389/fmed.2020.00453.

September/2020:

Cadegiani FA. Repurposing existing drugs for COVID-19: an endocrinology perspective. BMC Endocr Disord. 2020 Sep 29;20(1):149. doi: 10.1186/s12902-020-00626-0.

>> Response: We agree with the reviewer that mentioning spironolactone as an alternative would be interesting for readers. However, as shown in https://clinicalhypertension.biomedcentral.com/articles/10.1186/s40885-018-0098-0, the prescription rate of spironolactone in Korea is extremely low, so it was not feasible to conduct further study on this. Following your recommendation, we added as below to the Discussino section.

“Indeed, spironolactone has been proposed as an alternative of RAAS inhibitors and even as a potential therapy for Covid-19 [32].” (Line 228)

When only hospitalized patients are considered for the analysis, it is unexpected to detect differences between users and non-users of ECAi and ARB, because the potential damage caused by these drug classes is based on the enhanced viral cell entry due to increased attached ACE2 availability, which only occurs in the first stage.

Among hospitalized patients, that are in common all in the second or third stage, ECAi and ARB should no longer influence outcomes negatively.

Hence, to detect differences overall populations infected by COVID-19 would be more appropriate, and outcomes including hospitalization rate, WHO COVID Ordinal Outcomes, among others, would detect differences more accurately, if there is any.

>> Response: We agree with the reviewer that this needs clarification. In the very beginning of Covid-19 pandemic in Korea, every patients were hospitalized immediately after the diagnosis of Covid-19 regardless of symptom, and starting from April, a quarantine facility for those without symptom were operated. So, our study patients include overall population infected by Covid-19, but unfortunately hospitalization rate could not be extracted from the CDM system. Following your recommendation, we added as below to the Limiation section.

“Second, owing to the nature of the database that retrieved the information from insurance issued claims, clinical presentation, symptoms, and hospital course could not be evaluated. Furthermore, a need for hospitalization or a radiologic evidence of lung injury represents a difference in response to the first stage, but these parameters could not be curated.” (Line 240)

Lines 82-83: “Therefore, we used de-identified Covid-82 19 nationwide data from Korea to evaluate the association between RAAS inhibitor use and Covid-19 outcomes.”

- If authors only considered mechanical ventilator and mortality, the objective was to detect severe COVID-19 induced outcomes, not all outcomes.

>> Response: Following your recommendation, we changed it as below.

“Therefore, we used de-identified Covid-19 nationwide data from Korea to evaluate the association between RAAS inhibitor use and severe Covid-19 induced outcomes.” (Line 85)

Materials and methods:

- Please specify whether the data was extracted from all patients diagnosed with COVID-19, or only those who got hospitalized. In this matter, there are two options that need to be adjusted, regardless:

1. In case all positive COVID-19 using ACEi/BRA versus other antihypertensives were considered, regardless of needing hospitalization: Inclusion of additional outcomes, including hospitalization, presence of lung injury through chest CT scan, and other parameters that better detect differences in responses to the first stage, when ACEi/BRA could theoretically play as an aggravating factor, would provide more sensitive data, and unveil early differences. However, in this case, it will be important to mention that regardless of differences in these additional parameters, disease course in terms of severity and death were not different.

2. In case only hospitalized patients were included for the analysis, this must be highlighted: “We compared patients that were hospitalized for COVID-19”.

One of the two options above should be addressed.

>> Response: We agree with the reviewer that this needs to be clarified. For our study all the extracted data were among patients who were dignosed with Covid-19. As mentioned above, a quarantine facility for Covid-19 patients without symptom has been operated in Korea, but we could not extract hospitalization rate as well as other parameters that detects the difference in the first stage. Following your recommendation, we added as below to the script.

“Second, owing to the nature of the database that retrieved the information from insurance issued claims, clinical presentation, symptoms, and hospital course could not be evaluated. Furthermore, a need for hospitalization or a radiologic evidence of lung injury represents a difference in response to the first stage, but these parameters could not be curated.” (Line 240)

Results

I must congratulate the authors for the number of variables they adjusted for. Very few works have worked so well on this.

Discussion

I would bring to the discussion that whether there are differences in the early stage of COVID-19 between ACEi/ARB users and non-users is unclear, but regardless of whether these differences exist, they do not seem to impact the need of mechanical ventilation and death.

>> Response: Following your recommendation, we added as below.

“Although differences in the early stage of Covid-19 according to the use of RAAS inhibitor was unclear, we demonstrated that it was not associated with increased mortality of Covid-19 compared with other antihypertensive drugs.” (Line 186)

Again, please read the articles that I mentioned in the introduction. They may be helpful to increase the level of this already great paper.

>> Response: Following your recommendation, we added as below.

Indeed, spironolactone has been proposed as an alternative of RAAS inhibitors and even as a potential therapy for Covid-19 [32].” (Line 228)

Attachment

Submitted filename: responseletter_201102.docx

Click here for additional data file. (30.7KB, docx)

Decision Letter 1

Yoshihiro Fukumoto

19 Feb 2021

Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Covid-19 Patients in Korea

PONE-D-20-27008R1

Dear Dr. Lee,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Giuseppe Vergaro, M.D., Ph.D.

Academic Editor

PLOS ONE

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I'm Satisfied with the revision made by authors. The papaer has remarkably improved and is now suitable for publication. Well-Done!

Reviewer #2: Congratulations for the improvements. The only point is in the abstract: although authors changes the conclusion in the abstract of the main file, they did not change the conclusion of the abstract that authors include during the submission process.

**********

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Reviewer #1: No

Reviewer #2: Yes: Flavio A. Cadegiani, MD, MSc, Ph.D.

Acceptance letter

Yoshihiro Fukumoto

1 Mar 2021

PONE-D-20-27008R1

Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Covid-19 Patients in Korea

Dear Dr. Lee:

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Kind regards,

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on behalf of

Dr. Yoshihiro Fukumoto

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig

    (TIF)

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    S2 Fig

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    S3 Fig

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    S1 Table. Baseline characteristics of cohorts for ventilator care comparison.

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    Attachment

    Submitted filename: responseletter_201102.docx

    Click here for additional data file. (30.7KB, docx)

    Data Availability Statement

    We used de-identified data based on the insurance benefit claims sent to the Health Insurance Review and Assessment Service of Korea (HIRA). This data set is comprised of all patients who were tested for Covid-19 in Korea until May 15, 2020, including the history of medical service used by these patients for the past five years. The data are shared in the form of the Observational Medical Outcome Partnership Common Data Model (OMOP-CDM). Observational Health Data Sciences and Informatics (OHDSI) analysis tools are built into the ATLAS interactive analysis platform and the OHDSI Methods Library R packages. OHDSI's open‐source software is publicly available on the GitHub repository (https://github.com/OHDSI/). In addition, concept sets used to define baseline characteristics and study outcomes are also available (https://github.com/OHDSI/Covid-19/).

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