PLOS ONE

RESEARCH ARTICLE

Effect of renin-angiotensin-aldosterone
system inhibitors on Covid-19 patients in
Korea
Jungchan Park ID1‡, Seung-Hwa Lee ID2☯‡*, Seng Chan You3, Jinseob Kim4,
Kwangmo Yang5☯*
1 Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University
School of Medicine, Seoul, Korea, 2 Division of Cardiology, Department of Medicine, Heart Vascular Stroke
Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea,
a1111111111 3 Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Korea,
a1111111111 4 Department of Epidemiology, School of Public Health, Seoul National University, Seoul, Korea, 5 Center
a1111111111 for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
a1111111111
a1111111111 ☯ These authors contributed equally to this work.
‡ These authors share first authorship on this work and contributed equally to this work
* shuaaa.lee@samsung.com (S-HL); kmhi.yang@samsung.com (KY)

OPEN ACCESS Abstract

Citation: Park J, Lee S-H, You SC, Kim J, Yang K
(2021) Effect of renin-angiotensin-aldosterone
system inhibitors on Covid-19 patients in Korea. Background
PLoS ONE 16(3): e0248058. https://doi.org/
10.1371/journal.pone.0248058 The effect of renin-angiotensin-aldosterone system (RAAS) inhibitors in coronavirus dis-
ease 19 (Covid-19) patients has not been fully investigated. We evaluated the association
Editor: Yoshihiro Fukumoto, Kurume University
School of Medicine, JAPAN between RAAS inhibitor use and outcomes of Covid-19.

Received: August 27, 2020

Accepted: February 19, 2021 Methods

Published: March 11, 2021 This study was a retrospective observational cohort study that used data based on insur-
ance benefit claims sent to the Health Insurance Review and Assessment Service of Korea
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review by May 15, 2020. These claims comprised all Covid-19 tested cases and the history of medi-
process; therefore, we enable the publication of cal service use in these patients for the past five years. The primary outcome was all-cause
all of the content of peer review and author mortality, and the rate of ventilator care was compared between the groups.
responses alongside final, published articles. The
editorial history of this article is available here:
https://doi.org/10.1371/journal.pone.0248058
Results
Copyright: © 2021 Park et al. This is an open From a total of 7,590 patients diagnosed with Covid-19, two distinct cohorts were generated
access article distributed under the terms of the
Creative Commons Attribution License, which
based on RAAS inhibitors prescribed within 6 months before Covid-19 diagnosis. A total of
permits unrestricted use, distribution, and 1,111 patients was prescribed RAAS inhibitors, and 794 patients were prescribed antihyper-
reproduction in any medium, provided the original tensive drugs, excluding RAAS inhibitors. In propensity-score matched analysis, 666 pairs
author and source are credited.
of data set were generated, and all-cause mortality of the RAAS inhibitor group showed no
Data Availability Statement: We used de- significant difference compared with the non-RAAS inhibitor group (14.6% vs. 11.1%; haz-
identified data based on the insurance benefit
ard ratio [HR], 0.79; 95% confidence interval [CI], 0.54–1.15; p = 0.22). The rate of ventilator
claims sent to the Health Insurance Review and
Assessment Service of Korea (HIRA). This data set care was not significantly different between the two groups (4.4% vs. 4.1%; HR, 1.04; 95%
is comprised of all patients who were tested for CI, 0.60–1.79; p = 0.89).

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PLOS ONE Renin-angiotensin-aldosterone system inhibitors in Covid-19 patients

Covid-19 in Korea until May 15, 2020, including the Conclusions

history of medical service used by these patients
for the past five years. The data are shared in the RAAS inhibitor treatment did not appear to increase the mortality of Covid-19 patients com-
form of the Observational Medical Outcome pared with other antihypertensive drugs, suggesting that they may be safely continued in
Partnership Common Data Model (OMOP-CDM). Covid-19 patients.
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 Introduction
characteristics and study outcomes are also
available (https://github.com/OHDSI/Covid-19/).
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 char-
Funding: This research was funded by the Ministry
acterized the coronavirus disease 19 (Covid-19) as a pandemic on March 11, 2020, and Covid-
of Health and Welfare, Korea (grant number:
HI19C0811).
19 has become a global threatening disease with more than 6,000,000 confirmed cases world-
wide as of June 2020 [1]. In Korea, more than 11,629 cases of Covid-19 were diagnosed and
Competing interests: The authors declare no
273 deaths were reported through June 2020, and the government of Korea decided to share
conflicts of interest.
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-aldoste-
rone 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 miti-
gate this effect by upregulating ACE2 [4–6]. Based on these laboratory findings and consider-
ing 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 lim-
ited, 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 inhibi-
tors in Covid-19 patients leaves clinicians with no choice but to follow the old principle of “pri-
mum 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 princi-
ples 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

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PLOS ONE Renin-angiotensin-aldosterone system inhibitors in Covid-19 patients

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 pre-
scriptions, including angiotensin converting enzyme inhibitor (ACEi) or angiotensin II recep-
tor 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 accord-
ing 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 diag-
nosis, 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 inhibi-
tor 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).
For ventilator care comparison, 20 patients that needed ventilator care between antihyper-
tensive 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

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PLOS ONE Renin-angiotensin-aldosterone system inhibitors in Covid-19 patients

Fig 1. The flowchart of patients.

https://doi.org/10.1371/journal.pone.0248058.g001

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 insuffi-
cient 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 with-
drawal 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 asso-
ciation 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 rec-
ommendation against withdrawing RAAS inhibitors by presenting real-world data of a dedi-
cated 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 associ-
ated 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, sug-
gest that the effect of ARB may paradoxically be protective against Covid-19 [4]. The

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PLOS ONE Renin-angiotensin-aldosterone system inhibitors in Covid-19 patients

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
(Continued )

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PLOS ONE Renin-angiotensin-aldosterone system inhibitors in Covid-19 patients

Table 1. (Continued)

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)
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

Data are presented as %.

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

https://doi.org/10.1371/journal.pone.0248058.t001

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 stimu-
lates AT1 to increase pulmonary vascular permeability, thereby mediating increased lung
pathology [6]. Use of RAAS inhibitors may upregulate ACE2 to compensate for this downre-
gulation, 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.

Fig 2. Balance between the groups before and after propensity score matching.
https://doi.org/10.1371/journal.pone.0248058.g002

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PLOS ONE Renin-angiotensin-aldosterone system inhibitors in Covid-19 patients

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

Data are presented as %.

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

https://doi.org/10.1371/journal.pone.0248058.t002

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 anti-
hypertensive drugs that should be used in patients with heart failure and for secondary preven-
tion 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

Fig 3. Kaplan-Meier curves for mortality in the (A) entire population and (B) propensity score matched population.
https://doi.org/10.1371/journal.pone.0248058.g003

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PLOS ONE Renin-angiotensin-aldosterone system inhibitors in Covid-19 patients

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 previ-
ously 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 popula-
tion. 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 contin-
ued 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 poten-
tial 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 gov-
ernment 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 limita-
tions. 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 dif-
ference 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 inhib-
itors (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.

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PLOS ONE Renin-angiotensin-aldosterone system inhibitors in Covid-19 patients

Supporting information
S1 Fig.
(TIF)
S2 Fig.
(TIF)
S3 Fig.
(TIF)
S1 Table. Baseline characteristics of cohorts for ventilator care comparison.
(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 & Assess-
ment Service of Korea for sharing valuable national health insurance claims data in a prompt
manner.

Author Contributions
Conceptualization: Seung-Hwa Lee.
Data curation: Jungchan Park, Seng Chan You, Jinseob Kim.
Formal analysis: Seng Chan You, Jinseob Kim.
Funding acquisition: Seung-Hwa Lee, Kwangmo Yang.
Investigation: Jungchan Park, Seung-Hwa Lee, Kwangmo Yang.
Software: Jungchan Park, Seung-Hwa Lee, Seng Chan You.
Supervision: Kwangmo Yang.
Validation: Seng Chan You.
Visualization: Kwangmo Yang.
Writing – original draft: Jungchan Park, Seung-Hwa Lee.
Writing – review & editing: Seng Chan You, Jinseob Kim, Kwangmo Yang.

References
1. World Health Organization. Rolling updates on coronavirus disease (COVID-19) [Internet]. 2020 [cited
2020 Mar 31]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/
events-as-they-happen.
2. The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team China CDC. The Epide-
miological Characteristics of an Outbreak of 2019 Novel Coronaviurs Diseases. Vital Surveillances.
2020.
3. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-
Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020; 382:1653–9. https://doi.
org/10.1056/NEJMsr2005760 PMID: 32227760.
4. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020;
81:537–40. https://doi.org/10.1002/ddr.21656 PMID: 32129518.
5. Schindler C, Bramlage P, Kirch W, Ferrario CM. Role of the vasodilator peptide angiotensin-(1–7) in
cardiovascular drug therapy. Vasc Health Risk Manag. 2007; 3:125–37. PMID: 17583183.

PLOS ONE | https://doi.org/10.1371/journal.pone.0248058 March 11, 2021 9 / 11

PLOS ONE Renin-angiotensin-aldosterone system inhibitors in Covid-19 patients

6. Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, et al. Angiotensin-converting enzyme 2 protects from
severe acute lung failure. Nature. 2005; 436:112–6. https://doi.org/10.1038/nature03712 PMID:
16001071.
7. Danser AHJ, Epstein M, Batlle D. Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At
Present There Is No Evidence to Abandon Renin-Angiotensin System Blockers. Hypertension. 2020;
75:1382–5. https://doi.org/10.1161/HYPERTENSIONAHA.120.15082 PMID: 32208987.
8. Kuster GM, Pfister O, Burkard T, Zhou Q, Twerenbold R, Haaf P, et al. SARS-CoV2: should inhibitors of
the renin-angiotensin system be withdrawn in patients with COVID-19? Eur Heart J. 2020; 41:1801–3.
https://doi.org/10.1093/eurheartj/ehaa235 PMID: 32196087.
9. Bavishi C, Maddox TM, Messerli FH. Coronavirus Disease 2019 (COVID-19) Infection and Renin
Angiotensin System Blockers. JAMA Cardiol. 2020; 5:745–7. https://doi.org/10.1001/jamacardio.2020.
1282 PMID: 32242890.
10. ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic
[Internet]. 2020 [cited 2020 Mar 31]. Available from: https://www.escardio.org/Education/COVID-19-
and-Cardiology/ESC-COVID-19-Guidance.
11. You SC, Lee S, Cho SY, Park H, Jung S, Cho J, et al. Conversion of National Health Insurance Service-
National Sample Cohort (NHIS-NSC) Database into Observational Medical Outcomes Partnership-
Common Data Model (OMOP-CDM). Stud Health Technol Inform. 2017; 245:467–70. PMID:
29295138.
12. Overhage JM, Ryan PB, Reich CG, Hartzema AG, Stang PE. Validation of a common data model for
active safety surveillance research. J Am Med Inform Assoc. 2012; 19:54–60. https://doi.org/10.1136/
amiajnl-2011-000376 PMID: 22037893.
13. Lee N, Hui D, Wu A, Chan P, Cameron P, Joynt GM, et al. A major outbreak of severe acute respiratory
syndrome in Hong Kong. N Engl J Med. 2003; 348:1986–94. https://doi.org/10.1056/NEJMoa030685
PMID: 12682352.
14. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a
functional receptor for the SARS coronavirus. Nature. 2003; 426:450–4. https://doi.org/10.1038/
nature02145 PMID: 14647384.
15. Watkins J. Preventing a covid-19 pandemic. BMJ. 2020; 368:m810. https://doi.org/10.1136/bmj.m810
PMID: 32111649.
16. Trifiro G, Crisafulli S, Ando G, Racagni G, Drago F, Italian Society of P. Should Patients Receiving ACE
Inhibitors or Angiotensin Receptor Blockers be Switched to Other Antihypertensive Drugs to Prevent or
Improve Prognosis of Novel Coronavirus Disease 2019 (COVID-19)? Drug Saf. 2020; 43:507–9.
https://doi.org/10.1007/s40264-020-00935-2 PMID: 32303915.
17. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk
for COVID-19 infection? Lancet Respir Med. 2020; 8:e21. https://doi.org/10.1016/S2213-2600(20)
30116-8 PMID: 32171062.
18. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;
17:259–60. https://doi.org/10.1038/s41569-020-0360-5 PMID: 32139904.
19. Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme
(ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004;
383:45–51. https://doi.org/10.1042/BJ20040634 PMID: 15283675.
20. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, et al. Effect of angiotensin-
converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting
enzyme 2. Circulation. 2005; 111:2605–10. https://doi.org/10.1161/CIRCULATIONAHA.104.510461
PMID: 15897343.
21. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2
(ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005; 11:875–9. https://doi.org/10.1038/
nm1267 PMID: 16007097.
22. Yang G, Tan Z, Zhou L, Yang M, Peng L, Liu J, et al. Effects of Angiotensin II Receptor Blockers and
ACE (Angiotensin-Converting Enzyme) Inhibitors on Virus Infection, Inflammatory Status, and Clinical
Outcomes in Patients With COVID-19 and Hypertension: A Single-Center Retrospective Study. Hyper-
tension. 2020; 76:51–8. https://doi.org/10.1161/HYPERTENSIONAHA.120.15143 PMID: 32348166.
23. Mehta N, Kalra A, Nowacki AS, Anjewierden S, Han Z, Bhat P, et al. Association of Use of Angiotensin-
Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavi-
rus Disease 2019 (COVID-19). JAMA Cardiol. 2020; 5:1020–6. https://doi.org/10.1001/jamacardio.
2020.1855 PMID: 32936273.
24. Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angioten-
sin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hyperten-
sion. 2004; 43:970–6. https://doi.org/10.1161/01.HYP.0000124667.34652.1a PMID: 15007027.

PLOS ONE | https://doi.org/10.1371/journal.pone.0248058 March 11, 2021 10 / 11

PLOS ONE Renin-angiotensin-aldosterone system inhibitors in Covid-19 patients

25. Smith SC Jr., Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA, et al. AHA/ACCF Second-
ary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascu-
lar Disease: 2011 update: a guideline from the American Heart Association and American College of
Cardiology Foundation. Circulation. 2011; 124:2458–73. https://doi.org/10.1161/CIR.
0b013e318235eb4d PMID: 22052934.
26. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines
for the management of arterial hypertension. Eur Heart J. 2018; 39:3021–104. https://doi.org/10.1093/
eurheartj/ehy339 PMID: 30165516.
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. https://doi.org/10.1016/S0140-6736(20)
30183-5 PMID: 31986264.
28. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular Implications of Fatal Outcomes of
Patients With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020; 5:811–8. https://doi.org/
10.1001/jamacardio.2020.1017 PMID: 32219356.
29. Vuille-dit-Bille RN, Camargo SM, Emmenegger L, Sasse T, Kummer E, Jando J, et al. Human intestine
luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids. 2015;
47:693–705. https://doi.org/10.1007/s00726-014-1889-6 PMID: 25534429.
30. Lebek S, Tafelmeier M, Messmann R, Provaznik Z, Schmid C, Maier LS, et al. Angiotensin-converting
enzyme inhibitor/angiotensin II receptor blocker treatment and haemodynamic factors are associated
with increased cardiac mRNA expression of angiotensin-converting enzyme 2 in patients with cardio-
vascular disease. Eur J Heart Fail. 2020 https://doi.org/10.1002/ejhf.2020 PMID: 33017071.
31. Korean Society Hypertension, Hypertension Epidemiology Research Working Group, Kim HC, Cho
MC. Korea hypertension fact sheet 2018. Clin Hypertens. 2018; 24:13. https://doi.org/10.1186/s40885-
018-0098-0 PMID: 30288297.
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. https://doi.org/10.3389/
fmed.2020.00453 PMID: 32850920.

PLOS ONE | https://doi.org/10.1371/journal.pone.0248058 March 11, 2021 11 / 11