Effects of Angiotensin Receptor Blockers (ARBs) on In-Hospital Outcomes of Patients With Hypertension and Confirmed or Clinically Suspected COVID-19

Abstract

Background:
There is an ongoing controversy about harms and benefits of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in hypertensive patients with coronavirus disease 2019 (COVID-19). Given the unresolved debate, we investigated the association of ARBs with in-hospital outcomes of these patients.

Methods:
In this retrospective observational study, we studied patients with COVID-19 who referred to Sina Hospital in Tehran, Iran, from February 20 to May 29, 2020. Patients with either positive real-time reverse-transcriptase polymerase-chain-reaction test of swab specimens, or high clinical suspicion according to the World Health Organization's interim guidance were included. We followed-up patients for incurring death, severe COVID-19, and in-hospital complications.

Results:
We evaluated 681 patients with COVID-19 of whom 37 patients were excluded due to incomplete medical records and 8 patients who used ACEIs which left 636 patients in the analysis. In this cohort, 108 (17.0%) patients expired and 407 (64.0%) patients incurred severe COVID-19. Of 254 (39.9%) patients with hypertension, 122 (48.0%) patients were receiving an ARB. After adjustment for possible confounders, we found no independent association between taking ARBs and in-hospital outcomes except for acute kidney injury (AKI), in patients with confirmed or clinically suspected COVID-19, either hypertensive or not-hypertensive. We found that discontinuation of ARBs during hospitalization was associated with a greater risk of mortality, invasive ventilation, and AKI (All P˂0.002).

Conclusions:
We found that taking ARBs by patients with hypertension and confirmed or clinically suspected COVID-19 is not associated with poorer in-hospital outcomes after adjustment for possible confounders.

Full text

American Journal of Hypertension 1
ORIGINAL ARTICLE
1Department of Cardiology, Sina Hospital, Tehran University of
Medical Sciences, Tehran, Iran; 2Students’ Scientific Research
Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran;
3Non-Communicable Diseases Research Center, Endocrinology and
Metabolism Population Sciences Institute, Tehran University of Medical
Sciences, Tehran, Iran; 4Department of cardiology, Tehran Heart Center,
Tehran University of Medical Sciences, Tehran, Iran; 5Department
of Infectious Diseases, Sina Hospital, Tehran University of Medical
Sciences, Tehran, Iran; 6Department of Surgery, Sina Hospital, Tehran
University of Medical Sciences, Tehran, Iran; 7Department of Cardiology,
Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran;
8Department of Emergency Medicine, Sina Hospital, Tehran University
of Medical Sciences, Tehran, Iran; 9Department of Clinical Pharmacy,
Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran,
Iran; 10Research Development Center, Sina Hospital, Tehran University
of Medical Sciences, Tehran, Iran; 11Cardiac Primary Prevention Research
Center (CPPRC), Cardiovascular Diseases Research Institute, Tehran
University of Medical Sciences, Tehran, Iran.
© American Journal of Hypertension, Ltd 2020. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
*Contributed equally to this study as co-rst authors.
Correspondence: Haleh Ashraf (ha_as_ta@yahoo.com).
Initially submitted August 14, 2020; accepted for publication September
10, 2020; online publication September 12, 2020.
Severe acute respiratory syndrome-coronavirus-2 (SARS-
CoV-2) causes coronavirus disease 2019 (COVID-19) which
is a pandemic rst discovered in Wuhan, China, in December
2019.1 Up to 14 August 2020, it aected more than 21.2 mil-
lion persons worldwide with more than 338 thousand con-
rmed cases in Iran.2
Eects of Angiotensin Receptor Blockers (ARBs) on
In-Hospital Outcomes of Patients With Hypertension and
Conrmed or Clinically Suspected COVID-19
Abbas Soleimani,1,* Sina Kazemian,2,* Shahrokh KarbalaiSaleh,1 Arya Aminorroaya,3,4 Zahra Shajari,1
Azar Hadadi,5 Mohammad Talebpour,6 Hakimeh Sadeghian,7 Pooya Payandemehr,8
Mehran Sotoodehnia,8 Maryam Bahreini,8 Farhad Najmeddin,9 Ali Heidarzadeh,2 Ensieh Zivari,10 and
Haleh Ashraf10,11,
BACKGROUND
There is an ongoing controversy about harms and benets of
angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II
receptor blockers (ARBs) in hypertensive patients with coronavirus di-
sease 2019 (COVID-19). Given the unresolved debate, we investigated
the association of ARBs with in-hospital outcomes of these patients.
METHODS
In this retrospective observational study, we studied patients with
COVID-19 who referred to Sina Hospital in Tehran, Iran, from 20
February to 29 May 2020. Patients with either positive real-time reverse-
transcriptase polymerase-chain-reaction test of swab specimens, or
high clinical suspicion according to the World Health Organization’s in-
terim guidance were included. We followed-up patients for incurring
death, severe COVID-19, and in-hospital complications.
RESULTS
We evaluated 681 patients with COVID-19 of whom 37 patients were
excluded due to incomplete medical records and 8 patients who used
ACEIs which left 636 patients in the analysis. In this cohort, 108 (17.0%)
patients expired and 407 (64.0%) patients incurred severe COVID-
19. Of 254 (39.9%) patients with hypertension, 122 (48.0%) patients
were receiving an ARB. After adjustment for possible confounders,
we found no independent association between taking ARBs and
in-hospital outcomes except for acute kidney injury (AKI), in patients
with conrmed or clinically suspected COVID-19, either hypertensive or
not-hypertensive. We found that discontinuation of ARBs during hospi-
talization was associated with a greater risk of mortality, invasive venti-
lation, and AKI (all P ˂ 0.002).
CONCLUSIONS
We found that taking ARBs by patients with hypertension and con-
rmed or clinically suspected COVID-19 is not associated with poorer
in-hospital outcomes after adjustment for possible confounders.
Keywords: angiotensin receptor antagonists; angiotensin-converting
enzyme inhibitors; blood pressure; COVID-19; hypertension; renin–an-
giotensin system; SARS-CoV-2
doi:10.1093/ajh/hpaa149
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2 American Journal of Hypertension
Soleimani etal.
Given that angiotensin-converting enzyme 2 (ACE2)
serves as the main receptor for SARS-CoV-2, ACE2-
expressing cells are more prone to COVID-19 infection.3,4
According to the greater mortality of COVID-19 in patients
with hypertension,5 there is an ongoing controversy about
potential harms and benets of angiotensin-converting
enzyme inhibitors (ACEIs) and angiotensin II receptor
blockers (ARBs) in patients with hypertension and COVID-
19 which caused uncertainties in clinical practice.6–9 It is a
major challenge to change or continue these medications
in patients with hypertension and COVID-19. Hence, the
mechanistic speculations have been evaluated in some clin-
ical studies; nonetheless, they are not conclusive. Some
studies demonstrated benecial eects of ACEI/ARBs in
hypertensive patients with COVID-19 in terms of mortality
and severity of the disease10–12; however, other ones did not
nd any benecial or harmful eects.13–16 Moreover, no
study investigated the eects of these medications separately.
In this observational study, we aim to evaluate the asso-
ciation of ARBs with in-hospital outcomes of patients with
conrmed or clinically suspected COVID-19 from a tertiary
referral center in Tehran,Iran.
METHODS
Ethical considerations
e protocol of this study corresponds to the 2013 Helsinki
declaration and was approved by the Ethics Committee of
Tehran University of Medical Sciences (IR.TUMS.VCR.
REC.1399.018). All participants gave written informed con-
sent before inclusion in the study.
Study design and participants
We reported this study according to the Strengthening
the Reporting of Observational Studies in Epidemiology
(STROBE) statement.17 Sina Hospital is one of the major
tertiary teaching hospitals aliated by Tehran University
of Medical Sciences which is designated for treatment of
COVID-19 in the capital Tehran. We evaluated patients who
were admitted to Sina Hospital from 20 February to 29 May
2020. We included patients ≥18 years of age with a diag-
nosis of COVID-19 who met one of the following criteria: (i)
Positive real-time reverse-transcriptase polymerase-chain-
reaction (PCR) test of oropharyngeal or endotracheal swab
specimens. (ii) Highly suspicious patients according to the
World Health Organization’s interim guidance18 and Iranian
national committee of COVID-19,19 including patients with
ground-glass opacity, either isolated or with consolidation
in chest computed tomography scan, which cannot be fully
explained by volume overload, lobar or lung collapse, or
nodules along with the history compatible with COVID-19.
e details of patient care for individuals presenting with
respiratory symptoms to Sina Hospital emergency depart-
ment have been published previously.20
We collected demographic data, present, drug and past
medical history, admission vital signs and physical examina-
tion, baseline laboratory parameters, imaging ndings, and
in-hospital treatments from electronic medical records. We
followed-up patients for in-hospital acute respiratory dis-
tress syndrome (ARDS), invasive ventilation, acute cardiac
injury (ACI), acute kidney injury (AKI), acute liver injury
(ALI), multiorgan damage, the severity of the disease, and
mortality. Moreover, we compared in-hospital outcomes be-
tween 4 groups of patients with hypertension categorized
based on the history of ARB usage during hospitalization:
(i) Continued: patients who continued their ARBs at least
for 7days aer admission. (ii) Discontinued: patients who
discontinued their ARBs within 7days aer admission. (iii)
Newly started: patients who were newly started on an ARB
aer hospitalization. (iv) Never used: patients who never
used any ARB.
Denitions
Hypertension was dened as systolic blood pressure
≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or
antihypertensive treatment. We dened diabetes mellitus
(DM) in case of fasting blood sugar ≥126mg/dl on 2 occasions,
or blood sugar ≥200mg/dl on 2 occasions, or treatment with
oral antidiabetic agents or insulin. History of coronary ar-
tery disease (≥50% stenosis on coronary angiography), heart
failure, or receiving treatment for these conditions were des-
ignated as cardiac disease. Cerebrovascular disease was de-
ned as a history of transient ischemic attack or stroke. We
dened chronic lung disease as a history of asthma, chronic
obstructive pulmonary disease, or interstitial lung disease.
Patients with a glomerular ltration rate <30ml/hour or the
need for renal replacement therapy were designated to have
chronic kidney disease. History of malignancy was dened
as a history of a treated neoplasm. e systemic immune-
inammation index (SII) was calculated as (platelet count ×
neutrophil count)/(lymphocytecount).
ARDS was dened according to the Berlin denition
criteria.21 We dened ACI as an increased serum level of
high-sensitivity cardiac troponin I (hs-cTnI) above the
99th percentile upper limit normal (ULN).22,23 AKI was
diagnosed if serum creatinine increased by ≥0.3 mg/dl
within 48 hours except for patients with known end-stage
renal disease.24 Serum transaminases ≥3× ULN or alkaline
phosphatase ≥2× ULN, or total bilirubin ≥2× ULN were
designated as ALI.25 Patients with at least 2 complications
including ACI, AKI, ALI, or ARDS were considered to have
multiorgan damage. We dened severe COVID-19 in the
presence of at least one of the following criteria: dyspnea,
respiratory rate ≥30/min, oxygen saturation ≤93%, >50%
lung involvement on imaging, respiratory failure, shock, or
multiorgan damage. e rest of the patients were categorized
as nonsevere COVID-19. We employed this denition sim-
ilar to Wu and McGoogan26 and modied it to introduce a
binary outcome, severe vs. nonsevere COVID-19.
Statistical analysis
We reported the data as mean ± standard deviation or
median [interquartile range] for continuous variables with
normal or skewed distribution, respectively. Means of con-
tinuous variables were compared using independent group
t-test if the data were normally distributed; otherwise, the
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American Journal of Hypertension 3
ARBs and In-Hospital Outcomes of COVID-19
Mann–Whitney U-test was used. Categorical variables were
demonstrated by number (%) and compared using the chi-
square test. We compared in-hospital outcomes between
4 groups of hypertensive patients based on the history of
taking ARBs by the chi-square post hoc test, in which we
assumed P ≤ 0.00625 as statistically signicant according to
the Bonferroni correction. We tted binary logistic regres-
sion models to the data to predict in-hospital outcomes of
the whole cohort and hypertensive patients based on the
usage of ARBs. Moreover, we used Cox proportional hazard
models for prediction of mortality to take the eect of the
time into account. We employed a standard entry method
to adjust these models for possible confounders. Other than
age and sex, we adjusted for the comorbidities and laboratory
data that were signicantly (P<0.05) associated with mor-
tality and severity, and were not missed in more than 10% of
cases. Additionally, we performed a sensitivity analysis to in-
vestigate the prognostic value of ARB usage in patients with
positive PCR tests. All statistical analyses were performed
using IBM Corp. Released 2016. IBM SPSS Statistics for
Windows, Version 24.0, Armonk, NY: IBM Corp. P ≤ 0.05
was considered statistically signicant.
RESULTS
Baseline characteristics of patients
We evaluated 681 patients with conrmed or clinically
suspected COVID-19 of whom 37 patients were excluded
due to interhospital transfer or lack of key information in
their medical records. Furthermore, we excluded 8 patients
who used ACEIs to be more focused on the eects of
ARBs because the number of ACEI users was far less than
the number of ARB users. Eventually, we included 636
patients including 254 hypertensive patients in the analysis.
Although all patients were highly suspicious for COVID-
19 based on the national and international guidelines,18,19
348 (54.7%) patients underwent PCR test of whom 145
(41.7%) patients were denitely diagnosed with COVID-
19. PCR test was done for 165 (65.0%) hypertensive patients
of whom 67 (40.6%) specimens were positive for COVID-
19. Overall, 145 (22.8%) patients in the whole cohort and
67 (26.4%) hypertensive patients were denitely diagnosed
with COVID-19 based on a positive PCR test. e mean age
was 57.2 years (interquartile range: 45–69 years) and 397
(62.4%) were male. e most common comorbidities in all
patients were hypertension (39.9%), DM, and cardiac disease
(Supplementary Table S1 online). In this cohort, 108 (17.0%)
patients expired and 407 (64.0%) patients incurred severe
COVID-19. Although the data of history, mortality, severity,
ARDS, and invasive ventilation were complete and the rate of
missing data for most of the laboratory data is less than 5%,
we had not the data of lactate dehydrogenase, hs-cTnI, liver
transaminases, and erythrocyte sedimentation rate in 29.1%,
27.1%, 20.8%, and 15.0% of the patients. In comparison with
nonhypertensive patients, patients with hypertension were
signicantly older and more likely to have comorbidities ex-
cept for malignancy. Furthermore, they were at increased
risk of mortality, severe COVID-19, invasive ventilation,
ACI, AKI, and multiorgan damage (Supplementary Table S1
online). Of 254 hypertensive patients, 122 (48.0%) patients
were receiving an ARB (Losartan: N= 105 and Valsartan:
N =17). In comparison with non-ARB users, ARB users
were more likely to be older, have cardiac disease, receive
cardiovascular medications, have higher serum creatinine,
have longer hospital length of stay, and incur AKI during
hospitalization (Table1).
Predictors of mortality and severity in hypertensive
patients
In hypertensive patients, the severe form of COVID-19
was associated with lower serum sodium and higher erythro-
cyte sedimentation rate (Table2). We found history of cere-
brovascular and chronic lung diseases, history of metformin
use, lower lymphocyte counts and hemoglobin, and higher
white blood cells count, neutrophil count, platelet-to-
lymphocyte ratio, SII, and creatinine as risk factors of mor-
tality in these patients (Table2). Moreover, older age, history
of DM, and higher neutrophil-to-lymphocyte ratio, urea,
C-reactive protein, lactate dehydrogenase, hs-cTnI, and
liver transaminases were associated with increased risk of
both severity and mortality of COVID-19 in hypertensive
patients (Table2).
Discontinuation of ARBs and in-hospital outcomes
During the hospitalization of hypertensive patients, 79
patients continued and 43 patients discontinued their ARBs,
36 patients were newly started on an ARB, and 96 patients
never used any ARB (Table3). e most common reason for
discontinuation was the inclusion in an ongoing randomized
controlled trial in Sina Hospital in which we aim to investi-
gate the eects of ACEI/ARBs on in-hospital outcomes of
patients with COVID-19. e reason for discontinuation
was the inclusion in the trial in 23 (53.5%), both AKI and
shock in 11 (25.6%), AKI in 6 (14.0%), and shock in 3 (7.0%)
patients. ere were statistically signicant dierences be-
tween these groups regarding mortality, invasive ventilation,
and AKI (Table3). Chi-square post hoc analysis showed that
patients who discontinued their ARBs were more likely to
die (P= 0.0000171), be invasively ventilated (P=0.00194),
and incur AKI (P=0.000216) in comparison with the other
3groups.
History of ARB usage and in-hospital outcomes
We determined the independent eects of ARB usage
on in-hospital outcomes of the whole cohort and hyper-
tensive patients by using logistic regression analysis and
taking possible confounders into account (Table4). In the
all patients’ model, we adjusted for age, sex, DM, hyperten-
sion, cardiac disease, cerebrovascular disease, chronic lung
disease, chronic kidney disease, neutrophil-to-lymphocyte
ratio, urea, and C-reactive protein. In the hypertensive
patients’ model, we employed age, sex, DM, cerebrovas-
cular disease, chronic lung disease, chronic kidney disease,
neutrophil-to-lymphocyte ratio, urea, and C-reactive pro-
tein as confounders. Aer these adjustments, we found
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4 American Journal of Hypertension
Soleimani etal.
Table 1. Baseline characteristics and clinical outcomes of hypertensive patients with and without ARB treatment
CharacteristicaTotal (N=254) ARB users (N=122) Non-ARB users (N=132) P†
Demographics
Age (years) 66.4± 12.9 68.0± 11.7 64.9± 13.8 0.051
Sex
Female 105 (41.3%) 50 (41.0%) 55 (41.7%) 0.912
Male 149 (58.7%) 72 (59.0%) 77 (58.3%)
Comorbidities
DM 119 (46.9%) 57 (46.7%) 62 (47.0%) 0.968
Cardiac disease 89 (35.0%) 56 (45.9%) 33 (25.0%) <0.001
Cerebrovascular disease 21 (8.3%) 10 (8.2%) 11 (8.3%) 0.968
Chronic lung disease 22 (8.7%) 10 (8.2%) 12 (9.1%) 0.800
Chronic kidney disease 26 (10.2%) 15 (12.3%) 11 (8.3%) 0.298
Malignancy 8 (3.1%) 4 (3.3%) 4 (3.0%) 0.910
Drug history
Statin 66 (26.0%) 54 (44.3%) 12 (9.1%) <0.001
Aspirin 69 (27.2%) 54 (44.3%) 15 (11.4%) <0.001
Metformin 53 (20.9%) 29 (23.8%) 24 (18.2%) 0.273
Beta blocker 58 (22.8%) 42 (34.4%) 16 (12.1%) <0.001
Calcium channel blocker 33 (13.0%) 23 (18.9%) 10 (7.6%) 0.008
Baseline laboratory data
WBC (×109/l) 7.3 [5.4–10.0] 7.3 [5.2–9.9] 7.4 [5.4–10.0] 0.640
Neutrophil (×109/l) 5.4 [3.6–8.2] 5.3 [3.6–8.2] 5.6 [3.6–8.2] 0.903
Lymphocyte (×109/l) 1.3 [0.9–1.8] 1.2 [0.8–1.8] 1.3 [1.0–1.8] 0.180
Platelets (×109/l) 192.0 [149.0–263.0] 196.0 [145.7–267.0] 191.0 [149.5–260.0] 0.875
Neutrophil-to-lymphocyte ratio 4.0 [2.6–7.7] 4.4 [2.5–8.7] 3.9 [2.6–6.6] 0.476
Platelet-to-lymphocyte ratio 154.4 [113.4–220.0] 160.9 [118.7–255.5] 146.6 [107.8–216.8] 0.206
SII 816.6 [445.4–1,590.8] 825.8 [473.9–1,809.7] 778.5 [433.4–1,459.4] 0.329
RBC (×1012/l) 4.6 [4.1–5.0] 4.5 [4.0–5.0] 4.6 [4.1–5.0] 0.365
Hemoglobin (g/dl) 13.3 [12.1–15.0] 13.2 [11.8–14.9] 13.4 [12.1–15.0] 0.389
Urea (mg/dl) 41.0 [27.0–66.2] 45.5 [30.0–76.0] 39.0 [25.2–58.7] 0.060
Creatinine (mg/dl) 1.2 [0.9–1.5] 1.2 [1.0–1.7] 1.1 [0.9–1.4] 0.037
BUN/creatinine 17.6 [12.8–28.7] 17.8 [36.7–13.2] 16.9 [12.7–24.4] 0.330
Sodium (mmol/l) 136.2 [132.5–140.2] 136.1 [132.4–139.6] 136.7 [132.4–140.5] 0.386
Potassium (mmol/l) 4.3 [4.0–4.6] 4.3 [4.1–4.6] 4.3 [3.9–4.7] 0.260
CRP (mg/l) 60.9 [25.1–116.8] 66.5 [27.0–126.9] 57.6 [23.6–98.4] 0.122
ESR (mm/hour) 50.0 [28.0–83.0] 52.5 [33.5–87.2] 41.0 [27.0–77.5] 0.068
LDH (U/l) 550.0 [443.2–686.5] 565.0 [441.5–691.0] 531.0 [443.0–688.0] 0.926
hs-cTnI (pg/ml) 8.0 [2.2–35.4] 8.1 [2.3–41.0] 8.0 [1.9–28.8] 0.578
AST (U/l) 50.0 [37.0–69.0] 53.5 [38.0–67.7] 48.0 [36.0–71.5] 0.500
ALT (U/l) 36.0 [26.5–50.0] 36.0 [25.0–47.0] 37.0 [28.5–56.5] 0.126
ALP (U/l) 176.0 [140.7–228.0] 176.5 [142.2–232.5] 175.0 [140.2–223.5] 0.807
In-hospital outcomes
Hospital length of stay (day) 4.0 [3.0–8.0] 5.0 [3.0–9.0] 4.0 [2.0–6.0] 0.008
Severity 182 (71.7%) 91 (74.6%) 91 (68.9%) 0.318
Mortality 68 (26.8%) 33 (27.0%) 35 (26.5%) 0.923
ARDS 80 (31.5%) 41 (33.6%) 39 (29.5%) 0.486
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American Journal of Hypertension 5
ARBs and In-Hospital Outcomes of COVID-19
no independent association between taking ARBs and
in-hospital outcomes except for the higher incidence of AKI,
in patients with conrmed or clinically suspected COVID-
19, either hypertensive or not-hypertensive (Table4). Aer
adjustment for the same confounders in the whole cohort
and hypertensive patients, Cox proportional hazard models
(Figure1 and Supplementary Table S2 online) revealed that
taking ARBs is not associated with greater mortality either
in the whole cohort (hazard ratio (HR)=1.00, 95% con-
dence interval (CI): 0.57–1.77; P=0.997) or hypertensive
patients (HR=0.89, 95% CI: 0.51–1.54; P=0.679). In the
sensitivity analysis for patients with positive PCR tests, we
found similar ndings except that in patients with positive
PCR tests, there was no signicant association between his-
tory of ARB usage and in-hospital AKI (Supplementary
Table S3 online).
Sex disparities in in-hospital outcomes
We observed no signicant dierence between female and
male patients, either in the whole cohort or hypertensive
patients, in terms of in-hospital outcomes; however, female
hypertensive patients were more likely to incur ARDS rather
than male hypertensive patients (P=0.014) (Supplementary
Table S4 online). Furthermore, ARB usage was not associated
with worse clinical outcomes in men and women with con-
rmed or clinically suspected COVID-19 (Supplementary
Tables S5 and S6 online).
DISCUSSION
In this study, we found that taking ARBs in hypertensive
patients with conrmed or clinically suspected COVID-
19 was not associated with mortality, severity, or any other
in-hospital complication except for AKI. Aer adjustment for
possible confounders, we found that ARB usage in patients
with conrmed or clinically suspected COVID-19 was not
an independent risk factor for worse in-hospital outcomes
but AKI. Moreover, we observed poorer outcomes in patients
who discontinued their ARBs during hospitalization.
Studies have demonstrated that SARS-CoV-2 enters the
cell via ACE23,4 which has a 40% identity and 61% similarity
to ACE; however, this homology is not in their active sites
which means that they are 2 dierent enzymes with dierent
functions.27 us, ACEIs do not inhibit ACE2 and cannot in-
terfere with the entrance of SARS-CoV-2 to the cell through
this mechanism.
ere are 2 forms of ACE2 in the human body, membrane-
bound ACE2 (mACE2) and soluble ACE2 (sACE2). e
former exerts benecial eects including cardioprotective
eects through converting angiotensin II to angiotensin
1–7. e latter constitutes a very small portion of the total
body ACE2 which is not functional and its level is inversely
correlated with mACE2.28,29 Angiotensin II through angio-
tensin II type 1 receptor (AT1R) and activation of ADAM17
results in cleavage of mACE2 from the membrane to pro-
duce sACE2. Although studies have shown that ARBs may
upregulate mACE2 through this mechanism, this eect
varies widely between dierent ARBs and dierent organs.
Moreover, such an eect has not been observed by ACEIs
which is attributed to the fact that this upregulation is done
through blockade of AT1Rs which is achieved by ARBs
and not ACEIs.28 Even if we accept that this upregulation
happens in vivo, it is suggested to be of minimal clinical
signicance regarding the infectivity of SARS-CoV-2 be-
cause most of the total body ACE2 is as mACE2 and cannot
vary signicantly through these changes. Furthermore,
the virus can enter the cell via small amounts of ACE2.28,29
erefore, we may conclude that ACEI/ARBs do not facil-
itate virus entry and its infectivity. Additionally, it should
be emphasized that some evidence shows that increased
expression of ACE2 can be protective against acute lung
injuries by its anti-inammatory and antibrotic eects on
the lung.3,28,30
We found that taking ARBs is not independently associ-
ated with poorer in-hospital outcomes, except for AKI, aer
adjustment for confounders which is in line with several
previous reports13–16; nevertheless, some studies suggest that
ACEI/ARBs were associated with improved outcomes in
COVID-19 patients.10–12 Zhang etal.11 studied 1,128 hyper-
tensive patients with COVID-19 of whom 17% were taking
ACEI/ARBs and the medications were continued during hos-
pitalization in two-thirds of them. ey showed that treat-
ment with ACEI/ARBs is associated with a remarkably lower
28-day all-cause mortality (HR=0.37, 95% CI: 0.15–0.89;
P=0.03) and a borderline-signicantly lower incidence rate
CharacteristicaTotal (N=254) ARB users (N=122) Non-ARB users (N=132) P†
Invasive ventilation 42 (16.5%) 20 (16.4%) 22 (16.7%) 0.953
ACI 73 (28.7%) 38 (31.1%) 35 (26.5%) 0.415
AKI 49 (19.3%) 31 (25.4%) 18 (13.6%) 0.018
ALI 29 (11.4%) 11 (9.0%) 18 (13.6%) 0.247
Multiorgan damage 67 (26.4%) 36 (29.5%) 31 (23.5%) 0.276
Abbreviations: ACI, acute cardiac injury; AKI, acute kidney injury; ALI, acute liver injury; ALP, alkaline phosphatase; ALT, alanine
aminotransferase; ARB, angiotensin II receptor blocker; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; BUN,
blood urea nitrogen; CRP, C-reactive protein; DM, diabetes mellitus; ESR, erythrocyte sedimentation rate; hs-cTnI, high-sensitivity cardiac tro-
ponin I; LDH, lactate dehydrogenase; RBC, red blood cells; SII, systemic immune-inflammation index; WBC, white blood cells.
aData are presented as mean ± standard deviation, number (%), or median [interquartile range].
†Statistically significant P values are bolded.
Table 1. Continued
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6 American Journal of Hypertension
Soleimani etal.
Table 2. Severity and mortality rates of confirmed or clinically suspected COVID-19 in hypertensive patients
CharacteristicaTotal (N=254)
Severity Mortality
Severe (N=182) Nonsevere (N=72) P†Deceased (N=68) Survived (N=186) P†
Demographics
Age (years) 66.4± 12.9 67.7± 12.4 62.9± 13.5 0.007 73.3± 11.0 63.8± 12.8 <0.001
Sex
Female 105 (41.3%) 81 (44.5%) 24 (33.3%) 0.103 30 (44.1%) 75 (40.3%) 0.587
Male 149 (58.7%) 101 (55.5%) 48 (66.7%) 38 (55.9%) 111 (59.7%)
Comorbidities
DM 119 (46.9%) 96 (52.7%) 23 (31.9%) 0.003 39 (57.4%) 80 (43.0%) 0.043
Cardiac disease 89 (35.0%) 64 (35.2%) 25 (34.7%) 0.947 27 (39.7%) 62 (33.3%) 0.346
Cerebrovascular
disease
21 (8.3%) 18 (9.9%) 3 (4.2%) 0.136 13 (19.1%) 8 (4.3%) <0.001
Chronic lung disease 22 (8.7%) 19 (10.4%) 3 (4.2%) 0.109 10 (14.7%) 12 (6.5%) 0.038
Chronic kidney disease 26 (10.2%) 19 (10.4%) 7 (9.7%) 0.865 8 (11.8%) 18 (9.7%) 0.627
Malignancy 8 (3.1%) 5 (2.7%) 3 (4.2%) 0.559 4 (5.9%) 4 (2.2%) 0.132
Drug history
Statin 66 (26.0%) 52 (28.6%) 14 (19.4%) 0.135 17 (25.0%) 49 (26.3%) 0.829
Aspirin 69 (27.2%) 51 (28.0%) 18 (25.0%) 0.626 21 (30.9%) 48 (25.8%) 0.421
Metformin 53 (20.9%) 41 (22.5%) 12 (16.7%) 0.300 20 (29.4%) 33 (17.7%) 0.043
Beta blocker 58 (22.8%) 42 (23.1%) 16 (22.2%) 0.884 18 (26.5%) 40 (21.5%) 0.404
ARB 112 (48.0%) 91 (50.0%) 31 (43.1%) 0.318 33 (485%) 89 (47.8%) 0.923
Calcium channel
blocker
33 (13.0%) 25 (13.7%) 8 (11.1%) 0.575 9 (13.2%) 24 (12.9%) 0.944
Baseline laboratory data
WBC (×109/l) 7.3 [5.4–10.0] 7.8 [5.4–10.5] 7.0 [5.3–9.3] 0.227 9.7 [6.5–14.1] 6.7 [5.1–9.3] <0.001
Neutrophil (×109/l) 5.4 [3.6–8.2] 5.6 [3.8–8.4] 5.1 [3.3–6.9] 0.072 7.8 [5.5–10.6] 4.5 [3.4–7.2] <0.001
Lymphocyte (×109/l) 1.3 [0.9–1.8] 1.2 [0.8–1.8] 1.4 [1.0–1.8] 0.091 1.0 [0.7–1.6] 1.3 [1.0–1.8] <0.001
Platelets (×109/l) 192.0 [149.0–263.0] 189.5 [147.7–275.0] 200.0 [150.5–252.5] 0.667 207.0 [151.0–277.0] 190.0
[148.0–256.7]
0.356
Neutrophil-to-
lymphocyte ratio
4.0 [2.6–7.7] 4.4 [2.8–8.7] 3.5 [2.3–6.0] 0.011 6.7 [4.1–10.9] 3.5 [2.4–6.0] <0.001
Platelet-to-lymphocyte
ratio
154.4 [113.4–220.0] 156.5 [109.3–247.7] 149.0 [117.0–192.8] 0.336 206.1 [126.0–268.9] 143.2
[107.5–201.3]
0.002
SII 816.6 [445.4–1,590.8]881.1 [444.8–1,745.5]713.3 [449.3–1,150.2] 0.065 1,375.7
[783.2–3,093.1]
740.6
[407.6–1,234.6]
<0.001
RBC (×1012/l) 4.6 [4.1–5.0] 4.5 [4.0–5.0] 4.7 [4.1–5.0] 0.334 4.4 [3.9–4.9] 4.6 [4.1–5.0] 0.112
Hemoglobin (g/dl) 13.3 [12.1–15.0] 13.1 [12.0–14.9] 13.8 [12.3–15.0] 0.328 13.1 [11.2–14.7] 13.5 [12.2–15.1] 0.045
Urea (mg/dl) 41.0 [27.0–66.2] 45.5 [28.0–73.2] 35.0 [26.0–57.0] 0.044 59.0 [38.0–107.0] 36.0 [25.0–54.0] <0.001
Creatinine (mg/dl) 1.2 [0.9–1.5] 1.2 [1.0–1.6] 1.1 [0.9–1.4] 0.122 1.4 [1.1–2.1] 1.1 [0.9–1.4] <0.001
BUN/creatinine 17.6 [12.8–28.7] 18.8 [13.5–33.3] 14.8 [11.6–21.3] 0.016 23.1 [15.5–61.8] 16.5 [11.6–22.2] <0.001
Sodium (mmol/l) 136.2 [132.5–140.2] 135.6 [132.0–139.2] 138.1 [134.7–141.1] 0.003 135.9 [132.7–139.7] 136.7
[132.4–140.4]
0.881
Potassium (mmol/l) 4.3 [4.0–4.6] 4.3 [4.0–4.7] 4.3 [4.0–4.6] 0.753 4.3 [3.8–4.7] 4.3 [4.0–4.6] 0.591
CRP (mg/l) 60.9 [25.1–116.8] 67.5 [33.6–126.6] 47.2 [10.9–78.2] 0.001 80.2 [57.7–140.7] 53.4 [14.9–97.9] <0.001
ESR (mm/hour) 50.0 [28.0–83.0] 51.5 [30.0–87.0] 40.5 [21.0–76.2] 0.021 59.0 [27.0–90.0] 46.0 [29.0–79.0] 0.176
LDH (U/l) 550.0 [443.2–686.5] 598.5 [485.5–745.2] 460.0 [347.2–551.5] <0.001 677.0 [498.5–837.2] 528.5
[436.0–644.2]
0.001
hs-cTnI (pg/ml) 8.0 [2.2–35.4] 11.0 [3.1–52.9] 3.9 [1.5–8.0] <0.001 34.7 [7.2–144.5] 6.1 [1.7–18.0] <0.001
AST (U/l) 50.0 [37.0–69.0] 57.5 [42.2–75.0] 38.0 [30.5–43.0] <0.001 66.5 [49.5–90.7] 44.0 [36.0–60.5] <0.001
ALT (U/l) 36.0 [26.5–50.0] 38.0 [28.0–53.0] 30.0 [24.0–40.0] <0.001 45.5 [31.0–62.0] 34.0 [25.0–45.0] <0.001
ALP (U/l) 176.0 [140.7–228.0] 177.0 [140.7–230.5] 169.5 [140.7–215.0] 0.686 186.0 [140.0–248.0] 174.0
[141.0–222.0]
0.272
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American Journal of Hypertension 7
ARBs and In-Hospital Outcomes of COVID-19
of ARDS (HR=0.65, 95% CI: 0.41–1.04; P=0.07).11 In con-
trast, we found no benecial eects of ARBs on in-hospital
outcomes and demonstrated remarkably greater in-hospital
mortality, invasive ventilation, and AKI in patients who
discontinued ARBs during hospitalization which is a novel
nding. ese conicting results may be attributed to the
dierences in sample sizes, follow-up durations, statis-
tical approaches, and ethnicity of the patients; however, it
should be noted that discontinuation is linked with poorer
outcomes. Although this is an observational study with its
inherent biases and we cannot generalize this nding, it
supports the statement that discontinuing ARBs in COVID-
19 patients can be potentially harmful.30–33 Furthermore,
there is no study implying detrimental eects of ARBs on the
clinical outcomes of hypertensive patients with COVID-19.
erefore, the current debate is that if ARBs have neutral or
benecial eects on outcomes of patients with hypertension
and COVID-19. Future multicenter studies, randomized
controlled trials, and meta-analyses will help to respond to
this question.
We found that usage of ARBs is associated with an
increased risk of AKI both in the whole cohort and hyperten-
sive patients. Furthermore, we observed that the prevalence
of AKI was signicantly higher in patients who discontinued
their ARBs during hospitalization. ese ndings may be
attributed to the fact that AKI can be an adverse event of
ARBs. In a population-based cohort study, Manseld etal.34
demonstrated that treatment with ACEI/ARBs is associated
with a 12% increased risk of AKI. Moreover, our patients
must be managed with a conservative approach for uid
therapy for the treatment of ARDS which might contribute
to the occurrence of AKI.35
We found no sex disparity in terms of in-hospital
outcomes, except for the higher prevalence of ARDS in fe-
male hypertensive patients similar to some studies15; never-
theless, other studies demonstrated poorer outcomes in male
CharacteristicaTotal (N=254)
Severity Mortality
Severe (N=182) Nonsevere (N=72) P†Deceased (N=68) Survived (N=186) P†
In-hospital outcomes
Hospital length of stay
(day)
4.0 [3.0–8.0] 5.0 [3.0–8.5] 3.0 [2.0–5.0] <0.001 7.0 [3.0–10.0] 4.0 [3.0–7.0] 0.048
ARDS 80 (31.5%) 80 (44.0%) 0 <0.001 49 (72.1%) 31 (16.7%) <0.001
Invasive ventilation 42 (16.5%) 42 (23.1%) 0 <0.001 42 (61.8%) 0 <0.001
ACI 73 (28.7%) 69 (37.9%) 4 (5.6%) <0.001 34 (50.0%) 39 (21.0%) <0.001
AKI 49 (19.3%) 46 (25.3%) 3 (4.2%) <0.001 36 (52.9%) 13 (7.0%) <0.001
ALI 29 (11.4%) 25 (13.7%) 4 (5.6%) 0.065 18 (26.5%) 11 (5.9%) <0.001
Multiorgan damage 67 (26.4%) 67 (36.8%) 0 <0.001 48 (70.6%) 19 (10.2%) <0.001
Abbreviations: ACI, acute cardiac injury; AKI, acute kidney injury; ALI, acute liver injury; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ARB, angi-
otensin II receptor blocker; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRP, C-reactive protein; DM,
diabetes mellitus; ESR, erythrocyte sedimentation rate; hs-cTnI, high-sensitivity cardiac troponin I; LDH, lactate dehydrogenase; RBC, red blood cells; SII, systemic
immune-inflammation index; WBC, white blood cells.
aData are presented as mean ± standard deviation, number (%), or median [interquartile range].
†Statistically significant P values are bolded.
Table 2. Continued
Table 3. Comparison of in-hospital outcomes of hypertensive patients with confirmed or clinically suspected COVID-19 based on the history
of ARBs usage
In-hospital outcomesaContinued (N=79) Discontinued (N=43) Newly started (N=36) Never used (N=96) P†
Hospital length of stay (day) 5.0 [3.0–8.0] 7.0 [3.0–11.0] 6.0 [3.0–10.0] 4.0 [2.0–6.0] 0.069
Mortality 10 (12.7%) 23 (53.5%)‡7 (19.4%) 28 (29.2%) <0.001
ARDS 22 (27.8%) 19 (44.2%) 14 (38.9%) 25 (26.0%) 0.115
Invasive ventilation 6 (7.6%) 14 (32.6%)‡5 (13.9%) 17 (17.7%) 0.005
ACI 21 (26.6%) 17 (39.5%) 11 (30.6%) 24 (25.0%) 0.342
AKI 14 (17.7%) 17 (39.5%)‡5 (13.9%) 13 (13.5%) 0.003
ALI 7 (8.9%) 4 (9.3%) 5 (13.9%) 13 (13.5%) 0.718
Multiorgan damage 18 (22.8%) 18 (41.9%) 10 (27.8%) 21 (21.9%) 0.076
Abbreviations: ACI, acute cardiac injury; AKI, acute kidney injury; ALI, acute liver injury; ARBs, angiotensin II receptor blockers; ARDS, acute
respiratory distress syndrome.
aData are presented as number (%) or median [interquartile range].
†Statistically significant P values are bolded.
‡Chi-square post hoc P value ˂0.00625.
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8 American Journal of Hypertension
Soleimani etal.
patients with COVID-19.13,36 ese discrepancies may arise
from dierences in methodologies, sample sizes, or ethnic
dierences which necessitate future studies.
Limitations
Despite the several strengths of this study including its focus
on the eects of ARBs alone rather than combined ACEI/
ARBs, we emphasize that it has several limitations. First, this
is an observational study with possible inherent biases that
calls for caution to extrapolate its results. Future randomized
studies are warranted. Second, it is a single-center study on
the Iranian population, and future multicenter studies on
dierent ethnicities are needed. ird, survival Cox regres-
sion analysis appears to be the best approach for evaluating
associations between the characteristics and outcomes of the
Table 4. Prognostic value of ARB usage for prediction of in-hospital outcomes of patients with confirmed or clinically suspected COVID-19
In-hospital outcomes
All patientsaHypertensive patientsb
OR 95% CI P* OR 95% CI P*
Mortality 1.00 0.48–2.06 0.996 0.86 0.42–1.78 0.689
Severity 1.21 0.65–2.24 0.553 1.23 0.66–2.30 0.522
ARDS 1.06 0.58–1.94 0.844 1.12 0.61–2.06 0.709
Invasive ventilation 0.92 0.41–2.06 0.842 0.88 0.41–1.90 0.749
ACI 1.24 0.67–2.29 0.492 1.36 0.75–2.47 0.315
AKI 2.17 1.06–4.44 0.034 2.26 1.13–4.56 0.022
ALI 0.54 0.21–1.40 0.207 0.54 0.21–1.42 0.214
Multiorgan damage 1.50 0.77–2.90 0.230 1.53 0.80–2.94 0.200
Abbreviations: ACI, acute cardiac injury; AKI, acute kidney injury; ALI, acute liver injury; ARB, angiotensin II receptor blockers ARDS, acute
respiratory distress syndrome; CI, confidence interval; OR, odds ratio.
aMultivariate logistic regression adjusted for age, sex, diabetes mellitus, hypertension, cardiac disease, cerebrovascular disease, chronic
lung disease, chronic kidney disease, neutrophil-to-lymphocyte ratio, urea, and C-reactive protein.
bMultivariate logistic regression adjusted for age, sex, diabetes mellitus, cerebrovascular disease, chronic lung disease, chronic kidney di-
sease, neutrophil-to-lymphocyte ratio, urea, and C-reactive protein.
*Statistically significant P values are bolded.
Figure 1. Cumulative survival of patients based on the history of ARB usage in the (a) all patients model and the (b) hypertensive patients model.
Abbreviation: ARB: angiotensin II receptor blockers.
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American Journal of Hypertension 9
ARBs and In-Hospital Outcomes of COVID-19
patients; however, we employed binary logistic regression
models rather than this approach because we did not record
the exact occurrence time of each outcome except for mor-
tality. Another limitation is the rate of missing data in some
laboratory data, especially hs-cTnI and liver transaminases,
which might result in under- or overestimation in the rate of
the ACI andALI.
In this single-center observational study, we found that
taking ARBs by patients with hypertension and conrmed
or clinically suspected COVID-19 is not associated with
poorer in-hospital outcomes aer adjustment for pos-
sible confounders. We found that discontinuation of these
medications during hospitalization was associated with a
greater risk of mortality, invasive ventilation, and AKI. All
studies reported so far, along with the results of this ar-
ticle, provide tentative reassurance that taking ARBs is
not harmful in COVID-19 patients. e hypothesis that
these medications may be benecial or not needs more
prospective and clinical trials. Our ndings support the
recommendations of cardiology societies of continuing
treatment with their antihypertensive medications.32,33
SUPPLEMENTARY MATERIAL
Supplementary data are available at American Journal of
Hypertensiononline.
FUNDING
is study has been supported by Tehran University of
Medical Sciences (grant number: 99-1-101-47211 to H.A.).
e funding source had no role in the study design, data
collection, data analysis, data interpretation, writing of the
manuscript, or decision of submission.
ACKNOWLEDGMENTS
We acknowledge all healthcare workers involved in the diag-
nosis and treatment of patients in Sina Hospital. We are indebted
to the Research Development Center of Sina Hospital for its sup-
port. e authors are grateful to Mrs Masoumeh Taleh and Mr
Saeed Hejrani for their help and members of the COVID-19
Crisis Committee of the Sina Hospital for their help and consult.
DISCLOSURE
e authors declared no conict of interest.
AUTHORS’ CONTRIBUTION
Concept and design: A.S., S.K.S., Z.S., H.S., and H.A.
Acquisition, analysis, or interpretation of data: A.S., S.K.,
S.K.S., A.A., Z.S., A.H., M.T., H.S., P.P., M.S., M.B., F.N., E.Z.,
and H.A. Statistical analysis: S.K., A.A., and H.A. Draing
of the manuscript: S.K., A.A., Z.S., and E.Z. Critical revision
of the manuscript: A.S., S.K.S., A.H., M.T., H.S., P.P., M.S.,
M.B., F.N., and H.A. Supervision: A.S.and H.A. All authors
have read and approved the manuscript and are responsible
for its content.
DATA AVAILABILITY
Data are available upon a reasonable request to the corre-
sponding author.
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