Introduction: Use of certain antihypertensive medications has been an area of interest during the COVID-19 pandemic, and several hypotheses have been developed regarding the effects of renin-angiotensin system blockers as well as calcium channel blockers in those infected with COVID-19. We seek to determine the association between exposure to ACEI, ARB, and CCB and outcomes in those admitted to the hospital with COVID-19 infection. Methods: This retrospective cohort study included 841 adult patients hospitalized with COVID-19 infection at the University of Chicago Medical Center between March 25 and June 22, 2020. Out of these 841, 453 patients had a personal history of hypertension. For the first part, we evaluated primary outcomes of in-hospital mortality and ICU admission in hospitalized COVID-19 patients based on their exposure to particular medications regardless of a personal history of hypertension and compared them with those who were not on these medications. For the second part, we evaluated the aforementioned outcomes in 453 patients with a personal history of hypertension based on their medication exposure. Secondary outcomes of length of stay, readmission rate, and new-onset dialysis requirement were also compared across the study groups. Results: Out of 841 patients, 111 (13.19%) were on ACEI/ARB (median age: 66.1, SD 15.4; 52.25% females) and 730 (86.80%) were not on them (median age: 56.6, SD 20.3; 50.14% females), while 277 (32.93%) used CCB (median age: 64.6, SD 15.2; 57.04% females) and 564 (67.06%) did not use CCB (median age: 54.6, SD 21.2; 47.16% females). After adjusting for demographics and covariates, neither ACEI/ARB nor CCB exposure was associated with any effect on mortality, but ACEI/ARB exposure was associated with 42% reduction in risk of ICU admissions (OR 0.58, 95% CI [0.35, 0.95], p value 0.03). In addition, combined use of ACEI/ARB and CCB was associated with statistically significant (45%) reduction in ICU admission (OR 0.55, 95% CI [0.32, 0.94], p value 0.029). Out of 453 patients with a personal history of hypertension, 85 (18.76%) were taking ACEI/ARB (median age 65, SD 15.6; 56.47% females) and 368 (81.24%) were not on ACEI/ARB (median age 62.8, SD 16.4; 54.89% females), while 208 (45.92%) out of 453 were on CCB (median age 65; SD 14.8; 60.1% females) and 245 (54.08%) were not on CCB (median age 61.7, SD 17.3; 51.02% females). In the fully adjusted model in this group, ACEI use was associated with 71% reduction in in-house mortality (OR 0.29, 95% CI [0.09, 0.93], p value 0.03). Discussion/Conclusion: Among all hospitalized patients with COVID-19 infection, exposure to ACEI/ARB, as well as combined exposure to ACEI/ARB and CCB, were associated with reduced incidence of ICU admissions. In those admitted patients who had a personal history of hypertension, there was a trend towards reduced in-hospital mortality in those exposed to ACEI.

1.
COVID-19 Map [Internet]. Johns Hopkins Coronavirus Resource Center. [cited 2020 Dec 17]. Available from: https://coronavirus.jhu.edu/map.html
2.
Garg
S
,
Kim
L
,
Whitaker
M
,
O’Halloran
A
,
Cummings
C
,
Holstein
R
, et al.
Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 – covid-net, 14 states, march 1–30, 2020
.
MMWR Morb Mortal Wkly Rep
.
2020 Apr 17
;
69
(
15
):
458
64
. .
3.
CDC. Covid-19 and your health [Internet]. Centers for Disease Control and Prevention. 2020 [cited 2020 Dec 17]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html
4.
Pan
W
,
Zhang
J
,
Wang
M
,
Ye
J
,
Xu
Y
,
Shen
B
, et al.
Clinical features of covid-19 in patients with essential hypertension and the impacts of renin-angiotensin-aldosterone system inhibitors on the prognosis of covid-19 patients
.
Hypertension
.
2020
;
76
(
3
):
732
41
. .
5.
Hoffmann
M
,
Kleine-Weber
H
,
Schroeder
S
,
Krüger
N
,
Herrler
T
,
Erichsen
S
, et al.
Sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor
.
Cell
.
2020
;
181
(
2
):
271
e8
. .
6.
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 May 24
;
111
(
20
):
2605
10
. .
7.
Soler
MJ
,
Ye
M
,
Wysocki
J
,
William
J
,
Lloveras
J
,
Batlle
D
.
Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan
.
Am J Physiol Renal Physiol
.
2009 Feb
;
296
(
2
):
F398
405
. .
8.
Ishiyama
Y
,
Gallagher
PE
,
Averill
DB
,
Tallant
EA
,
Brosnihan
KB
,
Ferrario
CM
.
Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors
.
Hypertension
.
2004
;
43
(
5
):
970
6
. .
9.
Fang
L
,
Karakiulakis
G
,
Roth
M
.
Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?
Lancet Respir Med
.
2020 Apr
;
8
(
4
):
e21
. .
10.
Wysocki
J
,
Lores
E
,
Ye
M
,
Soler
MJ
,
Batlle
D
.
Kidney and lung ACE2 expression after an ACE inhibitor or an Ang II receptor blocker: implications for COVID-19
.
J Am Soc Nephrol
.
2020
;
31
(
9
):
1941
3
. .
11.
Zheng
YY
,
Ma
YT
,
Zhang
JY
,
Xie
X
.
COVID-19 and the cardiovascular system
.
Nat Rev Cardiol
.
2020
;
17
(
5
):
259
60
. .
12.
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
(
17
):
1653
9
. .
13.
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
(
19
):
1801
3
. .
14.
Tomasoni
D
,
Italia
L
,
Adamo
M
,
Inciardi
RM
,
Lombardi
CM
,
Solomon
SD
, et al.
COVID-19 and heart failure: from infection to inflammation and angiotensin II stimulation. Searching for evidence from a new disease
.
Eur J Heart Fail
.
2020 Jun
;
22
(
6
):
957
66
. .
15.
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
(
6
):
1382
5
. .
16.
Fosbøl
EL
,
Butt
JH
,
Østergaard
L
,
Andersson
C
,
Selmer
C
,
Kragholm
K
, et al.
Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with covid-19 diagnosis and mortality
.
JAMA
.
2020 Jul 14
;
324
(
2
):
168
77
.
17.
Mancia
G
,
Rea
F
,
Ludergnani
M
,
Apolone
G
,
Corrao
G
.
Renin-angiotensin-aldosterone system blockers and the risk of covid-19
.
N Engl J Med
.
2020
;
382
(
25
):
2431
40
. .
18.
Liu
X
,
Long
C
,
Xiong
Q
,
Chen
C
,
Ma
J
,
Su
Y
, et al.
Association of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with risk of COVID-19, inflammation level, severity, and death in patients with COVID-19: a rapid systematic review and meta-analysis
.
Clin Cardiol
.
2020 Aug 5
;
10.1002/clc.23421
. .
19.
Shah
P
,
Owens
J
,
Franklin
J
,
Jani
Y
,
Kumar
A
,
Doshi
R
.
Baseline use of angiotensin-converting enzyme inhibitor/AT1 blocker and outcomes in hospitalized coronavirus disease 2019 African-American patients
.
J Hypertens
.
2020
;
38
(
12
):
2537
41
. .
20.
Hippisley-Cox
J
,
Young
D
,
Coupland
C
,
Channon
KM
,
Tan
PS
,
Harrison
DA
, et al.
Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people
.
Heart
.
2020
;
106
(
19
):
1503
11
. .
21.
An
J
,
Wei
R
,
Zhou
H
,
Luong
TQ
,
Gould
MK
,
Mefford
MT
, et al.
Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers use and covid-19 infection among 824,650 patients with hypertension from a us integrated healthcare system
.
J Am Heart Assoc
.
2021 Dec 14
;
10
(
3
):
e019669
. .
22.
Morales
DR
,
Conover
MM
,
You
SC
,
Pratt
N
,
Kostka
K
,
Duarte-Salles
T
, et al.
Renin–angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis
.
Lancet Digit Health
.
2021 Feb
;
3
(
2
):
e98
114
.
23.
Christiansen
CF
,
Pottegård
A
,
Heide-Jørgensen
U
,
Bodilsen
J
,
Søgaard
OS
,
Maeng
M
, et al.
SARS-CoV-2 infection and adverse outcomes in users of ACE inhibitors and angiotensin-receptor blockers: a nationwide case-control and cohort analysis
.
Thorax
.
2020 Dec 8
. E-pub ahead of print.
24.
Lopes
RD
,
Macedo
AVS
,
de Barros E Silva
PGM
,
Moll-Bernardes
RJ
,
Dos Santos
TM
,
Mazza
L
, et al.
Effect of discontinuing versus continuing angiotensin-converting enzyme inhibitors and angiotensin ii receptor blockers on days alive and out of the hospital in patients admitted with covid-19: a randomized clinical trial
.
JAMA
.
2021 Jan 19
;
325
(
3
):
254
64
. .
25.
Cohen
JB
,
Hanff
TC
,
William
P
,
Sweitzer
N
,
Rosado-Santander
NR
,
Medina
C
, et al.
Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial
.
Lancet Respir Med
.
2021 Jan 7
:
221
. .
26.
Bean
DM
,
Kraljevic
Z
,
Searle
T
,
Bendayan
R
,
Kevin
O
,
Pickles
A
, et al.
Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are not associated with severe COVID-19 infection in a multi-site UK acute hospital trust
.
Eur J Heart Fail
.
2020 Jun
;
22
(
6
):
967
74
. .
27.
Zhang
P
,
Zhu
L
,
Cai
J
,
Lei
F
,
Qin
JJ
,
Xie
J
, et al.
Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with covid-19
.
Circ Res
.
2020 05
;
126
(
12
):
1671
81
. .
28.
Yan
F
,
Huang
F
,
Xu
J
,
Yang
P
,
Qin
Y
,
Lv
J
, et al.
Antihypertensive drugs are associated with reduced fatal outcomes and improved clinical characteristics in elderly COVID-19 patients
.
Cell Discov
.
2020 Oct 29
;
6
(
1
):
77
. .
29.
COVID-19: Is it time to revisit the research on calcium channel drug targets? [Internet]. European Medical Journal. 2020 [cited 2020 Dec 17]. Available from: https://www.emjreviews.com/diabetes/article/covid-19-is-it-time-to-revisit-the-research-on-calcium-channel-drug-targets/
30.
Navarese
EP
,
Musci
RL
,
Frediani
L
,
Gurbel
PA
,
Kubica
J
.
Ion channel inhibition against COVID-19: a novel target for clinical investigation
.
Cardiol J
.
2020
;
27
(
4
):
421
4
. .
31.
Zhang
LK
,
Sun
Y
,
Zeng
H
,
Wang
Q
,
Jiang
X
,
Shang
WJ
, et al.
Calcium channel blocker amlodipine besylate therapy is associated with reduced case fatality rate of COVID-19 patients with hypertension
.
Cell Discov
.
2020 Dec 22
;
6
(
1
):
96
. .
32.
Solaimanzadeh
I
.
Nifedipine and amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for covid-19
.
Cureus
.
2020 May 12
;
12
(
5
):
e8069
. .
33.
Neuraz
A
,
Lerner
I
,
Digan
W
,
Paris
N
,
Tsopra
R
,
Rogier
A
, et al.
Natural language processing for rapid response to emergent diseases: case study of calcium channel blockers and hypertension in the covid-19 pandemic
.
J Med Internet Res
.
2020 Aug 14
;
22
(
8
):
e20773
. .
34.
CDC. Coronavirus Disease 2019 (COVID-19) [Internet]. Centers for Disease Control and Prevention. 2020 [cited 2020 Dec 17]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-race-ethnicity.html.
35.
Golestaneh
L
,
Neugarten
J
,
Fisher
M
,
Billett
HH
,
Gil
MR
,
Johns
T
, et al.
The association of race and COVID-19 mortality
.
EClinicalMedicine
.
2020 Aug
;
25
:
100455
. .
36.
Bloch
MJ
.
Renin-angiotensin system blockade in covid-19: good, bad, or indifferent?
J Am Coll Cardiol
.
2020 21
;
76
(
3
):
277
9
. .
37.
Santos
RAS
,
Sampaio
WO
,
Alzamora
AC
,
Motta-Santos
D
,
Alenina
N
,
Bader
M
, et al.
The ace2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7)
.
Physiol Rev
.
2018 01
;
98
(
1
):
505
53
. .
38.
Esc guidance for the diagnosis and management of cv disease during the covid-19 pandemic [Internet]. [cited 2020 Dec 17]. Available from: https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance.
39.
Verdecchia
P
,
Cavallini
C
,
Spanevello
A
,
Angeli
F
.
The pivotal link between ACE2 deficiency and SARS-CoV-2 infection
.
Eur J Intern Med
.
2020
;
76
:
14
20
. .
40.
Hamming
I
,
Timens
W
,
Bulthuis
ML
,
Lely
AT
,
Navis
G
,
van Goor
H
.
Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis
.
J Pathol
.
2004 Jun
;
203
(
2
):
631
7
. .
41.
Abassi
Z
,
Knaney
Y
,
Karram
T
,
Heyman
SN
.
The lung macrophage in sars-cov-2 infection: a friend or a foe?
Front Immunol
.
2020
;
11
:
1312
. .
42.
Henry
C
,
Zaizafoun
M
,
Stock
E
,
Ghamande
S
,
Arroliga
AC
,
White
HD
.
Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia
.
Proc
.
2018 Oct
;
31
(
4
):
419
23
. .
43.
Nugent
KM
,
Shanley
JD
.
Verapamil inhibits influenza A virus replication
.
Arch Virol
.
1984
;
81
(
1–2
):
163
70
. .
44.
Fujioka
Y
,
Nishide
S
,
Ose
T
,
Suzuki
T
,
Kato
I
,
Fukuhara
H
, et al.
A sialylated voltage-dependent ca2+ channel binds hemagglutinin and mediates influenza a virus entry into mammalian cells
.
Cell Host Microbe
.
2018 13
;
23
(
6
):
809
. .
45.
Scherbik
SV
,
Brinton
MA
.
Virus-induced Ca2+ influx extends survival of west nile virus-infected cells
.
J Virol
.
2010 Sep
;
84
(
17
):
8721
31
. .
46.
Dionicio
CL
,
Peña
F
,
Constantino-Jonapa
LA
,
Vazquez
C
,
Yocupicio-Monroy
M
,
Rosales
R
, et al.
Dengue virus induced changes in Ca2+ homeostasis in human hepatic cells that favor the viral replicative cycle
.
Virus Res
.
2018 02
;
245
:
17
28
. .
47.
Johansen
LM
,
DeWald
LE
,
Shoemaker
CJ
,
Hoffstrom
BG
,
Lear-Rooney
CM
,
Stossel
A
, et al.
A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity
.
Sci Transl Med
.
2015
;
7
(
290
):
290ra89
. .
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