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\begin{document}

\title{Association Between COVID-19 Mortality and ICU Admission Rates and Prior
History of Angiotensin-Converting Enzyme or Angiotensin Receptor
Blockers Use Among Hospitalized COVID-19 Patients with Hypertension in
Michigan.}



\author[1]{Eiman M. Elhouderi}%
\author[1]{Eman A. Elsawaly}%
\author[1]{Najlaa K. Al-Sudani}%
\author[1]{Irum Mahmood}%
\author[1]{David M. Sengstock}%
\affil[1]{BHSH Beaumont Health}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
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\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Abstract:} \textbf{Importance:} There are conflicting data
regarding the safety of the use of Angiotensin-converting enzyme
inhibitors or Angiotensin receptor blockers (ACEI/ARBs ) medications in
hypertensive patients who are susceptible to COVID-19.
\textbf{Objective:} Our study assesses the association between COVID-19
severity and mortality and the use of ACEI/ARBs among hospitalized
patients with hypertension. \textbf{Research design, setting and
participants:} This was a retrospective cohort study. Using the EPIC
system of Beaumont Health, we identified 5490 patients with COVID-19 who
were admitted to the eight Beaumont hospitals. After excluding subjects
who have no hypertension and those with missing data, we included 2129
COVID-19 patients who have hypertension. Logistic regression and Cox
proportional hazard models were used to analyze the association history
of ACEI/ARBs use, ICU admission rate and COVID-19 mortality.
\textbf{Exposure:} Using of ACEI/ARBs as documented in the medical
records before admission to the hospitals. \textbf{Main outcome:} 30
days COVID-19 mortality and ICU admission rates .
\textbf{Results:~}There were 1281 subjects (60\%) with prior ACEI/ARBs
use and 848 subjects ( 40\%) with no ACEI/ARBs use. There was no
significant association between ICU admission and use of ACEI/ARBs (odds
ratio was 0.95, 95\% CI {[}0.76, 1.19{]} and p-value was 0.6). Although
the unadjusted logistic regression model demonstrated a statistically
significant association between history of use of ACEI/ARBs and COVID-19
mortality (odds ratio= 1.31, 95\% CI {[}1.05, 1.66{]}, p-value= 0.02),
the adjusted logistic regression model failed to show this statistically
significant association (odds ratio= 1.20, 95\% CI {[}0.93, 1.54{]},
p-value= 0.14). Moreover, we were not able to reveal a statistically
significant association between 30 days COVID-19 survival and prior use
of ACEI/ARBs in the adjusted Cox-proportional hazard model (Hazard ratio
(HR) = 1.11, 95\% CI {[}0.91, 1.40{]}, p-value =0.14).
\textbf{Conclusion:} In a large retrospective study, we conclude that
there was no statistically significant association between prior history
of ACEI/ARBs use and COVID-19 ICU admission rates or mortality in
hypertensive patients hospitalized with COVID-19.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

The number of people who got infected with COVID-19 virus were around
43.7 million and the number of deaths was around 710 thousand by October
2021 in the United States according to the Center for Disease Control
and Prevention (CDC) data tracker.

Recent data showed that patients with cardiovascular diseases such as
hypertension who tested positive for COVID-19 had worse outcomes.
Between 2017-2018, the prevalence of hypertension was 45\% among adults
in the USA. Millions of hypertensive patients use angiotensin-converting
enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) as the
first-line treatment.

There are conflicting data regarding the use of these medications, the
severity of the COVID-19 infection, and the mortality rate (Figure 1).
COVID-19 virus gains entry to pulmonary cells through binding to the
membrane angiotensin convertase enzyme receptor 2 (ACE-2). Hence there
is a concern about using ACEI and ARBs as these medications use the same
receptors. There is a debate regarding the increased risk of COVID-19
infection in patients who use ACEI and ARBs by increasing the viral
entry and subsequently increasing the viral load and the mortality risk.
On the other hand, studies have shown that ACEI and ARBs medications can
protect against COVID-19 infection by attaching to the ACE receptors,
thereby decreasing the availability of those receptors to the COVID-19
virus, leading to the deactivation of the virus and decreasing the virus
load. Hence many investigators have advised the use of ACEI and ARBs
medications in COVID-19-positive patients even with no history of
hypertension.

Figure 1: Two conflicting hypotheses of association between ACEI/ARB and
COVID-19.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Methods:}

This was a retrospective cohort study.~~We researched the EPIC system of
the Beaumont Health system, Michigan for subjects who were admitted to
the eight Beaumont hospitals and tested positive for COVID-19 from
February 1\textsuperscript{st} to April 30\textsuperscript{th} 2020. We
included only COVID-19 patients who have hypertension diagnoses in their
charts. We excluded subjects with missing information on one of the
possible predictor factors (BMI) (figure 2). We followed subjects for
thirty days after admission. The two primary outcomes were 30 days
COVID-19 mortality and ICU admission rates. We used ICU admission rate
as a marker of COVID-19 severity. We defined ICU admission as admission
to intensive care units or progressive care units (PCU)since the
admission criteria for both units include the use of invasive or
non-invasive ventilatory support or vasopressors which indicate severe
disease.

\textbf{Figure 2: Patient Flow Chart:}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Statistical analysis:}

We compared the baseline characteristics between subjects who had a
history of use of ACEI/ARB those who didn't use these medications using
the chi-square test and t-test (Table1). First, we performed a simple
logistic regression analysis to study the association between ICU
admission rates and the use of ACEI/ARBs. We then used a multivariate
logistic regression model to adjust for possible confounders including
age, sex, race, BMI, COPD, asthma, use of aldosterone antagonists, heart
failure, DM, and ESRD. Using the same methods, we studied the
association between COVID-19 mortality and the use of ACEI/ARB. We used
a Cox proportional hazards model to study the association between the
use of ACEI/ARB and 30 days-COVID-19 survival. We censored the time to
the event to 30 days. We first performed a univariate model and then
performed a multivariate-adjusted model. We adjusted for the same
possible confounders as those mentioned above.

R studio was used to analyze the data and a p-value of [?]0.05 was
considered statistically significant.

\textbf{Results:}

We identified 5490 patients with COVID-19 who were admitted to the
hospital. After excluding subjects with no hypertension and those with
missing data, we included 2129 COVID-19 patients who had hypertension.
Table 1 reveals the baseline subject characteristics of the two groups
(a group that has a history of ACEI/ARB use and a group with no history
of ACEI/ARBs use. Both groups are similar in terms of sex, BMI, and use
of steroid during hospitalization. There were more patients with DM,
heart failure, ESRD, asthma, and COPD in the ACEI/ARB group than in the
non-ACE/ARB group. A total of 532 (25\%) patients were admitted to ICU
or PCU (319 subjects (25\%) from ACEI/ARB group and 213 (25\%) subjects
from non-ACEI/ARB group). There was no statistically significant
difference in ICU admission rates between the ACEI/ARB and no ACEI/ARB
groups in both adjusted (odds ratio= 1.02, 95\% CI {[}0.04, 0.22{]},
p-value= 0.7) and unadjusted models (odds ratio= 0.95, 95\% CI
{[}0.76,1.19{]}, p-value= 0.6) ( Table 2).

Table 1: Baseline patients characteristics.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Variables\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
ACEI or ARBs N= 1281, 60\%,\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
NO ACEI or ARB N= 848, 40\%\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
P value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
68 (14)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
66 (15)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.007\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sex (F)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
649 (50\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
442 (52\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BMI\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
32.1 (8.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
31.8 (8.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Race\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
White=526 (41\%) African= 680 (53\%) Other= 75 (5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
White=272 (32\%) African= 525 (61\%) Other= 51 (6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.0001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
176 (14\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
91 (10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.04\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
COPD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
125 (10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
49 (6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
HF\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
186 (16\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
83 (10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
DM\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
628 (49\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
285 (33\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ESRD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
76 (5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
33 (4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.03\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Steroid use\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
627 (49\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
438 (52\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aldosterone antagonist\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
128 (84\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
23 (15\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviation: HF, heart failure; DM, diabetes mellitus; BMI, body mass
index.*We used N (\%) for categorical variables and mean (SD) for
continuous variables. COPD

Table 2: Adjusted logistic regression model exploring the association
between the use of ACEI/ARBs and ICU admission rates.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Odds ratio & 95 \% CI & P value\tabularnewline
\midrule
\endhead
ACEI\textsuperscript{a} & 1.02 & (0.04, 0.22) & 0.7\tabularnewline
Age & 1.01 & (1.002, 1.02) & 0.01\tabularnewline
Sex (F) & 0.89 & (0.72, 1.08) & 0.23\tabularnewline
BMI & 0.99 & (0.98, 1.01) & 0.4\tabularnewline
Race (African American) & 1.32 & (1.06, 1.64) & 0.01\tabularnewline
Asthma & 0.67 & (0.48, 0.92) & 0.01\tabularnewline
COPD & 1.08 & (0.75, 1.54) & 0.6\tabularnewline
HF & 1.22 & (0.90, 1.66) & 0.2\tabularnewline
DM & 1.43 & (1.18, 1.75) & \textless{}0.01\tabularnewline
ESRD & 2.45 & (1.62, 3.80) & \textless{}0.01\tabularnewline
Steroid use & 3.45 & (2.83, 4.24) & \textless{}0.01\tabularnewline
Aldosterone antagonist & 1.02 & (0.69, 1.49) & 0.9\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{a} Adjusted for age, sex, BMI, race, asthma, COVPD, HF,
DM,ESRD Aldosterone antagonist and steroid use.

A total of 391 patients (18\%) passed away within thirty days of
admission (256 (20\%) subjects from the ACEI/ARB group and 135 (16\%)
subjects from the non-ACEI/ARB group.

Although there was a statistically significant difference in the
COVID-19 mortality rates between the two groups in the unadjusted
logistic regression model (odds ratio= 1.31, 95\% CI{[}1.01,1.54{]},
p-value= 0.03), the difference in the odd of COVID-19 mortality between
the two groups was not statistically significant in the adjusted model
(odds ratio= 1.20, 95\% {[}(0.93, 1.54){]}, p-value= 0.14) (Table 3).

Table 3: Adjusted logistic regression model exploring the association
between the use of ACEI/ARBs and COVID-19 mortality.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Odds ratio\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
95 \% CI\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
P value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ACEI\textsuperscript{a}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.20\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.93, 1.54)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.14\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.06\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(1.05, 1.07)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sex (F)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.85\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.65, 1.07)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.16\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BMI\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.01\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.98, 1.023)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.47\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Race (African American)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.84\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.66, 1.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.23\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.93\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.62, 1.37)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.74\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
COPD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.07\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.72, 1.57)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.72\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
HF\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.19\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.85, 1.66)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.28\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
DM\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.30\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(1.02, 1.66)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.03\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ESRD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.30\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.75, 2.17)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.32\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Steroid use\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2.82\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(2.20, 3.64)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Aldosterone Antagonist\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.03\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
(0.64, 1.60)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.9\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{a} Adjusted for age, sex, BMI, race, asthma, COVPD, HF,
DM,ESRD Aldosterone antagonist and steroid use.

The Kaplan-Meier curve illustrated that ACEI/ARBs were associated with
increased COVID-19 mortality (Figure 3). Similarly, the unadjusted Cox
proportional hazard model showed that the use of ACEI/ARBs was
associated with an increase in COVID-19 mortality (HR= 1.25, 95\%
CI{[}1.01, 1.54), p-value= 0.03). However, we failed to find a
statistically significant association between the history of ACEI/ARB
use and 30 days-COVID-19 survival in the adjusted Cox proportional
hazard model (Table 4).

Figure 3: Kaplan-Meier curve demonstrating the association between the
use of ACEI/ARBS and COVID-19 mortality.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Table 4: Adjusted proportional hazard model illustrating the association
between the use of ACEI/ARB and COVID-19 mortality.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Odd ratio & 95 \% CI & P value\tabularnewline
\midrule
\endhead
ACEI & 1.12 & (0.91, 1.40) & 0.14\tabularnewline
Age & 1.04 & (1.037, 1.05) & \textless{} 0.01\tabularnewline
Sex (F) & 0.90 & (0.73, 1.11) & 0.34\tabularnewline
BMI & 0.99 & (0.98, 1.01) & 0.72\tabularnewline
Race (African American) & 0.83 & (0.67, 1.03) & 0.83\tabularnewline
Asthma & 1.01 & (0.72, 1.40) & 0.97\tabularnewline
COPD & 1.20 & (0.87, 1.66) & 0.24\tabularnewline
HF & 0.95 & (0.72, 1.25) & 0.73\tabularnewline
DM & 1.15 & (0.94, 1.41) & 0.16\tabularnewline
ESRD & 0.87 & (0.55, 1.37) & 0.56\tabularnewline
Steroid use & 1.01 & (0.83, 1.31) & 0.69\tabularnewline
Aldosterone antagonist use & 1.09 & (0.75, 1.58) & 0.63\tabularnewline
\bottomrule
\end{longtable}

The COX proportional hazard model showed no significant association
between ACEI/ARB use and the time to ICU admission in both the
unadjusted (HR=0.9, 95\% CI {[}0.8, 1.1{]}, p-value= 0.5) and adjusted
models (HR= 0.9, 95\% CI{[}0.79, 1.11{]}, p-value= 0.5) (Table 5).

Table 5: Adjusted proportional hazard model illustrating the association
between the use of ACEI/ARB ICU admission rates.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Hazard ratio\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
95 \% CI\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
P-value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ACEI\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.79, 1.11)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.01\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.99, 1.01)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sex (F)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.06\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.90, 1.25)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BMI\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.99\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.98, 1.00)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Race (African)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.02\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.86, 1.22)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.7\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.8\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.67, 1.16)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
COPD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.07\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.80, 1.43)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.6\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
HF\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.01\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.79, 1.28)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.9\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
DM\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.98\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.83, 1.16)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.8\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ESRD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.09\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.80, 1.49)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Steroid use\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.65\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(0.55, 0.78)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Aldosterone Antagonist\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.9\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
(0.73, 1.35)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.9\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Discussion:}

Among patients who were hospitalized for COVID-19, this study showed no
significant association between prior use of ACEI/ARBs and COVID-19
mortality or severity as evident by ICU admission rate after adjusting
for baseline characteristics, comorbidities, and steroid use, using the
adjusted logistic regression model and Cox-proportional hazard model.

The mean BMI in our study population was high (32). Eighty percent of
the patients had BMI equal or higher than 25. This finding correlates
with the findings of other studies on the association between BMI and
COVID-19 hospitalization rates.

Some studies have suggested that ACEI/ARB may increase viral entry, with
concerns that these drugs could increase the risk of developing severe
outcome with COVID-19

However, to date, there is insufficient data the association between
prior use of ACEI/ARBs associated and an increased risk of COVID-19
severity. A retrospective cohort study was conducted in two Saudi public
specialty hospitals, included 354 patients with COVID-19 (in which 146
were ACEI/ARB users and 208 were non-ACEI/ARB users) after controlling
for confounders, using multivariate logistic regression and sensitivity
analyses using propensity score matching (PSM) and inverse propensity
score weighting (IPSW) for high-risk patient subsets. The ACEI/ARB group
had an eight-fold higher risk of developing critical or severe COVID-19
(OR = 8.25, 95\%CI = 3.32--20.53); a nearly 7-fold higher risk of
intensive care unit (ICU) admission (OR = 6.76, 95\%CI = 2.88--15.89)
and a nearly 5-fold higher risk of requiring noninvasive ventilation (OR
= 4.77,95\%CI = 2.15--10.55). Concluding that ACEI/ARBs use was
associated with a higher risk of severe COVID-19 disease. However, this
study had a small sample size, some variables were overlooked including
the use of steroids, and the results showed a wide confidence interval.

On the other hand, a prospective cohort study in England involving
8.28 million participants showed reduced risk of COVID-19 positive
disease requiring hospitalization. This study is limited by
unavailability of standard systematic strategy for COVID-19 testing in
the UK and restricting the COVID-19 testing to only hospitalized
patients by UK health policy during the period of the study.

Despite that, a meta-analysis including 13 studies conducted in 2020
showed that ACEI/ARB use was not associated with an increased risk of
all-cause mortality or severe disease due to COVID-19. Among these 13
studies, 11 studies that reported odds ratio showed the thebACEI/ARB
group had a significantly lower risk of all-cause mortality than
non-ACEI/ARB group regardless of confounders of adjustment for
confounders. This meta-analysis was limited by inconsistencies in the
definition of severe diseases and in inclusion criteria that were
inconsistent across the studies.

In addition to this meta-analysis, an open randomized controlled trial
in Brazil including 659 hospitalized patients with mild to moderate
COVID-19 showed no effect of discontinuation of ACEIs or ARBs on
COVID-19 mortality. However, this study explored a different question
than our study. The two proposed two conflicting hypotheses state that
ARBs and ACEIs either increase ACE2 expression, allowing virus entry
into the cell and, therefore, increasing SARS-COV2 infectivity and
severity or coronavirus downregulates ACE2 receptors causing an
elevation of angiotensin II, which may lead to lung injury. Based on
this, prior use of ACEI/ARB would affect the COVID-19 infectivity,
severity or mortality or than the use of ACEIs/ARBs after establishment
COVID-19.

Another study conducted in New York in the March of 2020 showed a
reduced length of hospital stay in patients admitted with COVID-19 who
used ACEI/ARB in the hospital, most of whom belonged to ethnic
minorities. This limitations of this study include the disproportionate
size of the control vs. treatment group and the fact that study only
considered the ACEIARB during the hospitalization. The results were not
significant for the other primary outcome or the secondary outcomes.

We have a large high-quality database of hospitalized COVID-19 patients
at our hospitals. Our study is observational and we were able to reduce
the confounding effect by adjusting a wide range of confounders recorded
in electronic medical records including age, race, BMI, and other
comorbidities. Our sample was representative and was restricted to a
group of patients with hypertensive. Another great strength of our study
is the inclusion of a diverse group of patients as the eight hospitals
are spread out over the Southeast Michigan region where a majority of
Michigan's population resides and comprises of Caucasians, African
Americans, and Arabs. The limitations of our study include, the
retrospective nature of the study, the inability to specify the
chronicity of ACEI/ARB use based on the available data, overlooking of
unknown confounders and finally, and performing the study during the
early months of COVID-19 pandemic where little information about the
treatment and disease was available.

At this stage, there is insufficient clinical evidence for either, thus
we still need further studies. Until further data are available, we
should continue using ACEI and ARB to treat cardiovascular disease in
patients with COVID-19 given the significant cardiovascular benefits of
ACEI/ARBs. In addition, the sudden withdrawal of ACEI/ARBs in those
patients may result in adverse outcomes.

\textbf{Conclusion:}

In a large retrospective study, we concluded that there was no
statistically significant association between prior history of ACEI/ARB
use and COVID-19 ICU admission rates or mortality in patients
hospitalized with COVID-19.

\textbf{References:}

\textbf{Acknowledgments:}

Janice Weinberg, ScD, MS, Director of the Master of Science in Clinical
Research at the Boston University School of Medicine, USA.

Aisha Elhouderi, MEng, Loughborough University, UK.

Mostafa Hoderi, B.Eng., Texas A\&M University, USA.

\selectlanguage{english}
\FloatBarrier
\end{document}

