The Association Between COVID-19 Mortality and ICU Admission Rates and Prior History of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use Among Hospitalized COVID-19 Patients With Hypertension in Michigan

Importance There are conflicting data regarding the safety of the use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) medications in hypertensive patients who are susceptible to COVID-19. Objective Our study assesses the association between COVID-19 severity and mortality and the use of ACEIs/ARBs among hospitalized patients with hypertension. Research design, setting, and participants This was a retrospective cohort study. Using the EPIC system of Beaumont Health, Dearborn, Michigan, 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 hazards models were used to analyze the association between history of ACEI/ARB use, intensive care unit (ICU) admission rate, and COVID-19 mortality. Exposure Exposure refers to the use of ACEIs/ARBs as documented in the medical records before admission to the hospitals. Main outcome The main outcome was 30-day COVID-19 mortality and ICU admission rates. Results There were 1281 subjects (60%) with prior ACEI/ARB use and 848 subjects (40%) with no ACEI/ARB use. There was no significant association between ICU admission and the use of ACEIs/ARBs (odds ratio {OR} = 0.95, 95% CI = {0.76, 1.19}, p-value = 0.6). Although the unadjusted logistic regression model demonstrated a statistically significant association between history of ACEI/ARB use 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-day COVID-19 survival and prior use of ACEI/ARB in the adjusted Cox proportional hazards model (hazard ratio {HR} = 1.11, 95% CI = {0.91, 1.40}, p-value = 0.14). Conclusion In this large retrospective study, we conclude that there was no statistically significant association between prior history of ACEI/ARB use and COVID-19 ICU admission rates or mortality in hypertensive patients hospitalized with COVID-19.


Main outcome
The main outcome was 30-day COVID-19 mortality and ICU admission rates.

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

Introduction
The number of people who got infected with the COVID-19 virus was around 43.7 million, and the number of deaths was around 710000 by October 2021 in the USA according to the Centers for Disease Control and Prevention (CDC) data tracker [1].
Recent data showed that patients with cardiovascular diseases such as hypertension who tested positive for COVID-19 had worse outcomes.Between 2017 and 2018, the prevalence of hypertension was 45% among adults in the USA.Millions of hypertensive patients use angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) as the first-line treatment [2,3].
There are conflicting data regarding the use of these medications, the severity of the COVID-19 infection, and the mortality rate.The COVID-19 virus gains entry to pulmonary cells by binding to the membrane angiotensin-converting enzyme 2 (ACE-2) [4].Hence, there is a concern about using ACEIs and ARBs as these medications use the same receptors.

Materials And Methods
This was a retrospective cohort study.We researched the electronic health record system (EPIC system) of the Beaumont Health System, Dearborn, Michigan, for subjects who were admitted to the eight Beaumont hospitals and tested positive for COVID-19 from February 1, 2020, to April 30, 2020.We included only COVID-19 patients who have hypertension diagnoses in their charts.We excluded subjects with missing information on body mass index (BMI) (Figure 1).We retrieved information on the use of ACEIs and ARBs prior to admission to hospitals with COVID-19 diseases.We also obtained data on possible confounders including age, sex, race, BMI, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), asthma, heart failure (HF), end-stage renal disease (ESRD), prior use of aldosterone antagonists, and the use of steroid during hospital admission.We followed subjects for 30 days after hospital admission.The two primary outcomes were 30-day COVID-19 mortality and intensive care unit (ICU) admission rates.We used the 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 noninvasive ventilatory support or vasopressors, which indicate severe disease.

Statistical analysis
We compared the baseline characteristics between subjects who had a history of ACEI/ARB use and those who did not use these medications using the chi-square test and t-test.We performed a simple logistic regression analysis to study the association between ICU admission rates and the use of ACEI/ARB.We then used a multivariate logistic regression model to adjust for possible confounders including age, sex, race, BMI, COPD, asthma, the 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 both 30-day COVID-19 survival and ICU admission rate.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 (Posit PBC, Boston, MA) was used to analyze the data, and a p-value of ≤0.05 was considered statistically significant.

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.The Kaplan-Meier curve illustrated that ACEIs/ARBs were associated with increased COVID-19 mortality (Figure 2).Similarly, the unadjusted Cox proportional hazards model showed that the use of ACEI/ARB was associated with an increase in COVID-19 mortality (hazard ratio {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-day COVID-19 survival in the adjusted Cox proportional hazards model (Table 4).The Cox proportional hazards 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 (HR = 0.9, 95% CI = {0.79,1.11}, p-value = 0.5) models (Table 5).

Discussion
Among patients who were hospitalized for COVID-19, this study showed no significant association between prior use of ACEIs/ARBs and COVID-19 mortality or severity as evidenced by ICU admission rate after adjusting for baseline characteristics, comorbidities, aldosterone antagonist use, and steroid use, using the adjusted logistic regression model and Cox proportional hazards model.
The mean BMI in our study population was high (32).Eighty percent of the patients had a BMI equal to or higher than 25.This finding correlates with the findings of other studies on the association between BMI and COVID-19 hospitalization rates [8].
A retrospective cohort study was conducted in two Saudi public specialty hospitals and included 354 patients with COVID-19 (146 used ACEI/ARB in the last six months prior to COVID-19 infection, and 208 were non-ACEI/ARB users).This study showed that the ACEI/ARB group had an eightfold higher risk of developing critical or severe COVID-19 (OR = 8.25; 95% CI = {3.32,20.53}), nearly sevenfold higher risk of intensive care unit (ICU) admission (OR = 6.76; 95% CI = {2.88,15.89}), and a nearly fivefold higher risk of requiring noninvasive ventilation (OR = 4.77; 95% CI = {2.15,10.55}).However, this study had a small sample size, and it overlooked some confounders including the use of steroids [9].
On the other hand, a prospective cohort study in England involving 8.28 million participants showed that exposure to ACEI/ARB in the last 90 days is associated with reduced risk of COVID-19-positive disease requiring hospitalization.This study is limited by the unavailability of a standard systematic strategy for COVID-19 testing in the United Kingdom and restricting the COVID-19 testing to only hospitalized patients by UK health policy during the period of the study at that time [10].
Another study conducted in New York in March 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.The limitations of this study include the disproportionate size of the control versus the treatment group and the fact that the study only considered the ACEI/ARB during hospitalization [11].
Moreover, a meta-analysis including 13 studies conducted in 2020 showed that ACEI/ARB use was not

FIGURE 2 :
FIGURE 2: Kaplan-Meier curve demonstrating the association between the use of ACEI/ARB and COVID-19 mortality There is a debate regarding the increased risk of COVID-19 infection in patients who use ACEIs 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 ARB medications can protect

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/ARB use).Both groups are similar in terms of sex, BMI, and the 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.

TABLE 5 : Adjusted proportional hazards model illustrating the association between the use of ACEI/ARB and ICU admission rates
Adjusted for age, sex, body mass index (BMI), race, asthma, chronic obstructive pulmonary disease (COPD), heart failure (HF), diabetes mellitus (DM), end-stage renal disease (ESRD), aldosterone antagonist, and steroid use ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ICU, intensive care unit