key: cord-0892879-9t3tkzs0
authors: Liu, Xiulan; Liu, Yi; Chen, Keliang; Yan, Suying; Bai, Xiangrong; Li, Juan; Liu, Dong
title: Efficacy of ACEIs/ARBs versus CCBs on the progression of COVID‐19 patients with hypertension in Wuhan: A hospital‐based retrospective cohort study
date: 2020-07-20
journal: J Med Virol
DOI: 10.1002/jmv.26315
sha: 5d895b27d9a41a1579271392969a371c64186bb8
doc_id: 892879
cord_uid: 9t3tkzs0

BACKGROUND: To evaluate the efficacy of angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) versus calcium channel blockers (CCBs) on the progression of COVID‐19 patients with hypertension in Wuhan. METHODS: This retrospective single‐center case series analyzed COVID‐19 patients with hypertension, treated with ACEIs/ACEIs or CCBs at the Tongji Hospital of Wuhan City, Chin from January 25th to March 15th, 2020. After PSM analysis, 76 patients were selected into two groups. Univariate and multivariable analyses were conducted to determine factors related to improvement measures and outcome measures by Cox proportional hazard regression models. RESULTS: Among 157 patients with confirmed COVID‐19 combined hypertension, including 73 males and 84 females, a median age of 67.28 ±9.11 vs 65.39 ±10.85 years. A univariable analysis indicated that clinical classification, lymphp cyte count and interleukin‐2 receptor were associated with a lengthened negative time of nucleic acid, with a significant difference between two groups (p=0.036). Furthermore, we found no obvious difference in nucleic acid conversion time between ACEIs/ARBs group and CCBs group (HR 0.70, 95% CI [0.97, 3.38], p=0.18) in the multivariable analysis as well as chest CT improved time (HR 0.73, 95% CI [0.45, 1.2], p=0.87), and hospitalization time between ACEIs/ARBs group and CCBs group (HR 1.06, 95% CI [0.44, 1.1], p=0.83). CONCLUSION: Our study provided additional evidence of no obvious difference in progress and prognosis between ACEIs/ACEIs and CCBs group, which may suggest ACEIs/ARBs may have scarcely influence on increasing the clinical severe situations of COVID‐19 patients with hypertension. This article is protected by copyright. All rights reserved.

COVID-19 is a new respiratory illness caused by SARS-CoV-2, first reported in Wuhan, China, in December 2019. The outbreak of COVID-19 is currently This article is protected by copyright. All rights reserved.

continuously evolving globally, resulting in 1133758 confirmed cases including in health-care workers, worldwide by April 5, 2020 1 . On January 20, 2020, the National Health Commission issued No. 1 announcement, which included COVID-19 as an acute respiratory infectious disease into the class B infectious disease specified in the law of the people's Republic of China on the prevention and control of infectious diseases, and then managed it as class A infectious disease. The COVID-19 epidemic situation was classified as "public health emergencies of international concern" in January 31st, the highest level in the WHO infectious disease emergency mechanism by WHO.

There was of particular interest to clinicians and investigators with a major interest in cardiovascular disease and mortality on infected patients, particularly in elderly people with comorbidities. subsequently, in an analysis of 45,000 confirmed cases in China 2,3 , the crude case fatality rate was 0.9% for patients without any documented comorbidities, whereas the case fatality rate was much higher for patients with cardiovascular disease (10.5%), diabetes (7.3%), or hypertension (6.3%).

Well now current study report that hypertension may be associated with increased risk of severe in hospitalized COVID-19 patients. Previous experimental data 4, 5 revealed angiotensin-converting enzyme 2 (ACE2) receptors serve as binding sites for the anchoring spike (S) proteins on the exterior surfaces of beta coronaviruses. This article is protected by copyright. All rights reserved.

The beta coronavirus SARS-CoV causes the severe acute respiratory syndrome (SARS). The phylogenetically related beta coronavirus, SARS-Cov-2, causes the novel coronavirus disease (nCoV-2019) or COVID-19. S proteins anchor both beta coronaviruses to ACE2 receptors in the lower respiratory tract of infected patients in order to gain entry into the lungs. Viral pneumonia and potentially fatal respiratory failure may result in susceptible persons after 10-14 days.

Currently the hypertension patients are basically treated with blood pressure lowering drugs, mainly including RAS blockers-ACEIs/ARBs, CCBs, β-blockers, diuretics. In Southwest China, CCBs accounted for 58.6% of hypertension treatment, followed by ACEIs/ARBs accounted for 22.4% 6 . Since ACE2 was identified to functional receptor of SARS-CoV-2. ACE2 level was increased following treatment with ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). The current research 7, 8 revealed that intravenous infusions of ACEIs and ARBs in experimental animals increased the numbers of ACE2 receptors in the cardiopulmonary circulation. Patients taking ACEIs or ARBs chronically for cardiovascular diseases are assumed to have increased numbers of ACE2 receptors throughout their cardiopulmonary circulations as observed in experimental animal models.

Currently a corollary concern needed to identify through real-world clinical studies, whether these commonly used renin-angiotensin system (RAS) blockers-ACEIs/ARBs may increase the severity of COVID-19. The present study This article is protected by copyright. All rights reserved.

therefore retrospectively analyzed data from hospitalized COVID-19 patients with hypertension in a single center in Wuhan, China, to compare the difference between ACEIs/ARBs groups and CCB groups, which may provide clinical evidence on the impact of ACEIs/ARBs on the clinical course of COVID-19 infection.

We performed a retrospective study of COVID patients with the following conditions were excluded from our study: (1) Lung imaging was significantly improved before using antihypertensive;(2) Before using antihypertensive, ucleic acid was negative for two consecutive times; patients was classified into mild-moderate, severe, and critically ill. Baseline clinical data were collected at admission, including blood routine, such as white blood cell count (3.5-9.5)×10 9 /L, lymphp cyte count (1.1-3.2)×10 9 /L, coagulation This article is protected by copyright. All rights reserved.

function such as D-dimer < 0.5 mg/L, renal and liver function, such as alanine aminotransferase and aspartate aminotransferase < 40 U/L, creatinine (59-104) U/L, uric acid (202.3-416.5) mmol/L, urea (3.6-9.5) mmol/L, electrolytes such as potassium (3.5-5.1) mmol/L, sodium (136-145) mmol/L, C-reactive protein (CRP) < 5 mg/L, myocardial enzymes such as NT-ProBNP < 241 pg/mL, cytokine such as Interleukin-6 < 7 mmol. These were collected routinely on admission.

Radiologically, the area of affected lungs consistent with viral pneumonia in each patient's first chest CT after admission was measured and classified into one or two lungs. During hospitalization, lesion progression in chest CT was recorded.

Real-time reverse-transcriptase polymerase chain-reaction (RT-PCR) assay was used to analyze the SARS-CoV-2 viral nucleic acid. The outcome data were collected prospectively by physicians who un-knew the study group. The main improvement measures were the time from illness onset to negative nucleic acid for two time and chest CT gradually improved, and we selected firstly nucleic acid conversion time and chest CT improved. The secondary endpoints were worsened Chest CT during hospitalization and in-hospital mortality. The outcome measures were the time from illness onset to discharge from hospital.

Continuous data accorded with normal distribution were expressed as mean ± SD and compared by independent samples t-test or expressed as median (25th-75th This article is protected by copyright. All rights reserved.

percentile) and compared by Wilcoxon rank sum test. Categorical variables were expressed as number (percentage) and compared by chi-squared test or Fisher's exact test. Among patients diagnosed with COVID-19 combined hypertension using CCBs, ACEIs or ARBs antihypertensive drugs, we sought to investigate the ACEIs or ARBs medication on progress and prognosis of COVID-19 patients.

The main improvement measures, such as the firstly nucleic acid conversion time, firstly chest CT improved time and outcome measures such as the hospitalization time was also calculated. Univariable and multivariable Cox regression models were used to describe the progression and prognosis of COVID-19 patients between CCBs and ACEIs/ARBs. To account for sample size, we selected the variables with p<0.05 which were significantly associated with outcome measures in the univariable analysis. One-to-one (1:1) PSM was conducted to construct a matched sample consisting of pairs of CCBs and ACEIs/ARBs subjects by optimal matching algorithm. Variables that were significantly different between the two groups were utilized to generate propensity scores. Specifically, we also conducted a stratified analysis with respect to outcome measures by age, gender, clinical classification, comorbidities, temperature, respiratory rate, diastolic BP, systolic BP, heart rate, white blood cell count, lymphp cyte count, d-dimer, interleukin-6, interleukin-2 receptor, alanine amino transferase, aspartate amino transferase, lung image, NT-Pro BNP, creatinine, urea, uric acid, potassium, sodium and C-reactive protein, which was used to perform propensity score This article is protected by copyright. All rights reserved.

matching. The data were imported and analyzed using R language (3.6.2 ed, 2019), implemented in RStudio (Version 1.2.5003 ed, 2015) 9,10 . Package MatchIt, survival, and survminer were employed for propen sity score matching and survival analysis, separately [11] [12] [13] , with a two-sided P value of less than 0.05 considered statistically significant.

In total, 306 patients with a diagnosis of COVID-19 combined hypertension using CCBs, ACEIs or ARBs antihypertensive drugs between January 25th, 2020 to March 15th, 2020.The patient selection flow-chart was displayed in Figure 1 . All these patients were treated with one or multiple blood pressure lowering drugs, including RAS blockers-ACEIs/ARBs, calcium channel blockers, β-Blockers and diuretics. The ACEIs/ARBs group consisted of ACEIs or ARBs without CCBs, as well as CCBs group. Then, we selected 157 adult hypertension patients with COVID-19 infections, including 73 males (46.50%) and 84 females (53.50%).

The vast majority of patients were discharged from hospital. Unfortunately, there were 5 patients and 1 patient died from pneumonia in ACEIs / ARBs and CCBs groups, respectively. The in-hospital mortality showed no significant difference between two groups (P=0.191). After propensity score matching, we selected 76 adult hypertension patients with COVID-19 infections (Supplemental Figure 1-2) This article is protected by copyright. All rights reserved.

Before propensity score matching, a total of 157 adult hypertension patients with COVID-19 infections were involved in this study. Demographic features and clinical characteristics data are shown in Table 1 were observed between the two groups.

We performed a stratified analysis according to different variables in 1:1 matched (Table 2 ). In total, we found a significant difference on nucleic acid time between two groups in all univariable (p=0.036) ( Figure 2A) . Furthermore, we included all variables mentioned earlier in the multivariable analysis. After adjustment for potential confounders, we found no obvious difference in nucleic acid conversion time between ACEIs/ARBs group and CCBs group (HR 0.70, 95% CI [0.97，3.38], p=0.18) ( Table 2) . (Table 3) . However, we found no difference on chest CT improved time between two groups in all univariable(p=0.19) ( Figure   2B ). subsequently, we included all variables mentioned earlier in the multivariable analysis. After adjustment for potential confounders, we also found no obvious difference in chest CT improved time between ACEIs/ARBs group and CCBs group (HR 0.73, 95% CI [0.45，1.2], p=0.87) ( Table 3) .

This article is protected by copyright. All rights reserved.

In order to evaluate difference antihypertensive drugs on the outcome measures of patients diagnosed with COVID-19 combined hypertension, Cox proportional hazards model were performed to investigate these factors in the hospitalization time between ACEIs/ARBs and CCBs groups. As showed as in Table 4 Table 4 ).

During the spread of the severe acute respiratory syndrome coronavirus-2, some reports of data still emerging and in need of full analysis indicated that certain groups of patients are at risk of COVID-19, especially complicated with diabetes mellitus, hypertension and coronary artery disease 14 . Currently the hypertension patients are basically treated with blood pressure lowering drugs, mainly including RAS blockers-ACEIs/ARBs, CCBs, β-blockers, diuretics. However, it has been popularized in clinical treatment that RAS blockers might increase the risk of This article is protected by copyright. All rights reserved.

developing a severe and fatal severe acute respiratory syndrome coronavirus-2 infection 15 . Until now, the distinct effects of antihypertensives on prognosis remains unclear. The present study therefore retrospectively analyzed data from hospitalized COVID-19 patients with hypertension in a single center in Wuhan, China, to compare the difference between ACEIs/ARBs groups and CCB groups, which may provide clinical evidence on the impact of ACEIs/ARBs on the clinical course of COVID-19 infection.

Upon sufficient consideration of relationship that ACE2 was the receptor that allowed coronavirus entry into cells, ACE2 overexpression facilitated the replication in cells that were otherwise resistant to the virus. In the RAAS, ACE2 catalyses the conversion of angiotensin II to angiotensin 1-7, which acts as a vasodilator and exerts protective effects in the cardiovascular system 5 . In animal experiments, increased expression and activity of ACE2 in various organs including the heart were found in connection with ACEIs and ARBs administration 16 . In addition, more recent data 7 This article is protected by copyright. All rights reserved.

Nevertheless, we analyzed clinical characteristics of 76 essential hypertension patients with COVID-19, and then found a significant difference on nucleic acid time between two groups in all univariable (p=0.036) in the univariable analysis.

Specifically, compared with CCBs, we observed that clinical classification Especially if elderly hypertensive patients suffered with cardiovascular diseases, diabetes and renal insufficiency, with the highest level of evidence with regard to mortality reduction 18 Given that ACEIs/ARBs increase ACE2 expression and activity in the heart and kidneys in normotensive or hypertensive rats. ACE2 was This article is protected by copyright. All rights reserved.

also universally expressed in heart, liver, kidney, blood vessels and other tissues.

Several studies [19] [20] [21] [22] Limitations Our study has several limitations. First, only 76 patients with confirmed COVID-19 were included, and a larger cohort study is needed to verify our conclusions. Second, as a retrospective study, some other specific information regarding cardiovascular complications such as echocardiography were not presented in the study because the data were incomplete owing to the limited conditions in the isolation ward and the urgency of containing the COVID-19 epidemic. Third, we didn't observe mild cases who were treated at home. Four, we didn't observe whose changed past usage of ACEIs/ARBs medication at home to CCBs in hospital.

Here, the current analysis show that as compared with CCBs, ACEIs/ARBs didn't increase the risk of extended course and poor prognosis of hypertension patients 

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