key: cord-0857411-82m84n4w
authors: Felice, C; Nardin, C; Di Tanna, G L; Grossi, U; Bernardi, E; Scaldaferri, L; Romagnoli, M; Tonon, L; Cavasin, P; Novello, S; Scarpa, R; Farnia, A; De Menis, E; Rigoli, R; Cinetto, F; Pauletto, P; Agostini, C; Rattazzi, M
title: Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives
date: 2020-06-08
journal: Am J Hypertens
DOI: 10.1093/ajh/hpaa096
sha: 36e9358c2a067dfa90c963c20b03f87da7c582e0
doc_id: 857411
cord_uid: 82m84n4w

BACKGROUND: The effect of chronic use of renin–angiotensin–aldosterone system (RAAS) inhibitors on the severity of COVID-19 infection is still unclear in patients with hypertension. We aimed to investigate the association between chronic use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and COVID-19 related outcomes in hypertensive patients. METHODS: A single center study was conducted on 133 consecutive hypertensive subjects presenting to the Emergency Department with acute respiratory symptoms and/or fever who were diagnosed with COVID-19 infection between 9(th) and 31(st) March 2020. RESULTS: All patients were grouped according to their chronic antihypertensive medications (ACEIs, N=40; ARBs, N=42; not on RAAS inhibitors, N=51). There was no statistical difference between ACEIs and ARBs groups in terms of hospital admission rate, oxygen therapy and need for non-invasive ventilation. Patients chronically treated with RAAS inhibitors showed a significantly lower rate of admission to semi-intensive/intensive care units, when compared to the non-RAAS population (odds ratio [OR] 0.25, CI95% 0.09-0.66 p=0.006). Similarly, the risk of mortality was lower in the former group, although not reaching statistical significance (OR 0.56, CI95% 0.17-1.83, p=0.341). CONCLUSIONS: Our data suggest that chronic use of RAAS inhibitors does not negatively affect clinical course of COVID-19 in hypertensive patients. Further studies are needed to confirm this finding and determine whether RAAS inhibitors may have a protective effect on COVID 19-related morbidity and mortality.

Coronavirus disease pandemic has affected more than 3 million people [1]. It has been hypothesized that chronic use of renin-angiotensin-aldosterone system (RAAS) inhibitors may worsen disease outcome in patients with hypertension [2] . Indeed, a defined receptor-binding domain of COVID-19 spike specifically recognizes angiotensin-converting enzyme 2 (ACE2)-receptor. ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) determine upregulation of ACE2-receptors in cardiopulmonary circulation, making patients taking these drugs potentially more susceptible to increased severity [3] . Conversely, ACEIs and ARBs may act protectively by inhibiting RAAS hyperactivation and respiratory injury progression as a consequence of ACE2-receptors downregulation occurring after COVID-19

infection [4] . However, these hypotheses are based on experimental animal models and in vitro studies, while clinical data are scant. For this reason, a number of scientific societies have recently taken a clear position opposing the discontinuation of ACEIs and ARBs in COVID-19 patients [5] .

The aim of the current study was to investigate whether the chronic use of ACEIs and ARBs affects COVID-19 related outcomes in hypertensive patients. 

This is a single-center retrospective study including all consecutive hypertensive subjects who presented to the emergency department (ED) with acute respiratory symptoms/fever, and were diagnosed with COVID-19 infection between 9 th and 31 st March 2020. We considered as hypertensives all the subjects undergoing chronic treatment with blood pressure lowering agents. Diagnosis of COVID-19 was made by semi-quantitative real-time reverse transcription polymerase chain reaction on nasopharyngeal swab. Criteria for hospital admission of COVID-19 positive patients were established by local protocols and remained unchanged throughout the observation period. These included one or more of the following: a) respiratory failure, b) body temperature <35°C, c) presence of comorbidities, d) CURB-65 (confusion, uremia, respiratory rate, blood pressure, age ≥65 years) score >2, e) respiratory alkalosis, f) high levels of procalcitonin.

Patients' demographics and clinical characteristics were collected by medical records and entered into an anonymous database. Data included age, gender, body mass index (BMI), active smoking, duration of COVID-19 related symptoms prior to admission, as well as detailed medical history including previous cardiovascular events (myocardial infarction/stroke/decompensated heart failure), COPD, diabetes, and active cancer. Main clinical outcomes included hospitalization (immediate or delayed within 7 days after discharge from the ED), need for oxygen therapy, non-invasive ventilation, admission to semi-intensive/intensive care units (s-ICU/ICU, based on PaO 2 /FiO 2 ratio <250 and need for invasive or non-invasive ventilation), and death. Additional analyses were performed after grouping patients taking ACEIs and ARBs and comparing their clinical outcomes with those A c c e p t e d M a n u s c r i p t 5 of hypertensives who were not on RAAS inhibitors. The study was approved by the local Research Ethic Committee.

Continuous variables were presented by mean and standard deviation, while binary variables by proportions. Comparisons across groups were made using ANOVA and Fisher's exact tests, respectively. P-values were reported at their nominal value. The Benjamini-Hochberg procedure was performed to take account of multiple testing with a 30% false discovery rate. Uni-and multi-variable logistic regressions were performed with a predefined covariate set, which included age, gender, BMI, days with duration of symptoms prior to admission (days), previous cardiovascular events, diabetes and cancer, further to the use of ACEI/ARBs. All statistical analyses were performed using Stata 16 (College Station,

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A total of 133 hypertensive patients referred to ED and diagnosed with COVID-19 were enrolled throughout the study period. Among these, 40 (30%) were chronically using ACEIs, 42 (32%) ARBs, and 51 (38%) other blood pressure lowering medications. Among those treated with ACEis, 70% were taking ramipril, whereas olmesartan was used in more than 50% of patients treated with ARBs (see supplementary table 1). The mean follow-up was 15.8 ± 8.6 days. The general characteristics of the three groups are summarized in Table 1 .

No significant differences were observed for all demographics and clinical parameters, except for the history of chronic heart failure, which was more frequently observed in hypertensive patients not on RAAS inhibitors (31%; P=0.007).

At univariate analysis, the three groups had similar rates of hospital admission, as well as a comparable need for oxygen therapy and non-invasive ventilation during the hospital stay.

The rate of admission to s-ICU/ICU was lower among patients treated with ACEI (23%) or ARBs (29%) as compared to hypertensive patients who were not on RAAS inhibitors (49%).

The death rate was also similar between patients on ACEI and ARBs (20% and 17%, respectively), but lower than that observed in the third group (35%).

Odds ratios (ORs) for hospitalization, admission to s-ICU/ICU, need for oxygen therapy, noninvasive ventilation and death are shown in Table 2 

The present study shows that chronic assumption of ACEIs/ARBs did not worsen the clinical outcomes of COVID-19 infection in hypertensive patients. A significant lower risk of admission to s-ICU/ICU was observed in COVID-19 positive subjects chronically treated with ACEIs/ARBs as compared to other hypertensive patients, whereas the rates of hospitalization, oxygen therapy, non-invasive ventilation and death did not differ between the two groups.

While highly expressed in the vascular endothelium and lung, ACE2-receptors have been shown to represent the cellular entry receptor of COVID-19 [6, 7] . Based on experimental animal models demonstrating an upregulation of ACE2-receptors associated with intravenous infusion of ACEIs and ARBs [8], it has been warned that these medications might negatively impact clinical course of COVID-19 in hypertensives [3, 9] . However, two previous studies failed to demonstrate modification in ACE2 mRNA expression and plasma ACE2 Similarly to our data, two recent Chinese studies [14] [15] reported a lower risk of COVID-19 related mortality in hypertensive subjects associated with RAAS inhibitors during hospital stay. However, results were not stratified by type of chronic treatment (i.e. ARBs vs. ACEIs).

In addition, very recent reports, based on data from electronic health records, suggested that treatment with ARBs/ACEIs does not correlate to an increased susceptibility to SARS-COV-2 nor to the development of severe disease. [16] [17] [18] [19] These evidences have been confirmed by our analysis, which focused on clinical outcome of a specific cohort of hypertensive patients referring to the ED for acute symptoms of COVID-19 infection.

Specifically designed intervention studies are needed to confirm that the use of RAAS inhibitors can protect from clinical deterioration and to identify mechanisms associated with A c c e p t e d M a n u s c r i p t 9 these beneficial effects (such as potential anti-inflammatory activities or protective modulatory effects on ACE2 expression).

Our study presents some important limitations. First, the retrospective design and the limited sample size, which allowed us to only make an exploratory assessment of our working hypotheses. Second, only patients testing COVID-19 positive at the ED were enrolled in this study, thus not being representative of the entire infected population.

Furthermore, the potential association with other antihypertensive drugs, the prosecution of antihypertensive therapy throughout the hospital stay and different COVID-19 specific therapeutic strategies might have been other confounding factors.

In conclusion, our data suggest that chronic use of RAAS inhibitors does not correlate with an adverse clinical course in hypertensive patients. Conversely, discontinuing such a lifesaving therapy might be potentially harmful in line with societal recommendation [5] . 

Clinical Characteristics of Coronavirus Disease 2019 in China

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Renin-Angiotensin System Inhibition in Cardiovascular Patients at the Time of COVID19: Much Ado for Nothing? A Statement of Activity from the Directors of the Board and the Scientific Directors of the Italian Society of Hypertension

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China

Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19

Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19

Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19

Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19)

There are no conflicts of interest.

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