key: cord-0798224-7afpilq7
authors: Covino, Marcello; De Matteis, Giuseppe; Burzo, Maria Livia; Santoro, Michele; Fuorlo, Mariella; Sabia, Luca; Sandroni, Claudio; Gasbarrini, Antonio; Franceschi, Francesco; Gambassi, Giovanni
title: Angiotensin‐Converting Enzyme Inhibitors Or Angiotensin Ii Receptor Blockers And Prognosis Of Hypertensive Patients Hospitalized With Covid‐19
date: 2020-10-06
journal: Intern Med J
DOI: 10.1111/imj.15078
sha: ced2304730d6a37db6da25fc74800612a605f617
doc_id: 798224
cord_uid: 7afpilq7

BACKGROUND: Among hypertensive patients, the association between treatment with angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and the clinical severity of Covid‐19, remains uncertain. AIMS: To determine whether hypertensive patients hospitalized with Covid‐19 are at risk of worse outcomes if on treatment with ACEIs or ARBs compared to other anti‐hypertensive medications. METHODS: This is a retrospective study conducted at a single academic medical center [Fondazione Policlinico A.Gemelli IRCCS, Rome, Italy] from March 1(st) to 31 (st), 2020. We compared patients on treatment with an ACEIs/ARBs (ACEIs/ARBs group) to patients receiving other anti‐hypertensive medications (No‐ACEIs/ARBs group). The endpoints of the study were the all‐cause in‐hospital death and the combination of in‐hospital death or need for ICU admission. RESULTS: The sample included 166 Covid‐19 patients; median age was 74 years and 109 were men (66%). Overall, 111 patients (67%) were taking an ACEIs or ARBs. Twenty‐nine patients (17%) died during hospital stay, and 51 (31%) met the combined endpoint. After adjustment for comorbidities, age and degree of severity at the presentation, ACEIs or ARBs treatment was an independent predictor neither of in‐hospital death nor of the combination of in‐hospital death/need for ICU. No differences were documented between treatment with ACEIs compared to ARBs. CONCLUSIONS: Among hypertensive patients hospitalized for Covid‐19, treatment with ACEIs or ARBs is not associated with an increased risk of in‐hospital death. This article is protected by copyright. All rights reserved.

The severe acute respiratory coronavirus-2 (SARS CoV-2) is associated with a viral pneumonia named coronavirus disease-2019 (Covid- 19) , whose ongoing pandemic is posing great challenges to the healthcare systems worldwide. World Health Organization estimates there have been over 25 million of confirmed Covid-19 cases worldwide, with a mortality rate of approximately 4%, despite some differences across countries [1] . Older individuals, those with preexisting respiratory or cardiovascular medical conditions, as well as those with diabetes and hypertension, appear to be at higher risk of severe complications and death [2] [3] [4] [5] . Available data suggest that hypertension is the most frequent comorbidity in patients with Covid-19, and it is associated with more severe course of the disease and a higher mortality [6] [7] [8] [9] [10] [11] [12] . However, sparse data are available on hypertensive Covid-19 patients, and the role played by anti-hypertensive This article is protected by copyright. All rights reserved. medications is unclear. Since the SARS CoV-2 uses the receptor angiotensin-converting enzyme (ACE) 2 to infect target cells [13] , a controversial debate is ongoing about whether angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) should possibly be the reason for the emerging association between hypertension and worse outcomes in patients with Covid-19 [14] [15] [16] [17] [18] [19] . On one hand, it has been speculated that both these medications could increase SARS CoV-2 infection susceptibility, and worsen the course of the respiratory syndromes. Indeed, in animal models and in humans it has been shown that ACEIs and ARBs may increase ACE2 levels in the lungs [20] [21] [22] [23] . On the other hand, other authors have hypothesized that an increased level of the soluble form of ACE2, secondary to ACEIs/ARBs treatment, may act as a competitive interceptor of SARS-CoV-2, thus slowing virus entry and protecting the lungs from injury [24] .

Three recently published studies in China reported that hypertensive patients hospitalized with Covid-19 experienced a lower risk of all-cause mortality if on treatment with ACEIs/ARBs compared to ACEIs/ARBs non-users [10] [11] [12] . Moreover, latest reports showed no evidence that ACE inhibitors or ARBs affected the risk of Covid-19 [25] and did not confirm a harmful role of ACEIs or ARBs in admission to hospital or in-hospital death [26] .All the scientific societies have issued statements against any change in the current indications for the use of these medications in view of the well documented beneficial effects [27, 28] .

Hence, the aim of the current study is to analyze the association between treatment with ACEIs or ARBs and in-hospital death and/or the need of intensive care unit (ICU) admission, among hypertensive patients hospitalized with Covid-19.

This article is protected by copyright. All rights reserved. This is a retrospective study conducted at the Fondazione Policlinico A.Gemelli IRCCS, Rome, Italy, an academic medical center identified as one of the referral center for Covid-19 in central Italy.

We derived data from the electronic medical records of all the patients consecutively admitted to our Emergency Department (ED) for suspected Covid-19, between March 1 st and 31 st , 2020.

We identified all the patients with an established diagnosis of hypertension who have been continuously taking any oral antihypertensive medication for at least 3 months. All of the patients received a definitive diagnosis of Covid-19 as for the World Health Organization (WHO) interim guidance. In this respect, a definitive laboratory confirmation of SARS CoV-2 infection was defined as a positive result on real-time reverse-transcriptase-polymerase-chainreaction assay of nasal or oro-pharyngeal swab specimens [29] .

From the study sample were excluded patients aged <18 years old, pregnant women, and patients with a definitive diagnosis of Covid-19 who were discharged home because of mild symptoms and a normal chest x-ray.

Electronic medical records were identified and the following data elements were derived: age, gender, clinical symptoms at presentation, Glasgow Coma Scale (GCS) score, chest x-ray finding, and prior medical history including information on comorbid conditions and This article is protected by copyright. All rights reserved. pharmacological treatment. The comorbid conditions considered were: heart disease, here including a history of heart failure, coronary artery disease, cardiomyopathy, heart valve disease, arrhythmias; obesity, defined by a body mass index (BMI) > 30; chronic obstructive pulmonary disease (COPD) and diabetes. Furthermore, for each patient, at ED admission, six physiological parameters were routinely recorded for the National Early Warning Score (NEWS) calculation:

(i) respiratory rate, (ii) peripheral oxygen saturation (SpO2), (iii) temperature, (iv) systolic blood pressure, (v) heart rate, and (vi) the level of consciousness assessed by the response on AVPU (Alert, Voice, Pain, Unresponsive) scale [30] . NEWS scoring system, as described by the Royal College of Physicians, allows to divide patients into the following three risk categories: low score (NEWS 0-4 ); medium score (NEWS 5-6); and high score (NEW S ≥7) [31] .

Antihypertensive medications were classified in the following therapeutic classes: ACEIs, ARBs, Mineralcorticoid Receptor Antagonists, beta-Blockers, Calcium Channel Blockers, alpha-1 adrenergic blockers, Central alpha-adrenoceptor agonists, Nitrates, Diuretics.

For the analysis, we compared patients on treatment with an ACEIs/ARBs (ACEIs/ARBs group), and patients on treatment without an ACEIs/ARBs (No-ACEIs/ARBs group).

All patients included in the analysis were treated according to standard of care in the enrolling period, as defined by the Italian Society of Infectious and Tropical Diseases guidelines on management of Covid-19 [32] .

To adjust for disease severity, we stratified patients based on the NEWS score at ED admission.

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Criteria for ICU admission of Covid-19 patients were clearly established, did not change over the study period and they needed to be respected mandatorily. The criteria included the need for invasive respiratory support, the presence of extra-pulmonary organ failure such as circulatory shock requiring vasopressors, or renal failure.

The endpoints of the study were the all-cause in-hospital death and the combination of inhospital death and need for ICU admission. Variables with a statistically significant association at the univariate analysis were entered into logistic regression multivariate models. Age, gender and ACEIs/ARBs treatment were forced into all the logistic models. Since the NEWS score was included, the physiological parameters used for its calculation were excluded from the analysis to avoid estimation redundancy. As two variables were entered into each logistic regression model, a minimum number of 20 events would be needed for a correct parameter estimation. Therefore, our sample size was adequate for a correct estimation of both death and combined outcome of death/ICU admission.

A p value ≤ 0.05 was considered as statistically significant. Data were analyzed by SPSS v25®

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This study was approved by the local Ethics Committee and it was performed in accordance with good clinical practice established in the 1964 Declaration of Helsinki and its later amendments.

Between March 1st and 31 st, 2020, a total of 512 patients were admitted to the ED with a definitive diagnosis of Covid-19. One-hundred-seventy-six patients were excluded from the analysis for insufficient clinical data on electronic medical record and two patients were excluded because already intubated at ED arrival. Among the 334 eligible patients, the final study sample included 166 hypertensive patients aged between 30 and 98 years, for the great majority males (66%) (Figure 1 ).

Overall, 49 patients (30%) were taking ACEIs and 62 (37%) were taking ARBs, and none of the patients was receiving both at the same time. Collectively, among the 111 patients in the ACEIs/ARBs group, 77 patients (70%) were taking one or more additional anti-hypertensive medication. The most common combinations were with beta-blockers (42 patients), diuretics (32 patients) and calcium antagonists (30 patients). Among patients in the no-ACEIs/ARBs group, 62% was taking more than one antihypertensive drug; the more common medications were calcium-antagonists (56.4%), beta-blockers (45.4%), and diuretics (16.4%).

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Patients in the ACEIs/ARBs group had comparable baseline characteristics, including comorbidities, with those in the no-ACEIs/ARBs group (Table 1) . A NEWS score ≥ 2 was adjudicated for 53% of patients in the ACEIs/ARBs group, compared to 36% in the no-ACEIs/ARBs group, p<0.05 (Table 1) .

Overall, 29 patients (17%) died during hospital stay, 6 patients in the first 24 hours since hospital arrival. Age and gender did not differ between those who died and those who survived. Among the relevant comorbidities, COPD showed a higher prevalence among non-survivor patients (14%, p =0.028). Furthermore, the patients who died presented in worse general conditions with 86% of them with a NEWS score ≥ 2 compared to 44% of the survivors, p<0.001 (Table 2) .

Twenty out of 29 (69%) patients who died were on ACEIs/ARBs therapy, compared to the 91/137 (66%) survived, p=0.792.

Fifty-one patients (31%) met the combined outcome death and/or ICU admission during hospital stay (Table 1) , with an event occurring in the first 48 hours for nearly 90% of the patients.

Thirty-eight out of 51 (74%) patients that met the combined endpoint were on ACEIs/ARBs therapy, compared to the 73/115 (62.4%) non-ICU/survived, p=0.164 (Table 2) .

A NEWS score ≥ 2 was estimated to be an independent predictor of all outcomes, with a sevenfold increased risk of death and a six-fold increased risk of the combined outcome death/ICU admission ( Table 3 ). The association of COPD with death was not significant in the multivariate analysis. When forced into the regression models, only age was an independent predictor of death alone (OR 1.05), but not of the combined outcome death/ICU admission. Treatment with ACEIs/ARBs was not associated with both death and the combined outcome death/ICU admission.

The 49 patients taking ACEIs were comparable for all parameters to the 62 patients taking ARBs. Any of the outcomes occurred at a similar rate (Figure 2 ).

The main finding of the present study was that among patients with hypertension hospitalized for Covid-19, treatment with ACEIs or ARBs was not associated with an increased risk of inhospital death. Moreover, no differences were highlighted between treatment with ACEIs compared to ARBs. Initial epidemiological reports from China have shown that hypertension and diabetes, as well as other cardiovascular diseases, are highly prevalent among Covid-19 patients [6] [7] [8] . Among patients who experienced worse outcomes, including need for ICU admission, use of mechanical ventilation, and death [6, 7, 33, 34] , the prevalence of hypertension was much higher compared to that of less severe Covid-19 patients. Likewise, in a study evaluating the prognosis of SARS CoV-2 patients admitted to ICU, the prevalence of hypertension was higher among patients who died compared to that of patients who could be stabilized and discharged from the ICU [9] . In addition, an analysis of the characteristics of Covid-19 related deaths in Italy documented that This article is protected by copyright. All rights reserved.

73% of the patients (mean age 79 years) had an established diagnosis of hypertension, and 30% and 17% respectively, reported a treatment with ACEIs or ARBs [35] .

Collectively, these evidences have suggested a link between hypertension and the severity of Covid-19 infection. Furthermore, a growing concern has developed that the use of antihypertensive medications, mainly ACEIs and ARBs, may have contributed to the adverse outcomes observed in the initial studies of Covid-19 patients [2] [3] [4] [5] [6] [7] [8] . Indeed, since SARS-CoV2 binds to ACE2 receptor to infect host cells, it has been hypothesized that ACEIs and ARBs could up-regulate ACE2 expression leading to an increased susceptibility to viral entry and propagation [15, 17] . Furthermore, it has been postulated that the up-regulation of ACE2 could increase the lung viral load and worsen the respiratory disease severity [17] .

However, recent studies did not confirm these concerns. Yang et al [12] , conducted a retrospective study including 126 Covid-19 patients with hypertension of whom 43 patients (34%) were on ACEIs or ARBs treatment. Compared to ACEIs/ARBs non-users, those on ACEIs or ARBs experienced a lower death rate but such failed to reach statistical significance.

Another Chinese study on 362 hypertensive patients with Covid-19, of whom 115 (32%) were on ACEIs or ARBs, suggested that these medications were not associated with Covid-19 severity or mortality [11] . Furthermore, Zhang et al [10] had recently published a retrospective multi-center study in China including 1128 hypertensive adult patients diagnosed with Covid-19. One hundred eighty-eight patients (17%) using ACEIs/ARBs were paired at 1:1 based on a propensity matching with patients using other anti-hypertensive medications. Use of ACEIs/ARBs was associated with a lower risk of Covid-19 mortality at 28 days, albeit the authors themselves admit that residual confounding cannot be ruled out. More recently, a large population-based This article is protected by copyright. All rights reserved. study conducted in Italy did not provide evidences that ACEIs or ARBs could affect the risk of Covid-19 infection [25] .

In this study, we did not find an association between treatment with ACEIs or ARBs and the inhospital death (Figure 1) . Similarly, a case-population study done in Spain showed that there is no evidence of a causal relationship between ACE2 levels and outcomes in Covid-19 patients, nor it is known conclusively if a higher viral load is associated with a worse prognosis in SARS-CoV-2 infection. Moreover, ACEIs or ARBs did not increase the risk of Covid-19 requiring admission to hospital [26] .

The findings of our study failed to demonstrate that patients on ACEIs/ARBs could experience a higher risk of the combined endpoint of in-hospital death and ICU admission suggesting that ACEIs or ARBs treatment did not influence not only the risk of death, but also the course of disease. Furthermore, we could not document any differential impact on the outcomes between ACEIs and ARBs ( Figure 2 ) but, due the relatively small sample size, this finding remains questionable. Indeed, the evidence prior to the Covid-19 era was mixed. A systematic review has indicated that ACEIs, but not for ARBs, have a protective role toward the risk of community acquired pneumonia and its related mortality [36] . In contrast, among patients with chronic obstructive pulmonary disease (COPD), it has been suggested that ARB might be more effective than ACEI to reduce the severity and mortality due to COPD [37] .

Moreover, in our cohort of Covid-19 patients, among the comorbidities analyzed, a history of COPD showed a higher prevalence among non-survivor patients. Likewise, in a recent metaanalysis, Covid-19 infection was associated with substantial severity and mortality rates in patients with COPD [38] . In addition, although in a limited sample, the present data suggest that risk of death could be age dependent, confirming what stated in other surveys [9, 34, 39] .

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However, no sufficient data were available to demonstrate the independent role of age. Indeed, in a previous report mortality appeared not predicted by advanced age [40] .

Typically, Covid-19 patients present with fever, myalgia or fatigue and dry cough [7] . Severe cases progress to severe dyspnoea and hypoxemia usually within one week after the onset of symptoms [41] . In hospitalized Covid-19 patients, the prevalence of hypoxemic respiratory failure is around 20%, and more than 25% of them may require intensive care treatment [42] . In the present study, we elected to focus on the worse case scenario, e.g., death or the composite of death/ICU admission during hospital stay. In order to account for the different clinical severity at presentation, patients were stratified according to NEWS, a widely adopted early warning score.

The NEWS score is based on a rapid and quantitative assessment of changes in vital signs [43] , and was developed to identify and track patients at risk of deterioration in non-critical areas of the hospital in order to ensure an early stabilization and ICU transfer and to prevent avoidable cardiac arrest [44] . In recent years, the NEWS score has been validated in the ED setting to predict ICU admission and mortality [45] . Furthermore, although not yet validated, the NEWS score has recently been proposed for the triage of Covid-19 patients in ED [41] . The findings of our study document that patients with a more severe degree of respiratory illness, defined by a NEWS score ≥ 2 at presentation, were at high risk of rapid deterioration, with a consistent increased risk of death and death/ICU admission.

These results are consistent with those reported in a recent prospective cohort study in which the NEWS score at hospital admission appeared superior to the quick Sepsis Related Organ Failure Assessment (qSOFA) score and other widely used clinical risk scores in prediction of severe disease and in-hospital mortality from Covid- 19 [46] . However, larger studies are needed to confirm this finding, and to investigate the optimal cut-off value for clinical use.

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As for any retrospective study, several limitations are worth considering. First, despite a fair sample size, the number of events was small thus limiting the power of our study. The study was conducted at a single medical center and, as such, the findings might be not representative of the general population of Covid-19 patients. The study focused on the worse case scenarios, i.e., inhospital death or death/ICU admission. For this reason, we cannot extrapolate the findings to different outcomes as length of hospital stay, other complications, permanent need of oxygen support, loss of autonomy or need to transfer to residential nursing facilities. Similarly, the effect of ACEIs/ARBs might be different among patients managed in the outpatient setting. Finally, some patients might have been excluded from the analytical sample because suggested to interrupt ACEIs/ARBs treatment due to prior concerns.

Among patients with hypertension hospitalized for Covid-19, treatment with ACEIs or ARBs was not associated with an increased risk of in-hospital death. Moreover, noticeably, no differences were documented between treatment with ACEIs compared to ARBs.

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