key: cord-333960-pkpbts7s
authors: Genet, Bastien; Vidal, Jean-Sébastien; Cohen, Adrien; Boully, Clémence; Beunardeau, Maelle; Harlé, Louise; Goncalves, Anna; Boudali, Yasmina; Hernandorena, Intza; Bailly, Henri; Lenoir, Hermine; Piccoli, Matthieu; Chahwakilian, Anne; Kermanach, Léna; de Jong, Laura; Duron, Emmanuelle; Girerd, Xavier; Hanon, Olivier
title: COVID-19 in-hospital mortality and use of renin-angiotensin system blockers in geriatrics patients.
date: 2020-09-09
journal: J Am Med Dir Assoc
DOI: 10.1016/j.jamda.2020.09.004
sha: 
doc_id: 333960
cord_uid: pkpbts7s

Objective The role of treatment with renin-angiotensin-aldosterone system blockers at the onset of COVID-19 infection is not known in geriatric population. The aim of this study was to assess the relationship between angiotensin receptor blockers (ARB) and an ACE inhibitor (ACEI) use and in-hospital mortality in geriatric patients hospitalized for COVID-19. Design This observational retrospective study was conducted in a French geriatric department. Patients were included between March 17 and April 18, 2020. Setting and Participants: All consecutive 201 patients hospitalized for COVID-19 (confirmed by RT-PCR methods) were included. All non-deceased patients had 30 days of follow-up and no patient was lost to follow-up. Methods Demographic, clinical, biological data and medications were collected. In-hospital mortality of patients treated or not by ACEI/ARB was analyzed using multivariate Cox models. Results Mean age of the population was 86.3 (8.0) years old, 62.7% of patients were institutionalized, 88.6% had dementia and 53.5% had severe disability (ADL score < 2). Sixty-three patients were treated with ACEI/ARB and 138 were not. Mean follow-up was 23.4 (10.0) days, 66 (33.8%) patients died after an average of 10.0 days (6.0). Lower mortality rate was observed in patients treated with ACEI/ARB compared with patients not treated with ARB nor ACEI (22.2% (14) vs. 37.7% (52), HR = 0.54 (95% CI = 0.30-0.97), p=0.03). In a multivariate Cox regression model including age, sex, ADL score, Charlson index, renal function, dyspnea, CRP and white blood cells count, use of ACEI/ARB was significantly associated with lower in-hospital mortality (HR = 0.52 (0.27−0.99), p=0.048). Conclusion and Implications In very old subjects hospitalized in geriatric settings for COVID-19, mortality was significantly lower in subjects treated with ARB or ACEI prior to the onset of infection. The continuation of ACEI/ARB therapy should be encouraged during periods of coronavirus outbreak in older subjects.

Worldwide, as of June 15, 2020, according to John Hopkins University, more than 8 million people 31 have been affected by coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, and more than 32 400 thousands died of COVID-19 since December 31, 2019. 1 In France according to Santé Publique 33

France, the French health agency, more than 141 thousand people have been contaminated and 34 more than 29 thousands died of COVID-19. 2 35 COVID-19 predominantly affects elderly people. Subjects aged 75 years and older accounted 36 for 75% of all deaths related to COVID-19 in France 2 and mortality rate is 31.1% in Italy among 37 people > 80 years old. 3 SARS-CoV-2 virus belongs to the family of orthocoronavirinae, and shares 38 some similarities with the MERS-CoV (75% identical genome sequence) and the SARS-CoV (85 % of 39 identical genome sequence respectively) that were responsible for severe pneumonia. 4 Their S 40 protein (of their capsize) are 99% similar and they have the same binding site: the angiotensin 2 41 conversion enzyme. 4 Angiotensin 2 converting enzyme has a role in the entry of SARS-CoV-2 into 42 target cells and animal experimental data indicate an increase in enzyme expression after 43 administration of renin-angiotensin-aldosterone system blockers (i.e., angiotensin-converting-44 enzyme inhibitors (ACEI) and receptors blockers (ARB)). 5 Thus the question has arisen as to whether 45 ACEI/ARB treatment could increase severity and mortality of COVID-19. 6 

In observational studies, subjects with cardiovascular diseases and hypertension are often 47 treated with ACEI or ARB, and have an increased risk of in-hospital mortality related to COVID-19. 5, 7 48

Meanwhile some studies have found no effect 7, 8 or even a beneficial effect of ACEI/ARB on COVID-19 49 mortality. 5, 9, -11 Older people are frequently treated with ACEI/ARB, however few data are available 50 on their use in geriatric population affected by COVID-19. The aim of this study was to assess the 51 relationship between ACEI/ARB and in-hospital mortality among geriatric patients hospitalized for 52 COVID-19. 12 53

This retrospective study included all symptomatic patients admitted in Acute Geriatric Units 56 dedicated to treating COVID-19, between March 17 and April 18, 2020, in a geriatric department with 57 a positive reverse-transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 on nasal swabs. 58

Patients were followed-up until May 18, 2020. Before admittance in the Acute Geriatric Units, 59 patients with positive RT-PCR for SARS-CoV-2 were first examined in emergency room and had a 60 geriatric evaluation. Only patients who were assessed as not fit enough or had too severe 61 comorbidities for intensive care unit were admitted Acute Geriatric Units and included in the study. 62

As available, four different PCR tests were performed by the hospital's virology department (Abbott 63 real time SRAS CoV-2, Xpert Xpress SRAS CoV-2, Simplexa COVID 19 direct and Allplex 2019-nCoV 64 Assay). 65

The study was conducted in accordance with the ethical standards set forth in the Declaration of 66

Helsinki. The study protocol was approved by local ethics committee and the study complied with the 67 strengthening the reporting of observational studies in epidemiology statement guidelines 13 All 68 patients' data were anonymized prior to analysis. No consent to participate was sought for the 69 participants in accordance with the French law because the study was observational in nature (as 70 part of usual care), and no nominative data were collected. 14 71

72 All data were collected as part of usual care. In-hospital mortality was assessed during a follow up of 73 30 days after RT-PCR confirmation. All patients included in the study were hospitalized at least 30 74 days in the geriatric department (acute unit and then rehabilitation unit if needed). Thus all non-75 deceased patients had a full 30-day follow-up. 76

Ethnicity was not recorded but the sample was overwhelmingly white Caucasian (> 90%). 77 cancer (localized or metastatic), heart failure, coronary heart disease, atrial fibrillation, hypertension 79 (defined as systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg or use of 80 antihypertensive medications or history of hypertension), diabetes mellitus (defined as self-report or 81 use of oral hypoglycemic medication or insulin or a history of diabetes), chronic respiratory disease 82 (chronic obstructive pulmonary disease or asthma), stroke or transient ischemic attacks, dementia 83 (based on the Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition), 15 chronic kidney 84 disease and major depression. Nutritional status was assessed by body mass index (BMI) and serum 85 albumin level and malnutrition was defined as BMI <21 kg/m 2 or Albumin < 35 g/l as defined in a Best 86

Practice Guideline by the French health authority. 16 Comorbidity was evaluated with the Charlson 87 Comorbidity Index (CCI). 17 Functional status was assessed with Activities of Daily Living (ADL). 18 ADL 88 was regrouped in 3 classes, no disability to mild disability (ADL ≥4 to 6), moderate disability (ADl ≥ 2 89 to < 4) and severe disability (ADL 0 to < 2). 90

Symptoms that led to the COVID-19 diagnosis or occurred in the first 72 hours before or after 91 the RT-PCR confirmation, such as fever (defined as T° > 37.8°C), dyspnea, coughing, severe 92 hypotension (SBP < 95 mmHg), digestive disorders (diarrhea and nausea or vomiting) or falls were 93 also collected. 94

Ongoing treatments defined as treatment taken for at least 1 week before inclusion and 95 taken the day of the inclusion were recorded: ACEI, ARB, diuretics, beta-blockers, calcium channel 96 blockers, antiplatelet therapy, oral anticoagulants, benzodiazepines, neuroleptics, antidepressant 97 therapy and proton pump inhibitors. 98

Biological data were also collected at admission including hemoglobin level, white blood cell 99 count (WBC), lymphocyte and platelet count, C-reactive protein (CRP), serum creatinine, LDL and 100 albumin. Estimated glomerular filtration (eGFR) rate was calculated with CKD-EPI formula 19 and 101 categorized in 3 classes, eGFR ≥ 50 ml/min, 50 ml/min > eGFR ≥ 30 ml/min and eGFR < 30 ml/min. 102

Baseline characteristics of the participants were analyzed in the whole sample and according to death 105 at 30 days using descriptive statistics: means and standard deviations for continuous variables, and 106 percentages and counts for categorical variables and compare with t-tests and χ 2 respectively. 107

Variables were also compared with univariate Cox model to take into account the different follow-up 108 durations. 109

Baseline characteristics of the participants were also analyzed according to the use of ACEI/ARB and 110 Comorbidity Index were standardized in order to obtain HR for an increase of 1 SD of each of those 118 variables. HR for age was calculated for an increase of 10 years. 119

Another multivariate regression Cox model was built with 30-day in-hospital mortality as dependent 120 variable and use of ARB and ACEI taken separately as independent variable and with the same 121 adjustment as the first Cox regression model. 122 LDH was not included in this model because it was missing in 50 subjects. Proportional hazard 123 assumption was checked graphically for all covariates and using Schoenfeld residuals. 124

All analyses were two-sided and a p-value < 0.05 was considered statistically significant. Data analysis 125 was performed using R software version 3. Table 2) . 148

Among patients with hypertension, 46% (58/125) were treated with ACEI/ARB. Patients 149 receiving ACEI or ARB had more often hypertension and coronary artery disease and less often 150 dementia and lower level of hemoglobin. Overall they had a higher Charlson comorbidity index than 151 J o u r n a l P r e -p r o o f patients not treated with ACEI or ARB. They were more often treated with calcium channel blockers, 152 diuretics, and antiplatelet (table 3) . 153

In a multivariate Cox regression model including age, sex, ADL, CCI, renal function, dyspnea, 154 CRP and WBC, use of ACEI or ARB was significantly associated with lower in-hospital mortality (HR = 155 0.52 (0.27−0.99), p=0.048) (Figure 2) . Severe disability (ADL < 2), (HR = 2.54 (1.13-5.72)), high white 156 blood cells count (HR= 1.45 (1.16-1.81)) and high CRP (HR= 1.37 (1.11-1.69)) were significantly 157 associated with death (Figure 2) . 158

In the multivariate Cox regression model analyzing ARB and ACEI separately, HR was 0.40 159 (0.14-1.15), p=0.09 for ARB and 0.60 (0.28-1.31), p=0.20 for ACEI (Figure 2) . In this cohort of very old patients affected by COVID-19, a high rate of in-hospital mortality was 164 observed. The main factor associated with mortality was severe disability. In-hospital mortality 165 among patients treated with ACEI or ARB was significantly lower compared with patients without 166 ACEI or ARB therapy. 167

In our study, 33% of the patients died within 30 days of COVID-19 RP PCR confirmation. This 168 mortality is much higher than that of younger population and of other respiratory virus diseases like 169 influenza -and respiratory syncytial virus in elderly people. 20 Older age has already been found a 170 major risk factor for mortality from COVID-19 ranging from 14% to 30 % in patients aged > 80 years 171 old. 3, 21, 22 As of May 28, 2020 among the 59,134 peoples aged > 80 years old affected by COVID-19 in 172

Italy the mortality was 31.1% 3 . The relation of age and COVID-19 mortality is probably related to 173 immunosenescence that has been identified as a major risk factor for respiratory diseases and its 174 related mortality. 23 175

As already published, we also found that CRP and leukocytes increase were associated with 176 death. 8, 24, 25 However in our geriatric population, the main factor associated with mortality was 177 severe disability and not factors usually associated with higher mortality in COVID-19 like, 178 cardiovascular diseases, diabetes mellitus, obesity and chronic obstructive pulmonary disease. 26-28 . 179 Disability through ADL is an already known factor of all-cause mortality in the elderly. 29, 30 180 Interestingly, poor functional status was a most relevant factor associated with mortality than 181 respiratory symptoms like dyspnea that are major prognostic factors in younger population. 31-33 182 Conversely to other studies, age was not associated with in-hospital mortality in our study probably 183 because of the specificity of our population that was very old with a somewhat narrow age range. In our geriatric population no patient were managed in intensive care unit because of high 213 level of comorbidity, dementia and low physiologic reserves that make prolonged intensive care 214 unreasonable. Indeed, among critically ill elderly geriatric patients, ICU admission do not reduce 6-215 month mortality. 38 In this frail population at high risk of mortality, the need of effective treatment 216 before critical stage of COVID-19 is of paramount importance. 217

The high prevalence of dementia could be explained by the fact that only patients who were 218 assessed too debilitated or had too severe comorbidities for intensive care unit after a geriatric 219 evaluation were transferred in the Acute Geriatric Units and because 60% of our patients came from 220 nursing homes. 221

This study has several strengths. Very few data existed on geriatric population affected by 222 COVID-19, characterized by high risk of mortality and no access to intensive care unit. 38 Prevalence of 223 dementia was very high (89%) and few data exist on such population. There was no loss to follow-up 224 and all non-deceased patients were followed-up for 30 days enabling the estimate of the actual 30-225 day mortality. Our results were adjusted on confounding factors including symptoms, comorbidity, 226 disability and biological factors and suggest that in this population the ACEI/ARB therapy could be 227 associated with better prognosis and ought to be confirm in other geriatric populations. Randomized 228 controlled trials are much needed to assess the benefit on mortality associated with ACEI/ARB 229 treatment in elderly patients with This study has also some limitations, this cohort was monocentric and retrospective, so 231 causality between ACEI or ARB use and mortality cannot be ascertained. 

EPIDEMIA COVID-19. Aggiornamento nazionale

Receptor Recognition by the Novel Coronavirus from

Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

Cardiovascular Disease, Drug Therapy, and Mortality 264 in Covid-19

Hypertension, the renin-angiotensin 266 system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-267 19

Renin-Angiotensin-Aldosterone System

Blockers and the Risk of Covid-19

Association of Renin-Angiotensin System Inhibitors With 271

Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 272 2019 (COVID-19) Infection in Wuhan, China

Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality

Association of Inpatient Use of Angiotensin-Converting Enzyme 278

Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With 279

Hypertension Hospitalized With COVID-19

Angiotensin-Converting Enzyme) Inhibitors on Virus Infection, Inflammatory Status, and Clinical

We wish to thank the team of health-care workers from the Broca's hospital who collected the data and completed the study.J o u r n a l P r e -p r o o f

 II receptor blocker;  378  ACEI, angiotensin-converting-enzyme inhibitors; BMI, body mass index; TIA, transient ischemic  379 attack; COPD, chronic obstructive pulmonary disease; PPI, proton-pump inhibitor; WBC, white blood 380 cells; eGFR, glomerular filtration rate estimated with CPK-EPI formula; CRP, C-reactive protein. 
