Age and Multimorbidity Predict Death Among COVID-19 Patients

Several factors have been proposed to explain the high death rate of the coronavirus disease 2019 (COVID-19) outbreak, including hypertension and hypertension-related treatment with Renin Angiotensin System inhibitors. Also, age and multimorbidity might be confounders. No sufficient data are available to demonstrate their independent role. We designed a cross-sectional, observational, multicenter, nationwide survey in Italy to verify whether renin-angiotensin system inhibitors are related to COVID-19 severe outcomes. We analyzed information from Italian patients diagnosed with COVID-19, admitted in 26 hospitals. One thousand five hundred ninety-one charts (male, 64.1%; 66±0.4 years) were recorded. At least 1 preexisting condition was observed in 73.4% of patients, with hypertension being the most represented (54.9%). One hundred eighty-eight deaths were recorded (11.8%; mean age, 79.6±0.9 years). In nonsurvivors, older age, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, coronary artery diseases, and heart failure were more represented than in survivors. The Charlson Comorbidity Index was significantly higher in nonsurvivors compared with survivors (4.3±0.15 versus 2.6±0.05; P<0.001). ACE (angiotensin-converting enzyme) inhibitors, diuretics, and β-blockers were more frequently used in nonsurvivors than in survivors. After correction by multivariate analysis, only age (P=0.0001), diabetes mellitus (P=0.004), chronic obstructive pulmonary disease (P=0.011), and chronic kidney disease (P=0.004) but not hypertension predicted mortality. Charlson Comorbidity Index, which cumulates age and comorbidities, predicts mortality with an exponential increase in the odds ratio by each point of score. In the COVID-19 outbreak, mortality is predicted by age and the presence of comorbidities. Our data do not support a significant interference of hypertension and antihypertensive therapy on COVID-19 lethality. Registration— URL: https://www.clinicaltrials.gov; Unique identifier: NCT04331574.

[1]  Y. Hu,et al.  [Asymptomatic infection of COVID-19 and its challenge to epidemic prevention and control]. , 2020, Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi.

[2]  G. Mancia,et al.  Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19 , 2020, The New England journal of medicine.

[3]  A. Troxel,et al.  Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19 , 2020, The New England journal of medicine.

[4]  Qingbo Xu,et al.  Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19 , 2020, Circulation research.

[5]  M. Volpe,et al.  Might renin–angiotensin system blockers play a role in the COVID-19 pandemic? , 2020, European heart journal. Cardiovascular pharmacotherapy.

[6]  R. Sarzani,et al.  Severe acute respiratory syndrome coronavirus 2 infection, angiotensin-converting enzyme 2 and treatment with angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers. , 2020, European journal of preventive cardiology.

[7]  Gian Paolo Rossi,et al.  Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients , 2020, eLife.

[8]  G. Grassi,et al.  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 , 2020, High Blood Pressure & Cardiovascular Prevention.

[9]  Marc A Pfeffer,et al.  Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19 , 2020, The New England journal of medicine.

[10]  G. Ippolito,et al.  COVID-19, SARS and MERS: are they closely related? , 2020, Clinical Microbiology and Infection.

[11]  M. Harhay,et al.  Is There an Association Between COVID-19 Mortality and the Renin-Angiotensin System? A Call for Epidemiologic Investigations , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[12]  D. Batlle,et al.  Renin-Angiotensin System Blockers and the COVID-19 Pandemic , 2020, Hypertension.

[13]  A. Akbari,et al.  Prevalence of Underlying Diseases in Hospitalized Patients with COVID-19: a Systematic Review and Meta-Analysis , 2020, Archives of academic emergency medicine.

[14]  G. Onder,et al.  Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. , 2020, JAMA.

[15]  James H Diaz,et al.  Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19 , 2020, Journal of travel medicine.

[16]  Michael Roth,et al.  Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? , 2020, The Lancet Respiratory Medicine.

[17]  M. Esler,et al.  Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic? , 2020, Journal of hypertension.

[18]  Xiang Xie,et al.  COVID-19 and the cardiovascular system , 2020, Nature Reviews Cardiology.

[19]  D. Gurwitz Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics , 2020, Drug development research.

[20]  Wei Wang,et al.  Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis , 2020, European Respiratory Journal.

[21]  Zunyou Wu,et al.  Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. , 2020, JAMA.

[22]  Yan Zhao,et al.  Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. , 2020, JAMA.

[23]  Ting Yu,et al.  Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study , 2020, The Lancet.

[24]  M. Illario,et al.  We are What We Eat: Impact of Food from Short Supply Chain on Metabolic Syndrome , 2019, Journal of clinical medicine.

[25]  W. Siqueira,et al.  Losartan and isoproterenol promote alterations in the local renin-angiotensin system of rat salivary glands , 2019, PloS one.

[26]  2018 ESC/ESH Guidelines for the management of arterial hypertension. , 2019, Revista espanola de cardiologia.

[27]  W. Spiering,et al.  [2018 ESC/ESH Guidelines for the management of arterial hypertension. The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH)]. , 2018, Giornale italiano di cardiologia.

[28]  W. Kuebler,et al.  Therapeutic time window for angiotensin‐(1–7) in acute lung injury , 2016, British Journal of Pharmacology.

[29]  Lisa E. Gralinski,et al.  A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence , 2015, Nature Medicine.

[30]  G. Mancia,et al.  Blood pressure levels and control in Italy: comprehensive analysis of clinical data from 2000–2005 and 2005–2011 hypertension surveys , 2015, Journal of Human Hypertension.

[31]  M. Fox,et al.  Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors , 2014, Amino Acids.

[32]  Arthur S Slutsky,et al.  Angiotensin-converting enzyme 2 protects from severe acute lung failure , 2005, Nature.

[33]  D. Diz,et al.  Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2 , 2005, Circulation.

[34]  Christophe Fraser,et al.  The Epidemiology of Severe Acute Respiratory Syndrome in the 2003 Hong Kong Epidemic: An Analysis of All 1755 Patients , 2004, Annals of Internal Medicine.

[35]  M. Pahor,et al.  Undertreatment of hypertension in community-dwelling older adults: a drug-utilization study in Dicomano, Italy. , 1999, Journal of hypertension.

[36]  C. Mackenzie,et al.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. , 1987, Journal of chronic diseases.