Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19

Michael Pan; Alexi Vasbinder; Elizabeth Anderson; Toniemarie Catalan; Husam R. Shadid; Hanna Berlin; Kishan Padalia; Patrick O’hayer; Chelsea Meloche; Tariq U. Azam; Ibrahim Khaleel; Erinleigh Michaud; Pennelope Blakely; Abbas Bitar; Yiyuan Huang; Lili Zhao; Rodica Pop-Busui; Sven H. Loosen; Athanasios Chalkias; Frank Tacke; Evangelos J. Giamarellos-Bourboulis; Jochen Reiser; Jesper Eugen-Olsen; Salim S. Hayek

doi:10.1161/JAHA.121.023535

Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19

Michael Pan, Alexi Vasbinder, Elizabeth Anderson, Toniemarie Catalan, Husam R. Shadid, Hanna Berlin, Kishan Padalia, Patrick O’hayer, Chelsea Meloche, Tariq U. Azam, Ibrahim Khaleel, Erinleigh Michaud, Pennelope Blakely, Abbas Bitar, Yiyuan Huang, Lili Zhao, Rodica Pop-Busui, Sven H. Loosen, Athanasios Chalkias, Frank TackeEvangelos J. Giamarellos-Bourboulis, Jochen Reiser, Jesper Eugen-Olsen, Salim S. Hayek^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

BACKGROUND: Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) is thought to affect COVID-19 through modulating levels of angiotensin-converting enzyme 2, the cell entry receptor for SARS-CoV2. We sought to assess the association between ACEi/ARB, biomarkers of inflammation, and outcomes in patients hospitalized for COVID-19. METHODS AND RESULTS: We leveraged the ISIC (International Study of Inflammation in COVID-19), identified patients admitted for symptomatic COVID-19 between February 1, 2020 and June 1, 2021 for COVID-19, and examined the association between in-hospital ACEi/ARB use and all-cause death, need for ventilation, and need for dialysis. We estimated the causal effect of ACEi/ARB on the composite outcomes using marginal structural models accounting for serial blood pressure and serum creatinine measures. Of 2044 patients in ISIC, 1686 patients met inclusion criteria, of whom 398 (23.6%) patients who were previously on ACEi/ARB received at least 1 dose during their hospitalization for COVID-19. There were 215 deaths, 407 patients requiring mechanical ventilation, and 124 patients who required dialysis during their hospitalization. Prior ACEi/ARB use was associated with lower levels of soluble urokinase plasminogen activator receptor and C-reactive protein. In multivariable analysis, in-hospital ACEi/ARB use was associated with a lower risk of the composite outcome of in-hospital death, mechanical ventilation, or dialysis (adjusted hazard ratio 0.49, 95% CI [0.36– 0.65]). CONCLUSIONS: In patients hospitalized for COVID-19, ACEi/ARB use was associated with lower levels of inflammation and lower risk of in-hospital outcomes. Clinical trials will define the role of ACEi/ARB in the treatment of COVID-19. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

Original language	English (US)
Article number	e023535
Journal	Journal of the American Heart Association
Volume	10
Issue number	24
DOIs	https://doi.org/10.1161/JAHA.121.023535
State	Published - Dec 21 2021

Funding

The authors acknowledge the University of Michigan Medical School Research Data Warehouse and DataDirect for providing data aggregation, management, and distribution services in support of the research reported in this publication. The authors are grateful to the services of the Microbiome Core supported by U2CDK110768, especially Chris Blair; the Michigan Clinical Research Unit including Wrenn Woodard and Dexter Hobdy, and the University of Michigan Medical School Central Biorepository for providing biospecimen storage, management, and distribution services in support of the research reported in the publication. Vasbinder is supported by a National Heart, Lung, and Blood Institute funded postdoctoral fellowship (T32HL007853). Hayek is funded by National Heart, Lung, and Blood Institute 1R01HL153384-01, National Institute of Diabetes and Digestive and Kidney Diseases 1R01DK12801201A1, U01-DK119083-03S1, and the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor (U-M G024231) award. Pop-Busui is supported by NIDDK-1-R01-DK-107956-01, U01 DK119083, the Juvenile Diabetes Research Foundation 5-COE-2019-861-S-B, and by a Pilot and Feasibility Grant from the Michigan Diabetes Research Center (National Institutes of Health Grant P30-DK020572). Tacke is supported through intramural funds from Charité Universitaetsmedizin Berlin and the Berlin Institute of Health. Vasbinder is supported by a National Heart, Lung, and Blood Institute funded postdoctoral fellowship (T32HL007853). The authors acknowledge the University of Michigan Medical School Research Data Warehouse and DataDirect for providing data aggregation, management, and distribution services in support of the research reported in this publication. The authors are grateful to the services of the Microbiome Core supported by U2CDK110768, especially Chris Blair; the Michigan Clinical Research Unit including Wrenn Woodard and Dexter Hobdy, and the University of Michigan Medical School Central Biorepository for providing biospecimen storage, management, and distribution services in support of the research reported in the publication. Eugen-Olsen is a cofounder, shareholder, and chief scientific officer of Virogates. Reiser is cofounder of Trisaq, a biotechnology company developing drugs targeting suPAR. Hayek and Reiser are members of the scientific advisory board of Walden Biosciences. Giamarellos-Bourboulis has received honoraria from Abbott CH, Angelini Italy, InflaRx GmbH, MSD Greece, XBiotech Inc., and B·R·A·H·M·S GmbH (Thermo Fisher Scientific); independent educational grants from AbbVie Inc, Abbott CH, Astellas Pharma Europe, AxisShield, bioMérieux Inc, Novartis, InflaRx GmbH, and XBiotech Inc; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis). The remaining authors have no disclosures to report. Vasbinder is supported by a National Heart, Lung, and Blood Institute funded postdoctoral fellowship (T32HL007853). Hayek is funded by National Heart, Lung, and Blood Institute 1R01HL153384-01, National Institute of Diabetes and Digestive and Kidney Diseases 1R01DK12801201A1, U01-DK119083-03S1, and the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor (U-M G024231) award. Pop-Busui is supported by NIDDK-1-R01-DK-107956-01, U01 DK119083, the Juvenile Diabetes Research Foundation 5-COE-2019-861-S-B, and by a Pilot and Feasibility Grant from the Michigan Diabetes Research Center (National Institutes of Health Grant P30-DK020572). Tacke is supported through intramural funds from Charité Universitaetsmedizin Berlin and the Berlin Institute of Health. Vasbinder is supported by a National Heart, Lung, and Blood Institute funded postdoctoral fellowship (T32HL007853).

Keywords

ACE inhibitors
Angiotensin receptor blockers
COVID-19
Mortality
Outcomes

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/JAHA.121.023535

Cite this

Pan, M., Vasbinder, A., Anderson, E., Catalan, T., Shadid, H. R., Berlin, H., Padalia, K., O’hayer, P., Meloche, C., Azam, T. U., Khaleel, I., Michaud, E., Blakely, P., Bitar, A., Huang, Y., Zhao, L., Pop-Busui, R., Loosen, S. H., Chalkias, A., ... Hayek, S. S. (2021). Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19. Journal of the American Heart Association, 10(24), Article e023535. https://doi.org/10.1161/JAHA.121.023535

@article{50bb87c0f4ca4a2da5ef63db0b8f3877,

title = "Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19",

abstract = "BACKGROUND: Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) is thought to affect COVID-19 through modulating levels of angiotensin-converting enzyme 2, the cell entry receptor for SARS-CoV2. We sought to assess the association between ACEi/ARB, biomarkers of inflammation, and outcomes in patients hospitalized for COVID-19. METHODS AND RESULTS: We leveraged the ISIC (International Study of Inflammation in COVID-19), identified patients admitted for symptomatic COVID-19 between February 1, 2020 and June 1, 2021 for COVID-19, and examined the association between in-hospital ACEi/ARB use and all-cause death, need for ventilation, and need for dialysis. We estimated the causal effect of ACEi/ARB on the composite outcomes using marginal structural models accounting for serial blood pressure and serum creatinine measures. Of 2044 patients in ISIC, 1686 patients met inclusion criteria, of whom 398 (23.6\%) patients who were previously on ACEi/ARB received at least 1 dose during their hospitalization for COVID-19. There were 215 deaths, 407 patients requiring mechanical ventilation, and 124 patients who required dialysis during their hospitalization. Prior ACEi/ARB use was associated with lower levels of soluble urokinase plasminogen activator receptor and C-reactive protein. In multivariable analysis, in-hospital ACEi/ARB use was associated with a lower risk of the composite outcome of in-hospital death, mechanical ventilation, or dialysis (adjusted hazard ratio 0.49, 95\% CI [0.36– 0.65]). CONCLUSIONS: In patients hospitalized for COVID-19, ACEi/ARB use was associated with lower levels of inflammation and lower risk of in-hospital outcomes. Clinical trials will define the role of ACEi/ARB in the treatment of COVID-19. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.",

keywords = "ACE inhibitors, Angiotensin receptor blockers, COVID-19, Mortality, Outcomes",

author = "Michael Pan and Alexi Vasbinder and Elizabeth Anderson and Toniemarie Catalan and Shadid, \{Husam R.\} and Hanna Berlin and Kishan Padalia and Patrick O{\textquoteright}hayer and Chelsea Meloche and Azam, \{Tariq U.\} and Ibrahim Khaleel and Erinleigh Michaud and Pennelope Blakely and Abbas Bitar and Yiyuan Huang and Lili Zhao and Rodica Pop-Busui and Loosen, \{Sven H.\} and Athanasios Chalkias and Frank Tacke and Giamarellos-Bourboulis, \{Evangelos J.\} and Jochen Reiser and Jesper Eugen-Olsen and Hayek, \{Salim S.\}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.",

year = "2021",

month = dec,

day = "21",

doi = "10.1161/JAHA.121.023535",

language = "English (US)",

volume = "10",

journal = "Journal of the American Heart Association",

issn = "2047-9980",

publisher = "American Heart Association Inc.",

number = "24",

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Pan, M, Vasbinder, A, Anderson, E, Catalan, T, Shadid, HR, Berlin, H, Padalia, K, O’hayer, P, Meloche, C, Azam, TU, Khaleel, I, Michaud, E, Blakely, P, Bitar, A, Huang, Y, Zhao, L, Pop-Busui, R, Loosen, SH, Chalkias, A, Tacke, F, Giamarellos-Bourboulis, EJ, Reiser, J, Eugen-Olsen, J & Hayek, SS 2021, 'Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19', Journal of the American Heart Association, vol. 10, no. 24, e023535. https://doi.org/10.1161/JAHA.121.023535

TY - JOUR

T1 - Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19

AU - Pan, Michael

AU - Vasbinder, Alexi

AU - Anderson, Elizabeth

AU - Catalan, Toniemarie

AU - Shadid, Husam R.

AU - Berlin, Hanna

AU - Padalia, Kishan

AU - O’hayer, Patrick

AU - Meloche, Chelsea

AU - Azam, Tariq U.

AU - Khaleel, Ibrahim

AU - Michaud, Erinleigh

AU - Blakely, Pennelope

AU - Bitar, Abbas

AU - Huang, Yiyuan

AU - Zhao, Lili

AU - Pop-Busui, Rodica

AU - Loosen, Sven H.

AU - Chalkias, Athanasios

AU - Tacke, Frank

AU - Giamarellos-Bourboulis, Evangelos J.

AU - Reiser, Jochen

AU - Eugen-Olsen, Jesper

AU - Hayek, Salim S.

PY - 2021/12/21

Y1 - 2021/12/21

N2 - BACKGROUND: Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) is thought to affect COVID-19 through modulating levels of angiotensin-converting enzyme 2, the cell entry receptor for SARS-CoV2. We sought to assess the association between ACEi/ARB, biomarkers of inflammation, and outcomes in patients hospitalized for COVID-19. METHODS AND RESULTS: We leveraged the ISIC (International Study of Inflammation in COVID-19), identified patients admitted for symptomatic COVID-19 between February 1, 2020 and June 1, 2021 for COVID-19, and examined the association between in-hospital ACEi/ARB use and all-cause death, need for ventilation, and need for dialysis. We estimated the causal effect of ACEi/ARB on the composite outcomes using marginal structural models accounting for serial blood pressure and serum creatinine measures. Of 2044 patients in ISIC, 1686 patients met inclusion criteria, of whom 398 (23.6%) patients who were previously on ACEi/ARB received at least 1 dose during their hospitalization for COVID-19. There were 215 deaths, 407 patients requiring mechanical ventilation, and 124 patients who required dialysis during their hospitalization. Prior ACEi/ARB use was associated with lower levels of soluble urokinase plasminogen activator receptor and C-reactive protein. In multivariable analysis, in-hospital ACEi/ARB use was associated with a lower risk of the composite outcome of in-hospital death, mechanical ventilation, or dialysis (adjusted hazard ratio 0.49, 95% CI [0.36– 0.65]). CONCLUSIONS: In patients hospitalized for COVID-19, ACEi/ARB use was associated with lower levels of inflammation and lower risk of in-hospital outcomes. Clinical trials will define the role of ACEi/ARB in the treatment of COVID-19. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

AB - BACKGROUND: Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) is thought to affect COVID-19 through modulating levels of angiotensin-converting enzyme 2, the cell entry receptor for SARS-CoV2. We sought to assess the association between ACEi/ARB, biomarkers of inflammation, and outcomes in patients hospitalized for COVID-19. METHODS AND RESULTS: We leveraged the ISIC (International Study of Inflammation in COVID-19), identified patients admitted for symptomatic COVID-19 between February 1, 2020 and June 1, 2021 for COVID-19, and examined the association between in-hospital ACEi/ARB use and all-cause death, need for ventilation, and need for dialysis. We estimated the causal effect of ACEi/ARB on the composite outcomes using marginal structural models accounting for serial blood pressure and serum creatinine measures. Of 2044 patients in ISIC, 1686 patients met inclusion criteria, of whom 398 (23.6%) patients who were previously on ACEi/ARB received at least 1 dose during their hospitalization for COVID-19. There were 215 deaths, 407 patients requiring mechanical ventilation, and 124 patients who required dialysis during their hospitalization. Prior ACEi/ARB use was associated with lower levels of soluble urokinase plasminogen activator receptor and C-reactive protein. In multivariable analysis, in-hospital ACEi/ARB use was associated with a lower risk of the composite outcome of in-hospital death, mechanical ventilation, or dialysis (adjusted hazard ratio 0.49, 95% CI [0.36– 0.65]). CONCLUSIONS: In patients hospitalized for COVID-19, ACEi/ARB use was associated with lower levels of inflammation and lower risk of in-hospital outcomes. Clinical trials will define the role of ACEi/ARB in the treatment of COVID-19. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

KW - ACE inhibitors

KW - Angiotensin receptor blockers

KW - COVID-19

KW - Mortality

KW - Outcomes

UR - https://www.scopus.com/pages/publications/85122904185

UR - https://www.scopus.com/inward/citedby.url?scp=85122904185&partnerID=8YFLogxK

U2 - 10.1161/JAHA.121.023535

DO - 10.1161/JAHA.121.023535

M3 - Article

C2 - 34889102

AN - SCOPUS:85122904185

SN - 2047-9980

VL - 10

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

IS - 24

M1 - e023535

ER -

Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19

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UN SDGs

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