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[Preprint]. 2020 Jun 12:2020.06.11.20125849.

doi: 10.1101/2020.06.11.20125849.

Renin-angiotensin system blockers and susceptibility to COVID-19: a multinational open science cohort study

Daniel R Morales¹, Mitchell M Conover², Seng Chan You³, Nicole Pratt⁴, Kristin Kostka⁵, Talita Duarte-Salles⁶, Sergio Fernández-Bertolín⁶, Maria Aragón⁶, Scott L DuVall^{7

8}, Kristine Lynch^{7

8}, Thomas Falconer⁹, Kees van Bochove¹⁰, Cynthia Sung¹¹, Michael E Matheny^{12

13}, Christophe G Lambert¹⁴, Fredrik Nyberg¹⁵, Thamir M Alshammari¹⁶, Andrew E Williams¹⁷, Rae Woong Park³, James Weaver², Anthony G Sena^{2

18}, Martijn J Schuemie², Peter R Rijnbeek¹⁸, Ross D Williams¹⁸, Jennifer C E Lane¹⁹, Albert Prats-Uribe¹⁹, Lin Zhang^{20

21}, Carlos Areia²², Harlan M Krumholz²³, Daniel Prieto-Alhambra¹⁹, Patrick B Ryan^{2

9}, George Hripcsak⁹, Marc A Suchard^{24

25}

Affiliations

¹ Division of Population Health and Genomics, University of Dundee, UK.
² Observational Health Data Analytics, Janssen Research and Development, Titusville, NJ, USA.
³ Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea.
⁴ Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
⁵ Real World Solutions, IQVIA, Cambridge, MA, USA.
⁶ Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.
⁷ Department of Veterans Affairs, Salt Lake City, UT, USA.
⁸ University of Utah School of Medicine, Salt Lake City, UT, USA.
⁹ Department of Biomedical Informatics, Columbia University, New York, USA.
¹⁰ The Hyve, Utrecht, Netherlands.
¹¹ Translational Discovery, Bill & Melinda Gates Medical Research Institute, Seattle, WA, USA.
¹² Geriatric Research Education, and Clinical Care Center, Tennessee Valley Healthcare System VA, Nashville, TN.
¹³ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁴ Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
¹⁵ School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁶ Medication Safety Research Chair, King Saud University, Riyadh, Saudi Arabia.
¹⁷ Tufts Medical Center, Tufts University, Boston, MA, USA.
¹⁸ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands.
¹⁹ Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK.
²⁰ School of Public Health, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
²¹ Melbourne School of Public Health, The University of Melbourne, Victoria, Australia.
²² Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
²³ Section of Cardiovascular Medicine, Department of Medicine, Yale University, New Haven, CT, USA.
²⁴ Department of Biostatistics, UCLA Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.
²⁵ Department of Computational Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 32587982
PMCID: PMC7310640
DOI: 10.1101/2020.06.11.20125849

Renin-angiotensin system blockers and susceptibility to COVID-19: a multinational open science cohort study

Daniel R Morales et al. medRxiv. 2020.

[Preprint]. 2020 Jun 12:2020.06.11.20125849.

doi: 10.1101/2020.06.11.20125849.

Authors

Affiliations

¹ Division of Population Health and Genomics, University of Dundee, UK.
² Observational Health Data Analytics, Janssen Research and Development, Titusville, NJ, USA.
³ Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea.
⁴ Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
⁵ Real World Solutions, IQVIA, Cambridge, MA, USA.
⁶ Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.
⁷ Department of Veterans Affairs, Salt Lake City, UT, USA.
⁸ University of Utah School of Medicine, Salt Lake City, UT, USA.
⁹ Department of Biomedical Informatics, Columbia University, New York, USA.
¹⁰ The Hyve, Utrecht, Netherlands.
¹¹ Translational Discovery, Bill & Melinda Gates Medical Research Institute, Seattle, WA, USA.
¹² Geriatric Research Education, and Clinical Care Center, Tennessee Valley Healthcare System VA, Nashville, TN.
¹³ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁴ Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
¹⁵ School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁶ Medication Safety Research Chair, King Saud University, Riyadh, Saudi Arabia.
¹⁷ Tufts Medical Center, Tufts University, Boston, MA, USA.
¹⁸ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands.
¹⁹ Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK.
²⁰ School of Public Health, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
²¹ Melbourne School of Public Health, The University of Melbourne, Victoria, Australia.
²² Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
²³ Section of Cardiovascular Medicine, Department of Medicine, Yale University, New Haven, CT, USA.
²⁴ Department of Biostatistics, UCLA Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.
²⁵ Department of Computational Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 32587982
PMCID: PMC7310640
DOI: 10.1101/2020.06.11.20125849

Update in

Renin-angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis.
Morales DR, Conover MM, You SC, Pratt N, Kostka K, Duarte-Salles T, Fernández-Bertolín S, Aragón M, DuVall SL, Lynch K, Falconer T, van Bochove K, Sung C, Matheny ME, Lambert CG, Nyberg F, Alshammari TM, Williams AE, Park RW, Weaver J, Sena AG, Schuemie MJ, Rijnbeek PR, Williams RD, Lane JCE, Prats-Uribe A, Zhang L, Areia C, Krumholz HM, Prieto-Alhambra D, Ryan PB, Hripcsak G, Suchard MA. Morales DR, et al. Lancet Digit Health. 2021 Feb;3(2):e98-e114. doi: 10.1016/S2589-7500(20)30289-2. Epub 2020 Dec 17. Lancet Digit Health. 2021. PMID: 33342753 Free PMC article.

Abstract

Introduction: Angiotensin converting enzyme inhibitors (ACEs) and angiotensin receptor blockers (ARBs) could influence infection risk of coronavirus disease (COVID-19). Observational studies to date lack pre-specification, transparency, rigorous ascertainment adjustment and international generalizability, with contradictory results.

Methods: Using electronic health records from Spain (SIDIAP) and the United States (Columbia University Irving Medical Center and Department of Veterans Affairs), we conducted a systematic cohort study with prevalent ACE, ARB, calcium channel blocker (CCB) and thiazide diuretic (THZ) use to determine relative risk of COVID-19 diagnosis and related hospitalization outcomes. The study addressed confounding through large-scale propensity score adjustment and negative control experiments.

Results: Following over 1.1 million antihypertensive users identified between November 2019 and January 2020, we observed no significant difference in relative COVID-19 diagnosis risk comparing ACE/ARB vs CCB/THZ monotherapy (hazard ratio: 0.98; 95% CI 0.84 - 1.14), nor any difference for mono/combination use (1.01; 0.90 - 1.15). ACE alone and ARB alone similarly showed no relative risk difference when compared to CCB/THZ monotherapy or mono/combination use. Directly comparing ACE vs. ARB demonstrated a moderately lower risk with ACE, non-significant for monotherapy (0.85; 0.69 - 1.05) and marginally significant for mono/combination users (0.88; 0.79 - 0.99). We observed, however, no significant difference between drug- classes for COVID-19 hospitalization or pneumonia risk across all comparisons.

Conclusion: There is no clinically significant increased risk of COVID-19 diagnosis or hospitalization with ACE or ARB use. Users should not discontinue or change their treatment to avoid COVID-19.

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Figures

**Figure 1.**
International Covid-ACE Receptor Inhibition Utilization and Safety (ICARIUS) susceptibility study design schematic. We highlight eligibility criteria, exposure definitions, adjustment strategies, index date specification (horizontal black arrow) and outcome definitions and time-at-risk. Exposure involves prescriptions to drugs with RxNorm ingredients that map to the first-line antihypertensive angiotensin converting enzyme inhibitor (ACE), angiotensin receptor blocker (ARB), dihydropyridine calcium channel blockers (CCB) and thiazide or thiazide-like diuretic (THZ) classes.

**Figure 2.**
Cohort balance diagnostics comparing ACE/ARB and CCB/THZ monotherapy prevalent-use for the risk COVID-19 diagnosis. We plotted the absolute standardized difference of population proportions of all available patient characteristics (6,571 in SIDIAP, 11,183 in VA-OMOP, and 18,291 in CUIMC) before and after propensity score stratification or matching across data sources. Using stratification, CUIMC fails study diagnostics for this comparison as the absolute standardized difference is not consistently <0.1.

**Figure 3.**
Relative risk of COVID-19-related outcomes for ACE inhibitor, ARB, CCB and THZ prevalent-use across data sources. Outcomes are COVID-19 diagnosis, COVID-19 hospitalization (+Hospital), patients hospitalized with pneumonia (PNA) and patients hospitalized with pneumonia, acute respiratory distress syndrome, acute kidney injury or sepsis (PAAS). We plot calibrated hazard ratios (circles) and their 95% confidence intervals labeled by propensity score (PS) adjustment method (black/white). Grayed out entries do not pass study diagnostics.

See this image and copyright information in PMC

Comment in

Renin-angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis.
Morales DR, Conover MM, You SC, Pratt N, Kostka K, Duarte-Salles T, Fernández-Bertolín S, Aragón M, DuVall SL, Lynch K, Falconer T, van Bochove K, Sung C, Matheny ME, Lambert CG, Nyberg F, Alshammari TM, Williams AE, Park RW, Weaver J, Sena AG, Schuemie MJ, Rijnbeek PR, Williams RD, Lane JCE, Prats-Uribe A, Zhang L, Areia C, Krumholz HM, Prieto-Alhambra D, Ryan PB, Hripcsak G, Suchard MA. Morales DR, et al. Lancet Digit Health. 2021 Feb;3(2):e98-e114. doi: 10.1016/S2589-7500(20)30289-2. Epub 2020 Dec 17. Lancet Digit Health. 2021. PMID: 33342753 Free PMC article.
Renin-angiotensin system inhibitors and COVID-19: overwhelming evidence against an association.
de Abajo FJ. de Abajo FJ. Lancet Digit Health. 2021 Feb;3(2):e70-e71. doi: 10.1016/S2589-7500(20)30294-6. Epub 2020 Dec 17. Lancet Digit Health. 2021. PMID: 33342754 Free PMC article. No abstract available.

References

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1. Austin Peter C. 2009. “Using the Standardized Difference to Compare the Prevalence of a Binary Variable Between Two Groups in Observational Research.” Communications in Statistics - Simulation and Computation. 10.1080/03610910902859574 - DOI
1. Bauer Axel, and Massberg Steffen. n.d. “Stopping ACE-Inhibitors in COVID-19.” Accessed June 2, 2020 https://clinicaltrials.gov/ct2/show/NCT04353596.
1. Bidulka Patrick, Iwagami Masao, Mansfield Kathryn E., Kalogirou Fotini, Wong Angel Y. S., Douglas Ian J., Smeeth Liam, Summers Charlotte, and Tomlinson Laurie A. 2020. “Comparisons of Staphylococcus Aureus Infection and Other Outcomes between Users of Angiotensin-Converting-Enzyme Inhibitors and Angiotensin II Receptor Blockers: Lessons for COVID-19 from a Nationwide Cohort Study.” Wellcome Open Research 5 (77): 77. - PMC - PubMed
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This is a preprint.

Renin-angiotensin system blockers and susceptibility to COVID-19: a multinational open science cohort study

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Renin-angiotensin system blockers and susceptibility to COVID-19: a multinational open science cohort study

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