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Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people
  1. Julia Hippisley-Cox1,
  2. Duncan Young2,3,
  3. Carol Coupland4,
  4. Keith M Channon5,
  5. Pui San Tan6,
  6. David A Harrison7,
  7. Kathryn Rowan8,
  8. Paul Aveyard6,
  9. Ian D Pavord9,
  10. Peter J Watkinson5,10
  1. 1Primary Care Health Sciences, University of Oxford, Oxford, UK
  2. 2Adult Intensive Care Unit, John Radcliffe Hospital, Oxford, UK
  3. 3Kadoorie Centre, University of Oxford, Oxford, UK
  4. 4Division of Primary Care, School of Medicine, University of Nottingham, Nottingham, UK
  5. 5Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK
  6. 6Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
  7. 7Clinical Trials Unit, ICNARC, London, UK
  8. 8Intensive Care National Audit and Research Centre ICNARC, London, UK
  9. 9Respiratory Medicine Unit and Oxford Respiratory NIHR BRC Nuffield Department of MedicineNDM Research BuildingOld Road CampusUniversity of Oxford, Oxford, UK
  10. 10Nuffield Department of Clinical Neurosciences, Oxford NIHR BRC, University of Oxford, Oxford, UK
  1. Correspondence to Prof Julia Hippisley-Cox, Primary Care Health Sciences, University of Oxford, Oxford OX1 2JD, UK; Julia.Hippisley-Cox{at}phc.ox.ac.uk

Abstract

Background There is uncertainty about the associations of angiotensive enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) drugs with COVID-19 disease. We studied whether patients prescribed these drugs had altered risks of contracting severe COVID-19 disease and receiving associated intensive care unit (ICU) admission.

Methods This was a prospective cohort study using routinely collected data from 1205 general practices in England with 8.28 million participants aged 20–99 years. We used Cox proportional hazards models to derive adjusted HRs for exposure to ACE inhibitor and ARB drugs adjusted for sociodemographic factors, concurrent medications and geographical region. The primary outcomes were: (a) COVID-19 RT-PCR diagnosed disease and (b) COVID-19 disease resulting in ICU care.

Findings Of 19 486 patients who had COVID-19 disease, 1286 received ICU care. ACE inhibitors were associated with a significantly reduced risk of COVID-19 disease (adjusted HR 0.71, 95% CI 0.67 to 0.74) but no increased risk of ICU care (adjusted HR 0.89, 95% CI 0.75 to 1.06) after adjusting for a wide range of confounders. Adjusted HRs for ARBs were 0.63 (95% CI 0.59 to 0.67) for COVID-19 disease and 1.02 (95% CI 0.83 to 1.25) for ICU care.

There were significant interactions between ethnicity and ACE inhibitors and ARBs for COVID-19 disease. The risk of COVID-19 disease associated with ACE inhibitors was higher in Caribbean (adjusted HR 1.05, 95% CI 0.87 to 1.28) and Black African (adjusted HR 1.31, 95% CI 1.08 to 1.59) groups than the white group (adjusted HR 0.66, 95% CI 0.63 to 0.70). A higher risk of COVID-19 with ARBs was seen for Black African (adjusted HR 1.24, 95% CI 0.99 to 1.58) than the white (adjusted HR 0.56, 95% CI 0.52 to 0.62) group.

Interpretation ACE inhibitors and ARBs are associated with reduced risks of COVID-19 disease after adjusting for a wide range of variables. Neither ACE inhibitors nor ARBs are associated with significantly increased risks of receiving ICU care. Variations between different ethnic groups raise the possibility of ethnic-specific effects of ACE inhibitors/ARBs on COVID-19 disease susceptibility and severity which deserves further study.

  • primary care
  • epidemiology
  • hypertension
  • diabetes
  • cardiac risk factors and prevention
https://creativecommons.org/licenses/by/4.0/

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Footnotes

  • Twitter @juliahcox

  • Contributors JHC contributed to the inception of the study, development of study ideas, study design acquisition and linkage of data, undertook the data analysis, wrote the first draft of the paper. DY and PJW contributed to the inception of the study, development of the study ideas, study design, advised on the interpretation of the results and drafting of the paper. CC contributed to the study design and advised on the analysis, advised on the interpretation of the results and drafting of the paper. PST contributed to the literature review, classification of drugs, interpretation of the results and critically reviewed the paper. KC, PA and IDP critically reviewed the paper. All authors have approved the submitted version. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding This study was supported by funds from the NIHR Oxford Biomedical Research Centre and the Medical Sciences Division of the University of Oxford. QResearch is funded by the John Fell Oxford University Press Research Fund, the Oxford Wellcome Institutional Strategic Support Fund (204826/Z/16/Z), Cancer Research UK (CR-UK) grant number C5255/A18085, through the Cancer Research UK Oxford Centre and the Wellcome Trust (grant number is 221514/Z/20/Z). It also receives contributions in kind from EMIS Health (commercial supplier of NHS health computer systems). KC is supported by the British Heart Foundation (CH/16/1/32013). PA is an NIHR senior investigator and funded by NIHR Oxford Biomedical Research Centre and Applied Research Centre. JH is the guarantor of the study and had full access to all the data in the study and had final responsibility for the decision to submit for publication.

  • Competing interests JHC reports grants from National Institute for Health Research Biomedical Research Centre, Oxford, grants from John Fell Oxford University Press Research Fund, grants from Cancer Research UK (CR-UK) grant number C5255/A18085, through the Cancer Research UK Oxford Centre, grants from the Oxford Wellcome Institutional Strategic Support Fund (204826/Z/16/Z), during the conduct of the study; personal fees and other from ClinRisk Ltd (until 2019) outside the submitted work; and JH is an unpaid director of QResearch, a not-for-profit organisation which is a partnership between the University of Oxford and EMIS Health who supply the QResearch database used for this work. PW reports grants from National Institute for Health Research Biomedical Research Centre, Oxford and the Wellcome Trust (grant number is 221514/Z/20/Z), during the conduct of the study; grants from Sensyne Health, personal fees from Sensyne Health, outside the submitted work. PST reports consulting with AstraZeneca and Duke-NUS outside the submitted work. IDP reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Aerocrine, personal fees from Almirall, personal fees from Novartis, personal fees from GlaxoSmithKline, personal fees from Genentech, personal fees from Regeneron, Teva, Chiesi, Sanofi, Circassia, Knopp, grants from NIHR, outside the submitted work. DY, CC, PA, DAH, KR, KC have nothing to disclose.

  • Patient and public involvement Patients and/or the public were involved in the design, conduct, reporting or dissemination plans of this research. Refer to the 'Methods' section for further details.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data may be obtained from a third party and are not publicly available. To guarantee the confidentiality of personal and health information only the authors have had access to the data during the study in accordance with the relevant licence agreements. Access to the QResearch data is according to the information on the QResearch website (www.qresearch.org). ICNARC data were provided under a licence that does not permit sharing.

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