| Title:
|
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 |
| Abstract:
|
Background: Mice receiving angiotensin converting enzyme inhibitor (ACEI) drugs show increased susceptibility to infection by Staphylococcus aureus ( S. aureus). We sought to investigate whether humans using ACEI were at increased risk of S. aureus infection comparing them to users of Angiotensin II Receptor Blockers (ARB) with multiple control outcomes to assess the potential for residual confounding. Methods: Using the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics between 1997 and 2017 we identified adults starting ACEI or ARB (as an active comparator drug). We regarded prescription of ACEI or ARB as time-dependent exposure and used a Cox regression model to compare incidence of first hospitalisation with infection due to S. aureus in periods with ACEI to periods with ARB prescriptions. We repeated the analysis using control outcomes that we did not expect to be associated with use of ACEI versus ARB (Gram-negative sepsis hip fracture and herpes zoster) and one that we did (dry cough). Results: We identified 445341 new users of ACEI (mean age 64.014.0 male 51.7%) and 41824 new users of ARB (mean age 64.114.0 male 45.5%). The fully adjusted hazard ratio for S. aureus infection (ACEI vs. ARB) was 1.18 (95% CI 1.101.27) consistent across sensitivity analyses. However we also found associations with all control outcomes; rates of Gram-negative sepsis hip fracture and dry cough were also increased during periods of time treated with ACEI compared to ARB while herpes zoster was more common during time treated with ARB. Conclusions: Our results suggest that although ARB users appear an ideal control for analyses of ACEI effects there is residual confounding even after multivariable adjustment. This has implications for observational analyses comparing users of these drug classes in particular the effect of these drugs in relation to COVID-19 infection. |
| Published:
|
2020-04-27 |
| Journal:
|
Wellcome Open Res |
| DOI:
|
10.12688/wellcomeopenres.15873.1 |
| DOI_URL:
|
http://doi.org/10.12688/wellcomeopenres.15873.1 |
| Author Name:
|
Bidulka Patrick |
| Author link:
|
https://covid19-data.nist.gov/pid/rest/local/author/bidulka_patrick |
| Author Name:
|
Iwagami Masao |
| Author link:
|
https://covid19-data.nist.gov/pid/rest/local/author/iwagami_masao |
| Author Name:
|
Mansfield Kathryn E |
| Author link:
|
https://covid19-data.nist.gov/pid/rest/local/author/mansfield_kathryn_e |
| Author Name:
|
Kalogirou Fotini |
| Author link:
|
https://covid19-data.nist.gov/pid/rest/local/author/kalogirou_fotini |
| Author Name:
|
Wong Angel Y S |
| Author link:
|
https://covid19-data.nist.gov/pid/rest/local/author/wong_angel_y_s |
| Author Name:
|
Douglas Ian J |
| Author link:
|
https://covid19-data.nist.gov/pid/rest/local/author/douglas_ian_j |
| Author Name:
|
Smeeth Liam |
| Author link:
|
https://covid19-data.nist.gov/pid/rest/local/author/smeeth_liam |
| Author Name:
|
Summers Charlotte |
| Author link:
|
https://covid19-data.nist.gov/pid/rest/local/author/summers_charlotte |
| Author Name:
|
Tomlinson Laurie A |
| Author link:
|
https://covid19-data.nist.gov/pid/rest/local/author/tomlinson_laurie_a |
| sha:
|
be29c861a881c87b32b3a79d174b70a6e0ed40ee |
| license:
|
cc-by |
| license_url:
|
https://creativecommons.org/licenses/by/4.0/ |
| source_x:
|
Medline; PMC; WHO |
| source_x_url:
|
https://www.medline.com/https://www.ncbi.nlm.nih.gov/pubmed/https://www.who.int/ |
| pubmed_id:
|
32529041 |
| pubmed_id_url:
|
https://www.ncbi.nlm.nih.gov/pubmed/32529041 |
| pmcid:
|
PMC7262569 |
| pmcid_url:
|
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262569 |
| url:
|
https://www.ncbi.nlm.nih.gov/pubmed/32529041/
https://doi.org/10.12688/wellcomeopenres.15873.1 |
| has_full_text:
|
TRUE |
| Keywords Extracted from Text Content:
|
Blood
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Minassian C
Angiotensin-converting
Tonelli M
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UK General Practice Research Database
Kezouh A
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MT
Yin H
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Kleine-Weber H
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Coronavirus Disease 2019
Evans S
Quan H
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271-280.e8
Moon RJ
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Br J Clin
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Yu T
angiotensin converting enzyme inhibitor Background: (ACEI) drugs show
ACE2
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Rassen JA
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ACE
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van der Velde R
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alveolar epithelial cells
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Supplementary Table 2
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https://doi.org/10.21956/wellcomeopenres.17410.r38536 ©
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Cambridge NIHR Biomedical Research Centre
ACEI/ARB
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| Extracted Text Content in Record:
|
First 5000 Characters:Mice receiving angiotensin converting enzyme inhibitor Background: (ACEI) drugs show increased susceptibility to infection by Staphylococcus ( ). We sought to investigate whether humans using ACEI aureus S. aureus were at increased risk of infection, comparing them to users of S. aureus Angiotensin II Receptor Blockers (ARB) with multiple control outcomes to assess the potential for residual confounding.
Using the UK Clinical Practice Research Datalink linked to Methods: Hospital Episode Statistics between 1997 and 2017, we identified adults starting ACEI or ARB (as an active comparator drug). We regarded prescription of ACEI or ARB as time-dependent exposure and used a Cox regression model to compare incidence of first hospitalisation with infection due to in periods with ACEI to periods with ARB prescriptions.
We repeated the analysis using control outcomes that we did not expect to be associated with use of ACEI versus ARB (Gram-negative sepsis, hip fracture and herpes zoster) and one that we did (dry cough).
We identified 445,341 new users of ACEI (mean age 64.0±14.0, Results: male 51.7%) and 41,824 new users of ARB (mean age 64.1±14.0, male 45.5%). The fully adjusted hazard ratio for infection (ACEI vs. S. aureus ARB) was 1.18 (95% CI 1.10-1.27), consistent across sensitivity analyses. However, we also found associations with all control outcomes; rates of Gram-negative sepsis, hip fracture and dry cough were also increased during periods of time treated with ACEI compared to ARB while herpes zoster was more common during time treated with ARB.
Our results suggest that although ARB users appear an ideal Conclusions: control for analyses of ACEI effects, there is residual confounding even after multivariable adjustment. This has implications for observational analyses comparing users of these drug classes, in particular the effect of these drugs in relation to COVID-19 infection. PubMed Abstract | Publisher Full Text 6. Khan Z, Shen XZ, Bernstein EA, et al.: Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils. Blood. 2017; 130(3): 328-39. PubMed Abstract | Publisher Full Text | Free Full Text 7. Dial S, Nessim SJ, Kezouh A, et al.: Antihypertensive agents acting on the reninangiotensin system and the risk of sepsis. Br J Clin Pharmacol. 2014; 78(5): 1151-8. PubMed Abstract | Publisher Full Text | Free Full Text 8. Bhaskaran K, Douglas I, Evans S, et al.: Angiotensin receptor blockers and risk of cancer: cohort study among people receiving antihypertensive drugs in UK General Practice Research Database. BMJ. 2012; 344: e2697. PubMed Abstract | Publisher Full Text | Free Full Text 9. Goh KL, Bhaskaran K, Minassian C, et al.: Angiotensin receptor blockers and risk of dementia: cohort study in UK Clinical Practice Research Datalink. Br J Clin Pharmacol. 2015; 79(2): 337-50. PubMed Abstract | Publisher Full Text | Free Full Text 10. Hicks BM, Filion KB, Yin H, et al.: Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ. 2018; 363: k4209. PubMed Abstract | Publisher Full Text | Free Full Text 11. Hoffmann M, Kleine-Weber H, Schroeder S, et al.: SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181(2): 271-280.e8. PubMed Abstract | Publisher Full Text | Free Full Text 12. Zhou F, Yu T, Du R, et al.: Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395(10229): 1054-62. PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text | Free Full Text 22. James MT, Quan H, Tonelli M, et al.: CKD and risk of hospitalization and death with pneumonia. Am J Kidney Dis. 2009; 54(1): 24-32. PubMed Abstract | Publisher Full Text 23. Schmidt M, Mansfield KE, Bhaskaran K, et al.: Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study. BMJ. 2017; 356: j791. PubMed Abstract | Publisher Full Text | Free Full Text 24. Marra F, Parhar K, Huang B, et al.: Risk Factors for Herpes Zoster Infection: A Meta-Analysis. Open Forum Infect Dis. 2020; 7(1): ofaa005. PubMed Abstract | Publisher Full Text | Free Full Text 25. Curtis EM, van der Velde R, Moon RJ, et al.: Epidemiology of fractures in the United Kingdom 1988-2012: Variation with age, sex, geography, ethnicity and socioeconomic status. Bone. 2016; 87: 19-26. PubMed Abstract | Publisher Full Text | Free Full Text 26. Tacconelli E, De Angelis G, de Waure C, et al.: Rapid screening tests for meticillin-resistant Staphylococcus aureus at hospital admission: systematic review and meta-analysis. Lancet Infect Dis. 2009; 9(9): 546-54. PubMed Abstract | Publisher Full Text 27. Schneeweiss S, Rassen JA, Glynn RJ, et al.: High-dimensional propensity score adjustment in studies of treatment effects using health care claims data. Epidemiology. 2009; 20(4): 512-22 |
| Keywords Extracted from PMC Text:
|
angiotensin II receptor blockers
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angiotensin II receptor
"
counter-regulatory
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487,165
periods.- Supplementary Table 1
S72
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angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers.- Supplementary Table 3
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cardiovascular
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A49.0
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herpes zoster
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people
98,461
Angiotensin converting enzyme inhibitor (ACEI) drugs
ARB"
≥85
patient's
445,341
SARS-CoV-2
oral corticosteroids
National Health Service
diuretics
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body
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neutrophil
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human immunodeficiency virus
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heart
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alcohol
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angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers |
| Extracted PMC Text Content in Record:
|
First 5000 Characters:Angiotensin converting enzyme inhibitor (ACEI) drugs and angiotensin II receptor blockers (ARB) are commonly used drugs for the treatment of hypertension, proteinuric kidney diseases and heart failure
1–
4. The drugs block activation of different parts of the renin-angiotensin system, a hormone system that regulates fluid and electrolyte balance, and blood pressure
5. Despite their similar clinical uses, the separate mechanisms of action of the drug classes means that they may result in different effects on other biological systems. For example, in animal models, angiotensin converting enzyme (ACE) has a role in neutrophil antibacterial defences and this effect is independent of the angiotensin II receptor where ARB drugs act. Treatment of mice with ACEI leads to increased susceptibility to infection with
Staphylococcus aureus (
S. aureus)
6. These findings suggest that humans taking ACEI could be at increased risk of
S. aureus infection compared to users of ARB, but this result has not been examined in clinical studies.
The similar indications for ACEI and ARB mean that they could be ideal comparator groups in observational analyses of drug effects, reducing the potential confounding that can occur when comparing drug classes which are prescribed for different indications. Users of ACEI have been compared to ARB users in a number of important epidemiological studies, some of which have proposed a causal association between ACEI use and adverse outcomes
7–
10. Using anonymised primary health care records, we sought to compare rates of
S. aureus infection between users of ACEI and ARB, including Gram-negative infections as a predefined negative control where we did not expect to see an association based on previous research in animals.
During this analysis, the pandemic of coronavirus disease 2019 (COVID-19) due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began. SARS-CoV-2 uses the ACE2 protein, a counter-regulatory component of the renin-angiotensin system, to enter alveolar epithelial cells in the lungs
11. Early reports suggested that people with hypertension, chronic kidney disease, cardiovascular disease, and diabetes were at higher risk for severe outcomes from COVID-19 than people without these comorbidities
12. It has been proposed that use of drugs affecting the renin-angiotensin system could explain this increased risk via effects on the ACE2 enzyme
13. However, evidence for a possible benefit from these drugs is sufficiently strong that a clinical trial has been initiated using an ARB, Losartan, as a treatment for COVID-19
14.
Given the intense interest in this topic, it is likely that analyses of COVID-19 outcomes in relation to use of ACEI and ARB will be repeatedly investigated. We have previously discussed the epidemiological difficulty of comparing users of these drugs to non-users
15. Given the interest in potential differential effects of ACEI and ARB use in relation to COVID-19, we sought to investigate the possibility of residual confounding between users of these drug classes using a large, high-quality data source where multiple sensitivity analyses can be undertaken. Therefore, in addition to our original research question, we undertook analyses of further outcomes to explore the potential limitations of analyses between these two drug classes to inform future work regarding COVID-19.
The Clinical Practice Research Datalink (CPRD) is an observational data and interventional research service provided by the National Health Service (NHS). Nearly 700 general practices have contributed data meeting quality control standards to CPRD, representing nearly 7% of the UK population
16. The database includes the following data: patient demographics; coded diagnoses (Read codes); prescriptions; laboratory test results; and referrals recorded by general practitioners (GPs). In addition, the CPRD is linked to inpatient Hospital Episode Statistics (HES) in around 400 general practices, accounting for 75% of general practices in CPRD in England. HES contains details of all admissions to NHS hospitals in England since 1997
17, and consists of primary and subsidiary diagnoses recorded during admission using the 10th revision of International Classification of Disease (ICD-10) codes
18. This study was approved by the LSHTM Research Ethics Committee (reference 6536) and the Independent Scientific Advisory Committee, which oversees research involving CPRD data (Protocol 18_021R). Informed consent was not required because data are anonymised for research purposes.
We identified new users of ACEI or ARB (i.e. those without any previous prescriptions in the database), aged ≥18 years and registered in HES-linked CPRD for ≥1 year, between April 1997 and March 2017. We excluded people starting ACEI and ARB on the same day. Once individuals were included into the study cohort, they were followed up until the first incidence of an outcome or the end of CPRD eligibility, including death, cha |
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