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 445,341 new users of ACEI (mean age 64.0±14.0, 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 S. aureus infection (ACEI vs. 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. 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.
Highlights
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[1,2,3,4]
These findings suggest that humans taking angiotensin converting enzyme inhibitor (ACEI) could be at increased risk of S. aureus infection compared to users of Angiotensin II Receptor Blockers (ARB), but this result has not been examined in clinical studies
Our study demonstrated that rates of S. aureus infection are higher among users of ACEI than users of ARBs, consistent with the hypothesis from animal models we sought to examine[6]
Summary
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[1,2,3,4]. 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. 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. We found associations with all control outcomes; rates of Gram-negative sepsis, hip fracture and dry cough were increased during periods of time treated with ACEI compared to ARB while herpes zoster was more common during time treated with ARB
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