Supplementary data for “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”

Additional information regarding study design, baseline cohort characteristics, and results of sensitivity analyses

Pharmacoepidemiology for nephrologists: do proton pump inhibitors cause chronic kidney disease?

Pharmacoepidemiology studies are increasingly used for research into safe prescribing in chronic kidney disease (CKD). Typically, patients prescribed a drug are compared with patients who are not on the drug and outcomes are compared to draw conclusions about the drug effects. This review article aims to provide the reader with a framework to critically appraise such research. A key concern in pharmacoepidemiology studies is confounding, in that patients who have worse health status are prescribed more drugs or different agents and their worse outcomes are attributed to the drugs not the health status. It may be challenging to adjust for this using statistical methods unless a comparison group with a similar health status but who are prescribed a different (comparison) drug(s) is identified. Another challenge in pharmacoepidemiology is outcome misclassification, as people who are more ill engage more often with the health service, leading to earlier diagnosis in people who are frequent attenders. Finally, using replication cohorts with the same methodology in the same type of health system does not ensure that findings are more robust. We use two recent papers that investigated the association of proton pump inhibitor drugs with CKD as a device to review the main pitfalls of pharmacoepidemiology studies and how to attempt to mitigate against potential biases that can occur

Chronic kidney disease and cause-specific hospitalisation: a matched cohort study using primary and secondary care patient data.

BACKGROUND: Although chronic kidney disease (CKD) is associated with various outcomes, the burden of each condition for hospital admission is unknown. AIM: To quantify the association between CKD and cause-specific hospitalisation. DESIGN AND SETTING: A matched cohort study in primary care using Clinical Practice Research Datalink linked to Hospital Episode Statistics in England. METHOD: Patients with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 for ≥3 months) and a comparison group of patients without known CKD (matched for age, sex, GP, and calendar time) were identified, 2004-2014. Outcomes were hospitalisations with 10 common conditions as the primary admission diagnosis: heart failure; urinary tract infection; pneumonia; acute kidney injury (AKI); myocardial infarction; cerebral infarction; gastrointestinal bleeding; hip fracture; venous thromboembolism; and intracranial bleeding. A difference in the incidence rate of first hospitalisation for each condition was estimated between matched patients with and without CKD. Multivariable Cox regression was used to estimate a relative risk for each outcome. RESULTS: In a cohort of 242 349 pairs of patients, with and without CKD, the rate difference was largest for heart failure at 6.6/1000 person-years (9.7/1000 versus 3.1/1000 person-years in patients with and without CKD, respectively), followed by urinary tract infection at 5.2, pneumonia at 4.4, and AKI at 4.1/1000 person-years. The relative risk was highest for AKI with a fully adjusted hazard ratio of 4.90, 95% confidence interval (CI) = 4.47 to 5.38, followed by heart failure with 1.66, 95% CI = 1.59 to 1.75. CONCLUSION: Hospitalisations for heart failure, infection, and AKI showed strong associations with CKD in absolute and(or) relative terms, suggesting targets for improved preventive care

Prescription of renin-angiotensin system blockers and risk of acute kidney injury: a population-based cohort study.

OBJECTIVE: To investigate whether there is an association between use of ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) and risk of acute kidney injury (AKI). STUDY DESIGN: We conducted a new-user cohort study of the rate of AKI among users of common antihypertensives. SETTING: UK primary care practices contributing to the Clinical Practice Research Datalink (CPRD) eligible for linkage to hospital records data from the Hospital Episode Statistics (HES) database between April 1997 and March 2014. PARTICIPANTS: New users of antihypertensives: ACEI/ARB, β-blockers, calcium channel blockers and thiazide diuretics. OUTCOMES: The outcome was first episode of AKI. We estimated incidence rate ratio (RR) for AKI during time exposed to ACEI/ARB compared to time unexposed, adjusting for age, sex, comorbidities, use of other antihypertensive drugs and calendar period using Poisson regression. Covariates were time updated. RESULTS: Among 570 445 participants, 303 761 were prescribed ACEI/ARB with a mean follow-up of 4.1 years. The adjusted RR of AKI during time exposed to ACEI/ARB compared to time unexposed was 1.12 (95% CI 1.07 to 1.17). This relative risk varied depending on absolute risk of AKI, with lower or no increased relative risk from the drugs among those at greatest absolute risk. For example, among people with stage 4 chronic kidney disease (who had 6.69 (95% CI 5.57 to 8.03) times higher rate of AKI compared to those without chronic kidney disease), the adjusted RR of AKI during time exposed to ACEI/ARB compared to time unexposed was 0.66 (95% CI 0.44 to 0.97) in contrast to 1.17 (95% CI 1.09 to 1.25) among people without chronic kidney disease. CONCLUSIONS: Treatment with ACEI/ARB is associated with only a small increase in AKI risk while individual patient characteristics are much more strongly associated with the rate of AKI. The degree of increased risk varies between patient groups

A systematic review comparing the evidence for kidney function outcomes between oral antidiabetic drugs for type 2 diabetes.

Background: The development of kidney disease is a serious complication among people with type 2 diabetes mellitus, associated with substantially increased morbidity and mortality.  We aimed to summarise the current evidence for the relationship between treatments for type 2 diabetes and long-term kidney outcomes, by conducting a systematic search and review of relevant studies. Methods: We searched Medline, Embase and Web of Science, between 1st January 1980 and 15th May 2018 for published clinical trials and observational studies comparing two or more classes of oral therapy for type 2 diabetes. We included people receiving oral antidiabetic drugs. Studies were eligible that; (i) compared two or more classes of oral therapy for type 2 diabetes; (ii) reported kidney outcomes as primary or secondary outcomes; (iii) included more than 100 participants; and (iv) followed up participants for 48 weeks or more. Kidney-related outcome measures included were Incidence of chronic kidney disease, reduced eGFR, increased creatinine, 'micro' and 'macro' albuminuria. Results: We identified 15 eligible studies, seven of which were randomised controlled trials and eight were observational studies. Reporting of specific renal outcomes varied widely. Due to variability of comparisons and outcomes meta-analysis was not possible. The majority of comparisons between treatment with metformin or sulfonylurea indicated that metformin was associated with better renal outcomes. Little evidence was available for recently introduced treatments or commonly prescribed combination therapies. Conclusions: Comparative evidence for the effect of treatments for type 2 diabetes on renal outcomes, either as monotherapy or in combination is sparse

Lansoprazole use and tuberculosis incidence in the United Kingdom Clinical Practice Research Datalink: A population based cohort.

BACKGROUND: Recent in vitro and animal studies have found the proton pump inhibitor (PPI) lansoprazole to be highly active against Mycobacterium tuberculosis. Omeprazole and pantoprazole have no activity. There is no evidence that, in clinical practice, lansoprazole can treat or prevent incident tuberculosis (TB) disease. METHODS AND FINDINGS: We studied a cohort of new users of lansoprazole, omeprazole, or pantoprazole from the United Kingdom Clinical Practice Research Datalink to determine whether lansoprazole users have a lower incidence of TB disease than omeprazole or pantoprazole users. Negative control outcomes of myocardial infarction (MI) and herpes zoster were also studied. Multivariable Cox proportional hazards regression was used to adjust for potential confounding by a wide range of factors. We identified 527,364 lansoprazole initiators and 923,500 omeprazole or pantoprazole initiators. Lansoprazole users had a lower rate of TB disease (n = 86; 10.0 cases per 100,000 person years; 95% confidence interval 8.1-12.4) than omeprazole or pantoprazole users (n = 193; 15.3 cases per 100,000 person years; 95% confidence interval 13.3-17.7), with an adjusted hazard ratio (HR) of 0.68 (0.52-0.89). No association was found with MI (adjusted HR 1.04; 95% confidence interval 1.00-1.08) or herpes zoster (adjusted HR 1.03; 95% confidence interval 1.00-1.06). Limitations of this study are that we could not determine whether TB disease was due to reactivation of latent infection or a result of recent transmission, nor could we determine whether lansoprazole would have a beneficial effect if given to people presenting with TB disease. CONCLUSIONS: In this study, use of the commonly prescribed and cheaply available PPI lansoprazole was associated with reduced incidence of TB disease. Given the serious problem of drug resistance and the adverse side effect profiles of many TB drugs, further investigation of lansoprazole as a potential antituberculosis agent is warranted

Prevalence, incidence, indication, and choice of antidepressants in patients with and without chronic kidney disease: a matched cohort study in UK Clinical Practice Research Datalink.

PURPOSE: People with chronic kidney disease (CKD) have an increased prevalence of depression, anxiety, and neuropathic pain. We examined prevalence, incidence, indication for, and choice of antidepressants among patients with and without CKD. METHODS: Using the UK Clinical Practice Research Datalink, we identified patients with CKD (two measurements of estimated glomerular filtration rate < 60 mL/min/1.73m2 for ≥3 months) between April 2004 and March 2014. We compared those with CKD to a general population cohort without CKD (matched on age, sex, general practice, and calendar time [index date]). We identified any antidepressant prescribing in the six months prior to index date (prevalence), the first prescription after index date among non-prevalent users (incidence), and recorded diagnoses (indication). We compared antidepressant choice between patients with and without CKD among patients with a diagnosis of depression. RESULTS: There were 242 349 matched patients (median age 76 [interquartile range 70-82], male 39.3%) with and without CKD. Prevalence of antidepressant prescribing was 16.3 and 11.9%, and incidence was 57.2 and 42.4/1000 person-years, in patients with and without CKD, respectively. After adjusting for confounders, CKD remained associated with higher prevalence and incidence of antidepressant prescription. Regardless of CKD status, selective serotonin reuptake inhibitors were predominantly prescribed for depression or anxiety, while tricyclic antidepressants were prescribed for neuropathic pain or other reasons. Antidepressant choice was similar in depressed patients with and without CKD. CONCLUSIONS: The rate of antidepressant prescribing was nearly one and a half times higher among people with CKD than in the general population. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd

Acute kidney injury and infections in patients taking antihypertensive drugs: a self-controlled case series analysis.

BACKGROUND: The relative risk of acute kidney injury (AKI) following different infections, and whether angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) modify the risk, is unclear. We aimed to determine the risks of hospital admission with AKI following infections (urinary tract infection [UTI], lower respiratory tract infection [LRTI], and gastroenteritis) among users of antihypertensive drugs. METHODS: We used UK electronic health records from practices contributing to the Clinical Practice Research Datalink linked to the Hospital Episode Statistics database. We identified adults initiating ACEIs/ARBs or alternative antihypertensive therapy (β-blockers, calcium channel blockers, or thiazide diuretics) between April 1997 and March 2014 with at least 1 year of primary care registration prior to first prescription, who had a hospital admission for AKI, and who had a primary care record for incident UTI, LRTI, or gastroenteritis. We used a self-controlled case series design to calculate age-adjusted incidence rate ratios (IRRs) for AKI during risk periods following acute infection relative to noninfected periods (baseline). RESULTS: We identified 10,219 eligible new users of ACEIs/ARBs or other antihypertensives with an AKI record. Among these, 2,012 had at least one record for a UTI during follow-up, 2,831 had a record for LRTI, and 651 had a record for gastroenteritis. AKI risk was higher following infection than in baseline noninfectious periods. The rate ratio was highest following gastroenteritis: for the period 1-7 days postinfection, the IRR for AKI following gastroenteritis was 43.4 (95% CI=34.0-55.5), compared with 6.0 following LRTI (95% CI=5.0-7.3), and 9.3 following UTI (95% CI=7.8-11.2). Increased risks were similar for different antihypertensives. CONCLUSION: Acute infections are associated with substantially increased transient AKI risk among antihypertensive users, with the highest risk after gastroenteritis. The increase in relative risk is not greater among users of ACEIs/ARBs compared with users of other antihypertensives