Healthcare utilisation in people with long COVID: an OpenSAFELY cohort study.

BACKGROUND: Long COVID potentially increases healthcare utilisation and costs. However, its impact on the NHS remains to be determined. METHODS: This study aims to assess the healthcare utilisation of individuals with long COVID. With the approval of NHS England, we conducted a matched cohort study using primary and secondary care data via OpenSAFELY, a platform for analysing anonymous electronic health records. The long COVID exposure group, defined by diagnostic codes, was matched with five comparators without long COVID between Nov 2020 and Jan 2023. We compared their total healthcare utilisation from GP consultations, prescriptions, hospital admissions, A&E visits, and outpatient appointments. Healthcare utilisation and costs were evaluated using a two-part model adjusting for covariates. Using a difference-in-difference model, we also compared healthcare utilisation after long COVID with pre-pandemic records. RESULTS: We identified 52,988 individuals with a long COVID diagnosis, matched to 264,867 comparators without a diagnosis. In the 12 months post-diagnosis, there was strong evidence that those with long COVID were more likely to use healthcare resources (OR: 8.29, 95% CI: 7.74-8.87), and have 49% more healthcare utilisation (RR: 1.49, 95% CI: 1.48-1.51). Our model estimated that the long COVID group had 30 healthcare visits per year (predicted mean: 29.23, 95% CI: 28.58-29.92), compared to 16 in the comparator group (predicted mean visits: 16.04, 95% CI: 15.73-16.36). Individuals with long COVID were more likely to have non-zero healthcare expenditures (OR = 7.66, 95% CI = 7.20-8.15), with costs being 44% higher than the comparator group (cost ratio = 1.44, 95% CI: 1.39-1.50). The long COVID group costs approximately £2500 per person per year (predicted mean cost: £2562.50, 95% CI: £2335.60-£2819.22), and the comparator group costs £1500 (predicted mean cost: £1527.43, 95% CI: £1404.33-1664.45). Historically, individuals with long COVID utilised healthcare resources more frequently, but their average healthcare utilisation increased more after being diagnosed with long COVID, compared to the comparator group. CONCLUSIONS: Long COVID increases healthcare utilisation and costs. Public health policies should allocate more resources towards preventing, treating, and supporting individuals with long COVID.

Consistency, completeness and external validity of ethnicity recording in NHS primary care records: a cohort study in 25 million patients' records at source using OpenSAFELY.

BACKGROUND: Ethnicity is known to be an important correlate of health outcomes, particularly during the COVID-19 pandemic, where some ethnic groups were shown to be at higher risk of infection and adverse outcomes. The recording of patients' ethnic groups in primary care can support research and efforts to achieve equity in service provision and outcomes; however, the coding of ethnicity is known to present complex challenges. We therefore set out to describe ethnicity coding in detail with a view to supporting the use of this data in a wide range of settings, as part of wider efforts to robustly describe and define methods of using administrative data. METHODS: We describe the completeness and consistency of primary care ethnicity recording in the OpenSAFELY-TPP database, containing linked primary care and hospital records in > 25 million patients in England. We also compared the ethnic breakdown in OpenSAFELY-TPP with that of the 2021 UK census. RESULTS: 78.2% of patients registered in OpenSAFELY-TPP on 1 January 2022 had their ethnicity recorded in primary care records, rising to 92.5% when supplemented with hospital data. The completeness of ethnicity recording was higher for women than for men. The rate of primary care ethnicity recording ranged from 77% in the South East of England to 82.2% in the West Midlands. Ethnicity recording rates were higher in patients with chronic or other serious health conditions. For each of the five broad ethnicity groups, primary care recorded ethnicity was within 2.9 percentage points of the population rate as recorded in the 2021 Census for England as a whole. For patients with multiple ethnicity records, 98.7% of the latest recorded ethnicities matched the most frequently coded ethnicity. Patients whose latest recorded ethnicity was categorised as Other were most likely to have a discordant ethnicity recording (32.2%). CONCLUSIONS: Primary care ethnicity data in OpenSAFELY is present for over three quarters of all patients, and combined with data from other sources can achieve a high level of completeness. The overall distribution of ethnicities across all English OpenSAFELY-TPP practices was similar to the 2021 Census, with some regional variation. This report identifies the best available codelist for use in OpenSAFELY and similar electronic health record data.

OpenSAFELY: A platform for analysing electronic health records designed for reproducible research.

Electronic health records (EHRs) and other administrative health data are increasingly used in research to generate evidence on the effectiveness, safety, and utilisation of medical products and services, and to inform public health guidance and policy. Reproducibility is a fundamental step for research credibility and promotes trust in evidence generated from EHRs. At present, ensuring research using EHRs is reproducible can be challenging for researchers. Research software platforms can provide technical solutions to enhance the reproducibility of research conducted using EHRs. In response to the COVID-19 pandemic, we developed the secure, transparent, analytic open-source software platform OpenSAFELY designed with reproducible research in mind. OpenSAFELY mitigates common barriers to reproducible research by: standardising key workflows around data preparation; removing barriers to code-sharing in secure analysis environments; enforcing public sharing of programming code and codelists; ensuring the same computational environment is used everywhere; integrating new and existing tools that encourage and enable the use of reproducible working practices; and providing an audit trail for all code that is run against the real data to increase transparency. This paper describes OpenSAFELY's reproducibility-by-design approach in detail.

The risk of acute kidney injury in colorectal cancer survivors: an english population-based matched cohort study.

BACKGROUND: Colorectal cancer survival has improved in recent decades but there are concerns that survivors may develop kidney problems due to adverse effects of cancer treatment or complications of the cancer itself. We quantified the risk of acute kidney injury (AKI) in colorectal cancer survivors compared to people with no prior cancer. METHODS: Retrospective matched cohort study using electronic health record primary care data from the Clinical Practice Research Datalink GOLD linked to hospital data in England (HES-APC). Individuals with colorectal cancer between 1997-2018 were individually matched on age, sex, and GP practice to people with no prior cancer. We used Cox models to estimate hazard ratios for an incident hospital diagnosis of AKI in colorectal cancer survivors compared to individuals without cancer, overall and stratified by time since diagnosis adjusted for other individual-level factors (adj-HR). RESULTS: Twenty thousand three hundred forty colorectal cancer survivors were matched to 100,058 cancer-free individuals. Colorectal cancer survivors were at increased risk of developing AKI compared to people without cancer (adj-HR = 2.16; 95%CI 2.05-2.27). The HR was highest in the year after diagnosis (adj-HR 7.47, 6.66-8.37), and attenuated over time, but there was still increased AKI risk > 5 years after diagnosis (adj-HR = 1.26, 1.17-1.37). The association between colorectal cancer and AKI was greater for younger people, men, and those with pre-existing chronic kidney disease. CONCLUSIONS: Colorectal cancer survivors were at increased risk of AKI for several years after cancer diagnosis, suggesting a need to prioritise monitoring, prevention, and management of kidney problems in this group of cancer survivors.

Utilization and clinical outcomes of kidney transplants from deceased donors with albuminuria in the UK: a national cohort study.

BACKGROUND: Urinalysis is a standard component of potential deceased kidney donor assessment in the UK. The value of albuminuria as a biomarker for organ quality is uncertain. We examined the relationship between deceased donor albuminuria and kidney utilization, survival and function. METHODS: We performed a national cohort study on adult deceased donors and kidney transplant recipients between 2016 and 2020, using data from the UK Transplant Registry. We examined the influence of donor albuminuria, defined as ≥2+ on dipstick testing, on kidney utilization, early graft function, graft failure and estimated glomerular filtration rate (eGFR). RESULTS: Eighteen percent (1681/9309) of consented donors had albuminuria. After adjustment for confounders, kidneys from donors with albuminuria were less likely to be accepted for transplantation (74% versus 82%; odds ratio 0.70, 95% confidence interval 0.61 to 0.81). Of 9834 kidney transplants included in our study, 1550 (16%) came from donors with albuminuria. After a median follow-up of 2 years, 8% (118/1550) and 9% (706/8284) of transplants from donors with and without albuminuria failed, respectively. There was no association between donor albuminuria and graft failure (hazard ratio 0.91, 95% confidence interval 0.74 to 1.11). There was also no association with delayed graft function, patient survival or eGFR at 1 or 3 years. CONCLUSIONS: Our study suggests reluctance in the UK to utilize kidneys from deceased donors with dipstick albuminuria but no evidence of an association with graft survival or function. This may represent a potential to expand organ utilization without negatively impacting transplant outcomes.

Stopping Renin-Angiotensin System Inhibitors in Patients with Advanced CKD and Risk of Adverse Outcomes: A Nationwide Study.

BACKGROUND: It is unknown whether stopping renin-angiotensin system (RAS) inhibitor therapy in patients with advanced CKD affects outcomes. METHODS: We studied patients referred to nephrologist care, listed on the Swedish Renal Registry during 2007-2017, who developed advanced CKD (eGFR<30 ml/min per 1.73 m2) while on RAS inhibitor therapy. Using target trial emulation techniques on the basis of cloning, censoring, and weighting, we compared the risks of stopping within 6 months and remaining off treatment versus continuing RAS inhibitor therapy. These included risks of subsequent 5-year all-cause mortality, major adverse cardiovascular events, and initiation of kidney replacement therapy (KRT). RESULTS: Of 10,254 prevalent RAS inhibitor users (median age 72 years, 36% female) with new-onset eGFR <30 ml/min per 1.73 m2, 1553 (15%) stopped RAS inhibitor therapy within 6 months. Median eGFR was 23 ml/min per 1.73 m2. Compared with continuing RAS inhibition, stopping this therapy was associated with a higher absolute 5-year risk of death (40.9% versus 54.5%) and major adverse cardiovascular events (47.6% versus 59.5%), but with a lower risk of KRT (36.1% versus 27.9%); these corresponded to absolute risk differences of 13.6 events per 100 patients, 11.9 events per 100 patients, and -8.3 events per 100 patients, respectively. Results were consistent whether patients stopped RAS inhibition at higher or lower eGFR, across prespecified subgroups, after adjustment and stratification for albuminuria and potassium, and when modeling RAS inhibition as a time-dependent exposure using a marginal structural model. CONCLUSIONS: In this nationwide observational study of people with advanced CKD, stopping RAS inhibition was associated with higher absolute risks of mortality and major adverse cardiovascular events, but also with a lower absolute risk of initiating KRT.

Prediction of individuals at high risk of chronic kidney disease during treatment with lithium for bipolar disorder.

BACKGROUND: Lithium is the most effective treatment in bipolar disorder. Its use is limited by concerns about risk of chronic kidney disease (CKD). We aimed to develop a model to predict risk of CKD following lithium treatment initiation, by identifying individuals with a high-risk trajectory of kidney function. METHODS: We used United Kingdom Clinical Practice Research Datalink (CPRD) electronic health records (EHRs) from 2000 to 2018. CPRD Aurum for prediction model development and CPRD Gold for external validation. We used elastic net regularised regression to generate a prediction model from potential features. We performed discrimination and calibration assessments in an external validation data set. We included all patients aged ≥ 16 with bipolar disorder prescribed lithium. To be included patients had to have ≥ 1 year of follow-up before lithium initiation, ≥ 3 estimated glomerular filtration rate (eGFR) measures after lithium initiation (to be able to determine a trajectory) and a normal (≥ 60 mL/min/1.73 m2) eGFR at lithium initiation (baseline). In the Aurum development cohort, 1609 fulfilled these criteria. The Gold external validation cohort included 934 patients. We included 44 potential baseline features in the prediction model, including sociodemographic, mental and physical health and drug treatment characteristics. We compared a full model with the 3-variable 5-year kidney failure risk equation (KFRE) and a 3-variable elastic net model. We used group-based trajectory modelling to identify latent trajectory groups for eGFR. We were interested in the group with deteriorating kidney function (the high-risk group). RESULTS: The high risk of deteriorating eGFR group included 191 (11.87%) of the Aurum cohort and 137 (14.67%) of the Gold cohort. Of these, 168 (87.96%) and 117 (85.40%) respectively developed CKD 3a or more severe during follow-up. The model, developed in Aurum, had a ROC area of 0.879 (95%CI 0.853-0.904) in the Gold external validation data set. At the empirical optimal cut-point defined in the development dataset, the model had a sensitivity of 0.91 (95%CI 0.84-0.97) and a specificity of 0.74 (95% CI 0.67-0.82). However, a 3-variable elastic net model (including only age, sex and baseline eGFR) performed similarly well (ROC area 0.888; 95%CI 0.864-0.912), as did the KFRE (ROC area 0.870; 95%CI 0.841-0.898). CONCLUSIONS: Individuals at high risk of a poor eGFR trajectory can be identified before initiation of lithium treatment by a simple equation including age, sex and baseline eGFR. Risk was increased in individuals who were younger at commencement of lithium, female and had a lower baseline eGFR. We did not identify strong predicters of eGFR decline specific to lithium-treated patients. Notably, lithium duration and toxicity were not associated with high-risk trajectory.

The effect of initiation of renin-angiotensin system inhibitors on haemoglobin: A national cohort study.

AIMS: To determine whether initiation of treatment with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARBs) is associated with a subsequent reduction in haemoglobin in the general population. METHODS: We undertook a national cohort study over a 13-year period (2004-2016), using routine primary healthcare data from the UK Clinical Practice Research Datalink. We compared ACEI/ARB initiation with calcium channel blocker (CCB) initiation, to minimise confounding by indication. We included all first ACEI/ARB or CCB prescriptions in adults with at least 1 haemoglobin result in the 12 months before and 6 months after drug initiation. Our primary outcome was a ≥1 g/dL haemoglobin reduction in the 6 months after drug initiation. RESULTS: We examined 146 610 drug initiation events in 136 655 patients. Haemoglobin fell by ≥1 g/dL after drug initiation in 19.5% (16 936/86 652) of ACEI/ARB initiators and 15.9% (9521/59 958) of CCB initiators. The adjusted odds ratio of a ≥1 g/dL haemoglobin reduction in ACEI/ARB initiators vs CCB initiators was 1.15 (95% confidence interval 1.12-1.19). CONCLUSION: ACEI/ARBs are associated with a modest increase in the risk of a haemoglobin reduction. For every 100 patients in our study that initiated a CCB, 16 experienced a ≥1 g/dL haemoglobin decline. If the effect is causal, 3 additional patients would have experienced this outcome if they had received an ACEI/ARB. This may have implications for drug choice and monitoring for many patients in primary care. Further research could identify patients at higher risk of this outcome, who may benefit from closer monitoring.

Proton pump inhibitors and risk of all-cause and cause-specific mortality: A cohort study.

AIM: To investigate the association between proton pump inhibitors (PPIs) and both all-cause and cause-specific mortality. METHODS: We conducted a cohort study using the UK Clinical Practice Research Datalink GOLD database. We compared 733 885 new users of PPIs to 124 410 new users of H2 receptor antagonists (H2Ras). In a secondary analysis we compared 689 602 PPI new users to 1 361 245 nonusers of acid suppression therapy matched on age, sex and calendar year. Hazard ratios for all-cause and cause-specific mortality were estimated using propensity score (PS) weighted Cox models. RESULTS: PPI prescription was associated with increased risk of all-cause mortality, with hazard ratios decreasing considerably by increasing adjustment (unadjusted hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.62-1.69; PS-weighted HR 1.38, 95% CI 1.33-1.44; high-dimensional PS-weighted HR 1.31, 95% CI 1.26-1.37). Short-term associations were observed with mortality from causes where a causal short-term association is unexpected (eg, lung cancer mortality: PS-weighted HR at 6 months 1.77, 95% CI 1.39-2.25). Adjusted hazard ratios were substantially higher when compared to nonusers (PS-weighted HR all-cause mortality 1.96, 95% CI 1.94-1.99) rather than H2RA users. CONCLUSIONS: PPI prescription was strongly associated with all-cause and cause-specific mortality. However, the change in hazard ratios (a) by increasing adjustment and (b) between comparator groups indicates that residual confounding is likely to explain the association between poor health outcomes and PPI use, and fully accounting for this using observational data may not be possible.

Donor-Transmitted Cancer in Orthotopic Solid Organ Transplant Recipients: A Systematic Review.

Donor-transmitted cancer (DTC) has major implications for the affected patient as well as other recipients of organs from the same donor. Unlike heterotopic transplant recipients, there may be limited treatment options for orthotopic transplant recipients with DTC. We systematically reviewed the evidence on DTC in orthotopic solid organ transplant recipients (SOTRs). We searched MEDLINE, EMBASE, PubMed, Scopus, and Web of Science in January 2020. We included cases where the outcome was reported and excluded donor-derived cancers. We assessed study quality using published checklists. Our domains of interest were presentation, time to diagnosis, cancer extent, management, and survival. There were 73 DTC cases in liver (n = 51), heart (n = 10), lung (n = 10) and multi-organ (n = 2) recipients from 58 publications. Study quality was variable. Median time to diagnosis was 8 months; 42% were widespread at diagnosis. Of 13 cases that underwent re-transplantation, three tumours recurred. Mortality was 75%; median survival 7 months. Survival was worst in transmitted melanoma and central nervous system tumours. The prognosis of DTC in orthotopic SOTRs is poor. Although re-transplantation offers the best chance of cure, some tumours still recur. Publication bias and clinical heterogeneity limit the available evidence. From our findings, we suggest refinements to clinical practice. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020165001, Prospero Registration Number: CRD42020165001.

Stopping renin-angiotensin system blockers after acute kidney injury and risk of adverse outcomes: parallel population-based cohort studies in English and Swedish routine care.

BACKGROUND: The safety of restarting angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) after acute kidney injury (AKI) is unclear. There is concern that previous users do not restart ACEI/ARB despite ongoing indications. We sought to determine the risk of adverse events after an episode of AKI, comparing prior ACEI/ARB users who stop treatment to those who continue. METHODS: We conducted two parallel cohort studies in English and Swedish primary and secondary care, 2006-2016. We used multivariable Cox regression to estimate hazard ratios (HR) for hospital admission with heart failure (primary analysis), AKI, stroke, or death within 2 years after hospital discharge following a first AKI episode. We compared risks of admission between people who stopped ACEI/ARB treatment to those who were prescribed ACEI/ARB within 30 days of AKI discharge. We undertook sensitivity analyses, including propensity score-matched samples, to explore the robustness of our results. RESULTS: In England, we included 7303 people with AKI hospitalisation following recent ACEI/ARB therapy for the primary analysis. Four thousand three (55%) were classified as stopping ACEI/ARB based on no prescription within 30 days of discharge. In Sweden, we included 1790 people, of whom 1235 (69%) stopped treatment. In England, no differences were seen in subsequent risk of heart failure (HR 1.10; 95% confidence intervals (CI) 0.93-1.30), AKI (HR 0.90; 95% CI 0.77-1.05), or stroke (HR 0.99; 95% CI 0.71-1.38), but there was an increased risk of death (HR 1.27; 95% CI 1.15-1.41) in those who stopped ACEI/ARB compared to those who continued. Results were similar in Sweden: no differences were seen in risk of heart failure (HR 0.91; 95% CI 0.73-1.13) or AKI (HR 0.81; 95% CI 0.54-1.21). However, no increased risk of death was seen (HR 0.94; 95% CI 0.78-1.13) and stroke was less common in people who stopped ACEI/ARB (HR 0.56; 95% CI 0.34-0.93). Results were similar across all sensitivity analyses. CONCLUSIONS: Previous ACEI/ARB users who continued treatment after an episode of AKI did not have an increased risk of heart failure or subsequent AKI compared to those who stopped the drugs.

Comparative effects of sulphonylureas, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors added to metformin monotherapy: a propensity-score matched cohort study in UK primary care.

AIM: To assess the comparative effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors, sulphonylureas (SUs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on cardiometabolic risk factors in routine care. MATERIALS AND METHODS: Using primary care data on 10 631 new users of SUs, SGLT2 inhibitors or DPP-4 inhibitors added to metformin, obtained from the UK Clinical Practice Research Datalink, we created propensity-score matched cohorts and used linear mixed models to describe changes in glycated haemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), systolic blood pressure (BP) and body mass index (BMI) over 96 weeks. RESULTS: HbA1c levels fell substantially after treatment intensification for all drugs: mean change at week 12: SGLT2 inhibitors: -15.2 mmol/mol (95% confidence interval [CI] -16.9, -13.5); SUs: -14.3 mmol/mol (95% CI -15.5, -13.2); and DPP-4 inhibitors: -11.9 mmol/mol (95% CI -13.1, -10.6). Systolic BP fell for SGLT2 inhibitor users throughout follow-up, but not for DPP-4 inhibitor or SU users: mean change at week 12: SGLT2 inhibitors: -2.3 mmHg (95% CI -3.8, -0.8); SUs: -0.8 mmHg (95% CI -1.9, +0.4); and DPP-4 inhibitors: -0.9 mmHg (95% CI -2.1,+0.2). BMI decreased for SGLT2 inhibitor and DPP-4 inhibitor users, but not SU users: mean change at week 12: SGLT2 inhibitors: -0.7 kg/m2 (95% CI -0.9, -0.5); SUs: 0.0 kg/m2 (95% CI -0.3, +0.2); and DPP-4 inhibitors: -0.3 kg/m2 (95% CI -0.5, -0.1). eGFR fell at 12 weeks for SGLT2 inhibitor and DPP-4 inhibitor users. At 60 weeks, the fall in eGFR from baseline was similar for each drug class. CONCLUSIONS: In routine care, SGLT2 inhibitors had greater effects on cardiometabolic risk factors than SUs. Routine care data closely replicated the effects of diabetes drugs on physiological variables measured in clinical trials.

Propensity scores using missingness pattern information: a practical guide.

Electronic health records are a valuable data source for investigating health-related questions, and propensity score analysis has become an increasingly popular approach to address confounding bias in such investigations. However, because electronic health records are typically routinely recorded as part of standard clinical care, there are often missing values, particularly for potential confounders. In our motivating study-using electronic health records to investigate the effect of renin-angiotensin system blockers on the risk of acute kidney injury-two key confounders, ethnicity and chronic kidney disease stage, have 59% and 53% missing data, respectively. The missingness pattern approach (MPA), a variant of the missing indicator approach, has been proposed as a method for handling partially observed confounders in propensity score analysis. In the MPA, propensity scores are estimated separately for each missingness pattern present in the data. Although the assumptions underlying the validity of the MPA are stated in the literature, it can be difficult in practice to assess their plausibility. In this article, we explore the MPA's underlying assumptions by using causal diagrams to assess their plausibility in a range of simple scenarios, drawing general conclusions about situations in which they are likely to be violated. We present a framework providing practical guidance for assessing whether the MPA's assumptions are plausible in a particular setting and thus deciding when the MPA is appropriate. We apply our framework to our motivating study, showing that the MPA's underlying assumptions appear reasonable, and we demonstrate the application of MPA to this study.

Risk factors associated with biochemically detected and hospitalised acute kidney injury in patients prescribed renin angiotensin system inhibitors.

AIMS: Therapy with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is a mainstay of treatment for heart failure (HF), diabetes mellitus (DM) and chronic kidney disease (CKD). These agents have been associated with development of acute kidney injury (AKI) during intercurrent illness. Risk factors for AKI in patients prescribed ACEi/ARB therapy are not well described. METHODS: We captured the incidence of AKI in patients commencing ACEi/ARB during 2009-2015 using anonymised patient records. Hospital-coded AKI was defined from hospital episode statistics; biochemical AKI was ascertained from laboratory data. Risk factors for biochemically detected and hospitalised AKI were investigated. RESULTS: Of 61,318 patients prescribed ACEi/ARB, with 132 885 person years (py) follow-up, there were 1070 hospitalisations with AKI as a diagnosis recorded and a total of 4645 AKI events, including AKI episodes indicated by biochemical KDIGO-based creatinine change criteria. Incidence of any AKI event was 35.0 per 1000-py, hospital-coded AKI was 7.8 per 1000-py and biochemical AKI was 33.7 per 1000-py. Independent risk factors in a multivariable model for hospital-coded AKI events were age, male gender, HF, diabetes, cerebrovascular disease, lower estimated glomerular filtration rate, socioeconomic deprivation, diuretic or non-steroidal anti-inflammatory use (all P < 0.001). CONCLUSION: In patients prescribed ACEi/ARB, the highest risk of AKI is associated with conditions which are considered strong evidence-based indications for their prescription. Socio-economic status is an under-reported risk factor for AKI with these agents. Strategies targeted at prevention of AKI may be of benefit, such as enhanced awareness based on higher risk comorbidities.

How to estimate glomerular filtration rate in sub-Saharan Africa: design and methods of the African Research into Kidney Diseases (ARK) study.

BACKGROUND: Chronic kidney disease (CKD) is a substantial cause of morbidity and mortality worldwide with disproportionate effects in sub-Saharan Africa (SSA). The optimal methods to estimate glomerular filtration rate (GFR) and therefore to determine the presence of CKD in SSA are uncertain. We plan to measure iohexol excretion to accurately determine GFR in Malawi, South Africa and Uganda. We will then assess the performance of existing equations to estimate GFR and determine whether a modified equation can better improve estimation of GFR in sub-Saharan Africa. METHODS: The African Research on Kidney Disease (ARK) study is a three-country study embedded within existing cohorts. We seek to enrol 3000 adults > 18 years based on baseline serum creatinine. Study procedures include questionnaires on socio-demographics and established risk factors for kidney disease along with anthropometry, body composition, blood pressure, blood chemistry and urine microscopy and albuminuria. We will measure GFR (mGFR) by plasma clearance of iohexol at 120, 180 and 240 min. We will compare eGFR determined by established equations with mGFR using Bland-Altman plots. We will use regression methods to estimate GFR and compare the newly derived model with existing equations. DISCUSSION: Through the ARK study, we aim to establish the optimal approach to estimate GFR in SSA. The study has the advantage of drawing participants from three countries, which will increase the applicability of the findings across the region. It is also embedded within established cohorts that have longitudinal information and serial measures that can be used to characterize kidney disease over a period of time. This will help to overcome the limitations of previous research, including small numbers, selected population sub-groups, and lack of data on proteinuria. The ARK collaboration provides an opportunity for close working partnerships across different centres, using standardized protocols and measurements, and shared bio-repositories. We plan to build on the collaboration for this study for future work on kidney disease in sub-Saharan Africa, and welcome additional partners from across the continent.

Estimating treatment effects with partially observed covariates using outcome regression with missing indicators.

Missing data is a common issue in research using observational studies to investigate the effect of treatments on health outcomes. When missingness occurs only in the covariates, a simple approach is to use missing indicators to handle the partially observed covariates. The missing indicator approach has been criticized for giving biased results in outcome regression. However, recent papers have suggested that the missing indicator approach can provide unbiased results in propensity score analysis under certain assumptions. We consider assumptions under which the missing indicator approach can provide valid inferences, namely, (1) no unmeasured confounding within missingness patterns; either (2a) covariate values of patients with missing data were conditionally independent of treatment or (2b) these values were conditionally independent of outcome; and (3) the outcome model is correctly specified: specifically, the true outcome model does not include interactions between missing indicators and fully observed covariates. We prove that, under the assumptions above, the missing indicator approach with outcome regression can provide unbiased estimates of the average treatment effect. We use a simulation study to investigate the extent of bias in estimates of the treatment effect when the assumptions are violated and we illustrate our findings using data from electronic health records. In conclusion, the missing indicator approach can provide valid inferences for outcome regression, but the plausibility of its assumptions must first be considered carefully.

The comparative effectiveness of fourth-line drugs in resistant hypertension: An application in electronic health record data.

PURPOSE: To examine the utility of electronic health records from a routine care setting in assessing comparative effectiveness of fourth-line anti-hypertensive drugs to treat resistant hypertension. METHODS: We conducted a cohort study using the Clinical Practice Research Datalink: a repository of electronic health records from UK primary care. We identified patients newly prescribed fourth-line anti-hypertensive drugs (aldosterone antagonist , beta-blocker, or alpha-blocker). Using propensity score-adjusted Cox proportional hazards models, we compared the incidence of the primary outcome (composite of all-cause mortality, stroke, and myocardial infarction) between patients on different fourth-line drugs. AA was the reference drug in all comparisons. Secondary outcomes were individual components of the primary outcome, blood pressure changes, and heart failure. We used a negative control outcome, Herpes Zoster, to detect unmeasured confounding. RESULTS: Overall, 8639 patients were included. In propensity score-adjusted analyses, the hazard ratio for the primary outcome was 0.81 (95% CI, 0.55-1.19) for beta-blockers and 0.68 (95% CI, 0.46-0.96) for alpha-blockers versus AA. Findings for individual cardiovascular outcomes trended in a more plausible direction, albeit imprecise. A trend for a protective effect for Herpes Zoster across both comparisons was seen. CONCLUSIONS: A higher rate of all-cause death in the AA group was likely due to unmeasured confounding in our analysis of the composite primary outcome, supported by our negative outcome analysis. Results for cardiovascular outcomes were plausible, but imprecise due to small cohort sizes and a low number of observed outcomes.

Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors by level of kidney function: A population-based cohort study.

AIM: To estimate the risk of gastrointestinal (GI) bleeding associated with serotonin reuptake inhibitors (SSRIs) by level of kidney function. METHODS: We conducted a cohort study using the Clinical Practice Research Datalink linked to Hospital Episode Statistics. We identified patients with chronic kidney disease (CKD; estimated glomerular filtration rate <60 ml min-1  1.73 m-2 for ≥3 months), and a comparison group of patients without it. Patients with CKD were further classified as stage 3a (eGFR 45-59 ml min-1  1.73 m-2 ), 3b (30-44 ml min-1  1.73 m-2 ) and 4/5 (<30 ml min-1  1.73 m-2 ). We excluded prevalent SSRI users at cohort entry. Exposure was time-dependent SSRI prescription and outcome was first hospitalization for GI bleeding. We estimated adjusted rate ratio (aRR) and rate difference (aRD) of GI bleeding comparing periods with and without SSRI prescription at each level of kidney function. RESULTS: The aRRs and aRDs were: (i) no CKD (n = 202 121) aRR: 1.66 (95%CI 1.37-2.01), aRD: 2.0/1000 person-years (5.5 vs. 3.5/1000 person-years in period with and without SSRIs); (ii) CKD stage 3a (n = 153 316) aRR: 1.86 (1.62-2.15), aRD: 4.2/1000 person-years (8.3 vs. 4.1/1000 person-years); (iii) CKD stage 3b (n = 46 482) aRR: 1.61 (1.27-2.04), aRD: 4.8/1000 person-years (9.9 vs. 5.1/1000 person-years); and (iv) CKD stage 4/5 (n = 11 197) aRR: 1.84 (1.14-2.96), aRD: 7.9/1000 person-years (15.3 vs. 7.4/1000 person-years). While there was no evidence of increase in the aRR (P = 0.922), there was strong evidence that the aRD increased as kidney function deteriorated (P = 0.001). CONCLUSIONS: While the relative risk was constant, the excess risk of GI bleeding associated with SSRIs markedly increased among patients with decreased kidney function.

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.