Describing diversity of real world data sources in pharmacoepidemiologic studies: The DIVERSE scoping review.

PURPOSE: Real-world evidence (RWE) is increasingly used for medical regulatory decisions, yet concerns persist regarding its reproducibility and hence validity. This study addresses reproducibility challenges associated with diversity across real-world data sources (RWDS) repurposed for secondary use in pharmacoepidemiologic studies. Our aims were to identify, describe and characterize practices, recommendations and tools for collecting and reporting diversity across RWDSs, and explore how leveraging diversity could improve the quality of evidence. METHODS: In a preliminary phase, keywords for a literature search and selection tool were designed using a set of documents considered to be key by the coauthors. Next, a systematic search was conducted up to December 2021. The resulting documents were screened based on titles and abstracts, then based on full texts using the selection tool. Selected documents were reviewed to extract information on topics related to collecting and reporting RWDS diversity. A content analysis of the topics identified explicit and latent themes. RESULTS: Across the 91 selected documents, 12 topics were identified: 9 dimensions used to describe RWDS (organization accessing the data source, data originator, prompt, inclusion of population, content, data dictionary, time span, healthcare system and culture, and data quality), tools to summarize such dimensions, challenges, and opportunities arising from diversity. Thirty-six themes were identified within the dimensions. Opportunities arising from data diversity included multiple imputation and standardization. CONCLUSIONS: The dimensions identified across a large number of publications lay the foundation for formal guidance on reporting diversity of data sources to facilitate interpretation and enhance replicability and validity of RWE.

Hospitalization costs of adult community-acquired pneumonia in England.

OBJECTIVE: Accurate and up-to-date figures of the cost of community-acquired pneumonia (CAP) hospitalization are needed to understand the associated economic burden for public health decision-makers. Recent estimates are lacking, and previously published estimates differ markedly. Our objective was to estimate the current mean cost to the UK National Health Service (NHS) for adult hospitalized CAP. METHODS: All CAP hospitalizations in 2019 for those aged ≥18 years were identified from English Hospital Episode Statistics (HES). Each hospitalization was mapped to the tariff cost paid to the care provider within the NHS, including critical care costs and accounting for length of stay and complexity of the case. Mean hospitalization costs were estimated in total and in individuals with defined underlying comorbidities. RESULTS: A mean cost of £3,904 was estimated for 187,251 CAP admissions providing a total cost of approximately £731 million per annum. The mean cost was £3,402, excluding critical care costs, and £11,654 for critical care episodes in the 4.4% of admissions receiving this care. Groups at high risk of CAP had higher mean costs, ranging from £4,458 for people with diabetes to £5,215 for those with heart disease aged <65 years and £4,356 for those with heart disease to £4,751 for those with liver disease aged >65 years who comprised 74.3% of admissions overall. CONCLUSION: This estimate of the cost of hospitalization for CAP from the total population and in those with certain underlying comorbidities will allow a valid understanding of the cost-benefit of vaccination and evidence-based prioritization of pneumococcal vaccination to those at highest risk.

Community-acquired pneumonia (CAP) is a disease that is most commonly caused in England by the bacterium Streptococcus pneumoniae, which infects patients outside of a hospital. Patients who suffer from CAP often require hospitalization, which incurs a cost to the UK National Health Service (NHS). The goal of this study was to establish the annual cost of hospitalized CAP.The researchers used England's national healthcare database, known as Hospital Episodes Statistics (HES), to select all adults in England who were hospitalized for CAP in 2019. For the 187,251 patients hospitalized, an average cost of £3,904 per person was estimated, amounting to a total cost of £731 million per year to the NHS. Most people admitted to hospital with CAP were at risk for the disease (due to factors such as increased age or presence of another disease) and the cost of treatment for this subgroup was disproportionately larger than that for treatment of patients not at risk. Furthermore, while approximately 5% of patients admitted for CAP received critical care during treatment, the average cost for these patients was over £8,000 higher than for those outside this subsection.The costs of hospitalization reported in this analysis were higher than previously estimated. The researchers highlighted weaknesses in other studies and limitations of the current study which could explain the difference. This work provides up-to-date figures for the cost of treating CAP in hospital in England. Public health decision-makers can use these estimates to determine the cost-benefit of vaccines that can help protect against important causes of CAP, particularly vaccines that target S. pneumoniae.

Variation in access to specialist services for neurosurgical procedures in adults with epilepsy in England, a cohort study.

PURPOSE: To understand if primary consultation at tertiary epilepsy centres (TEC) in England impacts access to neurosurgical procedures (resective surgery, vagus nerve stimulator [VNS], deep brain stimulator [DBS]). METHODS: Adults with epilepsy, and with a first neurology outpatient visit (index) between 01/01/2013 and 31/12/2015, were followed using English Hospital Episode Statistics from index date to 31/12/2019. Analyses were stratified by geographic location, learning disability record, and whether the index or follow-up visits were at a TEC. RESULTS: 84,093 people were included, with mean 5.5 years of follow-up. 12.4% of the cohort had learning disability (range 10.1%-17.4% across regions). TEC consultations varied by National Health Service regions and Clinical Commissioning Groups. 37.5% of people (11.2%-75.0% across regions) had their index visit at a TEC; and, of those not initially seen at a TEC, 10.6% (6.5%-17.7%) subsequently attended a tertiary centre. During follow-up, 11.1% people (9.5%-13.2%) visited a neurosurgery department, and 2.3% of those (0.9%-5.0%) then underwent a neurosurgical procedure, mainly VNS implantation. Median time from index date to first visit at a neurosurgery centre was 7 months (range 6-8 months across regions) and 40 months to procedure (36.5-49 months, 37.0 months in people with index visit at a TEC and 49.0 months otherwise). People with learning disability were less likely to have resective surgery (<0.5% versus 1.0% in those without) and more likely to undergo VNS implantation (5.8% versus 0.8%). CONCLUSION: Although clinically recommended for suitable individuals, neurosurgical procedures in epilepsy remain uncommon even after consultation at a TEC. Geographical variation in access to TECs was present.

Post-licensure observational safety study after meningococcal B vaccine 4CMenB (Bexsero) vaccination within the routine UK immunisation program.

The study investigated the safety of 4-component meningococcal serogroup B vaccination (4CMenB) in routine care. 4CMenB exposure and seizures, febrile seizures and Kawasaki disease were identified from The Health Improvement Network (THIN) database of UK electronic primary healthcare records, 2015-2018. A self-controlled case series analysis was completed. Anaphylaxis, Guillain-Barré syndrome and acute disseminated encephalomyelitis were secondary outcomes. A total of 107,231 children aged 1-18 months received ≥1 doses of 4CMenB vaccination. Most 4CMenB exposure (93%) was on the same day as other vaccines within a complete national immunisation program stage. With day 0 as day of vaccination, 43 seizures occurred in days 0-6 after 239,505 doses, and 23 febrile seizures occurred in days 0-6, and 4 Kawasaki disease cases in days 1-28 after 194,929 4CMenB doses. Adjusted incidence rate ratios including all 4CMenB exposures were 1.43 (95%CI: 1.02-2.02) for seizures and 1.72 (95%CI: 1.08-2.75) for febrile seizures. There were insufficient cases to model Kawasaki disease, and no cases of the secondary outcomes in risk periods when they may be associated with the vaccination. This study shows few cases of the outcomes after vaccination including 4CMenB with an increased risk of seizures and febrile seizures. It is not possible to attribute the finding to one specific vaccination as the majority of 4CMenB was given with other vaccinations. Trial registration: NA.

Incorporating patient generated health data into pharmacoepidemiological research.

Epidemiology and pharmacoepidemiology frequently employ Real-World Data (RWD) from healthcare teams to inform research. These data sources usually include signs, symptoms, tests, and treatments, but may lack important information such as the patient's diet or adherence or quality of life. By harnessing digital tools a new fount of evidence, Patient (or Citizen/Person) Generated Health Data (PGHD), is becoming more readily available. This review focusses on the advantages and considerations in using PGHD for pharmacoepidemiological research. New and corroborative types of data can be collected directly from patients using digital devices, both passively and actively. Practical issues such as patient engagement, data linking, validation, and analysis are among important considerations in the use of PGHD. In our ever increasingly patient-centric world, PGHD incorporated into more traditional Real-Word data sources offers innovative opportunities to expand our understanding of the complex factors involved in health and the safety and effectiveness of disease treatments. Pharmacoepidemiologists have a unique role in realizing the potential of PGHD by ensuring that robust methodology, governance, and analytical techniques underpin its use to generate meaningful research results.

Outcome misclassification: Impact, usual practice in pharmacoepidemiology database studies and an online aid to correct biased estimates of risk ratio or cumulative incidence.

PURPOSE: It is well documented that outcome misclassification can bias a point estimate. We aimed to understand current practice in addressing this bias in pharmacoepidemiology database studies and to develop an open source application (app) from existing methodology to demonstrate the impact and mechanism of this bias on results. METHODS: Studies of an exposure and a clinical outcome were selected from all Pharmacoepidemiology and Drug Safety publications during 2017 and any reference to outcome misclassification described. An app to correct risk ratio (RR) and cumulative incidence for outcome misclassification was developed from a published methodology and used to demonstrate the impact of correction on point estimates. RESULTS: Eight (19%) of 43 papers selected reported estimates of outcome ascertainment accuracy with positive predictive value (PPV) the most commonly reported measure (7 of 8 studies). Three studies (7%) corrected for the bias, 1 by exposure strata, and 5 (12%) restricted analyses to confirmed cases. The app (app http://apps.p-95.com/ISPE/) uses values of PPV and sensitivity (or a range of possible values) in each exposure strata and returns corrected point estimates and confidence intervals. The app demonstrates that small differences between comparison groups in PPV or sensitivity can introduce bias even when accuracy estimates are high. CONCLUSIONS: Outcome misclassification is not usually corrected in pharmacoepidemiology database studies although correction methods using routinely measured indices are available. Error indices are needed for each comparison group to correct RR estimates for these errors. The app should encourage understanding of this bias and increase adjustment.

Observational safety study of specific outcomes after trivalent cell culture seasonal influenza vaccination (Optaflu® ) among adults in THIN database of electronic UK primary healthcare records.

PURPOSE: To investigate the safety of trivalent seasonal influenza vaccine (TIVc) (Optaflu® ), the first cell culture seasonal trivalent influenza vaccine available in Europe. METHODS: Codes and unstructured text in adult electronic healthcare records (The Health Improvement Network) were searched for a TIVc brand name or batch number and possible outcomes within a 3 month pre- to 6 month post-TIVc exposure study period (2012-2015). The outcomes were severe allergic reactions, Bell's palsy, convulsions, demyelination, paresthesia, noninfectious encephalitis, neuritis (optic and brachial), vasculitis, inflammatory bowel disease, and thrombocytopenia. Risk periods were defined based on biologically plausible time frame postvaccination when an outcome caused by the vaccine might be expected to occur. Possible outcomes were adjudicated against outcome specific case definitions and a date of onset assigned by using electronic and other medical records. Observed (risk period) to expected (outside risk and preexposure periods) rate ratios, postexposure incidence, and plots of time from exposure to outcome were reported. RESULTS: Sixteen of 1011 events from 4578 exposures fulfilled a primary case definition and had a date of onset during the study period. Three were in observed time. The observed-to-expected rate ratios were (3.3, 95% CI 0.3, 31.7) for convulsions and (1.5, 95% CI 0.2, 14.9) for thrombocytopenia with 1 outcome each in observed time. There was 1 incident inflammatory bowel disease in observed, but none in expected, time. CONCLUSION: The small sample size restricts interpretation; however, no hypothesis of an increased risk of a study outcome was generated. Adjudication of events against case definitions to reduce misclassification of onset and outcomes allowed use of precise risk periods. KEY POINTS This observational study did not generate a hypothesis of an association between the first cell-culture seasonal influenza vaccination available in the European Union and any of the study outcomes (severe allergic reactions, Bell's palsy, convulsions, demyelination, paresthesia, noninfectious encephalitis, neuritis [optic and brachial], vasculitis, inflammatory bowel disease [IBD], and thrombocytopenia). The small sample size limits interpretation of the results. The review of each possible outcome identified from electronic healthcare records against case definitions was included to minimize misclassification of time and outcomes and allow the use of precise risk-periods in an observed-to-expected within cohort analysis. Plots of time from exposure to outcome were included to assess the risk windows.

Factors Associated with Type 2 Diabetes Mellitus Treatment Choice Across Four European Countries.

PURPOSE: The aim of this analysis was to identify factors associated with the choice of type 2 diabetes mellitus (T2DM) therapy at the time of intensification of antidiabetic treatment across 4 European countries. METHODS: Antidiabetic drug prescription/dispensing records and patients' characteristics were obtained from the electronic health care records of patients with T2DM from the Netherlands (NL), Italy, and Spain (ES) (all, 2007-2011); and the United Kingdom (UK; 2008-2012). Oral monotherapy was defined as first-line; oral dual therapy, as second-line; >2 oral treatments or oral combined with an injectable, as third-line; and injectables only, as fourth-line treatment. Treatment intensification was defined as the start of a higher line of treatment. Comedication, comorbidities, clinical parameters, and other factors associated with treatment choice were identified using multivariate relative risk estimation by Poisson regression with robust error variance. FINDINGS: In the 5-year study period, 485,120 patients (79% of the treated T2DM population) underwent treatment intensification. Changes in treatment choice were clearly visible over the study period, such as a decline in the use of thiazolidinediones (NL, ES, UK) and increases in the use of dipeptidyl peptidase-4 inhibitors (DPP4i) (NL, ES, UK) and glucagon-like peptide-1 receptor agonists (UK). With first-line treatment, advanced age and renal comorbidity were associated with the use of sulfonylureas (SUs; all countries), whereas high body mass index (BMI) was inversely associated with SU use in the United Kingdom and Spain. With second-line treatment, advanced age was associated with metformin + SU use (all countries); and renal comorbidity with SU + DPP4i use in the United Kingdom and the Netherlands. High BMI was associated with metformin + thiazolidinedione (TZD) use in the United Kingdom and Spain, and with metformin + DPP4i in the United Kingdom. With third-line treatment, advanced age and renal comorbidity were associated with the use of SU + insulin (NL, ES, UK). Hemoglobin A1c >8.5% was positively associated, and high BMI was inversely associated, with the use of any third-line combination containing insulin. Across treatment lines TZD and metformin were negatively associated with renal and cardiac morbidity. Second and third line treatment choices strongly depended on prior treatments. With fourth-line treatment, women were more likely to receive glucagon-like peptide-1 receptor agonists than were men in the United Kingdom and Spain. IMPLICATIONS: The results suggest that the main factors driving treatment choice at any stage of intensification were age, hemoglobin A1c, BMI, renal and cardiac morbidity, and treatment history. These drivers were consistent with guidelines on, and contraindications of, specific medications. Differences between countries were generally consistent with, but not solely attributable to, differences in local guidelines and reimbursement policies.

Type 2 Diabetes Mellitus Treatment Patterns Across Europe: A Population-based Multi-database Study.

PURPOSE: The aim of this study was to determine the similarities and differences of type 2 diabetes mellitus (T2DM) treatment patterns in daily practice in 5 European countries and whether these reflect differences in guidelines. METHODS: Prescriptions for drugs used in diabetes treatment during a 5-year study period were obtained from electronic databases. Patients initiating T2DM treatment during the study period were included. An SAS analysis tool was developed to create episodes of use of drug classes, which resulted in treatment patterns. FINDINGS: A total of 253,530 patients initiating T2DM treatment during the study period were included; 52% to 55% were male, and the mean age ranged from 62 to 67 years. Metformin was the most common initial treatment in all countries. After initial therapy, most patients in the Netherlands, Spain, and the United Kingdom switched to a combination of metformin + a sulfonylurea derivative (SU). In Italy, metformin in combination with an SU was outnumbered by "other treatment," mainly because of repaglinide use. In France, treatments including dipeptidyl peptidase-4 inhibitors were most frequent as second- and fourth-line treatment. Metformin monotherapy was again most commonly observed as the third line of treatment in all countries. Fourth treatment was a combination of metformin + an SU in the Netherlands and Spain; in the United Kingdom and France, dipeptidyl peptidase-4 inhibitors were the most frequently used fourth line of treatment. IMPLICATIONS: This study provides a comprehensive overview of T2DM treatment patterns among patients initiating T2DM treatment in 5 European countries. There were differences, especially regarding the uptake of newer incretin-based treatments, which are usually prescribed as a second and/or third treatment in agreement with local guidelines. These variations reflect the differences between the national guidelines of these countries.

The incidence of Kawasaki disease after vaccination within the UK pre-school National Immunisation Programme: an observational THIN database study.

PURPOSE: To provide expected incidence rates of Kawasaki disease after vaccination in routine clinical practice and as recommended within a pre-school National Immunisation Programme (NIP). METHODS: A post-immunisation risk period when Kawasaki disease onset might be associated with vaccination was defined as 28 days. Immunisation records for children under 6 years were identified from The Health Improvement Network (THIN) database of electronic UK primary health care records (2008-2012) and linked to previously validated cases of Kawasaki disease with an assigned date of onset. Kawasaki disease incidence in the risk period after a complete NIP recommended set of vaccinations was estimated for five vaccination stages individually and in total. RESULTS: A total of 642 170 complete pre-school immunisation stages from 275 986 children were included. Six cases of Kawasaki disease had onset in the risk period after any NIP stage providing an incidence of 12.8 per 100 000 person years (95%CI 5.7, 28.4). The incidence after any single immunisation stage ranged from 0 to 27.4 (95%CI 8.8, 84.8) per 100 000 person years. CONCLUSION: There were few cases of Kawasaki disease in the risk period after any NIP vaccination combination. The incidence rates will aid in the interpretation of clinical trials and post-marketing surveillance of new vaccines. Copyright © 2016 John Wiley & Sons, Ltd.

Evidence generation from healthcare databases: recommendations for managing change.

There is an increasing reliance on databases of healthcare records for pharmacoepidemiology and other medical research, and such resources are often accessed over a long period of time so it is vital to consider the impact of changes in data, access methodology and the environment. The authors discuss change in communication and management, and provide a checklist of issues to consider for both database providers and users. The scope of the paper is database research, and changes are considered in relation to the three main components of database research: the data content itself, how it is accessed, and the support and tools needed to use the database. Copyright © 2016 John Wiley & Sons, Ltd.

High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort.

BACKGROUND & AIMS: Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment. METHODS: The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions. RESULTS: Moderate to severe hepatotoxicity [bilirubin >60µmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4-2.6]. High dose was classified as 40-80mg daily and low dose 10-20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2-12.7] for HDA, 1.4 [0.9-2.0] for LDA and 1.5 [1.0-2.2] for HDS. CONCLUSIONS: The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small.

Kawasaki disease incidence in children and adolescents: an observational study in primary care.

BACKGROUND: Kawasaki disease is reported to be increasing in incidence and is the commonest childhood cause of acquired heart disease in the Western world. AIM: To determine the current UK incidence of Kawasaki disease across childhood and adolescence; and investigate trends over time and season. DESIGN AND SETTING: An observational, descriptive study in the UK. METHOD: The Health Improvement Network (THIN) database of primary healthcare records was searched for codes or text indicating Kawasaki disease. Identified records were compared with a study case definition and a date of onset was assigned to cases. The incidence, age/sex distribution, and trend in seasonal and temporal distribution were estimated (2008-2012). RESULTS: A total of 110 episodes of Kawasaki disease in 109 children were identified from 3.9 million person-years observation. The incidence of Kawasaki disease was 2.8 per 100 000 person-years (95% confidence interval [CI] = 2.3 to 3.4) when aged <20 years; 9.1 (95% CI = 7.3 to 11.2) aged <5 years, and 3.0 per 100 000 (95% CI = 2.0 to 4.3) across the age groups when possible cases were included. More cases were identified in males (55%) with one-fifth of cases diagnosed after 5 years of age. There was no statistically significant trend in incidence over the study years (P = 0.10 adjusted for sex and month), or between seasons (P = 0.65 adjusted for year and sex). CONCLUSION: Although the incidence of Kawasaki disease remains low and has stabilised in the UK, GPs should recognise that the condition occurs throughout childhood and across the seasons.

Descriptive investigation of the recording of influenza vaccination details on The Health Information Network database.

BACKGROUND: The UK primary care databases are used in pharmacoepidemiology studies of vaccination type. We investigated vaccine recording and whether, and how, exposure to specific brands and batches can be identified. METHODS: Details of influenza vaccinations given in the 2010-2011 or 2011-2012 seasons were identified from coded and text fields in The Health Information Network UK primary care database. The proportion of people over 64 years of age vaccinated against influenza was compared with published regional rates. Searches for Fluvirin (Novartis Vaccines and Diagnostics GmbH, Marburg, Germany) batch numbers and name identified exposure to this specific vaccine. The recording of any brand name and batch number was described for a sample of 1000 vaccinations across 472 practices. RESULTS: A total of 767 904 influenza vaccinations were identified during the 2010-2011 season and 784 518 in 2011-2012. Vaccination rates for people aged over 64 years were 75.6%, 80.9%, 78.4% and 71.9% in England, Northern Ireland, Scotland and Wales, respectively (2011-2012 season), compared with published figures of 74.0%, 77.0%, 76.2% and 67.7%. Rates were slightly lower in 2010-2011 in both data sources. A Fluvirin brand was identified for 3.6% of all UK vaccinations but 26.2% of those in Scottish practices. Vaccination brand could be identified for 94.3% of the sample, 93.6% with a batch number. Batch number (98.5%) and brand name (50.3%) were most frequently recorded in an immunisation 'batch' text field. CONCLUSION: Patients exposed to an influenza vaccine in primary care can be identified from The Health Information Network. Identification of brand or batch number requires a text search. Regional variation in brand of vaccine should be considered when estimating sample size.

Observational study of ezetimibe discontinuation in primary care practices in the UK.

OBJECTIVE: We investigated the circumstances of ezetimibe discontinuation as its prescribing had been discouraged in some publications. RESEARCH DESIGN AND METHODS: Adults on stable lipid-modifying therapy (LMT) including ezetimibe, who then had >8 weeks cessation in their prescribed ezetimibe regimen (2010-2011) were identified from THIN UK primary care database. Lipid values and parallel changes to other LMT were described overall and in a sub-group with a history of diabetes, cardiovascular disease or familial hypercholesterolaemia (high-risk group). RESULTS: Ezetimibe therapy stopped in 7087 patients after a mean of 38 months; 67.0% were in the high-risk group. No lipid readings were recorded for 16.1% of patients in the year before and 26.2% in the year after ezetimibe stopped; 11.0% and 12.4% in the high-risk group respectively. In the prior year, 60.2% patients with any lipid reading had a total cholesterol (T-cholesterol) <5 mmol/l and 59.2% had a T-cholesterol <5 mmol/l and LDL-cholesterol <3 mmol/l. In the high-risk group, 66.8% had a T-cholesterol <5 mmol/l, 38.9% had either a T-cholesterol <4 or a LDL-cholesterol <2 mmol/l and 29.4% had reached both targets. In both populations, 42% patients had 6 months' follow-up after ezetimibe stopped with no change to other LMT. An LMT change within 8 weeks (19%) was usually a new statin while 27% overall had a further ezetimibe prescription after 8-26 weeks. LIMITATIONS: Only absolute lipid values were included, as percentage change from baseline level may not be reliable. The study included a larger proportion of patients in Scotland relative to the UK population. CONCLUSIONS: Prescribed ezetimibe often stopped without either a recent lipid value or attainment of optimal, or sometimes minimum, lipid targets. Patients did not always receive parallel intensification of other LMT or a further ezetimibe prescription within 6 months.

An observational descriptive study of the epidemiology and treatment of neuropathic pain in a UK general population.

BACKGROUND: This study updated our knowledge of UK primary care neuropathic pain incidence rates and prescribing practices. METHODS: Patients with a first diagnosis of post-herpetic neuralgia (PHN), painful diabetic neuropathy (PDN) or phantom limb pain (PLP) were identified from the General Practice Research Database (2006 - 2010) and incidence rates were calculated. Prescription records were searched for pain treatments from diagnosis of these conditions and the duration and daily dose estimated for first-line and subsequent treatment regimens. Recording of neuropathic back and post-operative pain was investigated. RESULTS: The study included 5,920 patients with PHN, 5,340 with PDN, and 185 with PLP. The incidence per 10,000 person-years was 3.4 (95% CI 3.4, 3.5) for PHN; and 0.11 (95% CI 0.09, 0.12) for PLP. Validation of the PDN case definition suggested that was not sensitive. Incident PHN increased over the study period. The most common first-line treatments were amitriptyline or gabapentin in the PDN and PLP cohorts, and amitriptyline or co-codamol (codeine-paracetamol) in PHN. Paracetamol, co-dydramol (paracetamol-dihydrocodeine) and capsaicin were also often prescribed in one or more condition. Most first-line treatments comprised only one therapeutic class. Use of antiepileptics licensed for neuropathic pain treatment had increased since 2002-2005. Amitriptyline was the only antidepressant prescribed commonly as a first-line treatment. CONCLUSION: The UK incidence of diagnosed PHN has increased with the incidence of back-pain and post-operative pain unclear. While use of licensed antiepileptics increased, prescribing of therapy with little evidence of efficacy in neuropathic pain is still common and consequently treatment was often not in-line with current guidance.

Observational study of the association of first insulin type in uncontrolled type 2 diabetes with macrovascular and microvascular disease.

AIMS: To compare the risk of vascular disease, HbA1c and weight change, between first prescribed insulins in people with type 2 diabetes. METHODS: People included in THIN United Kingdom primary care record database who began insulin (2000-2007) after poor control on oral glucose-lowering agents (OGLD) were grouped by the number of OGLDs in their treatment regimen immediately before starting insulin (n = 3,485). Within OGLD group, Cox regression compared macrovascular (all-cause mortality, myocardial infarction, acute coronary syndrome and stroke) and microvascular disease (peripheral neuropathy, nephropathy, and retinopathy) between insulin type (basal, pre-mix or Neutral Protamine Hagedorn, NPH) while ANCOVAs compared haemoglobin A(1c) (HbA(1c)) and weight change. RESULTS: Mean follow-up was 3.6 years. Rates of incident macrovascular events were similar when basal insulin was compared to pre-mix or NPH, adjusted hazard ratio versus basal: pre-mix 1.08 (95% CI 0.73, 1.59); NPH 1.00 (0.63, 1.58) after two OGLDs, and pre-mix 0.97 (0.46, 2.02); NPH 0.77 (0.32, 1.86) after three OGLDs. An increased risk of microvascular disease in NPH versus basal after 3 OGLDs, adjusted hazard ratio 1.87 (1.04, 3.36), was not seen after two agents or in comparisons of basal and pre-mix. At one year, after two OGLDs, weight increase was less with basal compared with pre-mix. After three OGLDs, mean HbA(1c) had reduced less in basal versus pre-mix or NPH at 6-8 and at 9-11 months, and versus pre-mix at 12-14 months. CONCLUSION: We found no difference in the risk of macrovascular events between first insulins in the medium term when started during poor glycaemia control. The increased risk of microvascular events with NPH warrants further study. In certain groups, first use of basal insulin was associated with less gain in weight and decrease in HbA(1c) compared to other insulins.

Meta-Analysis of Maternal and Neonatal Outcomes Associated with the Use of Insulin Glargine versus NPH Insulin during Pregnancy.

As glargine, an analog of human insulin, is increasingly used during pregnancy, a meta-analysis assessed its safety in this population. A systematic literature search identified studies of gestational or pregestational diabetes comparing use of insulin glargine with human NPH insulin, with at least 15 women in both arms. Data was extracted for maternal outcomes (weight at delivery, weight gain, 1st/3rd trimester HbA(1c), severe hypoglycemia, gestation/new-onset hypertension, preeclampsia, and cesarean section) and neonatal outcomes (congenital malformations, gestational age at delivery, birth weight, macrosomia, LGA, 5 minute Apgar score >7, NICU admissions, respiratory distress syndrome, neonatal hypoglycemia, and hyperbilirubinemia). Relative risk ratios and weighted mean differences were determined using a random effect model. Eight studies of women using glargine (331) or NPH (371) were analyzed. No significant differences in the efficacy and safety-related outcomes were found between glargine and NPH use during pregnancy.

Macrovascular and microvascular outcomes after beginning of insulin versus additional oral glucose-lowering therapy in people with type 2 diabetes: an observational study.

PURPOSE: In type 2 diabetes, the optimal stage to introduce insulin can be unclear. We compared the incidence of subsequent vascular disease between treatment regimens, that is, adding another oral glucose-lowering drug (OGLD) versus starting insulin treatment. METHODS: People with poor control on OGLDs who intensified treatment (2000-2007) were grouped by number of baseline OGLDs. Two composite endpoints, of macrovascular disease (all-cause mortality, myocardial infarction, acute coronary syndrome and stroke) and of microvascular disease (peripheral neuropathy, nephropathy or retinopathy), together with HbA(1c) and weight change over a year, were compared in those beginning insulin versus an additional OGLD. All data came from The Health Information Network UK primary care database. RESULTS: After exclusions, 14,904 people intensified treatment from one OGLD, 7231 from two and 978 from three, 9, 41 and 90%, respectively, started insulin. Average follow-up was 3.5 years. The adjusted hazard ratios for macrovascular events, OGLD versus insulin, were 0.53 (95%CI 0.42, 0.69) from one baseline treatment, 0.85 (0.70 1.04) from two and 1.07 (0.50, 2.30) from three, with no difference in risk of microvascular disease in any comparison. Mean body weight increased, and mean HbA(1c) fell across groups; the only significant adjusted comparison was greater weight increase when commencing insulin from one OGLD. CONCLUSIONS: Starting insulin rather than adding another OGLD to double or triple oral therapy did not significantly increase the incidence of vascular events. Beginning insulin from one OGLD was uncommon. More incident macrovascular disease in this group may be caused by residual confounding.

Guidelines for good database selection and use in pharmacoepidemiology research.

The use of healthcare databases in research provides advantages such as increased speed, lower costs and limitation of some biases. However, database research has its own challenges as studies must be performed within the limitations of resources, which often are the product of complex healthcare systems. The primary purpose of this document is to assist in the selection and use of data resources in pharmacoepidemiology, highlighting potential limitations and recommending tested procedures. This guidance is presented as a detailed text with a checklist for quick reference and covers six areas: selection of a database, use of multiple data resources, extraction and analysis of the study population, privacy and security, quality and validation procedures and documentation.