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Background: The Cohort Multiple Randomised Controlled Trial (cmRCT) is a newly proposed pragmatic trial design; recently several cmRCT have been initiated. This study tests the unresolved question of whether differential refusal in the intervention arm leads to bias or loss of statistical power and how to deal with this.Methods: We conduct simulations evaluating a hypothetical cluster cmRCT in patients at risk of cardiovascular disease (CVD). To deal with refusal, we compare the analysis methods intention to treat (ITT), per protocol (PP) and two instrumental variable (IV) methods: two stage predictor substitution (2SPS) and two stage residual inclusion (2SRI) with respect to their bias and power. We vary the correlation between treatment refusal probability and the probability of experiencing the outcome to create different scenarios.Results: We found ITT to be biased in all scenarios, PP the most biased when correlation is strong and 2SRI the least biased on average. Trials suffer a drop in power unless the refusal rate is factored into the power calculation.Conclusions: The ITT effect in routine practice is likely to lie somewhere between the ITT and IV estimates from the trial which differ significantly depending on refusal rates. More research is needed on how refusal rates of experimental interventions correlate with refusal rates in routine practice to help answer the question of which analysis more relevant. We also recommend updating the required sample size during the trial as more information about the refusal rate is gained.

BackgroundHealthcare sites (practices) may vary in quality of data recording and populations. Risk predictions models that use routinely collected data do not test generalisability to heterogeneous practices.AimTo assess the extent of variability between practices on individual patients’ risk of cardiovascular disease (CVD) that is not taken into account by the risk prediction model QRISK3.MethodA longitudinal cohort study from 1 Jan 1998 to Jan 2015 in 392 general practices (including 3.6 million patients) from the Clinical Practice Research Datalink (CPRD). This was a shared frailty model to incorporate QRISK3 predictors, practice variability, and simulations to measure random variability.ResultsThere was considerable variation in data recording between general practices. Practices on 5th percentile of missingness of body mass index have 18.7% patients with missing values and 60.1% on the 95th percentile. The crude incidence rates also varied considerably between practices (from 0.4 to 1.3 CVD events per 100 patient-years, respectively). The estimates of individual CVD risks with the random effect model were inconsistent with the estimated QRISK3 risk. For patients with a QRISK3 CVD risk of 10%, the 95% range of predicted risks were between 7.2% and 13.7% with the random effects model. Random variability only explained a small part of this. The random effects model was similar to QRISK3 for discrimination and calibration.ConclusionRisk prediction models that use routinely collected electronic health data can have limited generalisability and accuracy in predicting individual patient risks in heterogeneous settings. They need to be based on more robust evidence on causal risk factors.

ObjectiveClinical code sets are vital to research using routinely-collected electronic healthcare data. Existing code set engineering methods pose significant limitations when considering reproducible research. To improve the transparency and reusability of research, these code sets must abide by FAIR principles; this is not currently happening. We propose ‘term sets’, an equivalent alternative to code sets that are findable, accessible, interoperable and reusable.Materials and methodsWe describe a new code set representation, consisting of natural language inclusion and exclusion terms (term sets), and explain its relationship to code sets. We formally prove that any code set has a corresponding term set. We demonstrate utility by searching for recently published code sets, representing them as term sets, and reporting on the number of inclusion and exclusion terms compared with the size of the code set.ResultsThirty-one code sets from 20 papers covering diverse disease domains were converted into term sets. The term sets were on average 74% the size of their equivalent original code set. Four term sets were larger due to deficiencies in the original code sets.DiscussionTerm sets can concisely represent any code set. This may reduce barriers for examining and reusing code sets, which may accelerate research using healthcare databases. We have developed open-source software that supports researchers using term sets.ConclusionTerm sets are independent of clinical code terminologies and therefore: enable reproducible research; are resistant to terminology changes; and are less error-prone as they are shorter than the equivalent code set.

Oral anticoagulation (OAC) is used to prevent stroke in patients with atrial fibrillation or heart valve disorders. However, OAC may cause haemorrhagic stroke. We completed a randomized trial of stroke secondary prevention 1, using primary care electronic health records (EHRs) collected into the UK Clinical Practice Research Datalink (CPRD). A small proportion of participants were prescribed warfarin following a haemorrhagic stroke diagnosis. The present research aimed to explain this observation. Participants were selected from all 11 391 patients with prevalent stroke, from 106 family practices in England and Scotland, included in the trial 1. Patients were included if they had a record of haemorrhagic stroke before the trial and were treated with warfarin during the trial. Family physicians were sent a postal questionnaire asking respondents about the nature of the stroke suffered by the patient and indications for warfarin therapy. Type of stroke was coded using the International Classification of Diseases 10th Revision 2. Warfarin accounts for 99% of OAC prescriptions in the CPRD. The project was approved by an external scientific and ethical review committee (ISAC protocol 08_083A2). GPs consented to their practice's participation. Fully anonymized data were used and no patient consent was sought. There were 134 (1.2%) participants with EHRs documenting previous haemorrhagic stroke who were prescribed warfarin during the trial. The index stroke event was coded into the EHR as a sub-arachnoid haemorrhage for 25 (24%) of cases and as intracerebral haemorrhage (ICH) for 78 (76%) of cases. There were 40 (47%) women and the mean age was 75 years (range 40 to 94 years). Questionnaire responses were obtained for 103 (77%) patients with sufficient information to confirm the type of stroke obtained for 86 (64%) (Figure 1). Figure 1 Flow chart showing physician-reported data for confirmed stroke type and indication for OAC therapy in 103 participants with electronic records for haemorrhagic stroke Questionnaire responses revealed that there were 41 (48%) patients with a physician-confirmed diagnosis of cerebral infarction (n = 39) or other non-haemorrhagic stroke (n = 2). The diagnosis was confirmed by imaging reports recorded for 36 (88%) of patients. There were five patients with a code for ischaemic stroke recorded after the initial haemorrhagic stroke but only two of these were within 1 year of the index stroke, possibly representing a clarification of the initial diagnosis. Indications for OAC in this group of participants included atrial fibrillation (n = 27), disease of pre-cerebral and cerebral arteries (n = 4), venous thromboembolism and other and not known (n = 10). There were 45 patients with a physician-confirmed diagnosis of haemorrhagic stroke including sub-arachnoid haemorrhage (n = 17) and ICH (n = 28). The diagnosis was supported by imaging results for 38 (84%) patients. Indications for OAC therapy included atrial fibrillation (n = 20), venous thrombosis (n = 10), pulmonary embolism (n = 5), aortic valve replacement (n = 3), percutaneous coronary intervention, vasculitis and not known (n = 7). We conclude that in the EHRs of a large population of stroke patients, there may be appreciable numbers with a diagnosis of haemorrhagic stroke who are treated with OAC therapy. We reported previously on the clinical coding of stroke in EHRs 3 and the potential for misclassification of stroke diagnoses. The present results should not be considered to evaluate the overall reliability of stroke coding in EHRs, because the sample was one in which data discrepancies were expected. In about half of patients, the stroke event was mis-coded as a haemorrhagic stroke when the physician-reported diagnosis for the same event date was one of cerebral infarction. Misclassification might sometimes result from haemorrhagic transformation, which is not necessarily a contra-indication to OAC therapy. Physicians may draw on sources of data from outside the EHR. Nevertheless, it is concerning that appreciable numbers of stroke patients are prescribed OAC therapy with incorrect diagnostic information coded into their EHRs, with potential medico-legal implications. Improved information sharing between providers would be of benefit to physicians. A second group comprises patients with a confirmed diagnosis of haemorrhagic stroke who were treated with OAC therapy for co-existing thromboembolic disorders. This highlights the difficult balance of risks and benefits that may sometimes be required in clinical practice. However, the use of OAC therapy in patients with previous ICH remains controversial 4. Improved evidence and decision support are required for these high risk patients.

Rationale: Cohort evidence linking long-term exposure to outdoor particulate air pollution and mortality has come largely from the United States. There is relatively little evidence from nationally representative cohorts in other countries. Objectives: To investigate the relationship between long-term exposure to a range of pollutants and causes of death in a national English cohort. Methods: A total of 835,607 patients aged 40–89 years registered with 205 general practices were followed from 2003–2007. Annual average concentrations in 2002 for particulate matter with a median aerodynamic diameter less than 10 (PM10) and less than 2.5 μm (PM2.5), nitrogen dioxide (NO2), ozone, and sulfur dioxide (SO2) at 1 km2 resolution, estimated from emission-based models, were linked to residential postcode. Deaths (n = 83,103) were ascertained from linkage to death certificates, and hazard ratios (HRs) for all- and cause-specific mortality for pollutants were estimated for interquartile pollutant changes from Cox models adjusting for age, sex, smoking, body mass index, and area-level socioeconomic status markers. Measurements and Main Results: Residential concentrations of all pollutants except ozone were positively associated with all-cause mortality (HR, 1.02, 1.03, and 1.04 for PM2.5, NO2, and SO2, respectively). Associations for PM2.5, NO2, and SO2 were larger for respiratory deaths (HR, 1.09 each) and lung cancer (HR, 1.02, 1.06, and 1.05) but nearer unity for cardiovascular deaths (1.00, 1.00, and 1.04). Conclusions: These results strengthen the evidence linking long-term ambient air pollution exposure to increased all-cause mortality. However, the stronger associations with respiratory mortality are not consistent with most US studies in which associations with cardiovascular causes of death tend to predominate.

Evidence based largely on US cohorts suggests that long-term exposure to fine particulate matter is associated with cardiovascular mortality. There is less evidence for other pollutants and for cardiovascular morbidity. By using a cohort of 836,557 patients age 40 to 89 years registered with 205 English general practices in 2003, we investigated relationships between ambient outdoor air pollution and incident myocardial infarction, stroke, arrhythmia, and heart failure over a 5-year period.Events were identified from primary care records, hospital admissions, and death certificates. Annual average concentrations in 2002 for particulate matter with a median aerodynamic diameter10 (PM10) and2.5 microns, nitrogen dioxide (NO2), ozone, and sulfur dioxide at a 1 × 1 km resolution were derived from emission-based models and linked to residential postcode. Analyses were performed using Cox proportional hazards models adjusting for relevant confounders, including social and economic deprivation and smoking.While evidence was weak for relationships with myocardial infarction, stroke, or arrhythmia, we found consistent associations between pollutant concentrations and incident cases of heart failure. An interquartile range change in PM10 and in NO2 (3.0 and 10.7 µg/m, respectively) both produced a hazard ratio of 1.06 (95% confidence interval = 1.01-1.11) after adjustment for confounders. There was some evidence that these effects were greater in more affluent areas.This study of an English national cohort found evidence linking long-term exposure to particulate matter and NO2 with the development of heart failure. We did not, however, replicate associations for other cardiovascular outcomes that have been reported elsewhere.

Purpose Large electronic datasets are increasingly being used to evaluate healthcare delivery. The aim of this study was to compare information held by cancer registries with that of the General Practice Research Database (GPRD). Methods A convenience sample of 101 020 patients aged 40+ years drawn from GPRD formed the primary data source. This cohort was derived from a larger sample originally established for a cohort study of diabetes. GPRD records were linked with those from cancer registries in the National Cancer Data Repository (NCDR). Concordance between the two datasets was then evaluated. For cases recorded only on one dataset, validation was sought from other datasets (Hospital Episode Statistics and death registration) and by detailed analysis of a subset of GPRD records. Results A total of 5797 cancers (excluding non-melanomatous skin cancer) were recorded on GPRD. Of these cases, 4830 were also recorded on NCDR (concordance rate of 83.3%). Of the 976 cases recorded on GPRD but not on NCDR, 528 were present also in the hospital records or death certificates. Of the 341 cases recorded on NCDR but not on GPRD, 307 were recorded in these other two datasets. Rates of concordance varied by cancer type. Cancer registries recorded larger numbers of patients with lung, colorectal, and pancreatic cancers, whereas GPRD recorded more haematological cancers and melanomas. As expected, GPRD recorded significantly more non-melanomatous skin cancer. Concordance decreased with increasing age. Conclusion Although concordance levels were reasonably high, the findings from this study can be used to direct efforts for better recording in both datasets. Copyright © 2012 Crown copyright.

Background and Purpose— Stroke is a potentially fatal complication of total hip replacements (THR). However, timing of stroke in THR patients compared with matched controls and influence of drug use remain unknown. The objective of this study was to determine timing of stroke in patients with THR compared with matched control subjects. Methods— A nationwide cohort study was conducted within the Danish registers (1998–2007). Included patients were those with a primary THR in the study period (n=66 583) and were matched by age, sex, and region to three referent subjects without THR or total knee replacements. Time-dependent Cox models were used to derive hazard ratios and were adjusted for disease history and drug use. Results— A 4.7-fold increased risk of ischemic stroke (adjusted hazard ratio, 4.69; 95% CI, 3.12–7.06), and a 4.4-fold increased risk of hemorrhagic stroke (adjusted hazard ratio, 4.40; 95% CI, 2.01–9.62) were found within 2 weeks following THR, compared with matched controls. The risk remained elevated during the first 6 postoperative weeks for ischemic stroke, and the first 12 weeks for hemorrhagic stroke. Outpatient antiplatelet drug use lowered the 6-week hazard ratios for ischemic stroke by 70%, although not affecting risk of hemorrhagic stroke. Conclusions— This study shows, that THR patients have a 4.7-fold increased risk of ischemic stroke, and a 4.4-fold increased risk of hemorrhagic stroke during the first 2 weeks postsurgery. Risk assessment of stroke in individual patients undergoing THR (ie, evaluate other risk factors for stroke) should be considered during the first 6 to 12 weeks.

International audience; The optimal design and patient selection for interventional trials in radiogenomics seem trivial at first sight. However, radiogenomics do not give binary information like in e.g. targetable mutation biomarkers. Here, the risk to develop severe side effects is continuous, with increasing incidences of side effects with higher doses and/or volumes. In addition, a multi-SNP assay will produce a predicted probability of developing side effects and will require one or more cut-off thresholds for classifying risk into discrete categories. A classical biomarker trial design is therefore not optimal, whereas a risk factor stratification approach is more appropriate. Patient selection is crucial and this should be based on the dose-response relations for a specific endpoint. Alternatives to standard treatment should be available and this should take into account the preferences of patients. This will be discussed in detail.

Background Sleep disturbance is highly prevalent among people of working age, and has been linked with negative occupational outcomes including impaired productivity, absenteeism, risk of injuries, and health-related job loss. We aimed to describe the epidemiology of insomnia in HEAF, a cohort study of 50–64 year-olds from 24 English general practices, and to explore the relative importance of different occupational risk factors for insomnia. Methods Data came from the baseline questionnaire of the HEAF study. Participants reported on four problems with their sleep in the past 3 months, and insomnia was defined as having at least one severe problem. Socio-demographic variables, employment conditions and feelings about work were also ascertained. Analysis was restricted to those who answered the question on sleep disturbance (N = 8,067) and for the occupational analyses, to those in work (N = 5,470). Associations were assessed by logistic regression with adjustment for age and sex, and population attributable fractions (PAFs) were also computed. Results Insomnia was reported by 18.8% of the participants. It was more common among women, current smokers, manual social classes, and in those with lower educational level, living alone, experiencing financial hardship and who were obese. It was less prevalent among older people and those socialising with friends. Unemployed people tended to report more insomnia (OR = 3.1, 95% CI: 2.6–3.8), as did those in shift work (OR = 1.4, 95% CI: 1.2–1.7), dissatisfied with their job (OR = 3.9, 95% CI: 3.1–4.9), and rarely feeling appreciated (OR = 2.5, 95% CI: 2.1–3.1), or feeling unfairly criticised at work (OR = 4.2, 95% CI: 3.0–6.1). Population burden of insomnia was associated particularly with difficulties in coping with work demands, job insecurity and difficult colleagues (PAFs 17–33%). Conclusions Our data suggest that insomnia may be linked to several workplace elements that are potentially avoidable through better employment practices and policies.

Background: Smoking increases the risk of community-acquired pneumonia (CAP) and is also associated with Chronic Obstructive Pulmonary Disease (COPD) development. Until now, it is unclear whether CAP development in COPD is due to smoking-related increased susceptibility to infections, or due to COPD pathophysiology itself. Objective: To evaluate the association between COPD and CAP by smoking status. Methods: 62.621 patients with COPD and 191.656 control subjects, matched by year of birth, gender and primary care practice, were extracted from the Clinical Practice Research Datalink (CPRD) between 2005 and 2014. Time-varying Cox proportional hazard models were used to estimate the incidence rates and hazard ratios (HRs) for CAP with exposure to COPD vs. matched controls. Analyses were stratified by age, gender and smoking status. Stratified analyses were performed to calculate HRs by smoking status in COPD vs. matched controls and within both subgroups. Results: Incidence rates of CAP in COPD (32.0/1000 person-years) and matched controls (6.8/1000 person-years) increased with age and female gender. The risk of CAP in patients with COPD was higher compared with matched controls (HR 4.2, 95%CI 4.0-4.4). Current smoking COPD patients had comparable CAP risk (HR 0.9, 95%CI 0.8-1.0) than never smoking COPD patients (reference), while current smoking matched controls had a higher risk of CAP (HR 1.2, 95%CI 1.1-1.3) compared to never smoking matched controls. Conclusion: COPD patients have a fourfold increased risk to develop CAP, independent of smoking status. Identification of factors related with the increased risk of CAP in COPD is warranted, in order to improve the management of patients at risk.

Objectives Demographic changes are requiring people to work longer. Labour force participation might be promoted by tackling sources of job dissatisfaction. We aimed to describe the epidemiology of job dissatisfaction in older British workers, to explore which perceptions of work contribute most importantly, and to assess possible impacts on health. Methods Subjects aged 50-64 years were recruited from 24 English general practices. At baseline, those currently in work (N=5,437) reported on their demographic and employment circumstances, overall job satisfaction, perceptions of their work that might contribute to dissatisfaction, and their general health, mood and well-being. Associations of job dissatisfaction with risk factors and potential health outcomes were assessed cross-sectionally by logistic regression and the potential contributions of different negative perceptions to overall dissatisfaction were summarised by population attributable fractions (PAFs). Results Job dissatisfaction was more common among men, below age 60 years, those living in London and the South East, in the more educated and in those working for larger employers. The main contributors to job dissatisfaction among employees were feeling unappreciated and/or lacking a sense of achievement (PAF 55%-56%), while in the self-employed, job insecurity was the leading contributor (PAF 79%). Job dissatisfaction was associated with all of the adverse health outcomes examined (odds ratios of 3-5), as were most of the negative perceptions of work that contributed to overall dissatisfaction. Conclusions Employment policies aimed at improving job satisfaction in older workers may benefit from focussing particularly on relationships in the workplace, fairness, job security and instilling a sense of achievement.

Hubbard and colleagues report a study using the General Practice Research Database exploring the relationship between inhaled corticosteroids and the risk of hip fracture. In so doing, they replicate findings recently presented by our own group, but fail to interpret these with due care. Using the traditional epidemiological cohort study design, we identified all users of inhaled corticosteroids, and identified fracture incidence among them. We contrasted incidence rates with cohorts who used inhaled bronchodilator therapy, but did not use inhaled corticosteroids, and with a control cohort who were matched by age and sex to the inhaled corticosteroids users, but did not suffer from asthma. In contrast, Hubbard and colleagues commenced with the fractures and looked back at exposure history using a nested case–control design. The difference in methodology represents different types of sampling, and should give identical results if derived from the same population. The two studies did indeed produce almost identical results with respect to the relative rate of hip fracture in inhaled corticosteroid users, but varied in the evaluation of the role of the underlying disease.

The majority of knee arthroplasties (KAs) are performed in patients with osteoarthritis (OA). Although bone mass may be increased in these patients, subjects with knee OA may have an increased risk of hip fracture, possibly due to an increased severity of falls. However, in patients with KAs, risk of hip fracture has not been studied extensively. We evaluated the association between KAs and hip fracture risk in a population-based case-control study using the Dutch PHARMO Record Linkage System (1991-2002, n = 33,104). Cases were patients with a first admission for hip fracture; controls were matched by age, gender, and geographic location. Neither group had a previous history of fracture. Time since first KA was calculated. Analyses were adjusted for disease and drug history. A 54% increased hip fracture risk was found in patients who underwent KA (adjusted [adj.] OR = 1.54, 95% CI 1.19-2.00). We found a strong effect modification by age in these patients: the youngest patients (aged 18-70 years) were at more increased risk for hip fracture (adj. OR = 2.76, 95% CI 1.16-6.59), while we could not detect a statistical increase in patients aged >80 years. Furthermore, the association tended to be greater during the first few years after surgery, although it did not reach statistical significance. We found that KAs are associated with a 54% increased risk of hip fracture, in particular among adult patients aged

Failures in implementation of data sharing projects have eroded public trust. In the wake of NHS England’s decision to close down its care.data programme, Tjeerd-Pieter van Staa and colleagues examine how we can do better Better use of large scale health data has the potential to benefit patient care, public health, and research. The handling of such data, however, raises concerns about patient privacy, even when the risks of disclosure are extremely small. The problems are illustrated by recent English initiatives trying to aggregate and improve the accessibility of routinely collected healthcare and related records, sometimes loosely referred to as “big data.” One such initiative, care.data, was set to link and provide access to health and social care information from different settings, including primary care, to facilitate the planning and provision of healthcare and to advance health science.1 Data were to be extracted from all primary care practices in England. A related initiative, the Clinical Practice Research Datalink (CPRD), evolved from the General Practice Research Database (GPRD). CPRD was intended to build on GPRD by linking patients’ primary care records to hospital data, around 50 disease registries and clinical audits, genetic information from UK Biobank, and even the loyalty cards of a large supermarket chain, creating an integrated data repository and linked services for all of England that could be sold to universities, drug companies, and non-healthcare industries. Care.data has now been abandoned and CPRD has stalled. The flawed implementation of care.data plus earlier examples of data mismanagement have made privacy issues a mainstream public concern. We look at what went wrong and how future initiatives might gain public support. Key elements for success of big health data projects include public confidence that records are held securely and anonymised appropriately (information security)2; public awareness of and engagement …

Objectives: (1) To develop methods for conducting cluster randomised trials of text messaging interventions utilising routine electronic health records at low cost; (2) to assess the effectiveness of text messaging influenza vaccine reminders in increasing vaccine uptake in patients with chronic conditions. Design: Cluster randomised trial with general practices as clusters. Setting: English primary care. Participants: 156 general practices, who used text messaging software, who had not previously used text message influenza vaccination reminders. Eligible patients were aged 18-64 in 'at-risk' groups. Interventions: Practices were randomly allocated to either an intervention or standard care arm in the 2013 influenza season (September to December). Practices in the intervention arm were asked to send a text message influenza vaccination reminder to their at-risk patients under 65. Practices in the standard care arm were asked to continue their influenza campaign as planned. Blinding: Practices were not blinded. Analysis was performed blinded to practice allocation. Main outcome measures: Practice-level influenza vaccine uptake among at-risk patients aged 18-64 years. Results: 77 practices were randomised to the intervention group (76 analysed, n at-risk patients=51 121), 79 to the standard care group (79 analysed, n at-risk patients=51 136). The text message increased absolute vaccine uptake by 2.62% (95% CI -0.09% to 5.33%), p=0.058, though this could have been due to chance. Within intervention clusters, a median 21.0% (IQR 10.2% to 47.0%) of eligible patients were sent a text message. The number needed to treat was 7.0 (95% CI -0.29 to 14.3). Conclusions: Patient follow-up using routine electronic health records is a low cost method of conducting cluster randomised trials. Text messaging reminders are likely to result in modest improvements in influenza vaccine uptake, but levels of patients being texted need to markedly increase if text messaging reminders are to have much effect. Trial registration number: ISRCTN48840025.

Background:Fractures are common in childhood, and there is considerable variation in the reported incidence across European countries, but few data relating to ethnic and geographic differences within a single country. We therefore aimed to determine the incidence of childhood fractures in the United Kingdom (UK), and to describe age-, ethnicity- and region- specific variations.Methods:The Clinical Practice Research Datalink (CPRD) contains anonymised electronic health records for approximately 7% of the UK population. The occurrence of a fracture between 1988 and 2012 was determined from the CPRD for all individuals < 18 years of age, and used to calculate fracture incidence rates for age, sex and ethnicity. Regional fracture incidence rates were also calculated based on general practitioner location within 14 Strategic Health Authorities (SHA) within the UK.Results: The overall fracture incidence rate was 137 per 10,000 person-years (py). This was higher in boys (169 per 10,000 py) than girls (103 per 10,000 py) and white children (150 per 10,000 py) compared to those of black (64 per 10,000 py) and South Asian (81 per 10,000 py) ethnicity. Marked geographic variation in incidence was observed. The highest fracture rates were observed in Wales, where boys and girls had 1.82 and 1.97 times greater incidence, respectively, than those residing in Greater London.Conclusion: In the period 1988–2012, there was marked geographic and ethnic variation in childhood fracture incidence across the UK. These findings also implicate lifestyle and socio-economic differences associated with location and ethnicity, and are relevant to policy makers in the UK and internationally.

We aimed to characterize incident users of alendronate from Denmark and Spain, and investigate their eligibility for participation in the pivotal Fracture Intervention Trial (FIT). This is an international cross-sectional study, where the data were obtained from the SIDIAP database (Sistema d'Informació per al Desenvolupament de l'Investigació en Atenció Primària) from Catalonia (Spain) and the Danish Health Registries (DHR). This study included patients who were incident users of alendronate, ≥40 years old with no history of Paget's disease. Our measurements were the proportion of incident users of alendronate who were not eligible to participate in FIT. 14,316 and 21,221 subjects initiated alendronate in 2006-2007 (SIDIAP) and 2005-2006 (DHR), respectively. SIDIAP and DHR alendronate user cohorts had 2347 (16.4 %) and 5275 (24.9 %) subjects aged >80 years old, reported 9 (0.1 %) and 91 (0.4 %) diagnoses of myocardial infarction, 423 (3 %) and 368 (1.7 %) of erosive gastro-intestinal disease, 200 (1.4 %) and 1109 (5.2 %) of dyspepsia, and 349 (2.4 %) and 149 (0.7 %) of metabolic bone disease, all of which were exclusion criteria in FIT. Men [3818 (26.7 %) in SIDIAP and 3885 (18.3 %) in DHR] and glucocorticoid users [1229 (8.6 %) in SIDIAP and 4716 (22.2 %) in DHR] were also excluded from the FIT trial. Overall, 3447 (35.4 %) SIDIAP and 6228 (44.5 %) (when not considering men and glucocorticoid users) DHR of incident alendronate users would have been excluded from FIT. One in two real-life users of alendronate exhibited one or more clinical characteristics that would have led to them being excluded from the FIT trial.

Since its inception in the mid-1980s, the General Practice Research Database (GPRD) has undergone many changes but remains the largest validated and most utilised primary care database in the UK. Its use in pharmacoepidemiology stretches back many years with now over 800 original research papers. Administered by the Medicines and Healthcare products Regulatory Agency since 2001, the last 5 years have seen a rebuild of the database processing system enhancing access to the data, and a concomitant push towards broadening the applications of the database. New methodologies including real-world harm–benefit assessment, pharmacogenetic studies and pragmatic randomised controlled trials within the database are being implemented. A substantive and unique linkage program (using a trusted third party) has enabled access to secondary care data and disease-specific registry data as well as socio-economic data and death registration data. The utility of anonymised free text accessed in a safe and appropriate manner is being explored using simple and more complex techniques such as natural language processing.

In 1988 Julian Tudor Hart prescribed ‘A new kind of doctor’, calling for data-intensive, community-responsive primary care.1 He argued for a realignment of primary care with the needs of populations rather than individuals; and for greater emphasis on prevention.1 These principles are largely ingrained in modern UK general practice: clinical commissioning groups (CCGs), the Quality and Outcomes Framework (QOF), and audit all require primary care to consider information about practice populations; and disease prevention is routine practice. The new era of ‘big data’ is likely to escalate further such approaches but may also change the conversation of primary care between patients, practitioners, and the public. Systematic collection, collation, and analysis of data were core to Hart’s manifesto. Today’s primary care has more advanced tools at its disposal. Electronic health records are the foundations on which we build alerts and reminders to guide decisions at the point of care. Electronic templates help capture key data on conditions and care pathways. These data can be extracted across IT systems for research (for example, the Clinical Practice Research Datalink [CPRD], The Health Improvement Network [THIN], QResearch, and ResearchOne in the UK; the NIVEL Primary Care Database in the Netherlands; or SIDIAP in Spain), and across populations to support service development (for example, audit, www.openprescribing.net) and incentivise activity (for example, QOF in the UK, the Primary Health Organization [PHO] Performance Programme in New Zealand, or Practice Incentives Program [PIP] in Australia). Traditionally, large-scale data extracts of NHS care records have been seen as the way to realise the more systematic primary care that Hart envisioned. Extracted records may be combined with other data at a national level such as hospital admissions and discharges from claims data, or official government statistics such as death registrations. More detailed information at regional level, however, is …

Rates of fracture worldwide are changing. Using the Clinical Practice Research Datalink (CPRD), age, and gender, geographical, ethnic and socioeconomic trends in fracture rates across the United Kingdom were studied over a 24-year period 1988-2012. Previously observed patterns in fracture incidence by age and fracture site were evident. New data on the influence of geographic location, ethnic group and socioeconomic status were obtained.With secular changes in age- and sex-specific fracture incidence observed in many populations, and global shifts towards an elderly demography, it is vital for health care planners to have an accurate understanding of fracture incidence nationally. We aimed to present up to date fracture incidence data in the UK, stratified by age, sex, geographic location, ethnicity and socioeconomic status.The Clinical Practice Research Datalink (CPRD) contains anonymised electronic health records for approximately 6.9% of the UK population. Information comes from General Practitioners, and covers 11.3 million people from 674 practices across the UK, demonstrated to be representative of the national population. The study population consisted of all permanently registered individuals aged ≥18years. Validated data on fracture incidence were obtained from their medical records, as was information on socioeconomic deprivation, ethnicity and geographic location. Age- and sex-specific fracture incidence rates were calculated.Fracture incidence rates by age and sex were comparable to those documented in previous studies and demonstrated a bimodal distribution. Substantial geographic heterogeneity in age- and sex adjusted fracture incidence was observed, with rates in Scotland almost 50% greater than those in London and South East England. Lowest rates of fracture were observed in black individuals of both sexes; rates of fragility fracture in white women were 4.7 times greater than in black women. Strong associations between deprivation and fracture risk were observed in hip fracture in men, with a relative risk of 1.3 (95% CI 1.21-1.41) in Index of Multiple Deprivation category 5 (representing the most deprived) compared to category 1.This study presents robust estimates of fracture incidence across the UK, which will aid decisions regarding allocation of healthcare provision to populations of greatest need. It will also assist the implementation and design of strategies to reduce fracture incidence and its personal and financial impact on individuals and health services.

It was with great interest that we read the correspondence of Abud-Mendoza1 on our recent paper in which we described a decreased risk of developing systemic lupus erythematosus (SLE) in statin users who continued their therapy for >1 year.2 We agree that prevention of cardiovascular disease in rheumatic diseases is of great importance.3 Whether statins decrease disease activity in SLE is, however, controversial since a recent meta-analysis of five controlled trials did not suggest any significant effect of statin therapy on Systemic Lupus Erythematosus Disease Activity Index.4 Unfortunately, in the UK’s Clinical Practice Research Datalink (CPRD)—an ongoing primary care database of anonymised medical records from general practitioners that was used in our study—no measurements for SLE activity before or after initiating statin therapy are available.2 We, however, do not think that statin …

Objectives: The goal of comparative effectiveness analysis is to examine the relationship between two variables, treatment, or exposure and effectiveness or outcome. Unlike data obtained through randomized controlled trials, researchers face greater challenges with causal inference with observational studies. Recognizing these challenges, a task force was formed to develop a guidance document on methodological approaches to addresses these biases. Methods: The task force was commissioned and a Chair was selected by the International Society for Pharmacoeconomics and Outcomes Research Board of Directors in October 2007. This report, the second of three reported in this issue of the Journal, discusses the inherent biases when using secondary data sources for comparative effectiveness analysis and provides methodological recommendations to help mitigate these biases. Results: The task force report provides recommendations and tools for researchers to mitigate threats to validity from bias and confounding in measurement of exposure and outcome. Recommendations on design of study included: the need for data analysis plan with causal diagrams; detailed attention to classification bias in definition of exposure and clinical outcome; careful and appropriate use of restriction; extreme care to identify and control for confounding factors, including time-dependent confounding. Conclusions: Design of nonrandomized studies of comparative effectiveness face several daunting issues, including measurement of exposure and outcome challenged by misclassification and confounding. Use of causal diagrams and restriction are two techniques that can improve the theoretical basis for analyzing treatment effects in study populations of more homogeneity, with reduced loss of generalizability.

Background The aim of this study was to estimate trends in primary care consultations and antibiotic prescribing for acute respiratory tract infections (RTIs) in the UK from 1997 to 2006. Methods Data were analysed for 100 000 subjects registered with 78 family practices in the UK General Practice Research Database; the numbers of consultations for RTI and associated antibiotic prescriptions were enumerated. Results The consultation rate for RTI declined in females from 442.2 per 1000 registered patients in 1997 to 330.9 in 2006, and in males from 318.5 to 249.0. The rate of consultations for colds, rhinitis and upper respiratory tract infection (URTI) declined by 4.2 (95% CI 2.3–6.1) per 1000 per year in females and by 3.6 (2.3–4.8) in males. The rate of antibiotic prescribing for RTI was higher in females and declined by 8.5 (2.0–15.1) per 1000 in females and 6.7 (2.7–10.8) in males. For colds, rhinitis and URTI, the proportion of consultations with antibiotics was prescribed declined by 1.7% per year in females and 1.8% in males. Conclusions Decreasing frequency of consultation and antibiotic prescription for colds, rhinitis and ‘URTI’ continues to drive a reduction in the rate of antibiotic utilization for RTIs.

SummaryThe objective of this study was to evaluate the rate of stroke associated with aspirin and warfarin in routine clinical practice. The study included patients aged 40+ with chronic atrial fibrillation (cAF) registered in the UK General Practice Research Database. The outcome was the rate of stroke during current, past and no use of aspirin and warfarin. The study included 51,807 cAF patients. There was no difference in the rate of stroke between current and past use of aspirin (relative rate [RR]=1.04 [95% confidence interval (CI) 0.94 – 1.15]), while the rate of stroke was reduced during current warfarin use compared to past use (RR=0.62 [95% CI 0.54 – 0.71]). For warfarin, a pattern of lower rates of stroke during current exposure and higher rates with past exposure was seen only in patients treated for at least 6–12 months. For aspirin, no changes in the rates of stroke were observed with discontinuation of aspirin. The effectiveness of warfarin was dependent on the level of anticoagulation, with optimal risk reduction occurring within the recommended international normalised ratio (INR) range of 2.0 to 3.0. The proportion of patients achieving a stable INR within the target therapeutic range was at its lowest during the first three months of warfarin treatment. In conclusion, the results of this study support the effectiveness of warfarin treatment to reduce the rate of stroke in cAF patients in the general clinical practice setting, however the risk reduction is lower than that reported in clinical trials.

The effects of low persistence on fracture risk have not been fully addressed. The objectives of this study were to describe the persistence and compliance with bisphosphonates and to evaluate the association with fracture risk. The General Practice Research database was used to identify patients >or=18 yr of age prescribed alendronate or risedronate. The follow-up was divided into periods of current and past use. Time-dependent Cox regression was used. The study population included 44,531 patients; 58.3% of the patients continued bisphosphonate treatment for >1 yr and 23.6% for >5 yr. The risk of hip/femur fracture (adjusted relative rate [RR], 0.78; 95% CI, 0.64-0.94) and osteoporotic fracture (RR, 0.85; 95% CI, 0.76-0.94) were lower with current compared with past bisphosphonate use. The largest reduction in hip/femur and osteoporotic fracture risk was observed in patients treated for at least 6 mo and no reduction in those treated for

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Use of beta(2) agonists has been associated with tachycardia, an abnormal ECG and atrial fibrillation. * Previous observational studies of the association between use of beta(2) agonists and the risk of acute myocardial infarction (MI) have demonstrated conflicting results. * Instead of a causal effect, the positive association between beta(2) agonist use and MI may be explained by latent ischaemic heart disease, which has symptoms that appear similar to respiratory complaints in chronic obstructive pulmonary disease.WHAT THIS STUDY ADDS: * The majority of beta(2) agonist users in our study population did not have an increased risk of nonfatal acute MI. * Only patients with ischaemic heart disease and who had recently started beta(2) agonists had an increased risk of acute MI. * It is likely that this increased risk was related to latent cardiovascular disease rather than direct effects of beta(2) agonists.AIM: Observational retrospective studies of the association between use of beta(2) agonists and the risk of acute myocardial infarction (MI) have demonstrated conflicting results, particularly among first-time users. The aim of this study was to examine the association between beta(2) agonist use and first nonfatal acute MI.METHODS: We conducted a case-control study (2476 cases) nested in a cohort of antihypertensive drug users in the Dutch PHARMO RLS database. PHARMO RLS consists of drug dispensing linked to the national hospitalizations register. Each case of nonfatal acute MI was matched with up to 12 control patients by gender, age and region. Drug and disease history and the severity of the underlying respiratory disease were adjusted for.RESULTS: Risk of acute MI was increased in current beta(2) agonist users [crude odds ratio (OR) 1.36, 95% confidence interval (CI) 1.15, 1.61]. However, this excess risk was reduced after adjustment for severity of asthma and chronic obstructive pulmonary disease (adjusted OR 1.18, 95% CI 0.93, 1.49). The risk was highest in patients with ischaemic heart disease and low cumulative dose of beta(2) agonists (adjusted OR 2.47, 95% CI 1.60, 3.82).CONCLUSION: Most users of beta(2) agonists did not have an increased risk of acute MI. Only patients with ischaemic heart disease with low cumulative exposure to beta(2) agonists had an increased risk of acute MI. It is likely that this increased risk was related to latent cardiovascular disease rather than to the direct effects of beta(2) agonists.

BACKGROUND: Use of inhaled corticosteroids may reduce the risk of acute myocardial infarction (MI) through reductions in systemic inflammation and C-reactive protein. OBJECTIVES: To examine the association between the use of inhaled corticosteroids and the risk of non-fatal acute MI. METHODS: In the Dutch PHARMO record linkage system database, we conducted a case-control study (2476 MI cases), nested in a cohort of antihypertensive drug users. The use of inhaled corticosteroids 100 days before the index date was compared with never use. We adjusted the analyses for the severity of the underlying respiratory disease and general drug and disease history. RESULTS: We found that the use of inhaled corticosteroids was not associated with a decreased risk of non-fatal MI in antihypertensive drug users after adjustment for the underlying respiratory disease severity, adjusted odds ratio (OR) 1.24, 95% confidence interval (CI) 0.97-1.57. A higher daily dose (adjusted OR 1.82, 95% CI 0.80-4.13) and longer duration of use (adjusted OR 1.28, 95% CI 0.90-1.81) were not associated with a decreased risk of non-fatal MI. An inhaled corticosteroid dispensing in the 30 days before the index date was not protective but resulted in a 1.7-fold increased risk of non-fatal MI. CONCLUSION: Our results do not support the hypothesis that inhaled corticosteroids protect against the risk of non-fatal MI by a reduction of systemic inflammation.

Background Demographic trends in developed countries have prompted governmental policies aimed at extending working lives. However, working beyond the traditional retirement age may not be feasible for those with major health problems of ageing, and depending on occupational and personal circumstances, might be either good or bad for health. To address these uncertainties, we have initiated a new longitudinal study. Methods/design We recruited some 8000 adults aged 50–64 years from 24 British general practices contributing to the Clinical Practice Research Datalink (CPRD). Participants have completed questionnaires about their work and home circumstances at baseline, and will do so regularly over follow-up, initially for a 5-year period. With their permission, we will access their primary care health records via the CPRD. The inter-relation of changes in employment (with reasons) and changes in health (e.g., major new illnesses, new treatments, mortality) will be examined. Discussion CPRD linkage allows cost-effective frequent capture of detailed objective health data with which to examine the impact of health on work at older ages and of work on health. Findings will inform government policy and also the design of work for older people and the measures needed to support employment in later life, especially for those with health limitations. Electronic supplementary material The online version of this article (doi:10.1186/s12889-015-2396-8) contains supplementary material, which is available to authorized users.

Randomised point-of-care trials (POCT)1 or registry trials2 offer a potentially efficient, convenient and cost-effective alternative to conventional randomised controlled trials. By using information present in an existing database, registry or electronic patient record (EPR), POCT eliminate the need for duplicative data collection.1 Neonatal medicine is well placed to use this methodology; an existing national resource, the National Neonatal Research Database (NNRD), holds detailed data extracted from the neonatal EPR of all National Health Service neonatal units in England, Wales and Scotland; contributing units are known as the UK Neonatal Collaborative (UKNC). We assessed the acceptability of neonatal POCT using the NNRD in two surveys. In the first (March–June 2014), we emailed all English UKNC leads, proposed a neonatal POCT and asked whether their unit would be willing to participate. In the second, we examined attitudes towards the neonatal EPR. We emailed neonatal trainees (n=108) and lead nurses, and asked them …

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PURPOSE: To assess the association between exposure to antiepileptic drugs (AEDs) and the occurrence of aplastic anemia. METHODS: A retrospective case-control study was conducted using data from the U.K. General Practitioners Research Database (GPRD). Cases were defined as patients diagnosed with aplastic anemia. For each case, up to three control patients were matched on age, sex, and medical practice. Cases and controls were compared with respect to AED use. The effects of duration of AED use were assessed. Characteristics of individual cases with AED use were reviewed. RESULTS: The study population comprised 173 cases and 497 controls. AED use was more prevalent among cases (9.2%) than among controls (0.8%). After adjustment for confounders, the use of AEDs was significantly associated with aplastic anemia (adjusted odds ratio (OR), 9.5; 95% confidence interval (CI), 3.0-39.7). The most frequently used AEDs were carbamazepine (CBZ), valproic acid (VPA), and phenytoin. The 16 exposed cases were heterogeneous with respect to patient and exposure characteristics: the age of these patients varied from 1 to 92 years, and the duration of AED use varied from 17 days to 6.8 years. CONCLUSIONS: This study indicates that use of AEDs, in particular CBZ and VPA, is associated with a ninefold increased risk of aplastic anemia. Physicians should be alert to the possibility of AED-associated aplastic anemia.

Skeletal complications during or after treatment of acute lymphoblastic leukemia (ALL) have been frequently reported and can cause substantial morbidity, yet their incidence is not well established. The present study assessed the incidence of fractures, osteonecrosis (ON), and bone pain during ALL treatment and compared the fracture incidence with age- and sex-specific reference data from the UK General Practice Research Database (GPRD).Medical records of 122 ALL patients diagnosed at our institution from 1992 to 2004 were reviewed for information on fractures, ON, bone pain, and their anatomical location, risk group, phase of antileukemic therapy, and time since diagnosis. Evaluation of skeletal complications was followed up until July 2005 or the patient's death. Thirteen children were excluded as they were transferred to other institutions shortly after diagnosis.Skeletal complications occurred at a 5-year incidence of 32.7%. The 5-year incidence of fractures, ON, and isolated bone pain was 13.5%, 12.1%, and 12.3%, respectively. The relative rate of fractures adjusted for age and sex was 2.03 (95% confidence interval 1.15-3.57) compared to the GPRD, with greatest rates in children5 years. Thirty ON occurred in 10 patients with a 15 times greater incidence in children10 years than in those5 years. Nearly all skeletal complications occurred during maintenance therapy at a median of 14.92 months (range 0.0-53.8) after diagnosis and in weight-bearing bones.The doubled fracture rate and the high incidence of skeletal complications during the first years after diagnosis suggest the developing skeleton is very vulnerable in this period. Adolescents develop more ON whereas younger children may be more prone to fractures. Serious "immediate effects" of chemotherapy on bone appear of great concern and should entail preventative studies in this group of patients.

The objective of our study was to investigate whether use of antipsychotics is associated with hip/femur fractures and whether pharmacological differences between antipsychotics are related to the occurrence of fractures.A case-control study was conducted, in which cases were defined as patients with a hip/femur fracture. Each patient was matched to one control patient. The association between use of antipsychotics and the occurrence of hip/femur fractures was evaluated using conditional logistic regression.The study included 44,500 patients from 683 general practices from different geographical areas in the UK, registered within the General Practice Research Database (GPRD). Exposure to antipsychotics was categorized as "no use", "current use" and "prior use".Both current and prior use of antipsychotics were associated with an approximately two-fold increased risk of fractures. After adjustment for possible confounders, a small significant effect remained (Odds Ratios (OR) of 1.3). We did not find an association between dose of antipsychotics, or between the degree of blockade of the alpha-1 adrenoceptor or histamine-1 receptor and risk of fractures. The total number of days of antipsychotic use was significantly associated with an increased risk of hip/femur fractures.We conclude that there is a small increased risk of hip/femur fractures associated with the use of antipsychotics. This risk increases with long-term use. (c) 2005 Elsevier Inc. All rights reserved.

To compare the incidence of various fractures in a cohort of patients with epilepsy with a reference cohort of patients not having epilepsy.Patients were included in the epilepsy cohort if they had at least one diagnosis of epilepsy in their medical history and had sufficient evidence of "active" epilepsy (use of antiepileptic drugs, diagnoses) after the practice was included in the General Practice Research Database (GPRD). Two reference patients were sampled for each patient with epilepsy from the same practice. Primary outcome was the occurrence of any fracture during follow-up. Poisson regression analysis was used to estimate incidence density ratios (IDRs).The study population comprised 40,485 and 80,970 patients in the epilepsy and reference cohorts, respectively. The median duration of follow-up was approximately 3 years. The overall incidence rate in the epilepsy cohort was 241.9 per 10,000 person-years. This rate was about twice as high as that in reference cohort: age- and sex-adjusted IDR, 1.89 (95% CI, 1.81-1.98). When comparing IDRs among the different groups of fractures, the highest relative-risk estimate was found for hip and femur fractures (adjusted IDR, 2.79; 95% CI, 2.41-3.24). IDRs were consistently elevated across age and sex groups and across fracture subtypes.The overall risk of fractures was nearly twice as high among patients with epilepsy compared with the general population. The relative fracture risk was highest for hip and femur. Further study is necessary to elucidate whether this elevated risk is due to the disease, the use of antiepileptic drugs, or both.

We tested the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke), and CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient

Objectives Demographic changes are requiring people to work longer. No previous studies, however, have focused on whether the ‘frailty’ phenotype (which predicts adverse events in the elderly) is associated with employment difficulties. To provide information, we assessed associations in the Health and Employment After Fifty Study, a population-based cohort of 50–65-year olds.Methods Subjects, who were recruited from 24 English general practices, completed a baseline questionnaire on ‘prefrailty’ and ‘frailty’ (adapted Fried criteria) and several work outcomes, including health-related job loss (HRJL), prolonged sickness absence (>20 days vs less, past 12 months), having to cut down substantially at work and difficulty coping with work's demands. Associations were assessed using logistic regression and population attributable fractions (PAFs) were calculated.Results In all, 3.9% of 8095 respondents were classed as ‘frail’ and 31.6% as ‘prefrail’. Three-quarters of the former were not in work, while 60% had left their last job on health grounds (OR for HRJL vs non-frail subjects, 30.0 (95% CI 23.0 to 39.2)). Among those in work, ORs for prolonged sickness absence, cutting down substantially at work and struggling with work's physical demands ranged from 10.7 to 17.2. The PAF for HRJL when any frailty marker was present was 51.8% and that for prolonged sickness absence was 32.5%. Associations were strongest with slow reported walking speed. Several associations were stronger in manual workers than in managers.Conclusions Fried frailty symptoms are not uncommon in mid-life and are strongly linked with economically important adverse employment outcomes. Frailty could represent an important target for prevention.

This study aims to investigate the incidence and annual presentation rates of alcohol dependence in general practice in the UK, and examine age-, gender-, socioeconomic-, and region-specific variation. We conducted a retrospective 'open' cohort study using the Clinical Practice Research Datalink (CPRD), an anonymised primary care database. Prior to data extraction, a case definition for alcohol dependence in CPRD was established using 47 Read codes, which included primary alcohol dependence and consequences of alcohol dependence. Directly standardised rates for incidence and annual presentation were calculated for each year between 1990 and 2013. Rates were compared by gender, age, UK home nation, and practice-level Index of Multiple Deprivation. The directly standardised annual incidence rates were 8.3 and 3.7 per 10,000 male and female patients, respectively. The estimated annual rates of presentation per 10,000 were 17.1 for males and 7.6 for females. Female to male rate ratios were: 0.40 (95% CI: 0.39–0.41) for incident cases; and 0.37 (95% CI: 0.36–0.39) for annual presentation. Rates were highest in those aged 35–54 for both measures and across genders, and lowest in those aged over 75 years. With England as the reference nation, Northern Ireland and Scotland had significantly higher rates for both measures. Patients from the most deprived areas had the highest incidence and annual presentation rates. There is unequal distribution of patients with severe alcohol dependence across population subgroups in general practice. Given the health and economic burden associated with dependent drinking, these data will be useful in informing future public health initiatives.

AimTo evaluate drug therapy for alcohol dependence in the 12 months after first diagnosis in UK primary care.DesignOpen cohort study.SettingGeneral practices contributing data to the UK Clinical Practice Research Database.Participants39,980 people with an incident diagnosis of alcohol dependence aged 16 years or older between 1 January 1990 and 31 December 2013.Main outcome measureUse of pharmacotherapy (acamprosate, disulfiram, naltrexone, baclofen and topiramate) to promote abstinence from alcohol or reduce drinking to safe levels in the first 12 months after a recorded diagnosis of alcohol dependence.FindingsOnly 4,677 (11.7%) of the cohort received relevant pharmacotherapy in the 12 months following diagnosis. Of the 35,303 that did not receive pharmacotherapy, 3,255 (9.2%) received psychosocial support. The remaining 32,048 (80.2%) did not receive either mode of treatment in the first 12 months. Factors that independently reduced the likelihood of receiving pharmacotherapy included: being male (Odds Ratio [OR] 0.74; 95% CI 0.69 to 0.78); older (65-74 years: OR 0.61; 95% CI 0.49 to 0.77); being from a practice based in the most deprived quintile (OR 0.58; 95% CI 0.53 to 0.64); and being located in Northern Ireland (OR 0.78; 95% CI 0.67 to 0.91). The median duration to initiation of pharmacotherapy was 0.80 months (95% CI 0.70 to 1.00) for acamprosate and 0.60 months (95% CI 0.43 to 0.73) for disulfiram. Persistence analysis for those receiving acamprosate and disulfiram revealed that many patients never received a repeat prescription; persistence at 6 months was 27.7% for acomprosate and 33.2% for disulfiram. The median duration of therapy was 2.10 months (95% CI 1.87 to 2.53) for acamprosate and 3.13 months (95% CI 2.77 to 3.36) for disulfiram.ConclusionDrug therapy to promote abstinence in alcohol dependent patients was low, with the majority of patients receiving no therapy, either psychological or pharmacological. When drug therapy was prescribed, persistence was low with most patients receiving only one prescription. Our data show that treatment for alcohol dependence is haphazard, and there is an urgent need to explore strategies for improving clinical management of this patient group.

Observational drug safety studies may be susceptible to confounding or protopathic bias. This bias may cause a spurious relationship between drug exposure and adverse side effect when none exists and may lead to unwarranted safety alerts. The spurious relationship may manifest itself through substantially different risk levels between exposure groups at the start of follow-up when exposure is deemed too short to have any plausible biological effect of the drug. The restrictive proportional hazards assumption with its arbitrary choice of baseline hazard function renders the commonly used Cox proportional hazards model of limited use for revealing such potential bias. We demonstrate a fully parametric approach using accelerated failure time models with an illustrative safety study of glucose-lowering therapies and show that its results are comparable against other methods that allow time-varying exposure effects. Our approach includes a wide variety of models that are based on the flexible generalized gamma distribution and allows direct comparisons of estimated hazard functions following different exposure-specific distributions of survival times. This approach lends itself to two alternative metrics, namely relative times and difference in times to event, allowing physicians more ways to communicate patient's prognosis without invoking the concept of risks, which some may find hard to grasp. In our illustrative case study, substantial differences in cancer risks at drug initiation followed by a gradual reduction towards null were found. This evidence is compatible with the presence of protopathic bias, in which undiagnosed symptoms of cancer lead to switches in diabetes medication. Copyright © 2015 John Wiley & Sons, Ltd.

Introduction The UK government recommends that at least 75% of people aged under 64 with certain conditions receive an annual influenza vaccination. Primary care practices often fall short of this target and strategies to increase vaccine uptake are required. Text messaging reminders are already used in 30% of practices to remind patients about vaccination, but there has been no trial addressing their effectiveness in increasing influenza vaccine uptake in the UK. The aims of the study are (1) to develop the methodology for conducting cluster randomised trials of text messaging interventions utilising routine electronic health records and (2) to assess the effectiveness of using a text messaging influenza vaccine reminder in achieving an increase in influenza vaccine uptake in patients aged 18–64 with chronic conditions, compared with standard care. Methods and analysis This cluster randomised trial will recruit general practices across three settings in English primary care (Clinical Practice Research Datalink, ResearchOne and London iPLATO text messaging software users) and randomise them to either standard care or a text messaging campaign to eligible patients. Flu vaccine uptake will be ascertained using routinely collected, anonymised electronic patient records. This protocol outlines the proposed study design and analysis methods. Ethics and dissemination This study will determine the effectiveness of text messaging vaccine reminders in primary care in increasing influenza vaccine uptake, and will strengthen the methodology for using electronic health records in cluster randomised trials of text messaging interventions. This trial was approved by the Surrey Borders Ethics Committee (13/LO/0872). The trial results will be disseminated at national conferences and published in a peer-reviewed medical journal. The results will also be distributed to the Primary Care Research Network and to all participating general practices. Trial registration number This study is registered at controlled-trials.com ISRCTN48840025, July 2013.

Objective: UK primary care databases, which contain diagnostic, demographic and prescribing information for millions of patients geographically representative of the UK, represent a significant resource for health services and clinical research. They can be used to identify patients with a specified disease or condition (phenotyping) and to investigate patterns of diagnosis and symptoms. Currently, extracting such information manually is time-consuming and requires considerable expertise. In order to exploit more fully the potential of these large and complex databases, our interdisciplinary team developed generic methods allowing access to different types of user.\ud \ud Materials and methods: Using the Clinical Practice Research Datalink database, we have developed an online user-focused system (TrialViz), which enables users interactively to select suitable medical general practices based on two criteria: suitability of the patient base for the intended study (phenotyping) and measures of data quality.\ud \ud Results: An end-to-end system, underpinned by an innovative search algorithm, allows the user to extract information in near real-time via an intuitive query interface and to explore this information using interactive visualization tools. A usability evaluation of this system produced positive results.\ud \ud Discussion: We present the challenges and results in the development of TrialViz and our plans for its extension for wider applications of clinical research.\ud \ud Conclusions: Our fast search algorithms and simple query algorithms represent a significant advance for users of clinical research databases.

Background The study aimed to conduct a process evaluation for a cluster randomised trial of a computer-delivered, point-of-care intervention to reduce antibiotic prescribing in primary care. The study aimed to evaluate both the intervention and implementation of the trial. Methods The intervention comprised a set of electronic educational and decision support tools that were remotely installed and activated during consultations with patients with acute respiratory infections over a 12 month intervention period. A mixed method evaluation was conducted with 103 general practitioners (GPs) who participated in the trial. Semi-structured telephone interviews were conducted with 20 GPs who had been in the intervention group of the trial and 4 members of the implementation staff. Questionnaires, consisting of both intervention evaluation and theory-based measures, were self-administered to 83 GPs (56 control group and 27 intervention group). Results Interviews suggested that a key factor influencing GPs’ use of the intervention appeared to be their awareness of the implementation of the system into their practice. GPs who were aware of the implementation of the intervention reported feeling confident in using it if they chose to and understood the purpose of the intervention screens. However, GPs who were unaware that the intervention would be appearing often reported feeling confused when they saw the messages appear on the screen and not fully understanding what they were for or how they could be used. Intervention evaluation questionnaires indicated that GPs were satisfied with the usability of the prompts, and theory-based measures revealed that intervention group GPs reported higher levels of self-efficacy in managing RTI patients according to recommended guidelines compared to GPs in the control group. Conclusions Remote installation of a computer-delivered intervention for use at the point-of-care was feasible and acceptable. Additional measures to promote awareness of the intervention may be required to promote health care professionals’ utilisation of the intervention and these might sometimes compromise the pragmatic intention of a trial. Trial registration ISRCTN47558792 (registered on 17 March 2010).

OBJECTIVES: Atrial fibrillation (AF) is the most common cardiac rhythm disorder with a significant health burden. The aim of this study was to characterise patients with recently diagnosed AF and to estimate the rates of comorbidities and outcome events requiring hospitalisation in routine clinical practice. DESIGN: Pharmacoepidemiological cohort study using observational data. METHODS/SETTING: This study included 16 513 patients with a first diagnosis of AF between 1 January 2005 and 28 February 2010 (newly diagnosed patients) using data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and the Office for National Statistics mortality data. Exposure was stratified by vitamin K antagonist (VKA) exposure (non-use, current, recent and past exposure) based on prescriptions and/or international normalised ratio measurements, and followed for outcome events of interest based on diagnosis codes in the databases, that is, vascular outcomes, bleeding events and others. The main focus of the study was on outcome events requiring hospitalisation using the HES data. RESULTS: The incidence of vascular outcome hospitalisations (myocardial infarction (MI), stroke or systemic arterial peripheral embolism) was 3.8 (95% CI 3.5 to 4.0)/100 patient-years. The incidence of stroke was 0.9 (0.8 to 1.1) during current VKA exposure, 2.2 (1.6 to 2.9) for recent, 2.4 (1.9 to 2.9) for past and 3.4 (3.1 to 3.7) during non-use. MI incidence was 0.7 (0.6 to 0.9) for current VKA exposure, 0.7 (0.4 to 1.2) for recent, 1.1 (0.8 to 1.5) for past and 1.9 (1.7 to 2.1) during non-use. The incidence of bleeding event hospitalisations was 3.8 (3.4 to 4.2) for current VKA exposure, 4.5 (3.7 to 5.5) for recent, 2.7 (2.2 to 3.3) for past and 2.9 (2.6 to 3.2) during non-use; 38% of intracranial bleeds and 6% of gastrointestinal bleeds were fatal. CONCLUSIONS: This population-based study from recent years provides a comprehensive characterisation of newly diagnosed patients with AF and incidence estimates of common outcomes with a focus on hospitalised events stratified by VKA exposure. This study will help to place future data on new oral anticoagulants into perspective.

Composite outcomes seem an attractive method to increase statistical power, but they can mask the effect of treatment

BackgroundThere are concerns that metal-on-metal hip implants may cause cancer. The objective of this study was to evaluate patterns and timing of risk of cancer in patients with metal-on-metal total hip replacements (THR).MethodsIn a linkage study between the English National Joint Registry (NJR) and the Clinical Practice Research Datalink (CPRD), we selected all THR surgeries (NJR) between 2003 and 2010 (n = 11,540). THR patients were stratified by type of bearing surface. Patients were followed up for cancer and Poisson regression was used to derive adjusted relative rates (RR).ResultsThe risk of cancer was similar in patients with hip resurfacing (RR 0.69; 95% Confidence Interval [CI] 0.39-1.22) or other types of bearing surfaces (RR 0.96; 95% CI 0.64-1.43) compared to individuals with stemmed metal-on-metal THR. The pattern of cancer risk over time did not support a detrimental effect of metal hip implants. There was substantial confounding: patients with metal-on-metal THRs used fewer drugs and had less comorbidity.ConclusionsMetal-on-metal THRs were not associated with an increased risk of cancer. There were substantial baseline differences between the different hip implants, indicating possibility of confounding in the comparisons between different types of THR implants.

Objective. Antipsychotics have been associated with increased cardiac events including mortality. This study assessed cardiac events including mortality among antipsychotic users relative to nonusers.Methods. The General Practice Research Database (GPRD) was used to identify antipsychotic users, matched general population controls, and psychiatric diseased nonusers. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Sensitivity analyses were conducted for age, dose, duration, antipsychotic type, and psychiatric disease.Results. 183,392 antipsychotic users (115,491 typical and 67,901 atypical), 544,726 general population controls, and 193,920 psychiatric nonusers were identified. Nonusers with schizophrenia, dementia, or bipolar disorder had increased risks of all-cause mortality compared to general population controls, while nonusers with major depression had comparable risks. Relative to psychiatric nonusers, the adjusted relative ratios (aRR) of all-cause mortality in antipsychotic users was 1.75 (95% CI: 1.64–1.87); cardiac mortality 1.72 (95% CI: 1.42–2.07); SCD primary definition 5.76 (95% CI: 2.90–11.45); SCD secondary definition 2.15 (95% CI: 1.64–2.81); CHD 1.16 (95% CI: 0.94–1.44); and VA 1.16 (95% CI: 1.02–1.31). aRRs of the various outcomes were lower for atypical versus typical antipsychotics (all-cause mortality 0.83 (95% CI: 0.80–0.85); cardiac mortality 0.89 (95% CI: 0.82–0.97); and SCD secondary definition 0.76 (95% CI: 0.55–1.04).Conclusions. Antipsychotic users had an increased risk of cardiac mortality, all-cause mortality, and SCD compared to a psychiatric nonuser cohort.

Objective. Assess risk of cardiac events and mortality among users of olanzapine and other antipsychotics relative to nonusers. Methods. The General Practice Research Database was used to identify cohorts of antipsychotic users and nonusers with psychiatric illness. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Results. 183,392 antipsychotic users (including 20,954 olanzapine users) and 193,920 psychiatric nonusers were identified. There was a significantly higher rate of cardiac mortality (adjusted RR [aRR]: 1.53, CI, 1.12–2.09) in olanzapine users relative to psychiatric nonusers, consistent with findings for both atypical and typical antipsychotics. Relative to psychiatric nonusers, no increased risk of all-cause mortality was observed among olanzapine users (aRR: 1.04, CI, 0.93–1.17), but elevated all-cause mortality risk was observed when compared to all antipsychotic users (aRR: 1.75, CI, 1.64–1.87). There was no increased risk of CHD or VA among olanzapine users relative to psychiatric nonusers, consistent with findings for atypical but not typical antipsychotics. SCD cases were uncommon. Conclusions. Use of antipsychotic agents was associated with increased risk of all-cause and cardiac mortality. Patients treated with olanzapine were found to be at increased risk of cardiac mortality versus psychiatric nonusers.