Scientific
publications

INTRODUCTION: Risk scoring is an integral part of the prevention of cardiovascular disease (CVD) and should form the basis for the decision to offer medication to reduce cholesterol (statins). However, there is a suggestion in the literature that many patients are still initiated on statins based on raised cholesterol rather than a raised CVD risk. It is important, therefore, to investigate the role that lipid levels and CVD risks have in the decision to prescribe. This research will establish how cholesterol levels and CVD risk independently influence the prescribing of statins for the primary prevention of CVD in primary care. METHODS AND ANALYSIS: The Health Improvement Network (THIN) is a database of coded primary care electronic patient records from over 500 UK general practices. From this resource, a historical cohort will be created of patients without a diagnosis of CVD, not currently receiving a prescription for statins and who had a lipid profile measured. A post hoc QRISK2 score will be calculated for these patients and they will be followed up for 60 days to establish whether they were subsequently prescribed a statin. Primary analysis will consist of predictive modelling using multivariate logistic regression with potential predictors including cholesterol level, calculated QRISK2 score, sociodemographic characteristic and comorbidities. Descriptive statistics will be used to identify trends in prescribing and further secondary analysis will explore what other factors may have influenced the prescribing of statins and the degree of interprescriber variability. ETHICS AND DISSEMINATION: The THIN Data Collection Scheme was approved by the South-East Multicentre Research Ethics Committee in 2003. Individual studies using THIN require Scientific Review Committee approval. The original protocol for this study and a subsequent amendment have been approved (16THIN009A1). The results will be published in a peer review journal and presented at national and international conferences.

BACKGROUND: Perioperative mortality is low for patients undergoing abdominal aortic aneurysm (AAA) repair, but long-term survival remains poor. Although patients diagnosed with AAA have a significant burden of cardiovascular disease and associated risk factors, there is limited understanding of the contribution of cardiovascular risk management to long-term survival. METHODS: General practice records within The Health Improvement Network (THIN) were examined. Patients with a diagnosis of AAA and at least 1 year of registered medical history were identified from 2000 to 2012. Medical therapies for cardiovascular risk were classified as antiplatelet, statin or antihypertensive agents. Progression to death was investigated using the G-computation formula with time-dependent co-variables to account for differences in exposure to cardiovascular risk-modifying treatments and the confounding between exposure, co-morbidities and death. RESULTS: Some 12 485 patients had a recorded diagnosis of AAA. From 2000 to 2012, prescription of medications that modify cardiovascular risk increased: from 26·6 to 76·7 per cent for statins, from 56·5 to 73·9 per cent for antiplatelet agents and from 75·3 to 84·0 per cent for antihypertensive drugs. Adjusted Kaplan-Meier curves demonstrated a better 5-year survival rate in patients receiving statins (68·4 versus 42·2 per cent), antiplatelet agents (63·6 versus 39·7 per cent) or antihypertensive agents (61·5 versus 39·1 per cent), compared with rates in patients not receiving each therapy. CONCLUSION: Appropriate risk factor modification could significantly reduce long-term mortality in patients with AAA. In the UK, up to 30 per cent of patients are not currently receiving these medications.

AIMS: The presence of diabetic foot ulcers is strongly associated with an increased risk of death. In this study, we investigate whether the effects of diabetes-associated complications can explain the apparent relationship between diabetic foot ulcers and death. METHODS: We analysed data from 414 523 people with diabetes enrolled in practices associated with The Health Improvement Network in the United Kingdom. Our methods were designed to control for potential confounders in order to isolate the relationship between diabetic foot ulcers and death. Using proportional hazards models and the area under the receiver operator curve, we evaluated the effects of diabetic foot ulcers and the covariates on death. RESULTS: Among the patients, 20 737 developed diabetic foot ulcers; 5.0% of people with new ulcers died within 12 months of their first foot ulcer visit and 42.2% of people with foot ulcers died within 5 years. After controlling for major known complications of diabetes that might influence mortality, the correlation between diabetic foot ulcers and death remained strong with a fully adjusted hazard ratio of 2.48 (95% confidence interval: 2.43, 2.54). Geographic variance existed but was not spatially associated. CONCLUSIONS: Diabetic foot ulcers are linked to an increased risk of death. This cannot be explained by other common risk factors. These results suggest that either there are major unknown risk factors associated with both diabetic foot ulcers and death, or that diabetic foot ulceration itself is a serious threat, which seems unlikely. A diabetic foot ulcer should be seen as a major warning sign for mortality, necessitating closer medical follow-up.

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BACKGROUND: Limited information is available on whether antipsychotics prescribed in pregnancy are associated with increased risks of adverse outcomes. METHODS: We used electronic health records from pregnant women and their children to examine risks of adverse maternal and child outcomes in three cohorts of women who: (A) received antipsychotic treatment in pregnancy (n=416) (B) discontinued antipsychotic treatment before pregnancy (n=670), and (C) had no records of antipsychotic treatment before or during pregnancy (n=318,434). Absolute and risk ratios were estimated and adjusted for health and lifestyle and concomitant medications. RESULTS: Caesarean section was more common in cohort A (25%) than C (18%), but non-significant after adjustment for health and lifestyle factors (Risk Ratio (adj.) 1.09 (95% CI: 0.92, 1.30). Proportion of gestational diabetes was similar in cohort A (2.6%) and B (2.7%), but lower in A than B after adjustments (RRadj: 0.43 (0.20, 0.93). Premature birth/low birthweight were more common in cohort A (10%) than B (4.3%) and C (3.9%), A versus B (RRadj: 2.04 (1.13, 3.67), A versus C (RRadj: 1.43 (0.99, 2.05). Major congenital malformations were more common in A (3.4%), than B (2.2%) and C (2%). However no significant difference was observed (A versus B: RRadj: 1.79 (0.72, 4.47) A versus C RRadj: 1.59 (0.84, 3.00)). Risks estimates were similar for women prescribed atypical and typical antipsychotics. CONCLUSIONS: Antipsychotic treatment in pregnancy carries limited risks of adverse pregnancy and birth outcomes once adjustments have been made for health and lifestyle factors.

Continuous predictors are routinely encountered when developing a prognostic model. Investigators, who are often non-statisticians, must decide how to handle continuous predictors in their models. Categorising continuous measurements into two or more categories has been widely discredited, yet is still frequently done because of its simplicity, investigator ignorance of the potential impact and of suitable alternatives, or to facilitate model uptake. We examine three broad approaches for handling continuous predictors on the performance of a prognostic model, including various methods of categorising predictors, modelling a linear relationship between the predictor and outcome and modelling a nonlinear relationship using fractional polynomials or restricted cubic splines. We compare the performance (measured by the c-index, calibration and net benefit) of prognostic models built using each approach, evaluating them using separate data from that used to build them. We show that categorising continuous predictors produces models with poor predictive performance and poor clinical usefulness. Categorising continuous predictors is unnecessary, biologically implausible and inefficient and should not be used in prognostic model development. © 2016 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.

BACKGROUND: There are limited data to show the levels of prescribing of combined oral contraceptives (COCs) and other hormonal products containing estrogen/progestogen combinations that may be outside the product licence. AIMS: To determine the diagnosis/indication recorded at the time of prescription of cyproterone acetate/ethinylestradiol (CPA/EE) and two COCs, levonorgestrel/EE (LNG/EE) and drospirenone/EE (DRSP/EE). DESIGN AND SETTING: Retrospective study using a primary care database, The Health Improvement Network (THIN). METHODS: Women in THIN aged 12-49 years prescribed CPA/EE, LNG/EE or DRSP/EE in 2002-2010 were identified. Overall use of each product and proportion of new users each year were determined. Among new users, database codes were analysed to infer the reason for prescription. RESULTS: The proportion of new users of each product in 2002 and 2010, respectively, were: LNG/EE, 2.03% and 2.40%; CPA/EE, 0.45% and 0.27%; and DRSP/EE, 0.27% and 0.56%. Most new users prescribed CPA/EE had a record of acne (51.0% and 79.2% in 2002 and 2010, respectively) or hirsutism (3.0% and 5.0% in 2002 and 2010, respectively); the proportion of new users with a record only for contraception decreased from 32.9% in 2002 to 8.6% in 2010. Among new users prescribed DRSP/EE or LNG/EE in 2010, 43.2% and 30.8% of women, respectively, did not have a record indicating use for contraception. CONCLUSIONS: Adherence to prescribing guidelines for CPA/EE has improved over time. A substantial proportion of women using DRSP/EE or LNG/EE had records for hormone-responsive conditions only, suggesting that many women were prescribed these therapies for non-contraceptive use.

PURPOSE: Mutations in ion channels are common among patients with glioblastoma multiforme (GBM) and promote cell migration and invasion. We sought to evaluate the association between the use of specific ion channel blockers such as digoxin, amiodarone, diltiazem and verapamil and GBM risk and survival. METHODS: We conducted a nested case-control study in a large primary care database from the UK. Cases were defined as all individuals with incident diagnosis of GBM during follow-up. For each case, up to four controls were selected using incidence density sampling. The primary exposure of interest was active treatment with each of the four ion channel blockers. We used conditional logistic regression to estimate odds ratios and 95% confidence interval (CI) for the association between ion channel blocker use and GBM risk. We then performed a Cox regression analysis among those diagnosed with GBM in order to evaluate the association between use of ion channel blockers and overall survival. Both analyses were adjusted to common confounders. RESULTS: The study included 1076 cases and 4253 matched controls. There was no statistically significant difference between cases and controls in cardiac and metabolic risk factors. There was no change in GBM risk in active users of ion channel blockers compared with non-users. Among patients with GBM, active users of amiodarone had worse survival compared with never users with an HR of 4.41 (95%CI 1.95-9.96). There was no statistically significant change in survival among diltiazem, verapamil or digoxin users. CONCLUSION: Treatment with specific ion channel blockers was not associated with the risk of GBM but was associated with worse survival in patients with GBM. Copyright © 2016 John Wiley & Sons, Ltd.

OBJECTIVE: To identify publication and citation trends, most productive institutions and countries, top journals, most cited articles and authorship networks from articles that used and analysed data from primary care databases (CPRD, THIN, QResearch) of pseudonymised electronic health records (EHRs) in UK. METHODS: Descriptive statistics and scientometric tools were used to analyse a SCOPUS data set of 1891 articles. Open access software was used to extract networks from the data set (Table2Net), visualise and analyse coauthorship networks of scholars and countries (Gephi) and density maps (VOSviewer) of research topics co-occurrence and journal cocitation. RESULTS: Research output increased overall at a yearly rate of 18.65%. While medicine is the main field of research, studies in more specialised areas include biochemistry and pharmacology. Researchers from UK, USA and Spanish institutions have published the most papers. Most of the journals that publish this type of research and most cited papers come from UK and USA. Authorship varied between 3 and 6 authors. Keyword analyses show that smoking, diabetes, cardiovascular diseases and mental illnesses, as well as medication that can treat such medical conditions, such as non-steroid anti-inflammatory agents, insulin and antidepressants constitute the main topics of research. Coauthorship network analyses show that lead scientists, directors or founders of these databases are, to various degrees, at the centre of clusters in this scientific community. CONCLUSIONS: There is a considerable increase of publications in primary care research from EHRs. The UK has been well placed at the centre of an expanding global scientific community, facilitating international collaborations and bringing together international expertise in medicine, biochemical and pharmaceutical research.

OBJECTIVES: To analyse time to cardiovascular events and mortality in patients with type 2 diabetes (T2D) who received treatment intensification with insulin or a glucagon-like peptide-1 (GLP-1ar) analogue following dual therapy failure with metformin (MET) and sulphonylurea (SU). METHODS: A retrospective cohort study was conducted in 2003 patients who were newly treated with a GLP-1ar or insulin following dual therapy (MET+SU) failure between 2006 and 2014. Data were sourced from The Health Improvement Network database. Risks of major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, non-fatal stroke and all-cause mortality) were compared between MET+SU+insulin (N=1584) versus MET+SU+GLP-1ar (N=419). Follow-up was for 5 years (6614 person-years). Propensity score matching analysis and Cox proportional hazard models were employed. RESULTS: Mean age was 52.8±14.1 years. Overall, the number of MACE was 231 vs 11 for patients who added insulin versus GLP-1ar, respectively (44.5 vs 7.7 per 1000-person-years adjusted HR (aHR): 0.27; 95% CI 0.14 to 0.53; p<0.0001). Insulin was associated with significant increase in weight compared with GLP-1ar (1.78 vs -3.93 kg; p<0.0001) but haemoglobin A1c reduction was similar between both treatment groups (-1.29 vs -0.98; p=0.156). In a subgroup analysis of obese patients (body mass index >30 kg/m(2)) there were 84 vs 11 composite outcomes (38.6 vs 8.1 per 1000 person-years; aHR: 0.31; 95% CI 0.16 to 0.61; p=0.001) in the insulin and GLP-1ar groups, respectively. CONCLUSIONS: In this cohort of obese people with T2DM, intensification of dual oral therapy by adding GLP-1ar analogue is associated with a lower MACE outcome in routine clinical practice, compared with adding insulin therapy as the third glucose-lowering agent.