Scientific
publications

OBJECTIVE: To examine temporal changes in the incidence and patterns of vitamin D supplementation prescribing by general practitioners (GPs) between 2008 and 2016. DESIGN: Population-based cohort study. SETTING: UK general practice health records from The Health Improvement Network. PARTICIPANTS: Children aged 0 to 17 years who were registered with their general practices for at least 3 months. OUTCOME MEASURES: Annual incidence rates of vitamin D prescriptions were calculated, and rate ratios were estimated using multivariable Poisson regression to explore differences by sociodemographic factors. Data on the type of supplementation, dose, dosing schedule, linked 25-hydroxyvitamin D (25(OH)D) laboratory test results and clinical symptoms suggestive of vitamin D deficiency were analysed. RESULTS: Among 2 million children, the crude annual incidence of vitamin D prescribing increased by 26-fold between 2008 and 2016 rising from 10.8 (95% CI: 8.9 to 13.1) to 276.8 (95% CI: 264.3 to 289.9) per 100 000 person-years. Older children, non-white ethnicity and general practices in England (compared with Wales/Scotland/Northern Ireland) were independently associated with higher rates of prescribing. Analyses of incident prescriptions showed inconsistent supplementation regimens with an absence of pre-supplementation 25(OH)D concentrations in 28.7% to 56.4% of prescriptions annually. There was an increasing trend in prescribing at pharmacological doses irrespective of 25(OH)D concentrations, deviating in part from UK recommendations. Prescribing at pharmacological doses for children with deficient status increased from 3.8% to 79.4%, but the rise was also observed in children for whom guidelines recommended prevention doses (0% to 53%). Vitamin D supplementation at pharmacological doses was also prescribed in at least 40% of children with no pre-supplementation 25(OH)D concentrations annually. CONCLUSIONS: There has been a marked and sustained increase in vitamin D supplementation prescribing in children in UK primary care. Our data suggests that national guidelines on vitamin D supplementation for children are not consistently followed by GPs.

BACKGROUND: Meta-analysis of trial data suggests that in primary cardiovascular disease (CVD) prevention bodyweight modifies low-dose aspirin's effects on colorectal cancer (CRC) and major bleeding risk. We sought to investigate whether these effects are seen in patients with or without CVD in routine clinical practice by undertaking sub-analyses of data from two cohort studies with nested-case-control analyses. METHODS: We followed ~200,000 new users of low-dose aspirin (75-300 mg/day) and a matched cohort of non-users to identify incident cases of CRC/upper gastrointestinal bleeding (UGIB). Adjusted relative risks (RRs) with 95% confidence intervals (CIs) were calculated for current vs. non-use of low-dose aspirin using logistic regression stratified by bodyweight/body mass index (BMI) strata. RESULTS: RRs (95% CIs) for CRC by bodyweight were: 0.60 (0.50-0.72) for ≤70 kg, 0.68 (0.60-0.76) for >70 kg; and by BMI were 0.60 (0.52-0.68) for ≤28 kg/m , 0.76 (0.64-0.89) for >28 kg/m . For UGIB, estimates were: 1.49 (1.28-1.74) for ≤90 kg, 1.78 (1.29-2.45) for >90 kg/m , 1.44 (1.21-1.72) for ≤28 kg/m , 1.72 (1.38-2.16) for >28 kg/m . Results were similar in the primary CVD prevention population. CONCLUSION: Our findings suggest that the effects of low-dose aspirin in reducing CRC risk and increasing UGIB risk are not modified by bodyweight/BMI.

INTRODUCTION: Despite the fact that perianal fistulas are associated with significant morbidity and impaired quality of life, their prevalence in Europe is unknown. The aim of this study was to estimate the prevalence of perianal fistulas in Europe, overall and according to etiology. METHODS: Two independent literature reviews were performed using different search strategies to maximize the identification of potentially relevant studies. Data from relevant articles were used to estimate the prevalence of perianal fistulas in Europe. The robustness of the estimate was evaluated using data from a large population-based database from the UK. RESULTS: A total of 26 studies provided epidemiological data on perianal fistulas, of which 16 provided suitable data to estimate the prevalence. Estimations using these data yielded a total prevalence of 1.69 per 10,000 population. Cryptoglandular infection and Crohn's disease (CD) were the predominant etiologies, with prevalence rates at 0.86 and 0.76 per 10,000 population, respectively. Comparison of prevalence data from the UK population-based database with the European population resulted in a standardized prevalence estimate of all perianal fistulas of 1.83 per 10,000 population, confirming the robustness of the literature-based estimate. CONCLUSION: Although in terms of incidence cryptoglandular fistulas were clearly predominant, the prevalence of fistulas in CD and cryptoglandular infection appeared more balanced. This is due to the longer duration and higher frequency of relapses of fistulas in CD. The estimated prevalence implies that perianal fistulas meet the criteria to be considered as a rare condition in Europe (prevalence less than 5 per 10,000 population). FUNDING: This study was funded by Takeda Pharmaceutical U.S.A., Inc. and TiGenix SAU.

BACKGROUND: There is increasing evidence that vitamin D supplementation may only be beneficial in people with vitamin D deficiency, and the lack of sufficient people with very low vitamin D levels could explain the lack of protection against cardiovascular disease (CVD) reported in recent clinical trials of vitamin D supplementation. The aim of this study was to assess associations of low to moderate circulating concentrations of 25-hydroxyvitamin D (25(OH)D with risk of incident CVD and all-cause mortality, as well as the risk of ischaemic heart disease (IHD), cerebrovascular disease, and heart failure separately. METHODS AND RESULTS: Longitudinal analysis of electronic health records in The Health Improvement Network (THIN), a UK primary care database. The analysis included 180,263 patients age 18 years and older without a history of CVD and with circulating concentrations of 25(OH)D. After a mean follow-up of 2.2 (SD 1.7) years, there were 3747 patients diagnosed with CVD and 3912 patients died. Compared to patients in the highest quintile of 25(OHD) (≥ 67.5 nmol/L), those in the lowest 25(OH)D quintile (<23.1 nmol/L) had a hazard ratio (HR) of 1.24 (95% CI 1.12-1.38, P <  0.001) for CVD and 1.71 (1.55-1.88, P <  0.001) for mortality. The HR for both outcomes associated with 25(OH)D concentration was non-linear, being significantly increased in patients with 25(OH)D <35 nmol/L, and highest in those with 25(OH)D <25 nmol/L, although increased for mortality at 25(OH)D ≥100 nmol/L. The increased CVD HR in the lowest 25(OH)D quintile was more from IHD (1.35, 95% CI 1.13-1.60) and heart failure (1.38, 95% CI 1.08-1.77), than from cerebrovascular disease (1.13, 95% CI 0.97-1.31). CONCLUSION: Low 25(OH)D are associated with highest risk of CVD and mortality, and are consistent with accumulating evidence that increased risk of these diseases occurs primarily in people with vitamin D deficiency.

INTRODUCTION: Safety warnings relating to antipsychotic-associated stroke among older persons in the UK and Italy were issued. However, the impact of these safety warnings on stroke risk has not been measured to date. OBJECTIVE: The aim of this study was to measure the change in stroke incidence after two safety warnings in both the UK and Italy. METHOD: A cohort study was conducted using electronic medical records representative of the UK (The Health Improvement Network) and Italy (Health Search-IQVIA Health LPD), containing data on 11 million and 1 million patients, respectively. After each drug safety warning, elderly antipsychotic new initiators were propensity-score matched 1:1:1 on antipsychotic initiators before any safety warning. Stroke incidence within 6 months of antipsychotic initiation, using an intention-to-treat approach, was the main outcome. RESULTS: In the UK and Italy, 6342 and 7587 elderly antipsychotic initiators were identified, respectively. A 42% stroke incidence reduction was seen in the UK after the first safety warning [42.3 (95% confidence interval (CI) 35.2-50.8) vs. 24.4 [95% CI 19.0-31.2] events per 1000 person-years (PYs)], while there was a 60% stroke incidence reduction after the second warning (16.9 [95% CI 12.2-23.4] events per 1000 PYs) compared to before the first warning. There was no significant reduction in stroke incidence in Italy. CONCLUSION: Antipsychotic safety warnings were followed by a reduction in stroke incidence among older antipsychotic users in the UK, but not Italy.

PURPOSE: Antidepressants are frequently prescribed to older people with depression but little is known on predictors of discontinuation in this population. We, therefore, investigated factors associated with early discontinuation of antidepressants in older adults with new diagnoses or symptoms of depression in English primary care. METHODS: Data from a nationally representative cohort of patients aged 55 and over were used to evaluate the association between discontinuation of antidepressant medication after a single prescription and potential explanatory variables, including socio-demographic factors, polypharmacy and age-related problems such as dementia. RESULTS: Overall, during the study period we observed 34,715 new courses of antidepressant treatment initiated after recorded symptoms or diagnoses of depression. Antidepressant discontinuation after a single prescription was more common in people with depressive symptoms (32%) than in those with diagnosed depression (21.6%). In those diagnosed with depression and in women with depressive symptoms we found that, after adjusting for confounders, the odds of early discontinuation significantly increased after age 65 with a peak at around age 80 and then either levelled or reduced thereafter. Early discontinuation was also significantly less common in people with dementia and in those with diagnosed depression living in more rural areas. CONCLUSIONS: Early discontinuation of antidepressants increases in the post-retirement years and is higher in those with no formal diagnosis of depression, those without dementia and those with diagnosed depression living in urban areas. Alternative treatment strategies, such as non-drug therapies, or more active patient follow-up should be further considered in these circumstances.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus is associated with high levels of disease burden, including increased mortality risk and significant long-term morbidity. The prevalence of diabetes differs substantially among ethnic groups. We examined the prevalence of type 2 diabetes diagnoses in the UK primary care setting. METHODS: We analysed data from 404,318 individuals in The Health Improvement Network database, aged 0-99 years and permanently registered with general practices in London. The association between ethnicity and the prevalence of type 2 diabetes diagnoses in 2013 was estimated using a logistic regression model, adjusting for effect of age group, sex, and social deprivation. A multiple imputation approach utilising population-level information about ethnicity from the UK census was used for imputing missing data. RESULTS: Compared with those of White ethnicity (5.04%, 95% CI 4.95 to 5.13), the crude percentage prevalence of type 2 diabetes was higher in the Asian (7.69%, 95% CI 7.46 to 7.92) and Black (5.58%, 95% CI 5.35 to 5.81) ethnic groups, while lower in the Mixed/Other group (3.42%, 95% CI 3.19 to 3.66). After adjusting for differences in age group, sex, and social deprivation, all minority ethnic groups were more likely to have a diagnosis of type 2 diabetes compared with the White group (OR Asian versus White 2.36, 95% CI 2.26 to 2.47; OR Black versus White 1.65, 95% CI 1.56 to 1.73; OR Mixed/Other versus White 1.17, 95% CI 1.08 to 1.27). CONCLUSION: The prevalence of type 2 diabetes was higher in the Asian and Black ethnic groups, compared with the White group. Accurate estimates of ethnic prevalence of type 2 diabetes based on large datasets are important for facilitating appropriate allocation of public health resources, and for allowing population-level research to be undertaken examining disease trajectories among minority ethnic groups, that might help reduce inequalities.

Inhaled corticosteroids (ICS) adherence is important for asthma management. Current evidence on the impact of ICS adherence on outcomes is mostly based on correlational analyses of between-person data. Although it is widely acknowledged that asthma outcomes fluctuate over time, evidence on predictors of within-person change is scarce. We aimed to quantify these fluctuations and the longitudinal relationships between ICS adherence and outcomes at both between- and within-person levels.A prospective cohort of persistent asthma patients in France and the UK (n=847, age 6-40 years) provided 3756 reports over up to 2 years computer-assisted telephone interviews and text messages on ICS adherence, asthma control, reliever medication use and exacerbations. We examined adherence-outcome relationships longitudinal models, controlling for confounders, including severity.Considerable within-person variability was found for exacerbations (91%), asthma control (59%) and reliever use (52%); 431 (11.5%) reports signalled exacerbations and 2046 (54.5%) poor control. At between-person level, patients with higher average adherence were more likely to report asthma control (OR 1.25, 95% CI 1.06-1.47), but not asthma exacerbations (OR 0.99, 95% CI 0.87-1.12) or lower reliever use (b -0.0004, 95% CI -0.089-0.088). At within-person level, higher-than-usual adherence was associated with higher concomitant reliever use (b 0.092, 95% CI 0.053-0.131) and lower subsequent reliever use (b -0.047, 95% CI -0.005- -0.088); it was unrelated to asthma control (OR 0.93, 95% CI 0.84-1.02) or exacerbations (OR 1.04, 95% CI 0.94-1.16).Patients maintaining high ICS adherence over time have better asthma control. Temporarily increasing ICS adherence tends to be simultaneous to higher reliever use and reduces reliever use later on. Causes of within-person variation in outcomes require more investigation.

PURPOSE: Urolithiasis is a common condition that poses significant morbidity to patients. There are similarities in the development of certain cancers and urinary tract calculi (UTC), however, little is known about their temporal relationship. This study aims to identify if cancer is a risk factor for the development of UTC. METHODS: A population-based retrospective cohort study was conducted for the period 1st January 1990 to 1st May 2016. 124,901 exposed patients identified using clinical codes with newly diagnosed cancer were matched to 476,203 unexposed controls by age, gender, BMI, and general practice. The main outcome measure was the risk of developing UTC described by hazard ratios. RESULTS: There were 512 incident UTC events in the cancer group compared to 1787 in the unexposed controls. This translated to an adjusted hazard ratio of 1.26 (95% CI 1.14-1.39; p < 0.001). A sub-analysis assessing cancer-specific effects demonstrated increased risks for 10 out of 12 common cancers, most significantly in bladder, colorectal and prostate cancer. CONCLUSION: This study demonstrated a 26% increased risk of UTC in cancer patients suggesting wider recognition of this risk amongst clinicians could improve diagnosis and prevention of UTC, as well as encourage further research exploring this association.

BACKGROUND: There is uncertainty around whether to use unicompartmental knee replacement (UKR) or total knee replacement (TKR) for individuals with osteoarthritis confined to a single compartment of the knee. We aimed to emulate the design of the Total or Partial Knee Arthroplasty Trial (TOPKAT) using routinely collected data to assess whether the efficacy results reported in the trial translate into effectiveness in routine practice, and to assess comparative safety. METHODS: We did a population-based network study using data from four US and one UK health-care database, part of the Observational Health Data Sciences and Informatics network. The inclusion criteria were the same as those for TOPKAT; briefly, we identified patients aged at least 40 years with osteoarthritis who had undergone UKR or TKR and who had available data for at least one year prior to surgery. Patients were excluded if they had evidence of previous knee arthroplasty, knee fracture, knee surgery (except diagnostic), rheumatoid arthritis, infammatory arthropathies, or septic arthritis. Opioid use from 91-365 days after surgery, as a proxy for persistent pain, was assessed for all participants in all databases. Postoperative complications (ie, venous thromboembolism, infection, readmission, and mortality) were assessed over the 60 days after surgery and implant survival (as measured by revision procedures) was assessed over the 5 years after surgery. Outcomes were assessed in all databases, except for readmission, which was assessed in three of the databases, and mortality, which was assessed in two of the databases. Propensity score matched Cox proportional hazards models were fitted for each outcome. Calibrated hazard ratios (cHRs) were generated for each database to account for observed differences in control outcomes, and cHRs were then combined using meta-analysis. FINDINGS: 33 867 individuals who received UKR and 557 831 individuals who received TKR between Jan 1, 2005, and April 30, 2018, were eligible for matching. 32 379 with UKR and 250 377 with TKR were propensity score matched and informed the analyses. UKR was associated with a reduced risk of postoperative opioid use (cHR from meta-analysis 0·81, 95% CI 0·73-0·90) and a reduced risk of venous thromboembolism (0·62, 0·36-0·95), whereas no difference was seen for infection (0·85, 0·51-1·37) and readmission (0·79, 0·47-1·25). Evidence was insufficient to conclude whether there was a reduction in risk of mortality. UKR was also associated with an increased risk of revision (1·64, 1·40-1·94). INTERPRETATION: UKR was associated with a reduced risk of postoperative opioid use compared with TKR, which might indicate a reduced risk of persistent pain after surgery. UKR was associated with a lower risk of venous thromboembolism but an increased risk of revision compared with TKR. These findings can help to inform shared decision making for individuals eligible for knee replacement surgery. FUNDING: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative (2) Joint Undertaking (EHDEN).

BACKGROUND: Childhood maltreatment is a global public health, human rights, and moral issue that is associated with a substantial mental health burden. We aimed to assess the association between childhood maltreatment and the development of mental ill health and the initiation of new prescriptions for mental ill health. METHODS: In this population-based, retrospective, open cohort study, we used a dataset from individuals in The Health Improvement Network (THIN) database. THIN database comprises UK electronic medical records taken from 787 general practices throughout the UK. We used read codes in these records to identify exposed patients (those with a read code identifying officially confirmed childhood maltreatment or a maltreatment-related concern) and up to two unexposed patients (those without such read codes) from the same general practice, who were matched by age and sex. We evaluated the risk of developing depression, anxiety, or serious mental illness (a composite mental ill health outcome) or initiation of a prescription drug used to treat mental ill health, and the odds ratio of these events at baseline, in the exposed versus unexposed patients. FINDINGS: The first possible date for cohort entry (the study start date) was Jan 1, 1995, and patients could enter the cohort until the study end date, Dec 31, 2018. During the study period, 11 831 850 patients were eligible to participate. Of these patients, we identified 217 758 (1·8%) patients with any recorded childhood maltreatment. These patients were matched to 423 410 unexposed control patients with no recorded exposure to childhood maltreatment. The exposed group were followed up for a median of 1·8 years (IQR 0·6-4·3) versus 3·2 years (1·3-6·1) in the unexposed group. During the study period, 11 665 (5·9%) new diagnoses of mental ill health were made in the exposed group, giving an incidence rate of 16·8 events per 1000 person-years versus 15 301 (3·7%) new recorded diagnoses at an incidence rate of 8·3 events per 1000 person-years in the unexposed cohort, giving an adjusted IRR of 2·14 (95% CI 2·08-2·19). 30 911 (14·8%) patients in the exposed group received a new prescription for any type of mental ill health (incidence rate 46·5 events per 1000 person-years) versus 36 390 (8·9%) patients in the unexposed group (20·5 per 1000 person-years) resulting in an adjusted IRR of 2·44 (95% CI 2·40-2·48). INTERPRETATION: Childhood maltreatment is thought to affect one in three children globally; therefore, a doubled risk of developing mental ill health among these individuals represents a substantial contribution to the mental ill health burden in the UK. It is imperative that public health approaches, including those aimed at preventing and detecting childhood maltreatment and its associated negative consequences, are implemented to prevent mental ill health. FUNDING: None.

OBJECTIVES: To investigate whether the introduction of performance targets for anticoagulation in atrial fibrillation (AF) was associated with a change in use of the 'resolved AF' code. DESIGN: Retrospective cohort studies. SETTING: Data from The Health Improvement Network, a UK database of electronic patient records, from 2000 to 2016. PARTICIPANTS: 250 788 adult patients aged ≥18 years with a diagnosis of AF, including 14 757 with an incident diagnosis of 'resolved AF'. MAIN OUTCOME MEASURES: Annual and monthly incidence of 'resolved AF' from 2000 to 2016. Among patients with 'resolved AF', for each year we calculated median duration of the preceding AF diagnosis and the proportion prescribed anticoagulants prior to 'resolved AF'. RESULTS: Incidence of 'resolved AF' increased from 5.7 to 26.3 per 1000 person-years between 2005 and the introduction of AF performance targets in 2006. Compared with the years prior to the introduction of the performance targets, incidence has remained higher in every year since their implementation. Since 2007, monthly incidence has been highest between January and March. Between 2005 and 2006, median duration between AF and 'resolved AF' diagnoses increased from 276 days (9 months) to 1343 days (3 years 8 months). Among 'resolved AF' patients with CHA DS -VASc score ≥1, 81.9% (95% CI 81.1 to 82.6) had no current anticoagulant prescription, and 62.3% (95% CI 61.4 to 63.2) had no record of any anticoagulant prescription. CONCLUSION: The introduction of AF performance targets was followed by a large increase in use of the 'resolved AF' code, particularly in the months immediately before practices make their anticoagulant performance target submissions. Although most AF patients are prescribed anticoagulants, few patients diagnosed with 'resolved AF' are prescribed anticoagulants and most have never been prescribed them. Untreated patients are much more likely to be coded as having 'resolved AF'.

OBJECTIVE: To understand the association of seizure frequency with healthcare resource utilisation (HCRU) and mortality in UK children with epilepsy (CWE). DESIGN: Retrospective cohort study. SETTING: Routinely collected data in primary care from The Health Improvement Network UK database. PATIENTS: CWE ≥1 and<18 years of age with a record of seizure frequency were included in mortality analyses from 2005 to 2015 and HCRU analyses from 2010 to 2015. MAIN OUTCOME MEASURES: Frequency of HCRU contacts during the year following latest seizure frequency and mortality (descriptive and Cox proportional hazards regression) from first record of seizure frequency. RESULTS: Higher seizure frequency was related to increased HCRU utilisation and mortality. In negative binomial regression, each category increase in seizure frequency related to 11% more visits to general practitioners, 35% more inpatient admissions, 15% more outpatient visits and increased direct HCRU costs (24%). 11 patients died during 12 490 patient-years follow-up. The unadjusted HR of mortality per higher category of seizure frequency was 2.56 (95% CI: 1.52 to 4.31). Adjustment for age and number of prescribed anti-epileptic drugs at index attenuated this estimate to 2.11 (95% CI: 1.24 to 3.60). CONCLUSION: Higher seizure frequency is associated with greater HCRU and mortality in CWE in the UK. Improvement in seizure control may potentially lead to better patient outcomes and reduced healthcare use.

To assess the comparative effectiveness of two hypoallergenic formulae in managing cow's milk allergic infants. This study retrospectively analyzed the case records of 940 formula-fed cow's milk allergic infants in the UK extracted from The Health Improvement Network database. At 24 months after starting a formula, 77% of infants fed an extensively hydrolyzed casein formula supplemented with GG (eHCF LGG; n = 470) were estimated to have been successfully managed compared with 63% of matched infants who were fed an extensively hydrolyzed whey formula (eHWF; n = 470; p < 0.001). Additionally, significantly more eHWF-fed infants were estimated to be experiencing gastrointestinal symptoms, eczema and asthma (7.1 vs 3.1%; p < 0.02) at 24 months. First-line management of newly diagnosed cow's milk allergic infants with eHCF LGG may slow down the allergic march seen in cow's milk allergic children.