Publications
scientifiques

BACKGROUND: ADHD guidelines in the UK suggest that children and adults who respond to pharmacological treatment should continue for as long as remains clinically effective, subject to regular review. To what extent patients persist with treatment from childhood and adolescence into adulthood is not clear. This study aims to describe, in UK primary care, the persistence of pharmacological treatment for patients with ADHD who started treatment aged 6-17 years and to estimate the percentage of patients who continued treatment from childhood and adolescence into adulthood. METHODS: The Health Improvement Network (THIN) database was used to identify patients with ADHD who received their first prescription for methylphenidate/ dexamfetamine/atomoxetine, aged 6-17 years. Patients were monitored until their 'censored date' (the earliest of the following dates: date the last prescription coded in the database ended, end of the study period (31st December 2008), date at which they transferred out of their practice, date of death, the last date the practice contributed data to the database). Persistence of treatment into adulthood was estimated using Kaplan Meier analysis. RESULTS: 610 patients had follow-up data into adulthood. 213 patients (93.4% male) started treatment between 6-12 years; median treatment duration 5.9 years. 131 (61.5%) stopped before 18 years, 82 (38.5%) were still on treatment age ≥18 years. 397 patients (86.4% male) started treatment between 13-17 years; median treatment duration was 1.6 years. 227 (57.2%) stopped before 18 years, 170 (42.8%) were still on treatment age ≥18 years. The number of females in both age categories was too small to formally test for differences between genders in persistence of treatment. CONCLUSION: Persistence of treatment into adulthood is lower (~40%) compared with published rates of persistence of the condition (~65% when symptomatic definition of remission used). Due to the limited number of patients with data past 18 years, it is important that ongoing monitoring of prescribing into later adulthood is undertaken, particularly to observe the effects of recommendations in new guidelines.

BACKGROUND: Quinolone antibiotics are associated with increased risk of tendinopathy. Identifying at-risk individuals has important clinical implications. We examined whether age, sex, glucocorticoid use, obesity, diabetes, and renal failure/dialysis predispose individuals to the adverse effects of quinolones. METHODS: Among 6.4 million patients in The Health Improvement Network (THIN) database, 28,907 cases of Achilles tendonitis and 7685 cases of tendon rupture were identified in a case-crossover study. For each participant, we ascertained whether there was a prescription of a quinolone and comparison antibiotic within 30 days before the diagnosis of tendon disorder (case period) and a prescription of the same medications within 30 days 1 year before disease diagnosis (control period). RESULTS: Use of quinolones was strongly associated with an increased risk of Achilles tendonitis (odds ratio [OR], 4.3; 95% confidence interval [CI], 3.2-5.7) and tendon rupture (OR, 2.0; 95% CI, 1.2-3.3). No association was found between the use of other antibiotics and either outcome. The association with Achilles tendonitis was stronger among participants who were aged more than 60 years (OR, 8.3 vs 1.6), who were nonobese (OR, 7.7 vs 2.4), and who used oral glucocorticoids (OR, 9.1 vs 3.2). The association was nonsignificantly stronger in women (OR, 5.0 vs 3.6), diabetic persons (OR, 7.0 vs 4.1), and those in renal failure or receiving dialysis (OR, 20.0 vs 3.9). The effect for tendon rupture was stronger in women, with borderline significance in glucocorticoid users and nonobese persons. CONCLUSION: Quinolone-associated tendinopathy is more pronounced among elderly persons, nonobese persons, and individuals with concurrent use of glucocorticoids.

BACKGROUND: Preschool children have a high risk of poisoning. While medicines prescribed by primary care are potential poisoning agents, the risk factors for poisoning from medication are not well described. AIM: To identify risk factors for medicinal and non-medicinal poisoning in preschool children. DESIGN AND SETTING: Population-based nested case-control study using The Health Improvement Network primary care database 1988-2004. METHOD: Conditional logistic regression was used to identify child, maternal, and social risk factors for medicinal (1316 cases) and non-medicinal poisoning (503 cases), using 17 709 controls matched on general practice. RESULTS: Poisoning by medicines was independently associated with deprivation (test for trend P<0.001), maternal age (P<0.001), birth order (P<0.001), maternal alcohol misuse (odds ratio [OR] = 5.44, 95% confidence interval [CI] = 1.99 to 14.91), and perinatal depression (OR = 1.54, 95% CI = 1.26 to 1.88). Living in a household with two or more adults lowered the odds of injury compared to single-parent households (OR = 0.85, 95% CI = 0.74 to 0.96) and the odds varied by age, being highest in 2 year olds (OR = 9.61, 95% CI = 7.73 to 11.95). Non-medicinal poisoning was associated with deprivation (P = 0.001), maternal age (P<0.001), and birth order (P<0.001). The odds were raised in 1 year olds (OR = 5.44, 95% CI = 4.07 to 7.26) and 2 year olds (OR = 5.07, 95% CI = 3.73 to 6.90) compared to those aged <1 year. CONCLUSION: Primary care data can be used to target interventions to children at risk of poisoning. This is pertinent when prescribing for children/family members, as prescribed medications may become poisoning agents. Prompt identification of maternal depression and alcohol misuse, and delivery of poisoning-prevention interventions at this stage may help prevent poisonings.

BACKGROUND: An increasing prevalence of obesity in the UK has also seen a rise in the diagnosis of co-morbidities. Obstructive sleep apnoea (OSA) has previously been associated with body mass index (BMI) but has not been fully explored in a UK population. AIMS: To quantify the association between BMI and a recorded diagnosis of OSA in primary care for people aged 50 years or over in the UK. METHODS: A descriptive analysis is given of men and women aged 50 or over in the UK from The Health Improvement Network (THIN) database with regard to diagnosis of OSA, snoring, and BMI. Logistic regression was performed for the likelihood of OSA depending on BMI classification recorded after adjusting for gender, age, region, and socioeconomic status (Townsend quintile). The analyses were repeated for snoring. RESULTS: After adjusting for confounders, those with a BMI recorded of 40+ kg/m2 were 27.39 times (95% CI 24.64 to 30.46) more likely to have OSA (p<0.0001). There was a lower prevalence of OSA with increasing age and levels of deprivation. CONCLUSIONS: Obesity and snoring were both strongly associated with a diagnosis of OSA. The decreasing prevalence of OSA with increasing age and levels of deprivation needs further study to ensure that these groups are not being systematically under-investigated.

OBJECTIVE: Antiepileptic drugs (AEDs) are commonly prescribed for epilepsy and bipolar disorder but little is known about their use in pregnancy. We examined secular trends in AED prescribing in pregnancy and pregnancy as a determinant for stopping AED prescribing. METHODS: We identified 174,055 pregnancies from The Health Improvement Network UK primary care database. Secular trends in AED prescribing during pregnancy were examined between 1994 and 2009. We used Cox's regression analyses to compare time to discontinuation of AED prescriptions between pregnant and non-pregnant women and to identify predictors of discontinuation of AEDs in pregnancy. RESULTS: Prescribing of carbamazepine and sodium valproate have declined since 1994 despite being the most commonly prescribed AEDs in pregnancy up to 2004. Prescribing of lamotrigine in pregnancy has steadily increased and has been the most popular AED prescribed in pregnancy since 2004. Pregnant women with epilepsy were twice as likely to stop receiving AEDs (Hazard Ratio (HR) 2.00, 95% Confidence Interval (CI) 1.62-2.47) when compared to non-pregnant women and for women with bipolar disorder this was even higher (HR 3.07, 95% CI 2.04-4.62). For pregnant women with epilepsy, those receiving AEDs less regularly before pregnancy were more likely to stop receiving AEDs in pregnancy. CONCLUSIONS: Lamotrigine has been increasingly prescribed in pregnancy over older AEDs namely carbamazepine and sodium valproate. Pregnancy is a strong determinant for the discontinuation of AED prescribing particularly for women with bipolar disorder.

PURPOSE: To describe the design and rationale of a series of postmarketing studies to examine the safety of saxagliptin, an oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus, in real-world settings. METHODS: We are conducting a series of retrospective cohort studies using two UK (General Practice Research Database, and The Health Improvement Network) and two US (Medicare, HealthCore Integrated Research Database(SM) ) data sources. The primary outcomes of interest will include (i) hospitalization with acute liver failure, (ii) hospitalization for acute kidney injury, (iii) hospitalization for severe hypersensitivity reactions, (iv) hospitalization for severe infections, (v) hospitalization with infections associated with T-lymphocyte dysfunction (i.e., herpes zoster, tuberculosis, or nontuberculous mycobacteria), and (vi) major cardiovascular events. Diagnosis codes for the outcomes of interest will be validated by medical record review within each data source. Projected use and estimated incidence rates of outcomes of interest suggest there will be at least 80% statistical power to detect a minimum hazard ratio of 1.5 for major cardiovascular events, 2.0 for acute kidney injury and severe infections, 2.4 for acute liver failure, and 4.0 for severe hypersensitivity reactions. RESULTS: Forthcoming. CONCLUSIONS: This postmarketing safety assessment will provide important information regarding the safety of saxagliptin and could potentially identify important dipeptidyl peptidase-4 inhibitor class effects. The methods described may be useful to others planning similar evaluations.

AIMS: To evaluate the effect of tobacco control media campaigns and pharmaceutical company-funded advertising for nicotine replacement therapy (NRT) on smoking cessation activity. DESIGN: Multiple time series analysis using structural vector autoregression, January 2002-May 2010. SETTING: England and Wales. DATA SOURCES: Tobacco control campaign data from the Central Office of Information; commercial NRT campaign data; data on calls to the National Health Service (NHS) stop smoking helpline from the Department of Health; point-of-sale data on over-the-counter (OTC) sales of NRT; and prescribing data from The Health Improvement Network (THIN), a database of UK primary care records. MEASUREMENTS: Monthly calls to the NHS stop smoking helpline and monthly rates of OTC sales and prescribing of NRT. FINDINGS: A 1% increase in tobacco control television ratings (TVRs), a standard measure of advertising exposure, was associated with a statistically significant 0.085% increase in calls in the same month (P = 0.007), and no statistically significant effect in subsequent months. Tobacco control TVRs were not associated with OTC NRT sales or prescribed NRT. NRT advertising TVRs had a significant effect on NRT sales which became non-significant in the seasonally adjusted model, and no significant effect on prescribing or calls. CONCLUSIONS: Tobacco control campaigns appear to be more effective at triggering quitting behaviour than pharmaceutical company NRT campaigns. Any effect of such campaigns on quitting behaviour seems to be restricted to the month of the campaign, suggesting that such campaigns need to be sustained over time.

OBJECTIVES: To determine variation over time and between practices in recording of concerns related to abuse and neglect (maltreatment) in children's primary care records. DESIGN: Retrospective cohort study using a United Kingdom representative primary care database. SETTING: 448 General Practices. PARTICIPANTS: In total 1,548, 972 children (<18 y) registered between 1995 and 2010. MAIN OUTCOME MEASURES: Change in annual incidence of one or more maltreatment-related codes per child year of registration. Variation between general practices measured as the proportion of registered children with one or more maltreatment-related codes during 3 years (2008-2010). RESULTS: From 1995-2010, annual incidence rates of any coded maltreatment-related concerns rose by 10.8% each year (95% confidence interval 10.5, 11.2; adjusted for sex, age and deprivation). In 2010 the rate was 9.5 per 1000 child years (95%CI: 9.3, 9.8), equivalent to a prevalence of 0.8% of all registered children in 2010. Across all practices, the median prevalence of children with any maltreatment-related codes in three years (2008 to 2010) was 0.9% (range 0%-13.4%; 11 practices (2.5%) had zero children with relevant codes in the same period). Once we accounted for sex, age, and deprivation, the prevalence for each practice was within two standard errors of the grand mean. CONCLUSIONS: General Practitioners (GPs) are far from disengaged from safeguarding children; they are consistently and increasingly recording maltreatment concerns. As these results are likely to underestimate the burden of maltreatment known to primary care, there is much scope for increasing recording in primary care records with implications for resources to respond to concerns about maltreatment. Interventions and policies should build on this evidence that the average GP in the UK is engaged in child safeguarding activity.

Objective. To evaluate the association between the purported risk factors for chondrocalcinosis and gout and the risk of pseudogout in the general population. Methods. We conducted a case-control study nested within a UK general practice database (The Health Improvement Network) by identifying incident cases of pseudogout between 1986 and 2007 and up to 10 control subjects matched to each case, based on age, sex and follow-up time. We evaluated the purported risk factors for chondrocalcinosis (i.e. OA, RA, hyperparathyroidism and diuretics) and established risk factors for gout (as comparison exposures) using conditional logistic regression analysis. Results. We identified 795 cases of pseudogout and 7770 matched control subjects. The risk of pseudogout was associated with hyperparathyroidism [odds ratio (OR) 4.87; 95% CI 2.10, 11.3], OA (OR 2.91; 95% CI 2.48, 3.43) and loop diuretic use (OR 1.35; 95% CI 1.09, 1.67). RA, thiazide diuretic use, BMI and other gout risk factors were not associated with the risk of pseudogout, except for chronic renal failure (OR 2.29; 95% CI 1.30, 4.01). Conclusion. This general population study based on physician-recorded pseudogout suggests that most of the previously observed associations with chondrocalcinosis are replicable with the risk of pseudogout, but there are notable differences, such as thiazide diuretics, RA and chronic renal failure, highlighting the need to study the clinical outcome, pseudogout. Avoiding loop diuretics may help individuals with recurrent pseudogout.

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

BACKGROUND: Serum bilirubin is an endogenous antioxidant that is routinely measured before a statin is prescribed primarily to assess liver function, but the association with cardiovascular disease (CVD) in this population has not been explored. METHOD AND RESULTS: We identified patients from a United Kingdom primary care database (The Health Improvement Network) with measurements of serum total bilirubin levels recorded 3 months before the first statin treatment between January 1, 2000, and December 31, 2010, and no history of liver disease or CVD. In total, 130 052 patients met the inclusion criteria, and after a median follow-up of 43 months, there were 7850 CVD events. In men, the incidence of CVD in the lowest decile category of bilirubin (1-6 μmol/L [0.06-0.35 mg/dL]) was 215 per 10 000 person-years compared with 163 per 10 000 person-years in the highest decile (19-40 μmol/L [1.1-2.3 mg/dL]). Similar differences were seen for women. After conventional CVD risk factors were accounted for, the associations with bilirubin were nonlinear (L shaped), and the models predicted that, compared with patients with a bilirubin level of 10 μmol/L (0.6 mg/dL), those with a similar CVD risk profile but a bilirubin level of 5 μmol/L (0.3 mg/dL) had an 18% (95% confidence interval, 9-27) higher risk of any CVD event, a 34% (95% confidence interval, 13-56) higher risk of myocardial infarction, and a 33% (95% confidence interval, 21-46) higher risk of death resulting from any cause. CONCLUSIONS: Serum bilirubin level measured before a statin prescription to assess liver function is an independent risk factor for CVD and death in both men and women.

Searchable abstracts may be found at http://www.asbmr.org/Meetings/PastAnnualMeetings.aspx.