Publications
scientifiques

BACKGROUND: There are conflicting findings from observational studies of the arrhythrogenic potential of azithromycin. Our aim was to quantify the association between azithromycin use and the risk of ventricular arrhythmia. METHODS: We conducted a nested case-control study within a cohort of new antibiotic users identified from a network of 7 population-based health care databases in Denmark, Germany, Italy, the Netherlands and the United Kingdom for the period 1997-2010. Up to 100 controls per case were selected and matched by age, sex and database. Recency of antibiotic use and type of drug (azithromycin was the exposure of interest) at the index date (occurrence of ventricular arrhythmia) were identified. We estimated the odds of ventricular arrhythmia associated with current azithromycin use relative to current amoxicillin use or nonuse of antibiotics (≥ 365 d without antibiotic exposure) using conditional logistic regression, adjusting for confounders. RESULTS: We identified 14 040 688 new antibiotic users who met the inclusion criteria. Ventricular arrhythmia developed in 12 874, of whom 30 were current azithromycin users. The mean age of the cases and controls was 63 years, and two-thirds were male. In the pooled data analyses across databases, azithromycin use was associated with an increased risk of ventricular arrhythmia relative to nonuse of antibiotics (adjusted odds ratio [OR] 1.97, 95% confidence interval [CI] 1.35-2.86). This increased risk disappeared when current amoxicillin use was the comparator (adjusted OR 0.90, 95% CI 0.48-1.71). Database-specific estimates and meta-analysis confirmed results from the pooled data analysis. INTERPRETATION: Current azithromycin use was associated with an increased risk of ventricular arrhythmia when compared with nonuse of antibiotics, but not when compared with current amoxicillin use. The decreased risk with an active comparator suggests significant confounding by indication.

BACKGROUND: Heart failure is a common long term condition affecting around 900 000 people in the UK and patients commonly present to primary care. The prognosis of patients with a code of heart failure in their primary care record is unknown. OBJECTIVE: The study sought to determine the overall survival rates for patients with heart failure in a primary care population from the time of diagnosis. METHODS: Survival analysis was carried out using UK primary care records from The Health Improvement Network (THIN) between 1 January 1998 and 31 December 2012. Patients age 45 or over with a first diagnostic label of heart failure were matched by age, sex and practice to people without heart failure. Outcome was death in the heart failure and no heart failure cohorts. Kaplan-Meier curves were used to compare survival. Age-specific survival rates at 1, 5 and 10 years were determined for men and women with heart failure. Survival rates by year of diagnosis and case definition were also calculated. RESULTS: During the study period, 54313 patients had a first diagnostic code of heart failure. Overall survival rates for the heart failure group were 81.3% (95%CI 80.9-81.6), 51.5% (95%CI 51.0-52.0) and 29.5% (95%CI 28.9-30.2) at 1, 5 and 10 years respectively and did not change over time. CONCLUSIONS: In a primary care population, the survival of patients diagnosed with heart failure did not improved over time. Further research is needed to explain these trends and to find strategies to improve outlook.

OBJECTIVE: Subjects with rheumatoid arthritis (RA) are at higher risk of developing cardiovascular disease, which is their leading cause of death. Conflicting evidence exists regarding the efficacy of aspirin (ASA) as primary prevention. We evaluated whether a protective association exists between ASA and myocardial infarction (MI) in RA subjects. METHODS: In the United Kingdom, persons age ≥ 60 years receive free ASA by prescription and 75% of use is by prescription. Subjects ≥ 60 years with RA in the population-based The Health Improvement Network database constituted our study population. We excluded patients with history of MI, angina, stroke, peripheral vascular disease, or coronary artery procedures. Our main outcome was the occurrence of fatal and nonfatal MI. We performed a case-crossover study with each subject contributing a hazard period and a control period 90 days prior to the MI. In addition, to minimize confounding by indication, a propensity score (PS)-matched cohort study was performed, considering all patients with RA with an incident prescription of low-dose ASA as our exposed group. RESULTS: We did not find a protective effect in the case-crossover study (OR 1.83, 95% CI 0.71-4.71), with 55 subjects exposed in the hazard period and 44 in the control period. Similarly, among 1836 subjects included in the PS-matched cohort study (918 ASA users and 918 ASA non-users), we did not find a protective effect of low ASA on MI (HR 1.39, 95% CI 0.87-2.23). CONCLUSION: We did not find a protective effect of ASA on MI in patients with RA when used as primary prophylaxis.

BACKGROUND: Adrenaline auto-injectors (AAI) should be provided to individuals considered to be at high risk of anaphylaxis. There is some evidence that the rate of AAI prescription is increasing, but the true extent has not been previously quantified. AIM: To estimate the trends in annual GP-issued prescriptions for AAI among UK children between 2000 and 2012. DESIGN AND SETTING: Retrospective cohort study using data from primary care practices that contributed to The Health Improvement Network (THIN) database. METHOD: Children and young people aged between 0-17 years of age with a prescription for AAIs were identified, and annual AAI device prescription rates were estimated using Stata (version 12). RESULTS: A total of 1.06 million UK children were identified, providing 5.1 million person years of follow-up data. Overall, 23 837 children were deemed high risk by their GPs, and were prescribed 98 737 AAI devices. This equates to 4.67 children (95% confidence interval [CI] = 4.66 to 4.69), and 19.4 (95% CI = 19.2 to 19.5) devices per 1000 person years. Between 2000 and 2012, there has been a 355% increase in the number of children prescribed devices, and a 506% increase in the total number of AAI devices prescribed per 1000 person years in the UK. The number of devices issued per high-risk child during this period has also increased by 33%. CONCLUSION: The number of children being prescribed AAI devices and the number of devices being prescribed in UK primary care between 2000 and 2012 has significantly increased. A discussion to promote rational prescribing of AAIs in the NHS is needed.

The aim of this study was to estimate the patterns of care and annual levels of health care resource use attributable to the management of different wound types by the UK's National Health Service (NHS) in 2012/2013 and the annual costs incurred by the NHS in managing them. This was a retrospective cohort analysis of the records of 2000 patients in The Health Improvement Network (THIN) Database. Patients' characteristics, wound-related health outcomes and all health care resource use were quantified, and the total NHS cost of patient management was estimated at 2013/2014 prices. The NHS managed an estimated 2·2 million patients with a wound during 2012/2013. Patients were predominantly managed in the community by general practitioners (GPs) and nurses. The annual NHS cost varied between £1·94 billion for managing 731 000 leg ulcers and £89·6 million for managing 87 000 burns, and associated comorbidities. Sixty-one percent of all wounds were shown to heal in an average year. Resource use associated with managing the unhealed wounds was substantially greater than that of managing the healed wounds (e.g. 20% more practice nurse visits, 104% more community nurse visits). Consequently, the annual cost of managing wounds that healed in the study period was estimated to be £2·1 billion compared with £3·2 billion for the 39% of wounds that did not heal within the study year. Within the study period, the cost per healed wound ranged from £698 to £3998 per patient and that of an unhealed wound ranged from £1719 to £5976 per patient. Hence, the patient care cost of an unhealed wound was a mean 135% more than that of a healed wound. Real-world evidence highlights the substantial burden that wounds impose on the NHS in an average year. Clinical and economic benefits to both patients and the NHS could accrue from strategies that focus on (a) wound prevention, (b) accurate diagnosis and (c) improving wound-healing rates.

INTRODUCTION: The glucagon-like peptide-1 receptor agonists liraglutide and lixisenatide are effective at reducing glycated hemoglobin (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM). Although liraglutide has demonstrated superior efficacy in head-to-head clinical trials, real-world evidence of comparative effectiveness is lacking. This observational study aimed to assess the effectiveness of liraglutide versus lixisenatide in UK clinical practice. METHODS: Electronic medical records from The Health Improvement Network (THIN) UK primary care database were analyzed. Patients aged ≥18 years, diagnosed with T2DM, and prescribed liraglutide or lixisenatide between 01 May 2013 and 31 December 2015 were included in the study. Adjusted linear regression models compared the difference in mean change in HbA1c, body mass index (BMI), and systolic blood pressure (SBP) after 12-month follow-up. The proportion of patients achieving glycemic control (HbA1c <6.5%, <7.0%, <7.5%); HbA1c reduction >1%; and weight reduction ≥3% within 12 months were determined. Cox proportional hazards modeling was used to evaluate the effect of treatment on time to achieving HbA1c and weight reduction targets. Healthcare resource use (HCRU) (GP, secondary care, hospitalizations) was compared using analysis of covariance. RESULTS: The primary outcome was assessed in 579 liraglutide and 213 lixisenatide new users. Fully adjusted linear regression indicated that liraglutide reduced HbA1c significantly more than lixisenatide (mean treatment difference -0.30; 95% CI -0.56, -0.04; p = 0.025). Compared to lixisenatide, liraglutide recipients were 2.5 times more likely to achieve HbA1c <6.5% (p = 0.0002). Liraglutide users were also more likely to achieve HbA1c <7.0% (HR 2.10; p < 0.0001), <7.5% (HR 1.65; p < 0.0001), and >1% HbA1c reduction (HR 1.29; p = 0.0002). BMI and SBP reductions were greater for the liraglutide group but results were not significant. HCRU was comparable between treatment groups. CONCLUSION: These results from the THIN database indicate that liraglutide treatment provided better outcomes related to glycemic control. FUNDING: Novo Nordisk.

The factors that contribute to the development of psoriatic arthritis (PsA) among patients with psoriasis are not well known; however, systemic inflammation is believed to be important. On the basis of recent laboratory work demonstrating that major depressive disorder (MDD) is associated with increased systemic inflammation, we hypothesized that patients with psoriasis who develop MDD are at increased risk of subsequently developing PsA. We utilized The Health Improvement Network, a primary care medical records database, to identify 73,447 individuals with psoriasis. Patients were followed up to 25 years until the development of the primary outcome of PsA or the censor date. The exposure of interest was the development of MDD. Cox proportional-hazards models showed that patients with psoriasis who developed MDD were at significantly increased risk of subsequently developing PsA compared with patients who did not develop MDD, even after accounting for numerous covariates (hazard ratio 1.37, 95% confidence interval 1.05-1.80, P = 0.021). This result was maintained through numerous sensitivity analyses. These data support the hypothesis that MDD increases the risk of developing PsA among patients with psoriasis, suggesting a need for heightened prevention and management of MDD in patients with psoriasis.

BACKGROUND: Vitamin D has attracted considerable interest in recent years, and health care providers have reported large increases in vitamin D test requests. However, rates of diagnosis of vitamin D deficiency in clinical practice have not been investigated. We examined trends in diagnosis of vitamin D deficiency in children in England over time, and by sociodemographic characteristics. METHODS: Cohort study using primary care records of 711 788 children aged 0 to 17 years, from the Health Improvement Network database. Incidence rates for diagnosis of vitamin D deficiency were calculated per year between 2000 and 2014. Rate ratios exploring differences by age, sex, ethnicity, and social deprivation were estimated using multivariable Poisson regression. RESULTS: The crude rate of vitamin D deficiency diagnosis increased from 3.14 per 100 000 person-years in 2000 (95% confidence interval [CI], 1.31-7.54) to 261 per 100 000 person-years in 2014 (95% CI, 241-281). After accounting for changes in demographic characteristics, a 15-fold (95% CI, 10-21) increase in diagnosis was seen between 2008 and 2014. Older age (≥10 years), nonwhite ethnicity, and social deprivation were independently associated with higher rates of diagnosis. In children aged <5 years, diagnosis rates were higher in boys than girls, whereas in children aged ≥10 they were higher in girls. CONCLUSIONS: There has been a marked increase in diagnosis of vitamin D deficiency in children over the past decade. Future research should explore the drivers for this change in diagnostic behavior and the reasons prompting investigation of vitamin D status in clinical practice.

OBJECTIVES: To estimate the 'real-world effectiveness of statins for primary prevention of cardiovascular disease (CVD) and for lipid modification in people with severe mental illnesses (SMI), including schizophrenia and bipolar disorder. DESIGN: Series of staggered cohorts. We estimated the effect of statin prescribing on CVD outcomes using a multivariable Poisson regression model or linear regression for cholesterol outcomes. SETTING: 587 general practice (GP) surgeries across the UK reporting data to The Health Improvement Network. PARTICIPANTS: All permanently registered GP patients aged 40-84 years between 2002 and 2012 who had a diagnosis of SMI. Exclusion criteria were pre-existing CVD, statin-contraindicating conditions or a statin prescription within the 24 months prior to the study start. EXPOSURE: One or more statin prescriptions during a 24-month 'baseline' period (vs no statin prescription during the same period). MAIN OUTCOME MEASURES: The primary outcome was combined first myocardial infarction and stroke. All-cause mortality and total cholesterol concentration were secondary outcomes. RESULTS: We identified 2944 statin users and 42 886 statin non-users across the staggered cohorts. Statin prescribing was not associated with significant reduction in CVD events (incident rate ratio 0.89; 95% CI 0.68 to 1.15) or all-cause mortality (0.89; 95% CI 0.78 to 1.02). Statin prescribing was, however, associated with statistically significant reductions in total cholesterol of 1.2 mmol/L (95% CI 1.1 to 1.3) for up to 2 years after adjusting for differences in baseline characteristics. On average, total cholesterol decreased from 6.3 to 4.6 in statin users and 5.4 to 5.3 mmol/L in non-users. CONCLUSIONS: We found that statin prescribing to people with SMI in UK primary care was effective for lipid modification but not CVD events. The latter finding may reflect insufficient power to detect a smaller effect size than that observed in randomised controlled trials of statins in people without SMI.

OBJECTIVE: To investigate prescribing patterns of cyproterone acetate/ethinylestradiol (CPA/EE) in the United Kingdom before and after the 2013 prescribing guidance. STUDY DESIGN: We conducted a retrospective descriptive study in UK general practice. The study population included women with a first prescription (index date) for CPA/EE in The Health Improvement Network in 2011 (N=2760), 2012 (N=2923) and 2014 (N=2341). We evaluated the proportion of new CPA/EE users with (i) a diagnosis of a hyperandrogenic condition, menstrual problem, consultation for contraception management, and other acne treatment, in the year before the index date; and (ii) proportion of new CPA/EE users with concomitant use of another hormonal contraceptive (HC). RESULTS: The percentage of CPA/EE new users with a record of a hyperandrogenic condition was 61% in 2011, 62% in 2012 and 63% in 2014. Corresponding percentages for acne were 51%, 54% and 55%, respectively. When manually reviewing patient records for a sample of CPA/EE new users (n=200), the acne was recorded in 77% of women, hirsutism in 9.5% and polycystic ovary syndrome in 9.5%. Majority of CPA/EE users had a prior acne diagnosis and/or treatment, 76% (n=2091) in 2011, 79% (n=2296) in 2012 and 78% (n=1834) in 2014. Concomitant use of CPA/EE and another HC was rare, 1% of CPA/EE users in 2011 and fewer than 0.5% of CPA/EE users in both 2012 and 2014. CONCLUSIONS: Before and after 2013, the majority of UK women starting treatment with CPA/EE had a condition in line with its approved indication and had received prior acne treatment as per guidance.

BACKGROUND: There is mixed evidence that older people bereaved of a spouse or partner are at risk of adverse outcomes. The main difficulty is to take account of other explanatory factors. We tested for an association between a patient's death and the timing of any bereavement of a cohabitee. METHOD: Self-controlled case series study in which each case serves as his or her own control and which thereby accounts for all fixed measurable and unmeasurable confounders. We used the Health Improvement Network (THIN) primary care database to identify patients who died aged 50-99 years during the period 2003 to 2014. We used the household identifier in the database to determine whether they had an opposite sex cohabitee at the start of the observation period. RESULTS: 38,773 men and 23,396 women who had died and who had a cohabitee at the start of the observation period, were identified and included in male and female cohorts respectively. A higher risk of death was found in the 24 months after the death of the cohabitee than in the time classified as unexposed. The greatest risk was during the first 3 months after the death of the cohabitee (age-adjusted incidence rate ratio [IRR] 1.63, 95% CI 1.45-1.83 in the male cohort, and IRR 1.70, 95% CI 1.52-1.90 in the female cohort). CONCLUSION: Risk of death in men or women was significantly higher after the death of a cohabitee and this was greatest in the first three months of bereavement. We need more evidence on the effectiveness of interventions to reduce this increased mortality.

BACKGROUND: The incidence of herpes zoster (HZ) is increasing and poses a significant health concern to aging populations. Several studies suggest an increased risk of stroke following zoster infection, but the results are conflicting. We conducted a systematic review and meta-analysis to determine if stroke risk is increased following HZ infection. METHODS: A search of MEDLINE, EMBASE, Google scholar, Web of Science, CAB Direct, Cumulative Index to Nursing and Allied Health Literature, and Evidence Based Medicine Reviews was conducted for observational studies of adults with HZ infection that examined stroke and TIA risk from January 1, 1966 to May 31, 2016. Adjusted relative risks reported for similar follow-up durations were pooled across studies separately using random-effects inverse variance models. RESULTS: Data were pooled from nine studies. Relative risk for stroke after zoster was 1.78 (95% CI 1.70-1.88) for the first month following herpes zoster, dropping progressively to 1.43 (95% CI 1.38-1.47) after 3 months, to 1.20 (95% CI 1.14-1.26) after 1 year. We found that stroke risk increases by a larger margin during the first month after a herpes zoster ophthalmicus episode: relative risk 2.05 (95% CI 1.82-2.31). The risk remains elevated one year after the acute episode. CONCLUSIONS: Herpes zoster is an established risk factor for increasing the risk of stroke, especially shortly after infection. Vaccination should be encouraged in patients at high risk of cardiovascular disease.