Publications
scientifiques

OBJECTIVE: To explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures. DESIGN: Retrospective cohort study. SETTING: The Health Improvement Network (THIN), a database of electronic patient records from UK primary care. PARTICIPANTS: Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017. EXPOSURE: TSH concentration in patients with hypothyroidism. MAIN OUTCOME MEASURES: Ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome. RESULTS: 162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)). CONCLUSIONS: In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.

INTRODUCTION: In the UK, about a quarter of women give birth by caesarean section (CS) and are offered prophylactic broad-spectrum antibiotics to reduce the risk of maternal postpartum infection. In 2011, national guidance was changed from recommending antibiotics after the umbilical cord was cut to giving antibiotics prior to skin incision based on evidence that earlier administration reduces maternal infectious morbidity. Although antibiotics cross the placenta, there are no known short-term harms to the baby. This study aims to address the research gap on longer term impact of these antibiotics on child health. METHODS AND ANALYSIS: A controlled interrupted time series study will use anonymised mother-baby linked routine electronic health records for children born during 2006-2018 recorded in UK primary care (The Health Improvement Network, THIN and Clinical Practice Research Datalink, CPRD) and secondary care (Hospital Episode Statistics, HES) databases. The primary outcomes of interest are asthma and eczema, two common allergy-related diseases in childhood. In-utero exposure to antibiotics immediately prior to CS will be compared with no exposure when given after cord clamping. The risk of outcomes in children delivered by CS will also be compared with a control cohort delivered vaginally to account for time effects. We will use all available data from THIN, CPRD and HES with estimated power of 80% and 90% to detect relative increase in risk of asthma of 16% and 18%, respectively at the 5% significance level. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the University of Birmingham Ethical Review Committee with scientific approvals obtained from the independent scientific advisory committees from the Medicines and Healthcare products Regulatory Agency for CPRD and the data provider, IQVIA for THIN. The results will be published in peer-reviewed journals, presented at national and international conferences and disseminated to stakeholders.

INTRODUCTION: Many patients with type 2 diabetes mellitus (DM) fail to achieve glycaemic control despite recommended treatment strategies to reduce glycated haemoglobin (HbA1c). This real-world retrospective cohort study compared HbA1c change and treatment patterns between those intensifying and not intensifying therapy with oral antidiabetic drugs (OADs). MATERIALS AND METHODS: Patients suboptimally controlled on OADs (>58 mmol/mol [>7.5%] or >64 mmol/mol [>8.0%] for high risk, index 1) were included from IQVIA Medical Research Data. Intensifiers within 12 months of index 1 were matched (1:1) to nonintensifiers. Primary outcomes were HbA1c change and proportion of participants achieving HbA1c targets 6 and 12 months post-index 2 (date of intensification [intensifiers] or pseudodate [nonintensifiers]). Therapy adherence was also assessed. RESULTS: A total of 10 832 participants (5539 intensifiers and 5293 nonintensifiers) were included. Mean HbA1c decrease from baseline to 6 months was -1.13% (intensifiers) vs -0.75% (nonintensifiers), with no substantial further change at 12 months. Cox proportional hazards (PH) analysis suggested a nearly 20% greater chance of target achievement at 6 months for intensifiers vs nonintensifiers (hazard ratio [HR]: 0.79 [95% confidence interval [CI]: 0.73-0.86]), which was similar at 12 months (HR: 0.80 [95% CI: 0.74-0.86]). Intensifiers tended towards greater adherence to baseline therapy (90% [standard deviation (SD): 14.9] vs nonintensifiers 87% [SD: 16.0]), which decreased following intensification. CONCLUSIONS: Significant reductions in HbA1c were evident at 6 months and were greater in intensifiers vs nonintensifiers. Little additional clinical benefit was seen 12 months postintensification. Despite good treatment adherence, many participants failed to achieve target HbA1c; actions beyond improved adherence are needed to improve suboptimal HbA1c.

OBJECTIVE: Depression is associated with IBD, but the effect of antidepressants on IBD has been sparsely studied. We assessed the impact of depression and antidepressant therapies on the development of IBD. DESIGN: The Health Improvement Network (THIN) was used to identify a cohort of patients with new-onset depression from 1986 to 2012. THIN patients who did not meet the defining criteria for depression were part of the referent group. The outcome was incident Crohn's disease (CD) or ulcerative colitis (UC). Cox proportional hazards modelling was performed to evaluate the rate of Crohn's disease or UC development among patients with an exposure of depression after controlling for age, sex, socioeconomic status, comorbid conditions, smoking, anxiety and antidepressant use including atypical antidepressants, mirtazapine, monoamine oxidase inhibitors (MAOI), serotonin norepinephrine reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), serotonin modulators; and tricyclic antidepressants (TCA). RESULTS: We identified 403 665 (7.05%) patients with incident depression. Individuals with depression had a significantly greater risk of developing CD (adjusted HR=2.11, 95% CI 1.65 to 2.70) and UC (adjusted HR=2.23, 95% CI 1.92 to 2.60) after controlling for demographic and clinical covariates. SSRI and TCA were protective against CD, whereas mirtazapine, SNRI, SSRI, serotonin modulators and TCA were protective for UC. CONCLUSION: Patients with a history of depression were more likely to be diagnosed with IBD. In contrast, antidepressant treatments were selectively protective for Crohn's disease and UC. These results may impact counselling and management of depression and IBD.

BACKGROUND: two common anti-diabetic treatments used are sitagliptin and sulphonylureas however evidence examining their comparative effectiveness in older people is limited. OBJECTIVE: to evaluate effectiveness of sitagliptin vs sulphonylureas when added to metformin in older (aged ≥75) vs younger people (18-75). DESIGN: retrospective cohort study. SETTING: UK Primary Care. SUBJECTS: 2,904 individuals prescribed sitagliptin (223 aged≥75) and 13,683 prescribed sulphonylureas (1,725 aged ≥75). METHODS: multivariable regression to analyse difference in HbA1c and weight, 12 months after add-on initiation and proportion achieving different glycaemic targets. RESULTS: after multivariate adjustment to remove baseline differences, the HbA1c after 12 months of treatment was on average 1 mmol/mol (95%CI -0.7 to 2.8) higher with sitagliptin vs sulphonylureas in older people though this was not statistically significant. The weight however, was significantly lower -1.4 kg (95%CI -2.1 to -0.7) with sitagliptin vs sulphonylureas. A lower proportion prescribed sitagliptin vs sulphonylureas recorded HbA1c < 48 mmol/mol by study end: Odds Ratio 0.63 (95%CI 0.42-0.95). In younger people, similar HbA1c reductions were also observed with both treatments, however weight after 12 months was even lower with sitagliptin vs sulphonylureas: -2.3 kg (95%CI -2.5 to -2.0). CONCLUSIONS: similar HbA1c reduction was observed when sitagliptin or sulphonylureas were added to metformin in older and younger age-groups. Sitagliptin use led to modest comparative weight loss. There may be greater risk of over-treatment with sulphonylureas evidenced by greater proportion recording HbA1c < 48 mmol/mol by study end. This evidence supporting use of sitagliptin when add-on therapy is selected in older adults should be considered alongside the wider evidence-base and patient-preference.

IMPORTANCE: Cardiovascular disease (CVD) risk has not been previously evaluated in a large matched cohort study in idiopathic intracranial hypertension (IIH). OBJECTIVES: To estimate the risk of composite cardiovascular events, heart failure, ischemic heart disease, stroke/transient ischemic attack (TIA), type 2 diabetes, and hypertension in women with idiopathic intracranial hypertension and compare it with the risk in women, matched on body mass index (BMI) and age, without the condition; and to evaluate the prevalence and incidence of IIH. DESIGN, SETTING, AND PARTICIPANTS: This population-based matched controlled cohort study used 28 years of data, from January 1, 1990, to January 17, 2018, from The Health Improvement Network (THIN), an anonymized, nationally representative electronic medical records database in the United Kingdom. All female patients aged 16 years or older were eligible for inclusion. Female patients with IIH (n = 2760) were included and randomly matched with up to 10 control patients (n = 27 125) by BMI and age. MAIN OUTCOMES AND MEASURES: Adjusted hazard ratios (aHRs) of cardiovascular outcomes were calculated using Cox regression models. The primary outcome was a composite of any CVD (heart failure, ischemic heart disease, and stroke/TIA), and the secondary outcomes were each CVD outcome, type 2 diabetes, and hypertension. RESULTS: In total, 2760 women with IIH and 27 125 women without IIH were included. Age and BMI were similar between the 2 groups, with a median (interquartile range) age of 32.1 (25.6-42.0) years in the exposed group and 32.1 (25.7-42.1) years in the control group; in the exposed group 1728 women (62.6%) were obese, and in the control group 16514 women (60.9%) were obese. Higher absolute risks for all cardiovascular outcomes were observed in women with IIH compared with control patients. The aHRs were as follows: composite cardiovascular events, 2.10 (95% CI, 1.61-2.74; P < .001); heart failure, 1.97 (95% CI, 1.16-3.37; P = .01); ischemic heart disease, 1.94 (95% CI, 1.27-2.94; P = .002); stroke/TIA, 2.27 (95% CI, 1.61-3.21; P < .001); type 2 diabetes, 1.30 (95% CI, 1.07-1.57; P = .009); and hypertension, 1.55 (95% CI, 1.30-1.84; P < .001). The incidence of IIH in female patients more than tripled between 2005 and 2017, from 2.5 to 9.3 per 100 000 person-years. Similarly, IIH prevalence increased in the same period, from 26 to 79 per 100 000 women. Incidence increased markedly with BMI higher than 30. CONCLUSIONS AND RELEVANCE: Idiopathic intracranial hypertension in women appeared to be associated with a 2-fold increase in CVD risk; change in patient care to modify risk factors for CVD may reduce long-term morbidity for women with IIH and warrants further evaluation.

OBJECTIVE: To evaluate the appropriateness of the initial prescribed daily dose of non-vitamin K antagonist oral anticoagulants (NOACs) according to label in patients with non-valvular atrial fibrillation (NVAF) in the UK. DESIGN: Population-based cross-sectional study. SETTING: UK primary care. POPULATION: 30 467 patients with NVAF and a first prescription for apixaban, dabigatran or rivaroxaban between January 2011 and December 2016. MAIN OUTCOME MEASURES: Percentage of patients prescribed a NOAC dose according to the European Union (EU) labels (appropriately dosed), and not according to the EU labels (inappropriately dosed-including both underdosed and overdosed patients); percentage of patients prescribed an initial NOAC dose according to renal function status. RESULTS: A total of 15 252 (50.1%) patients started NOAC therapy on rivaroxaban, 10 834 (35.6%) on apixaban and 4381 (14.4%) on dabigatran. Among patients starting NOAC therapy on rivaroxaban, 17.3% were eligible to receive a reduced dose compared with 12.8% of patients starting on apixaban and 53.8% of patients starting on dabigatran. The majority of patients were prescribed an appropriate dose according to the EU labels: apixaban 74.9 %, dabigatran, 74.4%; rivaroxaban, 84.2%. Underdosing occurred in 21.6% (apixaban), 8.7% (dabigatran), 9.1% (rivaroxaban). Overdosing was more frequent for dabigatran (16.9%) than for rivaroxaban (6.6%) or apixaban (3.5%). There was a trend towards dose reduction with increasing renal impairment. Among patients with severe renal impairment, the majority received a reduced dose NOAC: apixaban, 91.1%, dabigatran, 80.0%, rivaroxaban, 83.0%. CONCLUSION: Between 2011 and 2016, the majority of patients starting NOAC therapy in UK primary care were prescribed a daily dose in line with the approved EU drug label. Underdosing was more than twice as common among patients starting on apixaban than those starting on dabigatran or rivaroxaban. Research into the patient characteristics that may influence inappropriate underdosing of NOACs in UK primary care is warranted.