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INTRODUCTION: The association between allergic diseases and autoimmune disorders is not well established. Our objective was to determine incidence rates of autoimmune disorders in allergic rhinitis/conjunctivitis (ARC), atopic eczema and asthma, and to investigate for co-occurring patterns. METHODS: This was a retrospective cohort study (1990-2018) employing data extracted from The Health Improvement Network (UK primary care database). The exposure group comprised ARC, atopic eczema and asthma (all ages). For each exposed patient, up to two randomly selected age- and sex-matched controls with no documented allergic disease were used. Adjusted incidence rate ratios (aIRRs) were calculated using Poisson regression. A cross-sectional study was also conducted employing Association Rule Mining (ARM) to investigate disease clusters. RESULTS: 782 320, 1 393 570 and 1 049 868 patients with ARC, atopic eczema and asthma, respectively, were included. aIRRs of systemic lupus erythematosus (SLE), Sjögren's syndrome, vitiligo, rheumatoid arthritis, psoriasis, pernicious anaemia, inflammatory bowel disease, coeliac disease and autoimmune thyroiditis were uniformly higher in the three allergic diseases compared with controls. Specifically, aIRRs of SLE (1.45) and Sjögren's syndrome (1.88) were higher in ARC; aIRRs of SLE (1.44), Sjögren's syndrome (1.61) and myasthenia (1.56) were higher in asthma; and aIRRs of SLE (1.86), Sjögren's syndrome (1.48), vitiligo (1.54) and psoriasis (2.41) were higher in atopic eczema. There was no significant effect of the three allergic diseases on multiple sclerosis or of ARC and atopic eczema on myasthenia. Using ARM, allergic diseases clustered with multiple autoimmune disorders. Three age- and sex-related clusters were identified, with a relatively complex pattern in females ≥55 years old. CONCLUSIONS: The long-term risks of autoimmune disorders are significantly higher in patients with allergic diseases. Allergic diseases and autoimmune disorders show age- and sex-related clustering patterns.

INTRODUCTION: Evaluation of risk minimization (RM) actions is an emerging area of regulatory science, often without tools to rapidly and systematically assess their effectiveness. PURPOSE: The aim of this study was to evaluate whether chronographs, typically used for rapid signal detection in observational longitudinal databases, could be used to visualize RM effectiveness. We evaluated the UK Medicines and Healthcare products Regulatory Agency (MHRA) 2012 proton-pump inhibitors (PPIs) class-wide label change that warned of increased risk of bone fracture, advocated to limit duration of use, and recommended to treat those at risk for osteoporosis according to clinical guidelines. METHODS: The cohort consisted of adults aged 18 years and above prescribed one of the five PPIs available in the UK The Health Improvement Network (THIN) database through September 2015. Four chronographs were compared using drug episodes that started before (PRE) and after (POST) the 20 April 2012 MHRA warning; fracture and osteoporosis were evaluated separately. Chronographs show a measure of observed/expected events, the Information Component (IC) and 95% credibility interval (CI), calculated at monthly time intervals relative to the start date of a prescription, and summed to estimate IC over a 3-year period; IC > 0 indicates observed > expected events. We hypothesized that chronographs may assess RM effectiveness if stratified by PRE/POST an RM intervention such as a label change. RESULTS: There were 1,588,973 and 664,601 PPI users in the PRE and POST periods, respectively. We observed a 4.6% reduction in the proportion of long-term PPI episodes and a 4.1% reduction in the overall proportion of the THIN population using PPIs. Compared with the PRE chronographs, when both visually comparing and when examining the summed ICs for fracture in the POST period, a significant reduction was observed overall (IC = 0.024 [95% CI 0.015 to 0.33] PRE vs - 0.141 [95% CI - 0.162 to - 0.120] POST), suggesting less observed events than expected, and prior to PPI start, suggestive of strong channeling (IC = - 0.027 [95% CI - 0.037 to - 0.017] PRE vs - 0.291 [95% CI - 0.308 to - 0.274] POST). Results were qualitatively similar for osteoporosis. CONCLUSIONS: This pilot demonstrated a novel application of a visual, rapid analysis technique to assess RM effectiveness, and supported a hypothesis that prescribers altered some behaviors after the MHRA label change, such as channeling patients at risk of fracture or osteoporosis away from PPI use and potentially reducing fracture outcomes. Limitations include lack of confounding control and outcomes defined only by diagnosis code. Results demonstrate the potential to use large healthcare databases with chronographs to rapidly assess RM effectiveness, similar to signal detection in pharmacovigilance, and may help design more comprehensive RM evaluation studies.

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OBJECTIVE: Thiazide diuretic use is associated with higher bone mineral density (BMD) and possibly lower serum magnesium levels than loop diuretic use, and both high BMD and low serum magnesium have been linked to high prevalent knee osteoarthritis. This study aimed to compare the risk of a clinically relevant endpoint, knee replacement (KR) surgery, among initiators of thiazide and loop diuretics. DESIGN: Among patients aged ≥50 years with a diagnosis of knee osteoarthritis in The Health Improvement Network (THIN) in United Kingdom, we conducted a propensity score-matched cohort study to examine the relation of thiazide diuretic initiation vs loop diuretic initiation to the risk of KR over 5 years. RESULTS: Among thiazide and loop diuretic initiators (n = 3,488 for each group; mean age: 73 years; female ratio: 59%), 359 (28.6/1,000 person-years) and 283 (24.1/1,000 person-years) KRs occurred during the follow-up period, respectively. The hazard ratio (HR) of KR for thiazide diuretic initiation vs loop diuretic initiation was 1.26 (95% confidence interval [CI]: 1.08-1.47). The adherence-adjusted HR of KR for continuous use of thiazide diuretics was 1.44 (95% CI: 1.21-1.72). CONCLUSIONS: In this population-based cohort of patients with knee osteoarthritis, thiazide diuretic use was associated with a higher risk of KR than loop diuretic use. This association may potentially be due to thiazide diuretics' effect on BMD and serum magnesium.

INTRODUCTION: Given prior safety experience with other 5-HT agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. OBJECTIVES: Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. METHODS: Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. RESULTS: In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. CONCLUSIONS: Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany.

OBJECTIVE: To estimate the risk of acute myocardial infarction (AMI) or stroke in adults with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). DESIGN: Matched cohort study. SETTING: Population based, electronic primary healthcare databases before 31 December 2015 from four European countries: Italy (n=1 542 672), Netherlands (n=2 225 925), Spain (n=5 488 397), and UK (n=12 695 046). PARTICIPANTS: 120 795 adults with a recorded diagnosis of NAFLD or NASH and no other liver diseases, matched at time of NAFLD diagnosis (index date) by age, sex, practice site, and visit, recorded at six months before or after the date of diagnosis, with up to 100 patients without NAFLD or NASH in the same database. MAIN OUTCOME MEASURES: Primary outcome was incident fatal or non-fatal AMI and ischaemic or unspecified stroke. Hazard ratios were estimated using Cox models and pooled across databases by random effect meta-analyses. RESULTS: 120 795 patients with recorded NAFLD or NASH diagnoses were identified with mean follow-up 2.1-5.5 years. After adjustment for age and smoking the pooled hazard ratio for AMI was 1.17 (95% confidence interval 1.05 to 1.30; 1035 events in participants with NAFLD or NASH, 67 823 in matched controls). In a group with more complete data on risk factors (86 098 NAFLD and 4 664 988 matched controls), the hazard ratio for AMI after adjustment for systolic blood pressure, type 2 diabetes, total cholesterol level, statin use, and hypertension was 1.01 (0.91 to 1.12; 747 events in participants with NAFLD or NASH, 37 462 in matched controls). After adjustment for age and smoking status the pooled hazard ratio for stroke was 1.18 (1.11 to 1.24; 2187 events in participants with NAFLD or NASH, 134 001 in matched controls). In the group with more complete data on risk factors, the hazard ratio for stroke was 1.04 (0.99 to 1.09; 1666 events in participants with NAFLD, 83 882 in matched controls) after further adjustment for type 2 diabetes, systolic blood pressure, total cholesterol level, statin use, and hypertension. CONCLUSIONS: The diagnosis of NAFLD in current routine care of 17.7 million patient appears not to be associated with AMI or stroke risk after adjustment for established cardiovascular risk factors. Cardiovascular risk assessment in adults with a diagnosis of NAFLD is important but should be done in the same way as for the general population.

AIMS: Non-Alcoholic Fatty Liver Disease (NAFLD) is one of the leading causes of liver transplantation in the West. This study seeks to examine whether women with gestational diabetes mellitus (GDM) are at increased risk of developing NAFLD compared to women without GDM. METHODS: We conducted a population-based retrospective matched-controlled cohort study utilising The Health Improvement Network (THIN), a large primary care database representative of the United Kingdom population, between 01/01/1990 to 31/05/2016 followed by systematic review of available literature. The study population included 9640 women with GDM and 31,296 controls without GDM, matched for age, body mass index (BMI) and time of pregnancy. All study participants were free from NAFLD diagnosis at study entry. Patients with GDM and patients developing NAFLD were identified by clinical codes. RESULTS: The median (range) follow-up duration was similar in women with and without GDM (2.95 (1.21-6.01) vs 2.85 (1.14-5.75) years respectively). Unadjusted incidence rate ratio (IRR) for NAFLD development in women with vs without GDM was 3.28 (95% CI 2.14-5.02), which remained significant after adjustment for wide range of potential confounders (IRR 2.70; 95% CI 1.744-4.19). The risk of NAFLD in GDM remained high (IRR 2.46: 95% CI 1.51-4.00) despite women being censored after they developed type 2 diabetes. The meta-analysis of 3 studies (including the current study) showed increased NAFLD risk in women with vs without GDM (OR 2.60; 95% CI 1.90-3.57, I  = 0%). As our study is based on routine clinical diagnosis of NAFLD, this study could potentially have underestimated the risk of NAFLD development. CONCLUSIONS: Women with GDM are at increased risk of developing NAFLD in their later life compared to women without GDM regardless of the development of type 2 diabetes. Clinicians should have a low threshold to investigate women with history of GDM for the presence of NAFLD. Further studies to identify screening strategies are needed.

INTRODUCTION: This retrospective, observational cohort study evaluated the effect of therapy intensification on change in glycated hemoglobin (HbA1c) at 6 and 12 months post intensification in patients with type 2 diabetes (T2D) suboptimally controlled on basal insulin (BI) (i.e., HbA1c ≥ 7.5% [≥ 58 mmol/mol]). METHODS: Patients with T2D with suboptimal glycemic control using BI were identified from The Health Improvement Network (THIN) database. Patients who underwent therapy intensification (intensifiers) within 12 months of index 1 (the date of the first incidence of suboptimally controlled HbA1c) were matched (1:1) to patients who did not intensify therapy (non-intensifiers). Index 2 was the date of therapy intensification for intensifiers, or a pseudo date for non-intensifiers that resulted in the same duration from index 1 to index 2 as their matched intensifier patient. Primary outcomes were HbA1c change and proportion of patients achieving the HbA1c target at 6 and 12 months post index 2. RESULTS: A total of 1342 patients (n = 646 intensifiers; n = 696 non-intensifiers) were included in the analysis. At post index 2, mean HbA1c change was substantially greater at 6 months for intensifiers than for non-intensifiers (- 0.81% vs. - 0.35%), with no additional benefit at 12 months (- 0.81% vs. - 0.49%, respectively). Compared with non-intensifiers, a greater proportion of intensifiers achieved target HbA1c at 6 months (25.1% vs. 18.8%) and at 12 months (33.4% vs. 28.2%). CONCLUSIONS: Many real-world patients with T2D suboptimally controlled with BI do not have their therapy intensified. The results of this study suggest that in this patient population, therapy intensification achieves significant reductions in HbA1c at 6 months post intensification, with little additional clinical benefit at 12 months. This suggests that, for patients who fail to achieve their glycemic targets at 6 months, since no meaningful additional clinical benefit is observed at 12 months when continuing the same therapy, further therapy intensification or change should be promptly considered. FUNDING: This study and the Rapid Service Fees were funded by Sanofi. TRIAL REGISTRATION: 17THIN068.

AIMS: To compare non-fatal cardiovascular (CV) events and metabolic outcomes, among obese patients with insulin-treated type 2 diabetes who underwent bariatric surgery compared with a propensity-matched non-bariatric cohort. METHODS: A retrospective cohort study was conducted among 11,125 active patients with type 2 diabetes from The Health Improvement Network (THIN) database. Propensity score matching (up to 1:6 ratio) was used to identify patients who underwent bariatric surgery (N = 131) with a non-bariatric cohort (N = 579). Follow-up was undertaken for 10 years (9686 person-years) to compare differences in metabolic outcomes and CV risk events that included the following: acute myocardial infarction (AMI), stroke, coronary heart disease (CHD), heart failure (HF) and peripheral artery disease (PAD). Cox proportional regression was used to compute the outcomes between groups. RESULTS: The mean age was 52 (SD 13) years (60% female); the baseline weight and BMI were 116 (SD 25) kg and 41 (SD 9) kg/m , respectively. Significant reductions in weight and BMI were observed in bariatric group during 10 years of follow-up. Bariatric surgery had a significant cardioprotective effect by reducing the risk of non-fatal CHD (adjusted hazard ratio [aHR] 0.29, 95% CI 0.16-0.52, p < 0.001) and PAD events (aHR 0.31, 95% CI 0.11-0.89, p = 0.03). However, the surgery had no significant effect on AMI (aHR 0.98, p = 0.95), stroke (HR 0.87, p = 0.76) and HF (HR 0.89, p = 0.73) risks. Bariatric surgery had favourable effects on insulin independence, HbA1c and BP. CONCLUSION: Among obese insulin-treated patients with type 2 diabetes, bariatric surgery is associated with significant reductions in non-fatal CHD and PAD events, lower body weight, HbA1c, BP and a greater likelihood of insulin independency during 10 years of follow-up.

OBJECTIVE: To determine discontinuation rates, patterns of use and predictors of discontinuation of non-vitamin K antagonist oral anticoagulants (NOACs) among patients with non-valvular atrial fibrillation (NVAF) in the first year of therapy. DESIGN: Population-based cohort study. SETTING: UK primary care. POPULATION: 11 481 patients with NVAF and a first prescription (index date) for apixaban, dabigatran or rivaroxaban (January 2012 to December 2016) with at least 1 year of follow-up and at least one further NOAC prescription in the year following the index date were identified. 1 year rates and patterns of discontinuation were described. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcome measures were the percentage of patients who, in the first year from starting NOAC therapy, discontinued with their oral anticoagulant (OAC) therapy (discontinuation was defined as a gap in OAC therapy of >30 days); switched OAC within 30 days; discontinued and reinitiated OAC therapy. Predictors of discontinuation were also evaluated. RESULTS: 1 year discontinuation rates according to the index NOAC were 26.1% for apixaban, 40.0% for dabigatran and 29.6% for rivaroxaban. Reinitiation rates were 18.1% for apixaban, 21.7% for dabigatran and 17.3% for rivaroxaban, and switching rates were 2.8% for apixaban, 8.8% for dabigatran and 4.9% for rivaroxaban. More than 93% of reinitiations were with the index NOAC. Patients starting on dabigatran were more likely to switch OAC therapy than those starting on apixaban; ORs 4.28 (95% CI 3.24 to 5.65) for dabigatran and 1.89 (95% CI 1.49 to 2.39) for rivaroxaban. Severely reduced renal function was a predictor of any discontinuation, OR 1.77 (95% CI 1.28 to 2.44). CONCLUSION: While the majority of patients with NVAF in the UK initiating NOAC treatment received continuous therapy in the first year of treatment, a substantial proportion of patients experienced gaps in treatment leaving them less protected against thromboembolism during these periods.

BACKGROUND: Folate deficiency may increase the risk of peripheral neuropathy but there is a paucity of data from large prospective studies examining this association. METHODS: Longitudinal analysis of electronic health records in The Health Improvement Network (THIN), a U.K. primary care database including 594,338 patients aged 18-70 years with a folate measurement and without a history of peripheral neuropathy. RESULTS: After a mean follow-up of 3.71 (standard deviation (SD) = 3.14) years, 1949 patients were diagnosed with peripheral neuropathy and 20,679 patients died. In those <40 years, compared to patients with folate ≥13.6 nmol/L, those with folate <6.8 (deficient) and 6.8-13.5 nmol/L (insufficient) had a hazard ratio (HR) for peripheral neuropathy of 1.83 (95% confidence intervals (CI) = 1.16-2.91) and 1.48 (95% CI = 1.04-2.08), respectively. There was no significant association between folate and peripheral neuropathy among those aged 41-70 years. Compared to patients with folate ≥ 13.6 nmol/L, folate <6.8 nmol/L was associated with a greater risk of death among all ages. CONCLUSION: Folate deficiency and insufficiency was associated with a greater risk of peripheral neuropathy among younger patients. This investigation should be replicated in other large datasets and it may be important to monitor peripheral neuropathy incidence after the introduction of mandatory folic acid fortification of flour in the U.K.

INTRODUCTION: The serotonin 5-HT receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. METHODS: This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding. RESULTS: The pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90-10.39) for patients initiating prucalopride and 10.24 (6.97-14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36-1.14). Results remained consistent in various sensitivity analyses. CONCLUSIONS: The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG.