Publications
scientifiques

OBJECTIVE: To evaluate temporal prevalence trend, cardiometabolic risk factors, and the risk of atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality (ACM) in incident young- and usual-onset type 2 diabetes. RESEARCH DESIGN AND METHODS: From the U.K. primary care database, 370,854 people with a new diagnosis of type 2 diabetes from 2000 to 2017 were identified. Analyses were conducted by age-group (18-39, 40-49, 50-59, 60-69, 70-79 years) and high-/low-risk status without history of ASCVD at diagnosis, with subjects with two or more of current smoking, high systolic blood pressure, high LDL cholesterol (LDL-C), or chronic kidney disease classified as high risk. RESULTS: The proportion of people aged <50 years at diagnosis increased during 2000-2010 and then stabilized. The incidence rates of ASCVD and ACM declined in people aged ≥50 years but did not decrease in people <50 years. Compared with people aged ≥50 years, those aged 18-39 years at diagnosis had a higher proportion of obesity (71% obese) and higher HbA (8.6%), and 71% had high LDL-C, while only 18% were on cardioprotective therapy. Although 2% in this age-group had ASCVD at diagnosis, 23% were identified as high risk. In the 18-39-year age-group, the adjusted average years to ASCVD/ACM in high-risk individuals (9.1 years [95% CI 8.2-10.0]/9.3 years [8.1-10.4]) were similar to the years in those with low risk (10.0 years [9.5-10.5]/10.5 years [9.7-11.2]). However, individuals aged ≥50 years with high risk were likely to experience an ASCVD event 1.5-2 years earlier and death 1.1-1.5 years earlier compared with low-risk groups ( < 0.01). CONCLUSIONS: Unlike usual-onset, young-onset type 2 diabetes has similar cardiovascular and mortality risk irrespective of cardiometabolic risk factor status at diagnosis. The guidelines on the management of young-onset type 2 diabetes for intensive risk factor management and cardioprotective therapies need to be urgently reevaluated through prospective studies.

BACKGROUND & AIMS: It is not clear what factors affect risk of chronic kidney disease (CKD) in patients with inflammatory bowel disease (IBD); increased risk has been inconsistently associated with use of 5-aminosalicylates (5-ASAs). We aimed to calculate the relative hazard of CKD among patients with IBD, adjusted for CKD risk factors, and to determine whether IBD medications are associated with change in estimated glomerular filtration rate (eGFR). METHODS: We performed a retrospective cohort study of data from The Health Improvement Network. Patients with IBD (n = 17,807) were matched for age, sex, and practice to individuals without IBD (n = 63,466). The relative hazard of CKD, stages 3 through 5D, in patients with IBD was calculated using a Cox proportional hazards model adjusted for common CKD risk factors. We also evaluated the association of 5-ASAs, azathioprine, and methotrexate with change in eGFR using a longitudinal model. RESULTS: After we controlled for risk factors associated with CKD, we found IBD to be associated with development of CKD in patients 16-77 years old. As patient age increased, the adjusted hazard ratio for CKD decreased monotonically, from 7.88 (95% CI, 2.56-24.19) at age 16 to 1.13 (95% CI, 1.01-1.25) at age 77. In the longitudinal analysis, exposure to 5-ASAs or methotrexate was not associated with change in eGFR, whereas azathioprine was associated with a slightly higher eGFR (0.32 mL/min/1.73 m ; 95% CI, 0.16-0.48). CONCLUSIONS: In a retrospective study of more than 80,000 persons, we found that IBD is associated with increased risk of CKD, and the hazard ratio is highest among younger patients. Commonly used non-biologic therapeutic agents were not associated with lower eGFR.

Neurological and psychiatric (mental health) disorders have a large impact on health burden globally. Cognitive disorders (including dementia) and stroke are leading causes of disability. Mental health disorders, including depression, contribute up to one-third of total years lived with disability. The Neurological and mental health Global Epidemiology Network (NeuroGEN) is an international multi-database network that harnesses administrative and electronic medical records from Australia, Asia, Europe and North America. Using these databases NeuroGEN will investigate medication use and health outcomes in neurological and mental health disorders. A key objective of NeuroGEN is to facilitate high-quality observational studies to address evidence-practice gaps where randomized controlled trials do not provide sufficient information on medication benefits and risks that is specific to vulnerable population groups. International multi-database research facilitates comparisons across geographical areas and jurisdictions, increases statistical power to investigate small subpopulations or rare outcomes, permits early post-approval assessment of safety and effectiveness, and increases generalisability of results. Through bringing together international researchers in pharmacoepidemiology, NeuroGEN has the potential to be paradigm-changing for observational research to inform evidence-based prescribing. The first focus of NeuroGEN will be to address evidence-gaps in the treatment of chronic comorbidities in people with dementia.

INTRODUCTION: There are reports that lung cancer in non-smokers (LCINS) is increasing in the United Kingdom (UK) and other high-income countries but evidence from large-scale cohort studies to support this claim is limited. MATERIAL AND METHODS: Using The Health Improvement Network (THIN) IQVIA™ Medical Research Data, we identified a cohort of 3,679,831 people from the UK self-reporting to their primary care physician as never or non-smokers. We estimated age-adjusted incidence rates for recorded lung cancer before (1998-2007) and after (2008-2018) the introduction of smoke-free legislation using multivariable Poisson regression. We also explored the impact of geographic location, social deprivation and urbanicity. RESULTS: The analysis included 3,212 lung cancer events and 28 million person-years (PYs). Between 1998 and 2007, the age-adjusted rates in men declined by 9% per year (95 %CI: 7-11%) from an estimated 5.6 to 1.5 per 10,000 PYs and by 3% per year (95 %CI: 1-5%) between 2008 and 2018. These trends for men were similar across sociodemographic strata. Between 1998 and 2007, age-adjusted rates were stable for women at 1.5 per 10,000 PYs. However, there was evidence that time trends for women differed depending on levels of social deprivation with rates increasing by 5% per year (95 %CI: 2-9%) from an estimated 1.3-2.1 per 10,000 PYs for women living in the least socially deprived areas. Sex-specific time trends from 2008 to 2016 were broadly similar in a separate cohort of self-reported never smokers from UK Biobank with cancer events linked to national registries. CONCLUSION: In summary, the incidence of LCINS has reduced or remained stable for most of the UK with the possible exception of women living in the least socially deprived areas.

OBJECTIVE: To determine risks of embolic events, bleeding, and mortality with direct oral anticoagulants (DOACs) vs warfarin in people with atrial fibrillation (AF) and dementia. DESIGN: New-user retrospective cohort study using The Health Improvement Network database. SETTING AND PARTICIPANTS: A population-based sample comprising people with AF and dementia prescribed DOACs or warfarin from August 2011 to September 2017. METHODS: Risk of ischemic stroke (IS), ischemic stroke/transient ischemic attack/systemic embolism (IS/TIA/SE), all-cause mortality, intracranial bleeding (ICB), gastrointestinal bleeding (GIB), and other bleeding were compared for DOACs vs warfarin using propensity score-adjusted Poisson regression. Incidence rate ratios (IRRs) and absolute risk differences (ARDs) were calculated. RESULTS: Overall, 2399 people with AF and dementia initiated DOACs (42%) or warfarin (58%). Before propensity score adjustment, patients who initiated DOACs were older and had more comorbidities. After adjustment, DOAC initiators demonstrated similar risks of IS, TIA, or SE; IS alone; and other bleeding but reduced ICB risk (IRR 0.27, 95% CI 0.08, 0.86; ARD -5.2, 95% CI -6.5, -1.0, per 1000 person-years) compared with warfarin. Increased risk of GIB (IRR 2.11, 95% CI 1.30, 3.42; ARD 14.8, 95% CI 4.0, 32.4, per 1000 person-years) and all-cause mortality (IRR 2.06, 95% CI 1.60, 2.65; ARD 53.0, 95% CI 30.2, 82.8, per 1000 person-years) were observed in DOAC initiators compared with warfarin. CONCLUSIONS AND IMPLICATIONS: Among people with AF and dementia, initiating treatment with DOACs compared with warfarin was associated with similar risks of IS, TIA, or SE and IS alone. DOAC-treated patients demonstrated reduced ICB risk but increased GIB and all-cause mortality risks. We cannot exclude the possible impact of residual confounding from channeling of DOACs toward older and sicker people, particularly for the outcome of all-cause mortality. Further safety data are urgently needed to confirm findings.

OBJECTIVE: To determine the risk of cardiovascular disease (CVD), microvascular complications, and mortality in patients with type 2 diabetes who subsequently develop obstructive sleep apnea (OSA) compared with patients with type 2 diabetes without a diagnosis of OSA. RESEARCH DESIGN AND METHODS: This age-, sex-, BMI-, and diabetes duration-matched cohort study used data from a U.K. primary care database from 1 January 2005 to 17 January 2018. Participants aged ≥16 years with type 2 diabetes were included. Exposed participants were those who developed OSA after their diabetes diagnosis; unexposed participants were those without diagnosed OSA. Outcomes were composite CVD (ischemic heart disease [IHD], stroke/transient ischemic attack [TIA], heart failure [HF]), peripheral vascular disease (PVD), atrial fibrillation (AF), peripheral neuropathy (PN), diabetes-related foot disease (DFD), referable retinopathy, chronic kidney disease (CKD), and all-cause mortality. The same outcomes were explored in patients with preexisting OSA before a diagnosis of type 2 diabetes versus diabetes without diagnosed OSA. RESULTS: A total of 3,667 exposed participants and 10,450 matched control participants were included. Adjusted hazard ratios for the outcomes were as follows: composite CVD 1.54 (95% CI 1.32, 1.79), IHD 1.55 (1.26, 1.90), HF 1.67 (1.35, 2.06), stroke/TIA 1.57 (1.27, 1.94), PVD 1.10 (0.91, 1.32), AF 1.53 (1.28, 1.83), PN 1.32 (1.14, 1.51), DFD 1.42 (1.16, 1.74), referable retinopathy 0.99 (0.82, 1.21), CKD (stage 3-5) 1.18 (1.02, 1.36), albuminuria 1.11 (1.01, 1.22), and all-cause mortality 1.24 (1.10, 1.40). In the prevalent OSA cohort, the results were similar, but some associations were not observed. CONCLUSIONS: Patients with type 2 diabetes who develop OSA are at increased risk of CVD, AF, PN, DFD, CKD, and all-cause mortality compared with patients without diagnosed OSA. Patients with type 2 diabetes who develop OSA are a high-risk population, and strategies to detect OSA and prevent cardiovascular and microvascular complications should be implemented.

AIM: To estimate the incidence and risk factors of chronic kidney disease (CKD) in patients with newly-diagnosed diabetes using different CKD definitions. METHODS: Using UK primary care data, patients with diabetes (type 1, 4691; type 2, 109,365) and no CKD were followed to identify newly-diagnosed CKD, classified by a broad and narrow CKD definition (to capture diabetes-induced CKD, termed diabetic kidney disease, DKD). Adjusted incidence rates of CKD/DKD were calculated, and risk factors identified using Cox regression. RESULTS: There were 404 CKD cases and 147 DKD cases among patients with type 1 diabetes (T1D), and 29,104 CKD cases, 9284 DKD cases among patients with type 2 diabetes (T2D). Adjusted incidence rates of CKD per 100 years were 5.4 (T1D) and 5.5 (T2D); for DKD they were 1.9 and 1.5, respectively. Risk factors for CKD/DKD were older age, high social deprivation, obesity, cardiovascular disease, hypertension and smoking. Poor glycaemic control in the year after diabetes diagnosis was a strong predictor of CKD/DKD occurrence beyond this first year, and a risk factor for CKD/DKD in T2D. CONCLUSIONS: CKD and DKD remain common in diabetics in the decade after diagnosis. Early prevention of T2D and aggressive treatment of risk factors is urgent.

BACKGROUND: Real world evidence (RWE) is becoming more frequently used in technology appraisals (TAs). This study sought to explore the use and acceptance of evidence from primary care databases, a key source of RWE in the UK, in National Institute for Health and Care Excellence (NICE) technology assessments and to provide recommendations regarding their use in future submissions. METHODS: A keyword search was conducted relating to the main primary care databases in the UK on the NICE website. All NICE TAs identified through this search were screened, assessed for duplication and information on the data source and the way the data was used in the submission were extracted. Comments by the evidence review group (ERG) and the appraisal committee were also extracted and reviewed. All data extraction was performed by two independent reviewers and all decisions were reached by consensus with an additional third reviewer. RESULTS: A total of 52 NICE TAs were identified, 47 used the General Practice Research Database /Clinical Practice Research Datalink (GPRD/CPRD) database, 10 used The Health Improvement Network (THIN) database and 3 used the QResearch databases. Data from primary care databases were used to support arguments regarding clinical need and current treatment in 33 NICE TAs while 36 were used to inform input parameters for economic models. The databases were sometimes used for more than one purpose. The data from the three data sources were generally well received by the ERGs/committees. Criticisms of the data typically occurred where the results had been repurposed from a published study or had not been applied appropriately. CONCLUSIONS: The potential of UK primary care databases in NICE submissions is increasingly being realised, particularly in informing the parameters of economic models. Purpose conducted studies are less likely to receive criticism from ERGs/committees, particularly when providing clinical input into cost effectiveness models.

INTRODUCTION: Inequalities in life expectancy and mortality by social deprivation in the general population of the United Kingdom are widening. For people with dementia, data on potential gradients in life expectancy and mortality by social deprivation are sparse. This study aimed to explore potential differentials in life expectancy and mortality in people with dementia according to social deprivation. METHODS: Using The Health Improvement Network (THIN) primary care database, we included people with a diagnosis of dementia in the United Kingdom in 2000 to 2016 and obtained data on age at death and mortality. Comparisons were made according to social deprivation quintiles adjusting for age at diagnosis. RESULTS: Among 166,268 people with dementia there were no differences in life expectancy and mortality in the most deprived compared with the least deprived. This pattern has been stable during the study period, as no increasing inequalities in life expectancy and mortality according to social deprivation were found. DISCUSSION: Contrary to the general population, there were limited inequalities in life expectancy and mortality according to social deprivation for people with dementia.

OBJECTIVES: We describe temporal trends in the recorded incidence of inflammatory bowel disease (IBD) in UK primary care patients between 2000 and 2018. DESIGN: A cohort study. SETTING: The IQVIA Medical Research data (IMRD) primary care database. PARTICIPANTS: All individuals registered with general practices contributing to IMRD during the period 01 January 2000-31 December 2018. MAIN OUTCOME MEASURES: The primary outcome was the recorded diagnosis of IBD. RESULTS: 11 325 025 individuals were included and 65 700 IBD cases were identified, of which 22 560 were incident diagnoses made during the study period. Overall, there were 8077 incident cases of Crohn's disease (CD) and 12 369 incident cases of ulcerative colitis (UC). Crude incidence estimates of 'IBD overall', CD and UC were 28.6 (28.2 to 28.9), 10.2 (10.0 to 10.5) and 15.7 (15.4 to 15.9)/100 000 person years, respectively. No change in IBD incidence was observed for adults aged 17-40 years and children aged 0-9 years. However, for adults aged over 40 years, incidence fell from 37.8 (34.5 to 41.4) to 23.6 (21.3 to 26.0)/100 000 person years (average decrease 2.3% (1.9 to 2.7)/year (p<0.0001)). In adolescents aged 10-16 years, incidence rose from 13.1 (8.4 to 19.5) to 25.4 (19.5 to 32.4)/100 000 person years (average increase 3.0% (1.7 to 4.3)/year (p<0.0001)). Point prevalence estimates on 31 December 2018 for IBD overall, CD and UC were 725, 276 and 397 per 100 000 people, respectively. CONCLUSIONS: This is one of the largest studies ever undertaken to investigate trends in IBD epidemiology. Although we observed stable or falling incidence of IBD in adults, our results are consistent with some of the highest reported global incidence and prevalence rates for IBD, with a 94% rise in incidence in adolescents. Further investigation is required to understand the aetiological drivers.

BACKGROUND: Worldwide the rate of unplanned pregnancies is more than 40%. Identifying women at risk of pregnancy can help prevent negative outcomes and also reduce healthcare costs of potential complications. It can also allow the investigation of the natural history of pregnancy outcomes, such as ectopic pregnancies or miscarriages. The use of medical records databases has been a crucial development in the field of pharmacoepidemiology - e.g. The Health Improvement Network (THIN) database is a validated database representative of the UK population. This project aimed to test the feasibility of identifying a population of women of childbearing age who are at risk of pregnancy not using any contraception in THIN database. METHODS: First a cohort of women of childbearing age (15-45yo) was identified. By applying a computer-based algorithm, containing codes for contraception methods or other suggestion of contraception, the risk of pregnancy was then ascertained. Next, two validation steps were implemented: 1) Revision of medical records/free text and 2) Questionnaires were sent to primary care practitioners (PCP) of women whose medical records had been reviewed. Positive predicted values (PPV) were calculated. RESULTS: A total of 266,433 women were identified in THIN. For the first validation step, 123 records were reviewed, with a PPV of 99.2% (95%CI: 95.5-99.9). For the questionnaires step, the PPV was of 82.3% (95%CI: 70-91.1). Information on sexual behaviour and attitudes towards conception was not captured by THIN. CONCLUSION: This study shows that by applying a comprehensive computer-based algorithm, THIN can be used to identify women at risk of pregnancy.

Patients with Type 2 diabetes mellitus (T2DM) have an increased risk of atrial fibrillation (AF). The current study aimed to investigate the prevalence and treatment of AF in patients with T2DM, assess the impact of direct oral anticoagulants (DOACs) introduction on oral anticoagulant (OACs) prescribing rates, and factors associated with OAC initiations in patients with T2DM and AF. The Health Improvement Network (THIN) database (2001-2016), was used to examine the annual prevalence and treatment of AF in T2DM. The impact of DOACs introduction on OAC prescribing rates were investigated using interrupted time series analysis (ITS). Factors associated with OAC initiations were also identified using multivariate logistic regression. The prevalence of AF increased from 2.7 [95% confidence intervals (CI) 2.5-2.8] in 2001 to 5.0 (4.9-5.1) in 2016 per 100 persons. OACs prescribing within 30-days of AF diagnosis increased from 21.5% in 2001 to 56.8% in 2016. ITS analysis showed that OAC prescribing increased after DOAC introduction (P < 0.001), however, no immediate change was observed (P = 0.29). T2DM patients with AF, aged 60-79, male gender and BMI ≥ 25 were more likely to receive OAC, adjusted OR 1.3 (1.2-1.5) for aged 60-79, 1.3 (1.2-1.4) for male gender and 2.0 (1.9-2.2) for BMI ≥ 25, respectively. This study highlighted an increase in prevalence of AF in patients with T2DM during the study period. Further studies are warranted to investigate factors contributing to the underuse of OAC in patients with T2DM and AF.

AIMS: Hydrochlorothiazide-induced photosensitivity may increase squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and lip cancer risk. The aim was to quantify these risks. METHODS: Nested case-control studies using data from the UK THIN database from 01 January 1999 to 01 May 2016. Adults with incident SCC, BCC, melanoma, lip cancer and oral cancer were matched (on age, sex and calendar year of cohort entry) to controls using incidence density sampling. Incidence rate ratios (IRR) for each outcome were calculated for ever and cumulative hydrochlorothiazide exposure, measuring the impact of additionally adjusting for smoking and body mass index (BMI). Adjusted rate differences were estimated, including the number needed to harm. RESULTS: Cumulative hydrochlorothiazide doses ≥50 000 mg were associated with a significantly increased risk of SCC IRR = 3.05 (1.93-4.81) and BCC IRR = 1.34 (1.06-1.69). Using a 5-year lag-period, hydrochlorothiazide exposure was also associated with a significantly increased risk of lip cancer (IRR 2.85, 95% confidence interval 1.32-6.15). No significantly increased risk of melanoma or oral cavity cancer was observed. Following adjustment for smoking and BMI, which had inverse associations with several skin cancer types, associations for hydrochlorothiazide remained significant. The overall number needed to harm with high-dose cumulative hydrochlorothiazide exposure was: 804 for SCC; 2463 for BCC, and 200 000 for lip cancer but varied by age and sex. CONCLUSION: Hydrochlorothiazide exposure was associated with an increased risk of SCC, BCC and lip cancer that is not explained following adjustment for smoking and BMI. These findings may support clinical and regulatory decision making.

Acute respiratory infection (ARI) accounts for over two-thirds of total antibiotic prescriptions although most are caused by viruses that do not benefit from antibiotics. Most antibiotics are prescribed in the outpatients setting. Antibiotic overuse leads to antibiotic-related adverse events (AEs), inclusive of secondary infections, resistance, and increased costs. Point-of-care tests (POCT) may reduce unnecessary antibiotics. A cost analysis was performed to assess diagnostic POCT options to identify patients with an ARI that may benefit from antibiotics in a United Kingdom (UK) outpatient setting. Healthcare savings were estimated using a budget impact analysis based on UK National Institute for Health and Care Excellence (NICE) data and direct costs (antibiotics, AEs, POCTs) derived from published literature. Otitis media, sinusitis, pharyngitis and bronchitis were considered the most common ARIs. Antibiotic-related AE costs were calculated using re-consultation costs for anaphylaxis, Stevens-Johnson syndrome, allergies/diarrhea/nausea, infection (CDI). Potential cost-savings from POCTs was assessed by evaluating NICE guideline-referenced POCTs (CRP, FebriDx, Sarasota, FL) as well as a target product profile (TPP). Fifty-percent (7,718,283) of ARI consultations resulted in antibiotics while guideline-based prescribing suggest appropriate antibiotic prescriptions are warranted 9% (1,444,877) of ARI consultations. Direct antibiotic costs for actual ARI consultations associated with antibiotics was £24,003,866 vs. £4,493,568 for guideline-based, "appropriate" antibiotic prescriptions. Antibiotic-related AEs and re-consultations for actual vs. appropriate prescribing totaled £302,496,486 vs. £63,854,269. ARI prescribing plus AE costs totaled £326,729,943 annually without the use of delayed prescribing practices or POCT while the addition of delayed prescribing plus POCT totaled £60,114,564-£78,148,933 depending on the POCT. Adding POCT to outpatient triage of ARI can reduce unnecessary antibiotics and antibiotic-related AEs, resulting in substantial cost savings. Further, near patient diagnostic testing can benefit health systems and patients by avoiding exposure to unnecessary drugs, side effects and antibiotic resistant pathogens.Key points for decision makersMany patients are unnecessarily treated with antibiotics for respiratory infections.Antibiotic misuse leads to unnecessary adverse events, secondary infections, re-consultations, antimicrobial resistance and increased costs.Point-of-care diagnostic tests used to guide antibiotic prescriptions will avoid unnecessary adverse health effects and expenses.