United Kingdom Clinical Practice Research Research Articles

Hormone Replacement Therapy, Synthetic Progestogens, and Breast Cancer Risk

Background: Hormone Replacement Therapy (HRT) has been associated with an increased risk of breast cancer. The study objective is to evaluate whether the increased risk is dependent on the formulation used. Methods: We carried out a population-based case-control study using data from the United Kingdom Clinical Practice Research Datalink on women age ≥50 years. Incident cases of breast cancer were age-matched (1:10) with controls of comparable follow-up time with no history of breast cancer. Exposures were classified as ever or never for the following HRT formulations: bioidentical estrogens, animal-derived estrogens, micronized progesterone, and synthetic progestin. Logistic regression analyses were performed to estimate the adjusted effect of HRT formulation on breast cancer. Findings: Between 1995-2014, 43,183 breast cancer cases were identified and matched to 431,830 controls. In adjusted analyses, compared with women who never used HRT, its use was associated with an increased risk of breast cancer (OR 1·12, 95% CI 1·09-1·15). Compared with never users, estrogens were not associated with breast cancer: bioidentical estrogens (OR 1·04,1·00-1·09), animal-derived estrogens (OR 1·01, 0·96-1·06), both (OR 0·96, 0·89-1·03). Progestogens appeared differentially associated with breast cancer: micronized progesterone (OR 0·99, 0·55-1·79), synthetic progestin (OR 1·28, 1·22-1·35), both (OR 1·32, 0·30-5·77). Interpretation: While HRT use appears to be associated with an overall increased risk of breast cancer, it appears uniquely in women prescribed formulations containing synthetic progestin. Hence, synthetic progestins should not be given as part of HRT regimens and counseling regarding the risk of breast cancer should consider the effect of formulation used. Funding Information: Supported by a grant from the Canadian Cancer Society, 703041. Declaration of Interests: Haim Abenhaim has no conflicts of interest to declare. Samy Suissa has been a Scientific Advisory Committee Member for Atara Bio, Boehringer-Ingelheim, Briston-Myers-Squibb, Merck, MorphoSys, and Seqirus. He has also been a speaker for AstraZeneca and Novartis. All work was unrelated to this study. Laurent Azoulay received consulting fees from Janssen and Pfizer for work unrelated to this study. Andrea Spence has no conflicts of interest to declare. Nicholas Czuzoj-Shulman has no conflicts of interest to declare. Togas Tulandi has no conflicts of interest to declare. Ethics Approval Statement: The Independent Scientific Advisory Committee of the Clinical Practice Research Datalink and the Research Ethics Board of the Jewish General Hospital, Montreal, Quebec, Canada approved the study.

Trends in prescribing patterns of proton pump inhibitors surrounding new guidelines

PurposeThe purpose of this study was to examine whether the latest National Institute for Health and Care Excellence proton pump inhibitor (PPI) guidelines changed physician prescribing patterns in clinical practice. MethodsUsing data from the United Kingdom Clinical Practice Research Datalink, we calculated monthly PPI prescribing rates in adults by dividing the number of PPI prescriptions by the number of patients in each calendar month. Using these rates, we conducted an interrupted time-series analysis to compare PPI prescription rates before (September 2010–August 2014) and after (September 2014–August 2018) guideline publication, estimating a slope and level change using segmented autoregression. ResultsIn the preguideline period, monthly PPI prescription rate increased by 46.9 (95% confidence interval (CI): 40.8 to 53.0) prescriptions per 100,000 persons. Following guideline publication, there was no immediate change in the monthly PPI prescribing rate (137.6, 95% CI: −36.7 to 311.9 prescriptions per 100,000 persons), but there was a modest attenuation of the change in monthly rate (−23.9, 95% CI: −14.0 to −33.6 prescriptions per 100,000 persons). However, the predicted rates mirror the observed rates after guideline publication, suggesting limited changes. ConclusionsDespite efforts to minimize the overprescribing of PPIs, there was little meaningful change in clinical practice following the 2014 National Institute for Health and Care Excellence recommendations.

Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: A population-based cohort study.

Glucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. We aimed to quantify glucocorticoid dose-dependent cardiovascular risk in people with 6 immune-mediated inflammatory diseases. We conducted a population-based cohort analysis of medical records from 389 primary care practices contributing data to the United Kingdom Clinical Practice Research Datalink (CPRD), linked to hospital admissions and deaths in 1998-2017. We estimated time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios (HRs) of first all-cause and type-specific cardiovascular diseases (CVDs). There were 87,794 patients with giant cell arteritis and/or polymyalgia rheumatica (n = 25,581), inflammatory bowel disease (n = 27,739), rheumatoid arthritis (n = 25,324), systemic lupus erythematosus (n = 3,951), and/or vasculitis (n = 5,199), and no prior CVD. Mean age was 56 years and 34.1% were men. The median follow-up time was 5.0 years, and the proportions of person-years spent at each level of glucocorticoid daily exposure were 80% for non-use, 6.0% for <5 mg, 11.2% for 5.0-14.9 mg, 1.6% for 15.0-24.9 mg, and 1.2% for ≥25.0 mg. Incident CVD occurred in 13,426 (15.3%) people, including 6,013 atrial fibrillation, 7,727 heart failure, and 2,809 acute myocardial infarction events. One-year cumulative risks of all-cause CVD increased from 1.4% in periods of non-use to 8.9% for a daily prednisolone-equivalent dose of ≥25.0 mg. Five-year cumulative risks increased from 7.1% to 28.0%, respectively. Compared to periods of non-glucocorticoid use, those with <5.0 mg daily prednisolone-equivalent dose had increased all-cause CVD risk (HR = 1.74; 95% confidence interval [CI] 1.64-1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus). Increased dose-dependent risk ratios were found regardless of disease activity level and for all type-specific CVDs. HRs for type-specific CVDs and <5.0-mg daily dose use were: 1.69 (95% CI 1.54-1.85) for atrial fibrillation, 1.75 (95% CI 1.56-1.97) for heart failure, 1.76 (95% CI 1.51-2.05) for acute myocardial infarction, 1.78 (95% CI 1.53-2.07) for peripheral arterial disease, 1.32 (95% CI 1.15-1.50) for cerebrovascular disease, and 1.93 (95% CI 1.47-2.53) for abdominal aortic aneurysm. The lack of hospital medication records and drug adherence data might have led to underestimation of the dose prescribed when specialists provided care and overestimation of the dose taken during periods of low disease activity. The resulting dose misclassification in some patients is likely to have reduced the size of dose-response estimates. In this study, we observed an increased risk of CVDs associated with glucocorticoid dose intake even at lower doses (<5 mg) in 6 immune-mediated diseases. These results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses.

Risk of Osteoarthritis in an Incident Cohort of People With Psoriatic Arthritis: A Population-based Cohort Study.

To determine the risk of a diagnosis of osteoarthritis (OA) in patients with psoriatic arthritis (PsA) compared to patients with psoriasis and a general population cohort. Incident PsA patients aged 18-89 years at diagnosis were identified from the United Kingdom Clinical Practice Research Datalink between 1998 and 2014. All patients with PsA were matched to 2 cohorts of patients, both at a 1:4 ratio. The first cohort included patients with psoriasis (and no PsA) and the second was a general population cohort (with no psoriasis or PsA). The baseline prevalence of OA was calculated for each study cohort. The incidence of OA was calculated, and adjusted relative risks (RRadj) were calculated using conditional Poisson regression. We identified 6783 incident PsA patients. The baseline prevalence of OA ranged from 22.1% (95% CI 21.1-23.1) in the PsA cohort to 12.6% (95% CI 12.2-13.0) and 11.0% (95% CI 10.6-11.3) in the psoriasis and general population cohorts, respectively. The incidence of OA was significantly higher in the PsA cohort compared to the psoriasis and general population cohorts after adjusting for BMI (RRadj 1.68, 95% CI 1.46-1.93, and RRadj 1.86, 95% CI 1.62-2.14, respectively). An increased risk of OA was observed in patients with PsA compared to patients with psoriasis alone and those in the general population. Further work is needed to determine whether this reflects a true increase in OA risk or misdiagnosed PsA, and the extent to which it can be explained by differences in the opportunity for OA diagnosis between cohorts.

The diagnostic performance of CA125 for the detection of ovarian and non-ovarian cancer in primary care: A population-based cohort study.

The serum biomarker cancer antigen 125 (CA125) is widely used as an investigation for possible ovarian cancer in symptomatic women presenting to primary care. However, its diagnostic performance in this setting is unknown. We evaluated the performance of CA125 in primary care for the detection of ovarian and non-ovarian cancers. We studied women in the United Kingdom Clinical Practice Research Datalink with a CA125 test performed between 1 May 2011-31 December 2014. Ovarian and non-ovarian cancers diagnosed in the year following CA125 testing were identified from the cancer registry. Women were categorized by age: <50 years and ≥50 years. Conventional measures of test diagnostic accuracy, including sensitivity, specificity, and positive predictive value, were calculated for the standard CA125 cut-off (≥35 U/ml). The probability of a woman having cancer at each CA125 level between 1-1,000 U/ml was estimated using logistic regression. Cancer probability was also estimated on the basis of CA125 level and age in years using logistic regression. We identified CA125 levels equating to a 3% estimated cancer probability: the "risk threshold" at which the UK National Institute for Health and Care Excellence advocates urgent specialist cancer investigation. A total of 50,780 women underwent CA125 testing; 456 (0.9%) were diagnosed with ovarian cancer and 1,321 (2.6%) with non-ovarian cancer. Of women with a CA125 level ≥35 U/ml, 3.4% aged <50 years and 15.2% aged ≥50 years had ovarian cancer. Of women with a CA125 level ≥35 U/ml who were aged ≥50 years and who did not have ovarian cancer, 20.4% were diagnosed with a non-ovarian cancer. A CA125 value of 53 U/ml equated to a 3% probability of ovarian cancer overall. This varied by age, with a value of 104 U/ml in 40-year-old women and 32 U/ml in 70-year-old women equating to a 3% probability. The main limitations of our study were that we were unable to determine why CA125 tests were performed and that our findings are based solely on UK primary care data, so caution is need in extrapolating them to other healthcare settings. CA125 is a useful test for ovarian cancer detection in primary care, particularly in women ≥50 years old. Clinicians should also consider non-ovarian cancers in women with high CA125 levels, especially if ovarian cancer has been excluded, in order to prevent diagnostic delay. Our results enable clinicians and patients to determine the estimated probability of ovarian cancer and all cancers at any CA125 level and age, which can be used to guide individual decisions on the need for further investigation or referral.

Validation of cardiovascular outcomes and risk factors in the Clinical Practice Research Datalink in the United Kingdom.

PurposeStrategies to identify and validate acute myocardial infarction (AMI) and stroke in primary‐care electronic records may impact effect measures, but to an unknown extent. Additionally, the validity of cardiovascular risk factors that could act as confounders in studies on those endpoints has not been thoroughly assessed in the United Kingdom Clinical Practice Research Datalink's (CPRD's) GOLD database. We explored the validity of algorithms to identify cardiovascular outcomes and risk factors and evaluated different outcome‐identification strategies using these algorithms for estimation of adjusted incidence rate ratios (IRRs).MethodsFirst, we identified AMI, stroke, smoking, obesity, and menopausal status in a cohort treated for overactive bladder by applying computerized algorithms to primary care medical records (2004–2012). We validated these cardiovascular outcomes and risk factors with physician questionnaires (gold standard for this analysis). Second, we estimated IRRs for AMI and stroke using algorithm–identified and questionnaire–confirmed cases, comparing these with IRRs from cases identified through linkage with hospitalization/mortality data (best estimate).ResultsFor AMI, the algorithm's positive predictive value (PPV) was >90%. Initial algorithms for stroke performed less well because of inclusion of codes for prevalent stroke; algorithm refinement increased PPV to 80% but decreased sensitivity by 20%. Algorithms for smoking and obesity were considered valid. IRRs based on questionnaire‐confirmed cases only were closer to IRRs estimated from hospitalization/mortality data than IRRs from algorithm‐identified cases.ConclusionsAMI, stroke, smoking, obesity, and postmenopausal status can be accurately identified in CPRD. Physician questionnaire–validated AMI and stroke cases yield IRRs closest to the best estimate.

Use of Hydrochlorothiazide and Risk of Melanoma and Nonmelanoma Skin Cancer.

There are concerns that hydrochlorothiazide may increase the risk of incident nonmelanoma (cutaneous squamous cell carcinoma [cSCC], basal cell carcinoma [BCC]) and melanoma skin cancer, with regulatory agencies and societies calling for additional studies. We conducted a propensity score-matched population-based cohort study using the United Kingdom Clinical Practice Research Datalink. A total of 20,513 new users of hydrochlorothiazide were propensity score matched, in a 1:1 ratio, to new users of other thiazide diuretics between January 1, 1988 and March 31, 2018, with follow-up until March 31, 2019. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for cSCC, BCC, and melanoma, comparing use of hydrochlorothiazide with use of other thiazide diuretics overall, by cumulative duration of use, and cumulative dose. After an 8.6-year median follow-up, hydrochlorothiazide was associated with an increased risk of cSCC (HR 1.50, 95% CI 1.06-2.11). HRs increased with cumulative duration of use, with evidence of an association after 5-10years (HR 2.10, 95% CI 1.20-3.67) and highest after > 10years (HR 3.70, 95% CI 1.77-7.73). Similarly, HRs increased with cumulative dose, with higher estimates for ≥ 100,000mg (HR 4.96, 95% CI 2.51-9.81). In contrast, hydrochlorothiazide was not associated with an increased risk of BCC (HR 1.01, 95% CI 0.91-1.13) or melanoma (HR 0.82, 95% CI 0.63-1.08), with no evidence of duration- or dose-response relationships. Use of hydrochlorothiazide was associated with an increased risk of cSCC and with evidence of a duration- and dose-response relationship. In contrast, no association was observed for BCC or melanoma.

Increasing cancer risk over calendar year in people with multiple sclerosis: a case\u2013control study

BackgroundData on cancer prevalence and incidence in multiple sclerosis (MS) patients are controversial. This study is aimed at estimating cancer risk in MS patients.MethodsNested case–control study using data collected between 01/01/1987 and 28/02/2016 from the United Kingdom Clinical Practice Research Datalink. Cancer diagnoses after first MS code (index date) was counted in 10,204 MS patients and 39,448 controls matched by sex, age, general practitioner, and registration year. Cancer rates were compared using multivariable Cox regression models. Ethics approval was not required.ResultsCancer was reported in 433 (4.41%) MS patients and 2014 (5.31%) controls after index date. Cancer risk was associated with gender (HR for female = 0.88, 95% CI = 0.81–0.96, p = 0.004), age at index date (HR = 1.06, 95% CI = 1.06–1.07, p < 0.001), and index year (HR = 1.01, 95% CI = 1.00–1.02, p = 0.016), but not with MS status (HR = 0.95, 95% CI = 0.86–1.05, p = 0.323). A significant interaction between MS status and index year was found (HR = 1.02, 95% CI = 1.00–1.04, p = 0.022). Cancer risk was positively associated with index year among MS patients (HR = 1.03, 95% CI = 1.01–1.05; p = 0.010), but not controls (HR = 1.01, 95% CI = 0.99–1.02; p = 0.144). MS patients compared to controls had no increased risk for any specific cancer type.ConclusionsOverall cancer risk was similar in multiple sclerosis patients and matched controls. The frequency of cancer diagnoses has increased over time among MS patients but not in controls.

The Number of Concomitant Drugs and the Safety of Direct Oral Anticoagulants in Routine Care Patients with Atrial Fibrillation.

Background The benefit of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on major bleeding was less prominent among atrial fibrillation (AF) patients with polypharmacy in post-hoc randomized controlled trials analyses. Whether this phenomenon also exists in routine care is unknown. The aim of the study is to investigate whether the number of concomitant drugs prescribed modifies safety and effectiveness of DOACs compared with VKAs in AF patients treated in general practice. Study Design Adult, nonvalvular AF patients with a first DOAC or VKA prescription between January 2010 and July 2018 were included, using data from the United Kingdom Clinical Practice Research Datalink. Primary outcome was major bleeding, secondary outcomes included types of major bleeding, nonmajor bleeding, ischemic stroke, and all-cause mortality. Effect modification was assessed using Cox proportional hazard regression, stratified for the number of concomitant drugs into three strata (0–5, 6–8, ≥9 drugs), and by including the continuous variable in an interaction term with the exposure (DOAC vs. VKA). Results A total of 63,600 patients with 146,059 person-years of follow-up were analyzed (39,840 person-years of DOAC follow-up). The median age was 76 years in both groups, the median number of concomitant drugs prescribed was 7. Overall, the hazard of major bleeding was similar between VKA-users and DOAC-users (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.87–1.11), though for apixaban a reduction in major bleeding was observed (HR 0.81; 95% CI 0.68–0.98). Risk of stroke was comparable, while risk of nonmajor bleeding was lower in DOAC users compared with VKA users (HR 0.92; 95% CI 0.88–0.97). We did not observe any evidence for an impact of polypharmacy on the relative risk of major bleeding between VKA and DOAC across our predefined three strata of concomitant drug use ( p -value for interaction = 0.65). For mortality, however, risk of mortality was highest among DOAC users, increasing with polypharmacy and independent of the type of DOAC prescribed ( p -value for interaction <0.01). Conclusion In this large observational, population-wide study of AF patients, risk of bleeding, and ischemic stroke were comparable between DOACs and VKAs, irrespective of the number of concomitant drugs prescribed. In AF patients with increasing polypharmacy, our data appeared to suggest an unexplained yet increased risk of mortality in DOAC-treated patients, compared with VKA recipients.

The Association between Oral Anticoagulants and Cancer Incidence among Individuals with Nonvalvular Atrial Fibrillation.

Existing evidence on the association between vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) and cancer is limited and contradictory. No observational studies have been conducted to simultaneously address the cancer safety of VKAs and DOACs. The objective of this study was to determine whether use of VKAs and DOACs, separately, when compared with nonuse, is associated with cancer overall and prespecified site-specific incidence. Using the United Kingdom Clinical Practice Research Datalink, we identified patients newly diagnosed with nonvalvular atrial fibrillation (NVAF) between 2011 and 2017. Using a time-varying exposure definition, each person-day of follow-up was classified as use of (1) VKAs, (2) DOACs, (3) VKAs and DOACs (drug switchers), and (4) nonuse of anticoagulants (reference). We also conducted a head-to-head comparison of new users of DOACs versus VKAs using propensity score fine stratification weighting. Hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer overall and prespecified subtypes were estimated using Cox proportional hazards models. Compared with nonuse, use of VKAs was not associated with cancer overall (HR: 1.05, 95% CI: 0.91-1.22) or cancer subtypes. Similarly, use of DOACs was not associated with cancer overall (HR: 1.13, 95% CI: 0.93-1.37), but an association was observed for colorectal cancer (HR: 1.73, 95% CI: 1.01-2.99), and pancreatic cancer generated an elevated, though nonsignificant HR (HR: 2.15, 95% CI: 0.72-6.44). Results were consistent in the head-to-head comparison. Use of oral anticoagulants is not associated with the incidence of cancer overall among patients with NVAF. Possible associations between DOACs and colorectal and pancreatic cancer warrant further study.

Probability of sepsis after infection consultations in primary care in the United Kingdom in 2002-2017: Population-based cohort study and decision analytic model.

Efforts to reduce unnecessary antibiotic prescribing have coincided with increasing awareness of sepsis. We aimed to estimate the probability of sepsis following infection consultations in primary care when antibiotics were or were not prescribed. We conducted a cohort study including all registered patients at 706 general practices in the United Kingdom Clinical Practice Research Datalink, with 66.2 million person-years of follow-up from 2002 to 2017. There were 35,244 first episodes of sepsis (17,886, 51%, female; median age 71 years, interquartile range 57-82 years). Consultations for respiratory tract infection (RTI), skin or urinary tract infection (UTI), and antibiotic prescriptions were exposures. A Bayesian decision tree was used to estimate the probability (95% uncertainty intervals [UIs]) of sepsis following an infection consultation. Age, gender, and frailty were evaluated as association modifiers. The probability of sepsis was lower if an antibiotic was prescribed, but the number of antibiotic prescriptions required to prevent one episode of sepsis (number needed to treat [NNT]) decreased with age. At 0-4 years old, the NNT was 29,773 (95% UI 18,458-71,091) in boys and 27,014 (16,739-65,709) in girls; over 85 years old, NNT was 262 (236-293) in men and 385 (352-421) in women. Frailty was associated with greater risk of sepsis and lower NNT. For severely frail patients aged 55-64 years, the NNT was 247 (156-459) in men and 343 (234-556) in women. At all ages, the probability of sepsis was greatest for UTI, followed by skin infection, followed by RTI. At 65-74 years, the NNT following RTI was 1,257 (1,112-1,434) in men and 2,278 (1,966-2,686) in women; the NNT following skin infection was 503 (398-646) in men and 784 (602-1,051) in women; following UTI, the NNT was 121 (102-145) in men and 284 (241-342) in women. NNT values were generally smaller for the period from 2014 to 2017, when sepsis was diagnosed more frequently. Lack of random allocation to antibiotic therapy might have biased estimates; patients may sometimes experience sepsis or receive antibiotic prescriptions without these being recorded in primary care; recording of sepsis has increased over the study period. These stratified estimates of risk help to identify groups in which antibiotic prescribing may be more safely reduced. Risks of sepsis and benefits of antibiotics are more substantial among older adults, persons with more advanced frailty, or following UTIs.

Hepatitis B virus infection and the risk of liver disease progression in type 2 diabetic patients with potential nonalcoholic fatty liver disease: a retrospective, observational, cohort study in the United Kingdom Clinical Practice Research Datalink.

Assess the risk of progression to cirrhosis and hepatocellular carcinoma (HCC) due to hepatitis B virus (HBV)-infection in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). Retrospective cohort study in the UK Clinical Practice Research Datalink with three cohorts: subjects with T2DM and HBV infection (T2DM+HBV cohort; N = 297), with T2DM without HBV-infection (T2DM cohort; N = 261 865), and with HBV-infection without T2DM (HBV cohort; N = 3630). Primary analyses were performed on the three cohorts and secondary analyses on subcohorts including patients with NAFLD diagnosis code (N = 6599). Case/outcome definitions were formulated with International Classification of Diseases/Read codes/laboratory results and classified using validated algorithms. Adjusted incidence rate ratios (IRR) were estimated with a Poisson regression model. When comparing the T2DM+HBV and T2DM cohorts, adjusted IRRs were 14.06 (95% confidence interval: 4.47-44.19) for cirrhosis and 2.83 (1.06-7.55) for HCC. When comparing the T2DM+HBV and HBV cohorts, adjusted IRRs were 0.68 (0.21-2.27) for cirrhosis and 1.39 (0.46-4.20) for HCC. No cirrhosis cases were identified in T2DM+NAFLD+HBV patients; IRs were 16.92/10 000 person-years (12.97-21.69) and 85.24/10 000 person-years (10.32-307.91) in the T2DM+NAFLD and NAFLD+HBV cohorts. HBV-infection increased significantly the risk for cirrhosis among T2DM patients, however, not beyond the expected incremental risk among infected non-T2DM subjects. Our approach to evaluate the role of T2DM/NAFLD and HBV-infection in liver disease progression could be applied to other settings with higher HBV prevalence.

One-year follow up of asthmatic patients newly initiated on treatment with medium- or high-dose inhaled corticosteroid-long-acting β2-agonist in UK primary care settings.

Global Initiative for Asthma (GINA) recommends medium- or high-dose inhaled corticosteroid-long-acting β2-agonist (ICS-LABA) as preferred treatments for patients with moderate-to-severe asthma. Limited data is available on how step 4/5 patients respond to ICS-LABA and how they step up/down in clinical practice. This retrospective cohort study assessed the characteristics, control status, treatment pathways, and healthcare resource utilization in patients with asthma during one year after initiating medium- or high-dose ICS-LABA. Data from the United Kingdom Clinical Practice Research Datalink were analysed between January 01, 2006 and February 28, 2016. Overall, 29,229 and 16,575 patients initiated medium- and high-dose ICS-LABA, and 35.1% and 45.7% of patients, respectively, remained uncontrolled. The proportions of patients who were adherent to treatment (Medication Possession Ratio ≥80%) were 37.8% and 49.1% in the medium- and high-dose ICS-LABA cohorts, respectively. Among these adherent patients, 63.8% in the medium- and 70% in the high-dose cohorts remained uncontrolled. In patients who stepped up therapy in the medium-dose cohort (19.0%), the common step-up choices were add-on leukotriene receptor antagonist (LTRA) (42.2%), long-acting muscarinic antagonist (LAMA) (23.3%), and increase in ICS dose (22.9%). In patients who stepped up therapy in the high-dose cohort (26.1%), the common step-up choices were add-on LAMA (43.8%) and LTRA (42.1%). Healthcare resource utilization was higher in uncontrolled patients, regardless of the ICS-LABA dose. Many patients remain uncontrolled on both medium- or high-dose ICS-LABA, highlighting the need for timely assessment of asthma control to increase treatment intensity, following evidence-based treatment pathways.

The Use of Long-Acting Insulin Analogs and the Risk of Colorectal Cancer Among Patients with Type 2 Diabetes: A Population-Based Cohort Study.

The association between long-acting insulin analogs and colorectal cancer is uncertain, with previous studies reporting discrepant findings. To determine whether the use of long-acting insulin analogs is associated with an increased risk of colorectal cancer, when compared with use of intermediate-acting human insulins among patients with type 2 diabetes. We conducted a population-based study using the United Kingdom Clinical Practice Research Datalink (CPRD). We identified patients newly treated with either a long-acting insulin analog or an intermediate-acting human insulin between September 1, 2002 and January 31, 2018, with follow-up until January 31, 2019. Each long-acting insulin analog user was propensity score-matched to one intermediate-acting human insulin user, and a lag of 1year was imposed. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of colorectal cancer, comparing long-acting insulin analogs with intermediate-acting human insulin. Secondary analysis was conducted to assess whether there was a duration-response relationship. A total of 10,734 new long-acting insulin analog users were matched to 10,734 new intermediate-acting human insulin users. After a median follow-up of 2.8years, the use of long-acting insulin analogs was not associated with an increased risk of colorectal cancer, compared with intermediate-acting human insulin (1.80 vs. 1.87 per 1000 person-years, respectively; HR 0.96, 95% CI 0.70-1.34). There was no evidence of a duration-response relationship. The results of this population-based study indicate that use of long-acting insulin analogs is not associated with an overall increased risk of colorectal cancer.

Allergic disease, corticosteroid use, and risk of Hodgkin lymphoma: A United Kingdom nationwide case-control study

BackgroundImmunodeficiency syndromes (acquired/congenital/iatrogenic) are known to increase Hodgkin lymphoma (HL) risk, but the effects of allergic immune dysregulation and corticosteroids are poorly understood.ObjectiveWe sought to assess the risk of HL associated with allergic disease (asthma, eczema, and allergic rhinitis) and corticosteroid use.MethodsWe conducted a case-control study using the United Kingdom Clinical Practice Research Datalink (CPRD) linked to hospital data. Multivariable logistic regression investigated associations between allergic diseases and HL after adjusting for established risk factors. Potential confounding or effect modification by steroid treatment were examined.ResultsOne thousand two hundred thirty-six patients with HL were matched to 7416 control subjects. Immunosuppression was associated with 6-fold greater odds of HL (adjusted odds ratio [aOR], 6.18; 95% CI, 3.04-12.57), with minimal change after adjusting for steroids. Any prior allergic disease or eczema alone was associated with 1.4-fold increased odds of HL (aOR, 1.41 [95% CI, 1.24-1.60] and 1.41 [95% CI, 1.20-1.65], respectively). These associations decreased but remained significant after adjustment for steroids (aOR, 1.25 [95% CI, 1.09-1.43] and 1.27 [95% CI, 1.08-1.49], respectively). There was no effect modification by steroid use. Previous steroid treatment was associated with 1.4-fold greater HL odds (aOR, 1.38; 95% CI, 1.20-1.59).ConclusionsIn addition to established risk factors (immunosuppression and infectious mononucleosis), allergic disease and eczema are risk factors for HL. This association is only partially explained by steroids, which are associated with increased HL risk. These findings add to the growing evidence that immune system malfunction after allergic disease or immunosuppression is central to HL development.

Antibiotic Use in Childhood and Adolescence and Risk of Inflammatory Bowel Disease: A Case-Control Study in the UK Clinical Practice Research Datalink.

Inflammatory bowel disease (IBD) causes serious morbidity and disability, and the incidence is increasing. The disease etiology is not well understood, though inflammatory reactions after antibiotic exposure may be associated with development of IBD. We investigated the association between IBD and prior antibiotic use. We conducted this case-control study among individuals in the United Kingdom Clinical Practice Research Datalink GOLD (CPRD GOLD). Each case of IBD was matched to 4 controls on age, sex, general practice, and registration year in the CPRD GOLD. Antibiotic exposure was classified by ever or never use, number of prescriptions, and class of antibiotic before the index date. Odds ratios were calculated using conditional logistic regression. We identified 461 cases of ulcerative colitis (UC) and 683 cases of Crohn's disease (CD). There was no association between ever use of any antibiotic and UC (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.72-1.44) or CD (OR, 1.01; 95% CI, 0.73-1.39) compared with never use. A slightly increased CD risk was observed among ever users of quinolones (OR, 1.76; 95% CI, 1.00-3.11) and metronidazole (OR, 1.43; 95% CI, 0.87-2.34) compared with never users. CD was associated with antibiotic exposure before age 5 (OR, 2.20; 95% CI, 0.75-6.43) in an analysis restricted to individuals followed from birth. There was no association between UC or CD and overall prior use of antibiotics, though prior use of metronidazole and quinolones was associated with a slightly increased risk of CD. Antibiotic use in early childhood may increase the risk of CD.

Androgen Deprivation Therapy for Prostate Cancer and the Risk of Rheumatoid Arthritis: A Population-Based Cohort Study.

Two recent observational studies have investigated the association between androgen deprivation therapy (ADT) and rheumatoid arthritis (RA), but generated discrepant findings and had important methodological limitations. Thus, the objective of this study was to determine whether the use of ADT is associated with an increased risk of RA in men with prostate cancer. We conducted a population-based cohort study using the United Kingdom Clinical Practice Research Datalink. The cohort included all men, at least 40 years of age, newly diagnosed with prostate cancer between 1 January 1988 and 31 March 2014, with follow-up until 30 September 2014. Exposure to ADT was treated as a time-varying variable and lagged by 1 year to account for diagnostic delays and latency. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of RA, comparing use of ADT with non-use. Secondary analyses were conducted to assess whether the association varied according to ADT type and cumulative duration of use. Finally, we conducted several sensitivity analyses to assess the robustness of our findings. The cohort included 32,302 men followed for a median of 3.3 years. During follow-up, 63 patients were newly diagnosed with RA, generating an incidence rate of 46.5/100,000 person-years. Compared with non-use, the use of ADT was not associated with an increased risk of RA (HR 0.84, 95% CI 0.49-1.45). In secondary analyses, the association did not vary according to ADT type or with cumulative duration of use (p trend=0.53). The results remained consistent in sensitivity analyses. In this population-based study, the use of ADT was not associated with an increased risk of RA in men with prostate cancer.

Clinical implications of the association between fluoroquinolones and tendon rupture: The magnitude of the effect with and without corticosteroids.

To estimate the relative, absolute and attributable risk of non-traumatic tendon rupture, at various sites, associated with use of fluoroquinolones, with and without concomitant corticosteroids. We conducted cohort and nested case-control studies among fluoroquinolone users in the United Kingdom Clinical Practice Research Datalink Gold. We estimated the excess risk (cohort analysis) and odds ratios (ORs) (case control) of tendon rupture by fluoroquinolone (current, recent and past use versus unexposed) and corticosteroid (current versus unexposed) use. Among 740926 patients with a fluoroquinolone prescription, 3957 cases of tendon rupture were identified. The excess risk due to current fluoroquinolone use was low: any tendon rupture 3.73 (95% confidence interval, CI, 2.08-5.39) per 10000 person-years (PY) and Achilles tendon rupture 2.91 (1.71-4.11) per 10000 PY. The excess risk of any tendon rupture was much higher for current concomitant fluoroquinolone and corticosteroid use versus corticosteroids alone: 21.2 (11.3-31.2) per 10000 PY. In the case-control, OR (95% CI) among current fluoroquinolone users versus unexposed patients was elevated: any tendon rupture 1.60 (1.22-2.09), Achilles tendon 2.71 (1.76-4.17) and bicep tendon 1.53 (0.85-2.73). The risk of any tendon rupture was higher among women (OR 2.27 [1.54-3.34]), patients aged 60+ (OR 2.42 [1.74-3.37]), and concomitant corticosteroid use (OR 6.64 [3.99-11.1]). Fluoroquinolones increase the risk of Achilles tendon rupture and, to a lesser extent, bicep tendon rupture, but the attributable risk is low. The risk is materially increased with concomitant use of corticosteroids.

What is the incidence of late detection of developmental dysplasia of the hip in England?: a 26-year national study of children diagnosed after the age of one.

The aim of this study was to establish the incidence of developmental dysplasia of the hip (DDH) diagnosed after one-year of age in England, stratified by age, gender, year, and region of diagnosis. A descriptive observational study was performed by linking primary and secondary care information from two independent national databases of routinely collected data: the United Kingdom Clinical Practice Research Datalink and Hospital Episode Statistics. The study examined all children from 1 January 1990 to 1 January 2016 who had a new first diagnostic code for DDH aged between one and eight years old. The incidence of late-diagnosed DDH was 1.28 per 1000 live births. Within the study population, 754 children were identified with a diagnosis of DDH after one-year of age. Of all late diagnoses, 536 (71.1%) were detected between one to two years of age. There were 608 female patients (80.6%) and 146 male patients (19.4%), giving a female-to-male ratio of 4.2:1. Distribution was evenly spread throughout England. The incidence of late-diagnosed DDH has not been reduced from that reported 35 years ago, prior to the introduction of the national selective screening programme for DDH. Cite this article: Bone Joint J 2019;101-B:281-287.

Minocycline and the risk of acute psychiatric events in adolescence: A self-controlled case series.

Minocycline has neurological anti-inflammatory properties and has been hypothesised to have antipsychotic effects. The aim of this study was to investigate, using routinely collected United Kingdom primary health care data, whether adolescent men and women are more or less likely to receive an urgent psychiatric referral during treatment for acne with minocycline compared with periods of non-treatment. A self-controlled case series using United Kingdom Clinical Practice Research Datalink to calculate the incidence rate ratio of urgent psychiatric referrals for individuals, comparing periods during which minocycline was prescribed with unexposed periods, adjusted for age. We found 167 individuals who were at the time exposed to minocycline for a mean of 99 days and who received an urgent psychiatric referral. There was no difference in psychiatric referral risk during periods of exposure compared with periods of non-exposure: incidence rate ratio first 6 weeks of exposure 1.96, 95% confidence interval 0.82-4.71, p=0.132; incidence rate ratio remaining exposure period=1.97, 95% confidence interval 0.86-4.47, p=0.107. We found no evidence in support of a protective effect of minocycline against severe psychiatric symptoms in adolescence.