The role of prenatal exposure to antidepressants, anxiolytic, and hypnotics and its underlying illness on the risk of miscarriage using BIFAP database.

PURPOSE: Despite the notable increase on the prescription of antidepressants and anxiolytics during pregnancy, recommendation on maintaining the treatment during prenatal period is still controversial. We aimed to separately assess the role of effects of the antidepressants and anxiolytic and the underlying illness, controlled by potential confounding associated with miscarriage onset. METHODS: We used data from a validated pregnant cohort aged 15-49 years from 2002 to 2016 using BIFAP database. All confirmed miscarriages were used to perform a nested control analysis using conditional logistic regression. Women were classified according to use of each drug of interest into four mutually exclusive groups: nonusers, users only during prepregnancy, continuers, and initiators during first trimester. Adjusted odds ratios (aORs) for major confounders during pregnancy such as number of visits to primary care practitioners visits, obesity, smoking, HTA, diabetes with 95% confidence intervals were calculated. RESULTS: Compared with nonusers, antidepressants continuers had the highest increased risk of miscarriage aOR (95%) of 1.29 (1.13-1.46), being continuers of paroxetine and fluoxetine the antidepressants with the strongest association. Likewise, continuers of anxiolytics and initiators showed an increased risk of 1.19 (1.04-1.37) and 1.30 (1.13-1.50). When separating the effect between the condition itself or the treatment, women exposed during first trimester, regardless treatment duration and/or the underlying illness, had the highest risk 1.27 (1.08-1.51) for antidepressants and 1.25 (1.13-1.39) for anxiolytics. CONCLUSIONS: Our analysis showed an association between prenatal exposure to antidepressants and anxiolytics and miscarriage onset after controlling by potential confounding adjusting for confounders and the underlying illness. This association was not supported for hypnotic medications. Further studies are warranted to evaluate the risk of miscarriage among subpopulation of pregnant women requiring these medications.

Heterogeneity in the association between prediabetes categories and reduction on glomerular filtration rate in a 5-year follow-up.

Prediabetes and not just diabetes can cause kidney damage. This study assess the association of prediabetes with development of impaired renal function (IRF). We used data from PREDAPS prospective study a cohort of 1072 subjects with prediabetes and another cohort of 772 subjects without prediabetes were follow-up from 2012 to 2017. Prediabetes was defined according to American Association of Diabetes criteria. IRF was defined as having a glomerular filtration rate < 60 mL/min/1.73 m2. Incidence rates of IRF in both cohorts and in different categories of prediabetes, based on impaired glycosylated hemoglobin (HbA1c) and/or fasting plasma glucose (FPG), were calculated. Hazard ratios (HR) for the association of the prediabetes with IRF, adjusting for potential confounders, were estimated by Cox regression models. Incidence rates of IRF per 100 person-years were 1.72 (95% confidence interval [CI]: 1.34-2.21) and 1.79 (95%CI: 1.45-2.20) for those without and with prediabetes, respectively .The HR of IRF in subjects with prediabetes with respect to subjects without prediabetes was 0.76 (95% CI: 0. 54-1.07). Corresponding HRs for type of prediabetes was 0.68 (95%CI: 0.40-1.15) for those with both altered parameters, 0.68 (95%CI: 00.40-1.15) for those with only impaired HbA1c and 1.12 (95%CI: 0.68-1.85) for those with only impaired FPG. The present study reflects an overall trend towards a slightly decreased risk of IRF onset associated to prediabetes except for individuals with only isolated impaired FPG. Further studies are warranted to fully assess the renal progression of each group.

Erosion of universal health coverage and trend in the frequency of physician consultations in Spain.

BACKGROUND: We studied the frequency of physician visits in the native and immigrant populations in Spain before and after implementation of a governmental measure to restrict the use of public healthcare services by undocumented immigrants beginning in 2012. METHODS: Data were taken from the 2009 and 2014 European Health Surveys carried out in Spain. We investigated any physician consultation in the last 4 weeks before the interview, as well as visits to a family physician, public specialist physician and private specialist physician. We estimated the frequency of visits in 2009 and in 2014 in the native and immigrant populations and the difference in the frequency between the two populations, by calculating the percentage ratio estimated by binomial regression and adjusted for different confounders that are indicators of the need for assistance. RESULTS: The percentage of persons who consulted any physician in 2009 and 2014 was 31.7 and 32.9% in the native population, and 25.6 and 30.1% in the immigrant population, respectively. In the immigrant population, the frequency of visits to the general practitioner and public specialist physician increased, whereas in the native population only public specialist physician visits increased. The frequency of private specialist visits remained stable in both populations. After adjusting for the indicators of need for healthcare, no significant differences between the immigrant and native populations were seen in the frequency of visits, except for private specialist consultations, which were less frequent among immigrants. CONCLUSION: The restriction of universal healthcare coverage in Spain did not reduce the frequency of physician visits between 2009 and 2014, as the frequency of these consultations was seen to increase in both the native and immigrant populations.

Low-dose aspirin and risk of gastric and oesophageal cancer: A population-based study in the United Kingdom using The Health Improvement Network.

There is increasing interest regarding potential protective effects of low-dose aspirin against various gastrointestinal cancers. We aimed to quantify the association between use of low-dose aspirin and risk of gastric/oesophageal cancer using a population-based primary care database in the UK. Between January 2005 and December 2015, we identified a cohort of 223 640 new users of low-dose aspirin (75-300 mg/day) and a matched cohort of nonusers at the start of follow-up from The Health Improvement Network. Cohorts were followed to identify incident cases of gastric/oesophageal cancer. Nested case-control analyses were conducted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for current vs nonuse of low-dose aspirin using logistic regression. Current use was defined as when low-dose aspirin lasted 0 to 90 days before the index date (event date for cases, random date for controls) and previous duration was ≥1 year. We identified 727 incident cases of gastric cancer and 1394 incident cases of oesophageal cancer. ORs (95% CIs) were 0.46 (0.38-0.57) for gastric cancer and 0.59 (0.51-0.69) for oesophageal cancer. The effect remained consistent with no clear change seen between previous duration of low-dose aspirin use of 1-3, 3-5 or >5 years. The reduced risks was seen with 75 mg/day, and effects were consistent in lag-time analyses. In conclusion, our results indicate that use of low-dose aspirin is associated with a 54% reduced risk of gastric cancer and a 41% reduced risk of oesophageal cancer as supported by mechanistic data.

No association between use of phosphodiesterase 5 inhibitors and colorectal cancer in men with erectile dysfunction.

PURPOSE: There is an increase interest on the potential chemoprotective effect of selective phosphodiesterase 5 (PDE5) inhibitors. Several authors have shown in vivo the immune-mediated anti-tumor effect of these inhibitors on tumors arising from the digestive tract. OBJECTIVES: To test the potential effect of selective PDE5 inhibitors against colorectal cancer (CRC) onset previously observed. METHODS: We used data from The Health Improvement Network database and identified an established cohort of 200 000 new users of low-dose aspirin and a matched comparison cohort aged 40-84 years between 1 January 2000 and 31 December 2011. A follow-up to identify CRC cases was performed within an extensive validation exercise. Nested case-control analyses compared PDE5 inhibitors vs non-use on CRC risk were performed. RESULTS: Restricting to males (59.3% controls and 59.5% cases), no association was observed among current users of PDE5 inhibitors (1.05 [95% CI: 0.69-1.60]) and neither among recent (1.36 [95% CI: 0.81-2.28]) or past users (1.06 [95% CI: 0.72-1.58]). No duration response effect was found. CONCLUSIONS: Our results do not support an increased risk of CRC associated with the use of PDE5 inhibitors among men with erectile dysfunction.

The effect of low-dose aspirin on colorectal cancer prevention and gastrointestinal bleeding according to bodyweight and body mass index: Analysis of UK primary care data.

BACKGROUND: Meta-analysis of trial data suggests that in primary cardiovascular disease (CVD) prevention bodyweight modifies low-dose aspirin's effects on colorectal cancer (CRC) and major bleeding risk. We sought to investigate whether these effects are seen in patients with or without CVD in routine clinical practice by undertaking sub-analyses of data from two cohort studies with nested-case-control analyses. METHODS: We followed ~200,000 new users of low-dose aspirin (75-300 mg/day) and a matched cohort of non-users to identify incident cases of CRC/upper gastrointestinal bleeding (UGIB). Adjusted relative risks (RRs) with 95% confidence intervals (CIs) were calculated for current vs. non-use of low-dose aspirin using logistic regression stratified by bodyweight/body mass index (BMI) strata. RESULTS: RRs (95% CIs) for CRC by bodyweight were: 0.60 (0.50-0.72) for ≤70 kg, 0.68 (0.60-0.76) for >70 kg; and by BMI were 0.60 (0.52-0.68) for ≤28 kg/m2, 0.76 (0.64-0.89) for >28 kg/m2. For UGIB, estimates were: 1.49 (1.28-1.74) for ≤90 kg, 1.78 (1.29-2.45) for >90 kg/m2, 1.44 (1.21-1.72) for ≤28 kg/m2, 1.72 (1.38-2.16) for >28 kg/m2. Results were similar in the primary CVD prevention population. CONCLUSION: Our findings suggest that the effects of low-dose aspirin in reducing CRC risk and increasing UGIB risk are not modified by bodyweight/BMI.

Mortality in working-age population during the Great Recession and austerity in Spain.

OBJECTIVE: To analyze the mortality trend in Spain before, during and after the economic crisis and austerity policies in the working-age population. METHODS: From 2005 to 2016 we calculated the annual all-cause mortality rate and the annual mortality rate from the main causes of death in the population aged 15 to 64. We also estimated the linear trends in mortality rates during four time intervals-2005-2007 (before crisis), 2008-2010 (first part of the crisis), 2011-2013 (second part of the crisis and implementation of austerity policies) and 2014-2016 (after the crisis)- by the annual percentage change (APC). RESULTS: The all-cause mortality rate in men and women showed the greatest decline in 2008-2010 and the smallest decline in 2014-2016. The decline in 2011-2013 was higher than in 2014-2016. The APCs in 2005-2007, 2008-2010, 2011-2013 and 2014-2016 were -2.8, -4.1, -3.0 and -1.5 in men and -1.0. -2.1, -1.1 and -0.6 in women, respectively, although the APC in 2014-2016 in women was not significant. In 2014-2016, cancer mortality showed the largest decrease, mortality from cardiovascular diseases (men), respiratory diseases and traffic accidents reversed and showed an upward trend, and the downward trend in mortality from infectious diseases and digestive diseases was equal to or greater than that observed before the crisis. CONCLUSION: The decline in all-cause mortality in the working-age population during the economic crisis and the introduction of austerity measures was greater than that observed before and after the economic crisis. The slowing of the decline after the crisis was due to the reversal of the trend in mortality from cardiovascular and respiratory diseases.

Feasibility and validity of The Health Improvement Network database of primary care electronic health records to identify and characterise patients with small cell lung cancer in the United Kingdom.

BACKGROUND: Epidemiological research on small cell lung cancer (SCLC) is limited and based on cancer registry data. We evaluated the feasibility and validity of using primary care electronic health records (The Health Improvement Network [THIN]) in the UK to identify and characterise SCLC. METHODS: We searched THIN records of individuals aged 18-89 years between 2000 and 2014 for a first diagnostic code suggestive of lung cancer (group 1) or small cell cancer (SCC; group 2) and for text strings among free text comments to identify and characterise incident SCLC cases. We validated our case identification strategy by manual review of patient EHRs, including free text comments, for a random sample of 400 individuals initially detected with a diagnostic code (300 from group 1 and 100 from group 2). RESULTS: Twenty five thousand two hundred fourty one individuals had a code for lung cancer (n = 24,508 [97.1%]) or SCC (733 [2.9%]). Following free-text searches, there were 3530 incident SCLC cases (2956 from group 1; 574 from group 2) corresponding to an incidence rate of 1.01 per 10,000 person-years. In the validation exercise, SCLC confirmation rates were 99% (group 1) and 85% (group 2). Mean age at diagnosis among confirmed cases was 68.5 years; staging information was present in 63.5% of cases of whom 17.8% had limited disease and 82.2% had extensive disease. The majority (84.5%) had a recorded symptom suggestive of lung cancer; chest infection was the most common (18%) followed by cough (15.8%) and chest/abdominal/back pain (15.2%). The first year crude mortality rates was 9.9 per 100 person-months (95% confidence interval [CI] 9.5-10.4), was higher among men and those aged 80 years and above. A total of 144 (37.8%) confirmed cases had metastases recorded. Median survival among the whole study cohort was 7.37 months. CONCLUSIONS: Our SCLC case identification method appears to be valid and could potentially be adapted to identify other cancer types. However, complete characterisation of staging requires information from additional data sources including cancer registries.

Incidence of Upper and Lower Gastrointestinal Bleeding in New Users of Low-Dose Aspirin.

BACKGROUND & AIMS: There are few data on the incidence of upper and lower gastrointestinal bleeding (UGIB and LGIB) from observational studies of low-dose aspirin users. We aimed to estimate incidence rates of UGIB and LGIB in a large cohort of new users of low-dose aspirin in the United Kingdom, with subanalyses of hospitalization status and fatalities. METHODS: We performed a population-based study of 199,079 new users of low-dose aspirin (median age, 64.0 years) identified from the Health Improvement Network primary care database (2000-2012). Individuals were followed for a median 5.4 years (maximum, 14 years) to identify new cases of UGIB and LGIB. Following multistep validation, we calculated overall and age- and sex-specific incidence rates; we performed subanalyses for health care use and death within 30 days of GIB. We also estimated rates within a matched (1:1) cohort of nonusers of low-dose aspirin at the start of the follow-up period. RESULTS: The low-dose aspirin users had 1115 UGIB events and 1936 LGIB events; most subjects with UGIB events (58.9%) were hospitalized, whereas most subjects with LGIB events were referred to secondary care (72.8%). Crude incidence rates of GIB per 1000 person-years were 0.97 for subjects with UGIB (95% CI, 0.91-1.02) and 1.68 for subjects with LGIB (95% CI, 1.60-1.75). Incidence rates per 1000 person-years for patients hospitalized for GIB were 0.57 for UGIB (95% CI, 0.53-0.61) and 0.45 for LGIB (95% CI, 0.42-0.49); for referred (but not hospitalized) cases, these values were 0.39 for UGIB (95% CI, 0.36-0.43) and 1.22 for LGIB (1.16-1.29). Incidence rates per 1000 person-years were 0.06 for fatal UGIB (95% CI, 0.04-0.07), 0.01 for fatal LGIB (95% CI, 0.01-0.02), 0.91 for nonfatal UGIB (95% CI, 0.86-0.97), and 1.66 for nonfatal LGIB (95% CI, 1.59-1.74). Among nonusers of low-dose aspirin, incidence rates per 1000 person-years were 0.67 (95% CI, 0.63-0.75) for UGIB and 0.76 (95% CI, 0.72-0.82) for LGIB. CONCLUSION: In a population-based study of low-dose aspirin users, the incidence of LGIB was higher than the incidence of UGIB. However, incidence rates of hospitalized GI bleeds and 30-day mortality rates were lower for LGIB than for UGIB. These estimates are valuable for benefit-risk assessments of low-dose aspirin for cardiovascular and colorectal cancer prevention.

Predictors of Bleeding in Patients with Symptomatic Peripheral Artery Disease: A Cohort Study Using The Health Improvement Network in the United Kingdom.

The purpose of this analysis was to assess potential predictors of intra-cranial bleeding (ICB) and gastrointestinal bleeding (GIB) in patients with symptomatic peripheral artery disease (PAD) in UK primary care. Patients with symptomatic PAD diagnosed from 2000 to 2010 were identified from The Health Improvement Network (THIN; N = 28,484). A nested case-control analysis, adjusted for potential confounders, was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for potential predictors of ICB or GIB. For GIB, follow-up was restricted to Hospital Episode Statistics-linked THIN practices. Median follow-up was 6 years. For ICB (153 cases), the OR (95% CI) was 3.85 (1.33-11.13) for previous ICB, 0.90 (0.61-1.34) for treated hypertension, 1.59 (0.65-3.87) for untreated hypertension and 1.38 (0.80-2.36) for current smoking. ORs for ICB were 0.78 (0.50-1.21), 0.40 (0.09-1.82) and 1.27 (0.47-3.47) with use of acetylsalicylic acid (ASA), clopidogrel and warfarin monotherapy, respectively, compared with non-use of such therapy. For GIB (506 cases), the OR was 1.40 (1.05-1.86) for peptic ulcer disease, 3.20 (1.81-5.64) for dual anti-platelet therapy use, 1.96 (1.46-2.64) for non-steroidal anti-inflammatory drug (NSAID) use and 1.01 (0.80-1.28) for proton pump inhibitor use. ORs for GIB were 1.78 (1.39-2.30), 2.03 (1.05-3.93) and 1.25 (0.72-2.16) with ASA, clopidogrel and warfarin monotherapy, respectively, compared with non-use. Previous ICB was a risk factor for ICB. Use of anti-platelet therapy or NSAIDs increased GIB risk. Identifying bleeding predictors could help optimize treatment strategies for patients with PAD.

Cardiovascular outcomes for patients with symptomatic peripheral artery disease: A cohort study in The Health Improvement Network (THIN) in the UK.

Background Few data are available on risk factors and associations with outcomes in symptomatic peripheral artery disease (PAD) populations in primary care. We assessed characteristics and cardiovascular outcomes in patients with and those without symptomatic peripheral artery disease in UK primary care, and quantified risk factors for cardiovascular outcomes in patients with peripheral artery disease. Methods Among patients in The Health Improvement Network (THIN) aged 50-89 years in 2000-2010, a symptomatic peripheral artery disease cohort ( n = 28,484) and a matched comparison cohort without peripheral artery disease ( n = 113,940) were identified using Read codes. Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) for cardiovascular outcomes were calculated, adjusted for potential confounders. Results The incidence of all-cause death per 1000 person-years was 83.22 and 50.46 in the peripheral artery disease and non-peripheral artery disease cohort, respectively (HR 1.41; 95% CI 1.68-1.43). The incidence of composite cardiovascular outcome (myocardial infarction, ischaemic stroke or cardiovascular-related death) per 1000 person-years was 31.87 and 14.63 in the peripheral artery disease and non-peripheral artery disease cohort, respectively (HR 1.71; 95% CI 1.65-1.77). Risk factors for composite cardiovascular outcome in patients with peripheral artery disease were older age (≥75 years vs. 50-64 years: HR 2.37; 95% CI 2.20-2.55), current smoking (1.26; 1.17-1.35), comorbid diabetes (1.42; 1.32-1.52), heart failure (1.31; 1.20-1.44), atrial fibrillation (1.32; 1.18-1.47, previous myocardial infarction (1.29; 1.20-1.39) and previous ischaemic stroke (1.77; 1.63-1.93). Conclusion Patients with symptomatic peripheral artery disease in a clinical practice population have a high risk of death and cardiovascular-related outcomes. Minimising risk is important in the ongoing management of these patients.

New use of low-dose aspirin and risk of colorectal cancer by stage at diagnosis: a nested case-control study in UK general practice.

BACKGROUND: Evidence from clinical trial populations suggests low-dose aspirin reduces the risk of colorectal cancer (CRC). Part of this reduction in risk might be due to protection against metastatic disease. METHODS: We investigated the risk of CRC among new-users of low-dose aspirin (75-300 mg), including risk by stage at diagnosis. Using The Health Improvement Network, we conducted a cohort study with nested case-control analysis. Two cohorts (N = 170,336 each) aged 40-89 years from 2000 to 2009 and free of cancer were identified: i) new-users of low-dose aspirin, ii) non-users of low-dose aspirin, at start of follow-up, matched by age, sex and previous primary care practitioner visits. Patients were followed for up to 12 years to identify incident CRC. 10,000 frequency-matched controls were selected by incidence density sampling where the odds ratio is an unbiased estimator of the incidence rate ratio (RR). RRs with 95% confidence intervals were calculated. Low-dose aspirin use was classified 'as-treated' independent from baseline exposure status to account for changes in exposure during follow-up. RESULTS: Current users of low-dose aspirin (use on the index date or in the previous 90 days) had a significantly reduced risk of CRC, RR 0.66 (95% CI 0.60-0.74). The reduction in risk was apparent across all age groups, and was unrelated to dose, indication, gender, CRC location or case-fatality status. Reduced risks occurred throughout treatment duration and with all low-dose aspirin doses. RRs by aspirin indication were 0.71 (0·63-0·79) and 0.60 (0.53-0.68) for primary and secondary cardiovascular protection, respectively. Among cases with staging information (n = 1421), RRs for current use of low-dose aspirin were 0.94 (0.66-1.33) for Dukes Stage A CRC, 0.54 (0.42-0.68) for Dukes B, 0.71 (0.56-0.91) for Dukes C, and 0.60 (0.48-0.74) for Dukes D. After 5 years' therapy, the RR for Dukes Stage A CRC was 0.53 (0.24-1.19). CONCLUSIONS: Patients starting low-dose aspirin therapy have a reduced risk of Stages B-D CRC, suggesting a role for low-dose aspirin in the progression of established CRC; a substantial reduction in the risk of Dukes A CRC may occur after 5 years' therapy.

Incidence, treatment and recurrence of endometriosis in a UK-based population analysis using data from The Health Improvement Network and the Hospital Episode Statistics database.

PURPOSE: This retrospective study used medical records from The Health Improvement Network (THIN) and Hospital Episode Statistics (HES) database to evaluate endometriosis (incidence, treatment and need for recurrent invasive procedures) in the general UK population. MATERIALS AND METHODS: Women aged 12-54 years between January 2000 and December 2010, with a Read code for endometriosis, were identified in THIN. Cases were validated by manual review of free-text comments in medical records and responses to physician questionnaires. False-negative cases were identified among women with Read codes for hysterectomy or dysmenorrhea. Prescriptions of medical therapies for endometriosis were identified in THIN. Cases of single and recurrent invasive procedures were identified in women with medical records in both THIN and HES. RESULTS: Overall, 5087 women had a Read code for endometriosis, corresponding to an incidence of 1.02 (95% confidence interval [CI]: 0.99-1.05) per 1000 person-years. After case validation, the estimate was 1.46 (95% CI: 1.43-1.50) per 1000 person-years. Medical therapy was prescribed to 55.5% of women with endometriosis in the first year after diagnosis. In total, 48.3% of women received invasive treatment during the study period; approximately one-fifth of these women required further invasive treatment, mainly in the 3 years after the index procedure. CONCLUSIONS: Using Read codes as the only method to identify women with endometriosis underestimates incidence. Over half of women with recorded endometriosis are prescribed medical therapy in the first year after diagnosis. Women with diagnosed endometriosis are at risk of requiring recurrent invasive procedures.

Incidence of colorectal cancer in new users and non-users of low-dose aspirin without existing cardiovascular disease: A cohort study using The Health Improvement Network.

BACKGROUND: Evidence regarding the chemo-protective effects of aspirin has influenced expert opinion in favour of low-dose aspirin use in certain patient populations without cardiovascular disease (CVD). The effects of aspirin in reducing the incidence of colorectal cancer (CRC) may be a large contributor to this favourable risk-benefit profile of low-dose aspirin in primary CVD prevention. METHODS: Using The Health Improvement Network, we estimated the incidence of CRC in individuals free of CVD and either prescribed or not prescribed prophylactic low-dose aspirin. Two cohorts - new-users of low-dose aspirin (N=109,426) and a comparator cohort of non-users (N=154,056) at start of follow-up - were followed (maximum 13years) to identify incident CRC cases. Individuals with a record of CVD, cancer or low-dose aspirin prescription before start of follow-up were excluded. RESULTS: 2330 incident cases of CRC occurred; 885 in the aspirin cohort and 1445 in the comparator cohort, after mean follow-ups of 5.43years and 5.17years, respectively. Incidence rates of CRC per 10,000 person-years (95% confidence interval) were 14.90 (13.95-15.92) in the aspirin cohort and 18.15 (17.24-19.12) in the comparator cohort; incidence rate ratio 0.82 (0.76-0.89) adjusted for age, sex and primary care practitioner (PCP) visits in the previous year. Lower incidence rates were seen in the aspirin cohort for all strata evaluated (gender, age group and number of PCP visits in the previous year) except those aged ≥80years. CONCLUSION: Among most individuals without established CVD, initiation of low-dose aspirin is associated with a reduced incidence of CRC.

Prescribing of cyproterone acetate/ethinylestradiol in UK general practice: a retrospective descriptive study using The Health Improvement Network.

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

The Protective Effect of Low-Dose Aspirin against Colorectal Cancer Is Unlikely Explained by Selection Bias: Results from Three Different Study Designs in Clinical Practice.

BACKGROUND: We conducted three differently designed nested case-control studies to evaluate whether the protective effect of low-dose aspirin against colorectal cancer (CRC) is explained by selection bias. METHODS: Using a large validated UK primary care database, we followed different cohorts of patients, who varied in their demographic and clinical characteristics, to identify first ever cases of CRC. In Studies 1 and 2, two cohorts were followed, i) new users of low-dose aspirin at start of follow-up (N = 170,336 in Study 1, N = 171,527 in Study 2) and either ii) non-users of low-dose aspirin (Study 1, N = 170,336) or new users of paracetamol (Study 2, N = 149,597) at start of follow-up. In Study 3 a single cohort of individuals näive to low-dose aspirin at the start of observation was followed. Controls were selected using incidence sampling and logistic regression used to obtain an unbiased estimate of the incidence rate ratio (RR) with 95% confidence intervals (CIs). Low-dose aspirin exposure was analyzed 'as-treated' before the index date (CRC date for cases, random date for controls). RESULTS: In the three studies, median (maximum) follow-up was 5.1 (12), 5.8 (12) and 7.5 (13) years, respectively. 3033 incident CRC cases were identified in Study 1, 3174 in Study 2, and 12,333 in Study 3. Current use of low-dose aspirin was associated with a significantly reduced risk of 34%, 29% and 31% in the three studies, respectively; corresponding RRs (95% CIs) were 0.66 (0.60-0.73), 0.71 (0.63-0.80) and 0.69 (0.64-0.74). In each study, significantly reduced risks of CRC were seen when low-dose aspirin was used for primary or secondary cardiovascular disease prevention, in both sexes, and across all age groups evaluated. CONCLUSION: Low-dose aspirin is associated with a significantly reduced risk of CRC. The consistency of our findings across different studies makes selection bias an unlikely explanation.

Validity and completeness of colorectal cancer diagnoses in a primary care database in the United Kingdom.

PURPOSE: To validate the recorded diagnoses of colorectal cancer (CRC) and identify false negatives in The Health Improvement Network (THIN) primary care database. METHODS: We conducted a validation study of incident CRC cases in THIN among patients aged 40-89 years from 2000-2011. CRC Read code entries (N = 3805) were verified by manual review of patients' electronic medical records (EMRs) including free-text comments. Incident CRC cases in THIN ascertained following manual review were validated against two data sources deemed gold standards: (i) questionnaires sent to primary care practitioners (PCPs; for a random sample of 100 potential CRC cases), and (ii) Hospital Episode Statistics (HES) among linked practices. False negatives in THIN were identified by searching for International Classification of Diseases-10 codes related to CRC in HES. RESULTS: Of 3805 CRC cases identified in THIN via Read codes, 3033 patients (80.0%) were considered definite cases after manual review of EMRs. The positive predictive value (PPV) of CRC Read codes was 86.0% after removing patients identified from THIN via a Read code for 'fast track referral for suspected CRC'. The response rate from PCPs was 87.0% (n = 87), and the PPV of CRC in THIN was 100% based on PCP questionnaires. Using HES, the PPV for CRC in THIN was 97.9% (556/568), and false negative rate was 6.1% (36/592). CONCLUSIONS: CRC diagnostic Read codes in THIN have a high PPV, which is increased further following manual review of free-text comments. The false negative rate of CRC diagnoses in THIN is low.

Cardiovascular events and all-cause mortality in a cohort of 57,946 patients with type 2 diabetes: associations with renal function and cardiovascular risk factors.

BACKGROUND: Diabetes and chronic kidney disease (CKD) are independent predictors of death and cardiovascular events and their concomitant prevalence has increased in recent years. The aim of this study was to characterize the effect of the estimated glomerular filtration rate (eGFR) and other factors on the risk of death and cardiovascular events in patients with type 2 diabetes. METHODS: A cohort of 57,946 patients with type 2 diabetes who were aged 20-89 years in 2000-2005 was identified from The Health Improvement Network, a UK primary care database. Incidence rates of death, myocardial infarction (MI), and ischemic stroke or transient ischemic attack (IS/TIA) were calculated overall and by eGFR category at baseline. eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) study equation. Death, MI and IS/TIA cases were detected using an automatic computer search and IS/TIA cases were further ascertained by manual review of medical records. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) for death, MI, and IS/TIA associated with eGFR category and other factors were estimated using Cox regression models adjusted for potential confounders. RESULTS: Overall incidence rates of death (mean follow-up time of 6.76 years), MI (6.64 years) and IS/TIA (6.56 years) were 43.65, 9.26 and 10.39 cases per 1000 person-years, respectively. A low eGFR (15-29 mL/min) was associated with an increased risk of death (HR: 2.79; 95% CI: 2.57-3.03), MI (HR: 2.33; 95% CI: 1.89-2.87) and IS/TIA (HR: 1.77; 95% CI: 1.43-2.18) relative to eGFR ≥ 60 mL/min. Other predictors of death, MI and IS/TIA included age, longer duration of diabetes, poor control of diabetes, hyperlipidemia, smoking and a history of cardiovascular events. CONCLUSIONS: In patients with type 2 diabetes, management of cardiovascular risk factors and careful monitoring of eGFR may represent opportunities to reduce the risks of death, MI and IS/TIA.

The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a UK population-based outpatient cohort study.

BACKGROUND: Recent hospital-based studies have suggested a sixfold increased risk of pulmonary embolism (PE) in rheumatoid arthritis (RA) in the year following admission. We evaluated the risk of PE and deep vein thrombosis (DVT) and associated time trend among RA patients (84.5% without a history of hospitalisation during the past year) derived from the general population. METHODS: We conducted a cohort study using an electronic medical records database representative of the UK general population, collected from 1986 to 2010. Primary definitions of the RA cohort (exposure) and PE/DVT outcomes required physician diagnoses followed by corresponding treatments. We estimated relative risks (RRs) of PE and DVT compared with a matched non-RA comparison cohort, adjusting for age, sex, smoking, body mass index, comorbidities and hospitalisations. RESULTS: Among 9589 individuals with RA (69% female, mean age of 58 years), 82 developed PE and 110 developed DVT (incidence rates, 1.5 and 2.1 per 1000 person-years). Compared with non-RA individuals (N=95 776), the age-, sex- and entry-time-matched RRs were 2.23 (95% CI 1.75 to 2.86) for PE and 2.20 (CI 1.78 to 2.71) for DVT. Adjusting for other covariates, the corresponding RRs were 2.16 (CI 1.68 to 2.79) and 2.16 (CI 1.74 to 2.69). The time-specific RRs for PE were 3.27, 1.88 and 2.35 for follow-up times of <1 year, 1-4.9 years, and ≥5 years, and corresponding RRs for DVT were 3.16, 1.82 and 2.32. CONCLUSIONS: This population-based study indicates an increased risk of PE and DVT in RA, supporting increased monitoring of venous-thromboembolic complications and risk factors in RA, regardless of hospitalisation.

Coxibs: pharmacology, toxicity and efficacy in cancer clinical trials.

This chapter briefly summarizes the current knowledge about the role of nonsteroidal anti-inflammatory drugs (NSAIDs), specially focusing on those selective for cyclooxygenase (COX)-2 (coxibs), on colorectal cancer (CRC) onset, and progression. Both epidemiological and experimental studies have reported that these drugs reduce the risk of developing colonic tumors. However, the promising use of coxibs in chemoprevention was halted abruptly due to the detection on enhanced cardiovascular (CV) risks. Thus, we discuss the clinical data and plausible mechanisms of CV hazards associated with traditional NSAIDs and coxibs. The extent of inhibition of COX-2-dependent prostacyclin, an important vasoprotective and anti-thrombotic pathway, in the absence of a complete suppression of COX-1-dependent platelet function, at common doses of NSAIDs, might play a role in CV toxicity. Coxibs might still be reserved for younger patients with familial adenomatous polyposis (FAP). However, it should be taken into consideration that recent findings of enhanced thromboxane (TX)A(2) biosynthesis in colon tumorigenesis, detected in humans. In this context, the use of low-dose aspirin (which mainly acts by inhibiting platelet COX-1-dependent TXA(2)) may have a place for chemoprevention of CRCs (see also Chap. 3 ). The possible use of coxibs to prevent CRC will depend mainly on research progresses in biomarkers able to identify the patients uniquely susceptible to developing thrombotic events by inhibition of COX-2.