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Introduction: Although direct oral anticoagulants' (DOACs) prescriptions have experienced immense growth in the last decade, the proportion of discontinuers is still common yielding an increased risk of ischemic stroke (IS) onset. Aims: We aimed to estimate the association between DOACs discontinuation and risk of IS among patients with non‐valvular atrial fibrillation (NVAF). Methods: We used data from a cohort of new DOACs users, followed patients from the first DOAC prescription date up to IS (index date) and conducted a nested case–control analysis using conditional logistic regression. Adjusted odds ratios, 95% confidence intervals were calculated for discontinuation of DOACs (current use compared with past use). The latter, subdivided among those stopping treatment 3 to 2 months and 6 and 3 months prior to index date. The effect of naïve current users against IS onset compared with non‐naïve current users was also evaluated. Results: DOACs discontinuation showed an OR of IS of 1.47 (95% CI: 1.02–2.12); estimates were 2.51 (95% CI: 1.84–3.42) for whom discontinued treatment within months 3 and 2 and 1.43 (95% CI: 0.96–2.13) for those between months 6 and 3 prior to index date. Analyzing DOACs individually, risk of IS associated with past users compared with current users: 1.98 (95% CI: 1.25–3.12) for apixaban, 1.38 (95% CI: 0.40–4.72) for edoxaban, 1.98 (95% CI: 1.24–2.65) for dabigatran and 1.87 (95% CI: 1.26–2.76) for rivaroxaban. Similar results were found when stratified by naïve and non‐naïve users. Conclusions: DOACs' discontinuation is associated with higher risk of IS, especially in the second and third months following interruption. [ABSTRACT FROM AUTHOR]

Background Some research has suggested a potential link between prenatal exposure to proton pump inhibitors (PPIs) or H2-receptor antagonists (H2RAs) and the development of childhood asthma. Aim To quantify the relative risk of asthma in children who experienced prenatal exposure to PPIs and/or H2RAs, adjusting for potential confounders. Methods In this observational cohort study (NCT01787435), women aged 18-45 years with completed pregnancies between January 1996 and December 2010 were identified from The Health Improvement Network in the United Kingdom, and were linked to infants. Hazard ratios (HRs) were estimated using Cox proportional hazard models. Results Our analysis identified 2371 prenatally exposed and 7745 unexposed infants. The incidence of asthma (per 1000 person-years) was 19.52 in the unexposed cohort, 23.88 in the PPI cohort and 32.16 in the H2RA cohort. After adjusting for maternal healthcare utilisation during the year before pregnancy, the HR for asthma in infants whose mothers received prescriptions at any time during pregnancy was 1.12 (95% confidence interval: 0.88-1.44) for PPIs and 1.43 (1.20-1.70) for H2RAs, when compared with unexposed infants. With further adjustment for maternal comorbidities and other medications, the HR for asthma was 1.03 (0.76-1.40) for PPIs and 1.32 (1.05-1.64) for H2RAs. Conclusions Our analysis showed no association between prenatal exposure to PPIs and asthma in childhood after adjusting for confounders. The association found for H2RAs may be explained largely by underlying environmental or genetic factors, as suggested by reductions in hazard ratio estimates following adjustment for maternal comorbidities. [ABSTRACT FROM AUTHOR]

Introduction: Data on the increase in mortality during the COVID-19 pandemic based on individuals' socioeconomic positions are limited. This study examines this increase in mortality in Spain during the epidemic waves of 2020 and 2021., Methods: We calculated the overall and cause-specific mortality rates during the 2017-2019 pre-pandemic period and four epidemic periods in 2020 and 2021 (first, second, third-fourth, and fifth-sixth waves). Mortality rates were analyzed based on educational levels (low, medium, and high) and across various age groups (25-64, 65-74, and 75+). The increase in mortality during each epidemic period compared to the pre-pandemic period was estimated using mortality rate ratios (MRR) derived from Poisson regression models., Results: An inverse educational gradient in overall mortality was observed across all periods; however, this pattern was not consistent for COVID-19 mortality in some age groups. Among those aged 75 years and older, highly educated individuals showed higher COVID-19 mortality during the first wave. In the 25-64 age group, individuals with low education experienced the highest overall mortality increase, while those with high education had the lowest increase. The MRRs were 1.21 and 1.06 during the first wave and 1.12 and 0.97 during the last epidemic period. In the 65-74 age group, highly educated individuals showed the highest overall mortality increase during the first wave, whereas medium-educated individuals had the highest increase during the subsequent epidemic periods. Among those aged 75 and older, highly educated individuals exhibited the highest overall mortality increase while the individuals with low education showed the lowest overall mortality increment, except during the last epidemic period., Conclusion: The varying educational patterns of COVID-19 mortality across different age groups contributed to the disparities of findings in increased overall mortality by education levels during the COVID-19 pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pulido, Donat, Moreno, Politi, Cea-Soriano, Sordo, Mateo-Urdiales, Ronda, Belza, Barrio and Regidor.)

Background and Aims: In recent years, mortality from ischemic heart disease and diabetes has decreased. There is an inequality in mortality reduction between urban and non-urban areas. This study aims to estimate the trend in mortality from ischemic heart disease and diabetes mellitus in urban and non-urban areas in Italy and Spain, throughout the first two decades of the 21st century., Methods: Deaths and population data by age and sex, according to the area de residence, were obtained from the National Institutes of Statistics. Annual age-standardized mortality rates from ischemic heart disease and diabetes mellitus were calculated from 2003 to 2019, in each of the two areas of residence in both countries. The average annual percentage change (APC) in the mortality rate in each area was estimated using linear regression models and taking age-standardized mortality rates as dependent variable., Results: Mortality rates from both causes of death decreased between the beginning and the end of the period analysed. In Italy, the APC in was -4.0% and -3.6% in mortality rate from ischemic heart disease and -1.5% and -1.3% in mortality rate from diabetes mellitus, in urban and non-urban areas, respectively. In Spain, the APC in was -4.4% and -3.7% in mortality rate from ischemic heart disease and -3.3% and -2.0% in mortality rate from diabetes mellitus, in urban and non-urban areas, respectively., Conclusion: Mortality from ischemic heart disease and mortality from diabetes have shown a greater reduction in urban than in non-urban areas since the first years of the 21st century in Spain and Italy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Pregnant women might have an increased risk of SARS-COV-2 infection. Although evidence towards the efficacy and safety of COVID-19 is growing still there is room for improvement on the knowledge towards pregnancy adverse events, such as miscarriage. We explored the association of COVID-19 vaccine with the risk of miscarriages using the Real-World. We identified a cohort of vaccinated pregnancies using the BIFAP database which contains systematically recorded data on care patients in Spain (N = 4054). We then restricted it to those women who had a miscarriage using a validated algorithm (N = 607). Among them, we performed a case-crossover design to evaluate the effect of intermittent exposures on the risk of miscarriage. Adjusted Odds Ratio with their confidence intervals were calculated using two analytical approaches: conditional logistic regression and Generalized Linear Mixed-Effects Models. A total of 225 (37.1%) were aged 35-39 years. The most common comorbidities were asthma, migraine, gastritis, and hypothyroidism. A total of 14.7% received only one dose of COVID-19 and 85.3% two doses, respectively. A total of 36.8% of women with one dose and 27.6% with two doses received the vaccine 7 days prior to the miscarriage. Corresponding adjusted estimates for the risk of miscarriage using the conditional logistic regression where as follows: 1.65 (95% CI 0.85-3.23) when using as the sum of 3 control moments among women with one dose, 1.02 (95% CI 0.72-1.46) among women with two doses and 1.03 (95% CI 0.72, 1.46) using the whole study population. Very similar results were obtained when conducting the Generalized Linear Mixed-Effects Models. There was no overall increased risk of miscarriage onset associated with COVID-19 vaccine although contradictory results were found according to the number of doses. Further studies are required with larger sample sizes to assess this association., (© 2024. The Author(s).)

Objective: The objective of this work was to study mortality increase in Spain during the first and second academic semesters of 2020, coinciding with the first 2 waves of the Covid-19 pandemic; by sex, age, and education., Methods: An observational study was carried out, using linked populations and deaths' data from 2017 to 2020. The mortality rates from all causes and leading causes other than Covid-19 during each semester of 2020, compared to the 2017-2019 averages for the same semester, was also estimated. Mortality rate ratios (MRR) and differences were used for comparison., Results: All-cause mortality rates increased in 2020 compared to pre-covid, except among working-age, (25-64 years) highly-educated women. Such increases were larger in lower-educated people between the working age range, in both 2020 semesters, but not at other ages. In the elderly, the MMR in the first semester in women and men were respectively, 1.14, and 1.25 among lower-educated people, and 1.28 and 1.23 among highly-educated people. In the second semester, the MMR were 1.12 in both sexes among lower-educated people and 1.13 in women and 1.16 in men among highly-educated people., Conclusion: Lower-educated people within working age and highly-educated people at older ages showed the greatest increase in all-cause mortality in 2020, compared to the pre-pandemic period.

Although pregnant women were considered a risk population for COVID-19, little is known of their drug use during the pandemic. We aimed to investigate COVID-19 distribution, drug use patterns and COVID-19 medication. We conducted a retrospective cohort of validated pregnancies aged 15-49 years, from January 2020 to December 2022, using the BIFAP database. An identified cohort of pregnant women with COVID-19 was matched by age, gestational age, length of pregnancy and outcome to a cohort free of COVID-19 (8413 vs. 24,975). We performed a descriptive analysis on COVID-19 cases, estimated the drug use patterns and assessed COVID-19-specific drugs within the week prior/after diagnosis, stratified by pandemic wave and gestational week. The results showed that 72% of pregnant women with COVID-19 received at least one prescription vs. 66.6% of those free of COVID-19, with analgesics, antibiotics and thyroid hormones being the most prescribed drugs in both groups. In the COVID-19 group, they were antithrombotics (40 prescriptions per 100 women), analgesic/NSAIDs (19.64/6.29) and antibiotics (6.95). COVID-19 cases gradually increased, peaking at the fifth and second waves. Prescription rates were similar when compared to pre-pandemic studies. The use of drugs compatible with COVID-19 treatments was in line with recommendations.

Introduction: Patients seeking first time treatment for opioid consumption reflect the characteristics of the consumer population. This group has not been studied in Spain in decades. The objective of this study was to characterize the opioid user population seeking first time treatment (incidents) and compare them group with those with prior treatment (prevalents)., Methods: Cross-sectional study (N = 3325) with patients with opioid addiction seeking care at public addiction centers in the Community of Madrid from 2017 through 2019. Differentiation and comparisons were carried out using bivariate analysis, adjusted by sociodemographic characteristics related and those related to substance use consumption in incident and prevalent patients., Results: About 12.2% were incidents. Compared to prevalents, there were more foreigners (34.1% vs 19.1% P  < .001), but with a better social network. Regarding opioid use, incidents were less likely to use injection (10.7% compared to 16.8% P  = .008), but had greater daily frequency (75.8% vs 52.2%, P  < .001). The age of initial consumption was greater (27 years vs 21.3 years, ( P  < .001)). About 15.5% of incidents sought care for non-heroin opioids, compared to 4.8% of prevalents ( P  < .001). Women sought care at twice the rate of men (29.3% vs 12.3%; P  > .001)., Discussion: New patients presented a profile with many stable characteristics, but which highlighted an increase in the use of other opioids, as occurs in the international context. Surveillance of the new patient characteristics can serve as an early indicator of consumption changes in. Thus, periodic monitoring is important., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: It has been suggested that women experiencing during pregnancy several physiological and immunological changes that might increase the risk of any infection including the SARS-CoV-2., Objective: We aimed to quantify the risk of SARS-CoV-2 infection during pregnancy compared with women with no pregnancies., Methods: We used data from the BIFAP database and a published algorithm to identify all pregnancies during 2020. Pregnancies were matched (1:4) by age region, and length of pregnancy with a cohort of women of childbearing age. All women with SARS-CoV-2 infection before entering the study were discarded. We estimated incidence rates of SARS-CoV-2 with 95% confidence intervals (CIs) expressed by 1000 person-months as well as Kaplan-Meier figures overall and also stratified according to pregnancy period: during pregnancy, at puerperium (from end of pregnancy up to 42 days) and after pregnancy. (from 43 days after pregnancy up to end pf study period (i.e., June 2021). We conducted a Cox regression to assess risk factors for SARS-COV infection. The incidence rate of SARS-CoV-2 infection expressed by 1000 person-months were., Results: There was a total of 103,185 pregnancies and 412,740 matched women at childbearing, with a mean age of 32.3 years. The corresponding incidence rates of SARS-CoV-2 infection according to cohorts were: 2.44 cases per 1000 person-months (confidence interval (CI) 95%: 2.40-2.50) and 4.29 (95% CI: 4.15-4.43) for comparison cohort. The incidence rate ratio (IRR) of SARS-CoV-2 was 1.76 (95% CI: 1.69-1.83). When analyzing according to pregnancy period, the IRRs were 1.30 (95% CI: 11.20-1.41) during the puerperium and 1.19 (95% CI: 41.15-1.23) after pregnancy. In addition to pregnancy itself, other important risk factors were obesity (1.33 (95% CI: 1.23-1.44)) and diabetes (1.23 (95% CI: 11.00-1.50)., Conclusion: Pregnant women are at increased risk of SARS-CoV-2 infection compared with women of childbearing age not pregnant. Nevertheless, there is a trend towards reverting during puerperium and after pregnancy.

Background: Reducing stroke occurrence requires the effective management of cardiovascular and other stroke risk factors., Purpose: To describe pre- and post-stroke medication use, focusing on antithrombotic therapy and mortality risk, in individuals hospitalised for ischaemic stroke (IS) in the United Kingdom., Method: Using primary care electronic health records from the United Kingdom, we identified patients hospitalised for IS (July 2016-September 2019) and classed them into three groups: atrial fibrillation (AF) diagnosed pre-stroke, AF diagnosed post-stroke, and non-AF stroke (no AF diagnosed pre-/post-stroke). We determined use of cardiovascular medications in the 90 days pre- and post-stroke and calculated mortality rates., Results: There were 3201 hospitalised IS cases: 76.2% non-AF stroke, 15.7% AF pre-stroke, and 8.1% AF post-stroke. Oral anticoagulant (OAC) use increased between the pre- and post-stroke periods as follows: 54.3%-78.7% (AF pre-stroke group), 2.3%-84.8% (AF post-stroke group), and 3.4%-7.3% (non-AF stroke group). Corresponding increases in antiplatelet use were 30.8%-35.4% (AF pre-stroke group) 38.5%-47.5% (AF post-stroke group), and 37.5%-87.3% (non-AF stroke group). Among all IS cases, antihypertensive use increased from 66.8% pre-stroke to 78.8% post-stroke; statin use increased from 49.6%-85.2%. Mortality rates per 100 person-years (95% CI) were 17.30 (14.70-20.35) in the AF pre-stroke group and 9.65 (8.81-10.56) among all other stroke cases., Conclusion: Our findings identify areas for improvement in clinical practice, including optimising the level of OAC prescribing to patients with known AF, which could potentially help reduce the future burden of stroke., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

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., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Aims: Randomized controlled trials have demonstrated the efficacy of several dietary patterns plus physical activity to reduce diabetes onset in people with prediabetes. However, there is no evidence on the effect from the Mediterranean diet on the progression from prediabetes to diabetes. We aimed to evaluate the effect from high adherence to Mediterranean diet on the risk of diabetes in individuals with prediabetes., Methods: Prospective cohort study in Spanish Primary Care setting. A total of 1184 participants with prediabetes based on levels of fasting plasma glucose and/or glycated hemoglobin were followed up for a mean of 4.2 years. A total of 210 participants developed diabetes type 2 during the follow up. Hazard ratios of diabetes onset were estimated by Cox proportional regression models associated to high versus low/medium adherence to Mediterranean diet. Different propensity score methods were used to control for potential confounders., Results: Incidence rate of diabetes in participants with high versus low/medium adherence to Mediterranean diet was 2.9 versus 4.8 per 100 persons-years. The hazard ratios adjusted for propensity score and by inverse probability weighting (IPW) had identical magnitude: 0.63 (95% confidence interval, 0.43-0.93). The hazard ratio in the adjusted model using propensity score matching 1:2 was 0.56 (95% confidence interval, 0.37-0.84)., Conclusions: These propensity score analyses suggest that high adherence to Mediterranean diet reduces diabetes risk in people with prediabetes., (© 2021 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

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 m 2 . 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., (© 2022. The Author(s).)

Acknowledgement of the prevalence of recreational opioid use (PROU) is key to the planning and evaluation of care services. However, in Spain, the prevalence of PROU in recent years is unknown. The objective of this study was to estimate the PROU between 2005 and 2019 in the general populations of six Spanish cities. A benchmark-multiplier methodology was used to estimate the PROU population size. The benchmark used was overdose deaths from recreational opioid use in Spain's six most populated cities. The multiplier was the overdose death rate in a cohort of heroin users. Linear regression was used to estimate the trend of the PROU estimate over the set period of years. In 2005, the PROU was 4.78 (95%CI 3.16-7.91) per 1000 people. The estimated trend decreased, with the two lowest values being 2.35 per 1000 in 2015 and 2.29 in 2018. In 2019 the PROU was 2.60 per 1000 (95%CI 1.72-4.31), 45% lower than in 2005. While the decline in the PROU continues, its deceleration over the last four years calls for increased vigilance, especially in light of the opioid crisis in North America that has occurred over the last few years.

Purpose: To evaluate time trends in the prevalence of antithrombotic and statin use in four European countries., Methods: Using population-based data from the United Kingdom, Denmark, Spain and Italy between 2010 and 2018, we calculated standardized annual prevalence proportions of antithrombotics and statin use, and changes in prevalence proportions (2018 vs. 2010)., Results: Prevalence proportion of statins increased from 24.8% to 24.6% (UK), 21.0% to 22.3% (Region of Southern Denmark [RSD]), 12.9% to 14.3% (Udine, Italy), and 20.3% to 23.2% (Spain). Prevalence proportions of antithrombotics declined in all four countries: 18.7% to 15.9% (UK; - 2.8% points), 18.9% to 18.1% (RSD; - 0.8% points), 17.7% to 16.6% (Udine; - 1.1% points) and 15.0% to 13.6% (Spain; - 1.4% points). These declines were driven by reductions in low-dose aspirin use: 15.3% to 8.9% (UK; - 6.4% points), 16.3% to 9.5% (RSD; - 6.8% points), 13.5% to 11.6% (Udine; - 1.9% points), and 10.2% to 8.8% (Spain; - 1.4% points). In the UK, low-dose aspirin use declined from 9.1% to 4.3% (- 4.8% points) for primary CVD prevention, and from 49.6% to 36.9% (- 12.7% points) for secondary prevention. Oral anticoagulant use gradually increased but did not fully account for the decrease in low-dose aspirin use., Conclusions: Antithrombotic use in the UK, RSD, Udine and Spain declined between 2010 and 2018, driven by a reduction in use of low-dose aspirin that is not completely explained by a gradual increase in OAC use. Use of statins remained constant in the UK, and increased gradually in the RSD, Udine and Spain., (© 2021. The Author(s).)

Objective: Information about prognostic outcomes can be of great help for people with prediabetes and for physicians in the face of scientific controversy about the cutoff point for defining prediabetes. We aimed to estimate different prognostic outcomes in people with prediabetes., Design: Prospective cohort of subjects with prediabetes according to American Diabetes Association guidelines., Main Outcome Measures: The probabilities of diabetes onset versus non-onset, the odds against diabetes onset, and the probability of reverting to normoglycemia according to different prediabetes categories were calculated., Results: The odds against diabetes onset ranged from 29:1 in individuals with isolated FPG of 100-109 mg/dL to 1:1 in individuals with FPG 110-125 mg/dL plus HbA1c 6.0-6.4%. The probability of reversion to normoglycemia was 31.2% (95% CI 24.0-39.6) in those with isolated FPG 100-109 mg/dL and 6.2% (95% CI 1.4-10.0) in those with FPG 110-125 mg/dL plus HbA1c 6.0-6.4%. Of every 100 participants in the first group, 97 did not develop diabetes and 31 reverted to normoglycemia, while in the second group those figures were 52 and 6., Conclusions: Using odds of probabilities and absolute numbers might be useful for people with prediabetes and physicians to share decisions on potential interventions.Key pointsCommunicating knowledge on the course of the disease to make clinical decisions is not always done appropriately.Prediabetes is an example where risk communication is important because the prognosis of subjects with prediabetes is very heterogeneous.Depending on fasting plasma glucose and HbA1c levels, the odds of probabilities against diabetes onset ranged from 29: 1 to 1: 1.Depending on fasting plasma glucose and HbA1c levels, the number of subjects in 100 who revert to normoglycemia ranged from 31 to 6.Using probabilities and number absolutes on the prognosis of prediabetes may be useful for people with prediabetes and physicians to share decisions on potential interventions.

(1) Background: There is a major gap of knowledge towards the natural history of miscarriages in electronic medical records. We aimed to calculate the frequency of miscarriages using data from BIFAP database. (2) Methods: We identified all pregnancy losses and carried out a multistep validation exercise. Potential cases with positive predictive values (PPV) of miscarriage confirmation <85% or those confirming other pregnancy loss were excluded. Kaplan-Meier figures and incidence rates (IRs) of miscarriage with 95% confidence intervals (CIs) expressed by 1000 person-weeks were calculated. Stratifying analysis by age, specific high-risk groups, and drug exposure within the pre-pregnancy period were performed restricted to women with recording last menstrual period (LMP). (3) Results: Women with confirmed miscarriage ( N = 18,070), tended to be older, with higher frequency of comorbidities and drug utilization. Restricting to women with LPM recorded, IR of miscarriage was 10.89 (CI 95% 10.68-11.10) per 1000 women-weeks, with a median follow-up of 10 weeks (IQR: 8-12). The IR according to age was: 2.71 (CI 95% 2.59-2.84) in those aged <30 years compared to 9.11 (CI 95% 8.55-9.70) in women aged ≥40 years. Advanced maternal age (Hazard Ratio (HR, 95% confidence interval) CI 95%: 3.34 (3.08-3.62)), use of antihypertensives (1.49 (1.21-1.84), and use of drugs classified as D or X during pregnancy (1.17 (1.07-1.29)) showed to be positive predictors associated with increased risk of miscarriages. (4) Conclusion: BIFAP database can be used to identify women suffering from miscarriages, which will serve to further study risk factors associated with miscarriages with special attention to drug utilization.

Healthy lifestyle interventions and drug therapies are proven to have a positive preventative influence on normal glucose regulation in prediabetes. However, little is known on the specific role that these factors play on reversion to normal glycemia according to type of prediabetes. We used data from the Observational prospective cohort study, The Cohort study in Primary Health Care on the Evolution of Patients with Prediabetes from 2012 to 2015. A total of 1184 individuals aged 30-74 years old were included and classified based on the ADA in three mutually exclusive groups using either fasting plasma glucose (FPG) levels (from 100 to 125 mg/dl, FPG group), HbA 1c (5.7-6.4%, HbA1c group) or both impaired parameters. Information on lifestyle factors and biochemical parameters were collected at baseline. Reversion to normal glucose regulation was calculated at third year of follow-up. Relationship of lifestyle factor and type of prediabetes with reversion were estimated using odds ratios (ORs) with 95% confidence intervals (95% CIs) adjusting by different groups of confounders. Proportion of reversion rates were 31% for FPG group, 31% for HbA1c group and 7.9% for both altered parameters group, respectively. Optimal life style factors such as BMI < 25 kg/m 2 [OR (95% CI): 1.90 (1.20-3.01)], high adherence to Mediterranean diet 1.78 (1.21-2.63) and absence of abdominal obesity 1.70 (1.19-2.43) were the strongest predictors for reversion to normal glucose. However, those did not modify the ORs of reversion to normal glucose. Taking as reference those with both impaired parameters, subjects with FPG impairment (FPG group) had an OR of 4.87 (3.10-7.65) and 3.72 (2.39-5.78) for HbA1c group. These estimates remained almost the same after further adjustment for biochemical parameters and lifestyle factors (4.55(2.84-7.28) and 3.09 (1.92-4.97), respectively). Optimal lifestyle factors showed to be a positive predictor for reversion to normal glucose regulation however, the differences of reversion risk according type of prediabetes are not explained by lifestyle factors.

Objective: To evaluate associations between oral anticoagulant (OAC) discontinuation and risk of ischaemic stroke (IS) among patients with atrial fibrillation (AF)., Methods: We undertook a population-based cohort study with nested case-control analysis using UK primary care electronic health records (IQVIA Medical Research Data-UK) and linked registries from the Region of Southern Denmark (RSD). Patients with AF (76 882 UK, 41 526 RSD) were followed to identify incident IS cases during 2016-2018. Incident IS cases were matched by age and sex to controls. Adjusted ORs for OAC discontinuation (vs current OAC use) were calculated using logistic regression., Results: We identified 616 incident IS cases in the UK and 643 in the RSD. ORs for IS with any OAC discontinuation were 2.99 (95% CI 2.31 to 3.86, UK) and 2.30 (95% CI 1.79 to 2.95, RSD), for vitamin K antagonist discontinuation they were 2.38 (95% CI 1.72 to 3.30, UK) and 1.83 (95% CI 1.34 to 2.49, RSD), and for non-vitamin K antagonist oral anticoagulant discontinuation they were 4.59 (95% CI 2.97 to 7.08, UK) and 3.37 (95% CI 2.35 to 4.85, RSD). ORs were unaffected by time since discontinuation and duration of use. Annually, up to 987 IS cases in the UK and 132 in Denmark could be preventable if OAC therapy is not discontinued., Conclusions: Our results suggest that patients with AF who discontinue OAC therapy have a significant twofold to threefold higher risk of IS compared with those who continue therapy. Addressing OAC discontinuation could potentially result in a significant reduction in AF-attributed IS., Competing Interests: Competing interests: LAGR works for CEIFE, which has received other research funding from Bayer AG. LAGR has also received honoraria for serving on advisory boards for Bayer AG. DG has received honoraria from AstraZeneca (Sweden) for participation as a co-investigator on a research project outside the submitted work, and receiving speaker honorarium from Bristol-Myers Squibb outside the submitted work. YB and PV are employees of Bayer AG. GB is an employee of Bayer AB. MS has served on the steering committees and led sub-studies from trials sponsored by Bayer and has served as a consultant and received speaker’s honoraria from Bayer. MS has also served as a consultant to Portola, Bristol Myers Squibb and Janssen. LCS, SMH and JH report no potential conflicts of interest., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Randomized controlled trials (RCTs) have strong internal validity but often have limited external validity. Observational studies have good generalizability and an increasing role in key healthcare decision making. We compared incidence rates of intracranial and major gastrointestinal bleeds in the low-dose aspirin arm (N = 9126) of the COMPASS double-blind RCT (conducted at 602 centres in 33 countries) with those from an observational cohort of preventative low-dose aspirin users (N = 54,140) in a primary care database representative of the UK general population - The IQVIA Medical Research Data UK (IMRD-UK). In our observational study analysis, we restricted follow-up to 2 years to be comparable with the duration of the COMPASS trial. Among low-dose aspirin users, incidence rates per 1000 person-years (95% confidence intervals [CIs]) in the IMRD-UK cohort and COMPASS trial participants, respectively, were 0.6 (0.5-0.8) vs. 1.4 (0.9-2.1) for intracranial bleeds, and 3.5 (3.1-3.8) vs. 3.7 (2.9-4.8) for major gastrointestinal bleeds. These broadly comparable bleeding rates among COMPASS trial participants and an observational cohort of low-dose aspirin users in IMRD-UK support the use of the latter for generating robust therapeutic evidence, and indicate that the rates from the COMPASS trial are broadly consistent with realistic population-based rates., Competing Interests: Declaration of Competing Interest LAGR, AR and LCS work for CEIFE, which has received research funding from Bayer AG for other studies. LAGR has previously received honoraria for serving on advisory boards for Bayer AG. PV and MS-G are employees of Bayer AG and GB is an employee of Bayer AB., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Objectives: To study the effect of risk minimization measures taken in 2013 for cyproterone acetate/ethinylestradiol (CPA/EE) on initiation, concomitant use of other hormonal contraceptives (HC) and potential indications., Study Design: This retrospective study included data on CPA/EE use in 2011-2017 from the Netherlands, UK, and Italy., Results: The initiation rate of CPA/EE decreased by 44%-91% between 2011 and 2017. Proportions with concomitant use of other HC (<3%) and approved indications did not change over time., Conclusion: Apart from a strong reduction in CPA/EE use following risk minimization measures, no major changes were observed regarding concomitant use of other HC or potential reasons for use., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

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.

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., (© 2020 John Wiley & Sons Ltd.)

Estimates of the effect of proton pump inhibitors (PPIs) on risks of upper and lower gastrointestinal bleeding (UGIB and LGIB) among low-dose aspirin users in routine clinical practice are variable (UGIB) or lacking (LGIB). We aimed to establish these risks in the same observational study population. Using UK primary care data, we followed 199,049 new users of low-dose aspirin (75-300 mg/day) and matched non-users at start of follow-up to identify incident UGIB/LGIB cases. In nested case-control analyses, adjusted odds ratios (ORs) were calculated for concomitant PPI use vs. past (discontinued) PPI use among current low-dose aspirin users. For UGIB ( n = 987), ORs (95% CIs) were 0.69 (0.54-0.88) for >1 month PPI use and 2.65 (1.62-4.3) for ≤1 month PPI use. Among the latter group, ORs (95% CIs) were 3.05 (1.75-5.33) for PPI initiation after start of aspirin therapy, and 1.66 (0.63-4.36) for PPI initiation on/before start of aspirin therapy. For LGIB ( n = 1428), ORs (95% CIs) were 0.98 (0.81-1.17) for >1 month PPI use and 1.12 (0.73-1.71) for ≤1 month PPI use. Among low-dose aspirin users, maintaining PPI use (>1 month) was associated with a significantly reduced UGIB risk. Neither short nor long-term PPI use affected LGIB risk.

Background: Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice., Methods: CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50% eGFR decline or end-stage kidney disease., Findings: After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9%, 34·1%, 5·7%, 1·4%, 0·5%, and 0·4% of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3%) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA 1c was 72 mmol/mol (8·71%), and mean eGFR was 90·7 mL/min per 1·73 m 2 . During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m 2 per year, 95% CI 1·34-1·72, p<0·0001). During a mean follow-up of 14·9 months, 351 composite kidney outcomes occurred: 114 (3·0 events per 10 000 patient-years) among initiators of SGLT2 inhibitors and 237 (6·3 events per 10 000 patient-years) among initiators of other glucose-lowering drugs (hazard ratio 0·49, 95% CI 0·35-0·67; p<0·0001). These findings were consistent across countries (p heterogeneity 0·10) and prespecified subgroups., Interpretation: In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice., Funding: AstraZeneca., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: There has been a notable progress on the development of methods for identification of pregnancies using primary care databases. We aimed to evaluate the prescription of medications during pregnancy applying a novel algorithm., Methods: We identified pregnancies in women aged 15 to 49 years registered in the Database for Pharmacoepidemiological Research in Primary Care (BIFAP) between 2002 and 2015. The algorithm applied sequential cycles that searched in hierarchical order for indicators of conception, delivery or pregnancy loss, and other codes suggestive of pregnancy. Length of pregnancy was assessed by searching for last menstrual period (LMP) date, gestational age, and outcomes of pregnancy. Prescription of specific drugs during the pre-pregnancy period and first trimester and time trends during pregnancy were evaluated., Results: We identified a total of 155 419 pregnancies during the study period (77.5% completed pregnancies, 21.5% pregnancies losses, 0.8% ectopic pregnancies, and 0.2% stillbirths). Excluding vitamins and supplements, 43.8% of women received at least one prescription during the pre-pregnancy period and 68.4% during the first trimester. During the first trimester, the most commonly drugs prescribed were analgesics (16.3%) followed by antibiotics (11.8%). From 2002/2003 to 2014/2015, there was an increase of prescriptions for thyroid hormones (1.0% vs 4.7%), H2 blockers (1.0% vs 2.2%), and PPIs (1.4% vs 2.2%). While antidepressants (2.0% vs 1.5%) and benzodiazepines (3.1% vs 2.4%) decreased in the last period., Conclusion: Having in mind the challenges of identifying pregnancies in health care databases, this study demonstrates the usefulness of BIFAP database for studies on drug utilization during pregnancy., (© 2019 John Wiley & Sons, Ltd.)

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/m 2 , 0.76 (0.64-0.89) for >28 kg/m 2 . For UGIB, estimates were: 1.49 (1.28-1.74) for ≤90 kg, 1.78 (1.29-2.45) for >90 kg/m 2 , 1.44 (1.21-1.72) for ≤28 kg/m 2 , 1.72 (1.38-2.16) for >28 kg/m 2 . 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., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: We studied the role of lifestyle factors associated to type 2 diabetes (T2DM) onset according to type of prediabetes., Methods: We used data from the observational prospective cohort study in Primary Health Care on the Evolution of Patients with Prediabetes in Spain (PREDAPS). Participants were classified by American Diabetes Association criteria using either fasting plasma glucose levels (100-125 mg/dL) (group 1), HbA1c (5.7%-6.4%) (group 2) or both impaired parameters (group 3). Relationship between lifestyles and diabetes onset according to prediabetes at third year of follow up were estimated by Hazard Ratios (HRs) using three sequential models., Results: Incidence rate of diabetes was 2.27 cases per 1000 person-years (95% CI: 1.4-3.6) for group 1, 1.18 (95% CI: 0.65-2.13) for group 2 and 6.68 (95% CI: 5.71-8.23) for group 3. The most important risk factors were: abdominal obesity (HR: 2.29 (95% CI: 1.49-3.52)) and hypertension (HR: 2.16 (95% CI: 1.41-3.30)). Using as reference group 2, group 3 had a HR of 5.82 (3.13-10.82) and 1.83 (95% CI: 0.85-3.93) for group 1, estimates remained constant when adjusting by lifestyle and metabolic factors., Conclusions: Lifestyle and metabolic do not seem to explain the differences on T2DM onset by type of prediabetes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

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., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Risks of low-dose aspirin-associated upper and lower gastrointestinal bleeds (UGIB/LGIB) may vary by severity and presence of cardiovascular disease (CVD). No study has quantified these risks for UGIB and LGIB in the same real-world study population. Patients and methods: Using UK primary care data, 199,049 new users of low-dose aspirin (75-300 mg/day) and 1:1 matched non-users were followed to identify incident UGIB ( N  = 1843)/LGIB ( N  = 2763) cases. Nested case-control analyses compared current low-dose aspirin vs. non-use on UGIB/LGIB risk. Results: Adjusted incidence rate ratios (ORs; 95% CIs) were 1.62 (1.42-1.86) for non-fatal UGIB, 1.63 (1.47-1.81) for non-fatal LGIB, 0.77 (0.51-1.16) for fatal UGIB, 1.29 (0.50-3.36) for fatal LGIB. For hospitalizations, adjusted ORs (95% CIs) were 1.55 (1.32-1.81) for UGIB and 1.89 (1.58-2.27) for LGIB; for referred only cases, they were 1.52 (1.26-1.84) for UGIB and 1.54 (1.37-1.73) for LGIB. In primary CVD prevention, adjusted ORs (95% CI) were 1.62 (1.38-1.90) for UGIB and 1.60 (1.42-1.81) for LGIB; in secondary CVD prevention, they were 1.16 (0.89-1.50) for UGIB and 1.67 (1.34-2.09) for LGIB. Conclusion: Low-dose aspirin was associated with increased risks of non-fatal but not fatal UGIB/LGIB. Key message Low-dose aspirin is associated with an increased risks of non-fatal UGIB/LGIB but not fatal UGIB/LGIB.

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.

Purpose: Our goal was to describe the management of pregestational diabetes in pregnant women in the United Kingdom., Methods: We used electronic medical records from The Health Improvement Network database between January 1995 and June 2012 to identify the first pregnancy in women 15 to 45 years of age with pregestational diabetes type 1 or type 2. Information on lifestyle factors, demographic characteristics, prescription of specific antidiabetic medications, and glycemic control measures (HbA1c) was obtained from primary care provider records. We evaluated treatment patterns and HbA1c levels within 90 days before the last menstrual period (prepregnancy period) and within each trimester of pregnancy., Results: In a cohort of 1511 pregnant women with pregestational diabetes, 60% had type 1 and 40% type 2 diabetes. Among women with type 1 diabetes, 90% received antidiabetic medication (primarily insulin) prepregnancy and 92% during the first trimester. Among women with type 2 diabetes, 54% received antidiabetic medication (primarily metformin) during the prepregnancy period and 60% during the first trimester. Among women with nontreated diabetes type 2 before pregnancy, 22% initiated treatment by the first trimester (primarily insulin); those on noninsulin antidiabetic medications often switched to insulin. The proportion of women with at least 1 HbA1c value recorded within the prepregnancy period was 33% for type 1 (n = 299) and 31% for type 2 diabetes (n = 189); the corresponding proportions within the first trimester were 48% and 40%, respectively. Among women with recorded HbA1c, the prevalence of HbA1c > 7% prepregnancy was 70% for type 1 and 52% for type 2 diabetes; the proportions within the first trimester were 73% and 46%, respectively., Conclusions: Management of pregnant women with diabetes seems to follow recommendations for pharmacological treatment. However, there is substantial room for improvement in HbA1c control, that is, in the planning of pregnancy in women with diabetes, in the initiation of antidiabetic medication among women with diabetes type 2 who may need it, and likely in the compliance with treatments in women with type 2 and type 1 diabetes., (Copyright © 2018 John Wiley & Sons, Ltd.)

Aims: To evaluate the association between use of non-insulin antidiabetics in early pregnancy and the risk of miscarriages, stillbirths and major structural malformations., Materials and Methods: A cohort of 1511 pregnant women with pre-gestational diabetes linked to live births was identified using electronic medical records from The Health Improvement Network (THIN) for the period 1995 to 2012. Information on prescriptions, foetal outcomes and potential confounders was ascertained from both codes and free text in the THIN database. Odds ratios (OR) and 95% confidence intervals (CI) of adverse foetal outcomes in women treated with non-insulin antidiabetics during the first trimester compared to those on insulin were estimated using logistic regression to adjust for type of diabetes, glycaemic control and other maternal characteristics., Results: Among 311 pregnant women on non-insulin antidiabetics, 21.9% had a miscarriage and 1.6% a stillbirth; 1.9% of live births had major malformations. The corresponding frequencies for the 883 women on insulin were 13.3%, 1.7% and 9.6%. Insulin users more often had type 1 diabetes and poor glycaemic control. Compared to women with type 1 diabetes, those with type 2 diabetes had a higher risk of miscarriages (20.5% vs 12.8%) but a lower prevalence of malformations (4.0% vs 9.2%). Compared to women with HbA1c ≤7%, those with HbA1c >7% had a higher prevalence of malformations (12.6% vs 2.7%). After adjustment for diabetes type and glycaemic control, compared to insulin, non-insulin antidiabetic patients were associated with an OR for miscarriage of 1.19 (95% CI, 0.75-1.89), for stillbirths of 0.65 (95% CI, 0.16-2.58), and for major malformations of 0.25 (95% CI, 0.08-0.84)., Conclusion: Among women with diabetes, use of non-insulin antidiabetics early in pregnancy was not associated with greater risks of foetal losses or major malformations than was insulin., (© 2018 John Wiley & Sons Ltd.)

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., Competing Interests: L.C.S. and L.A.G.R. are employees of CEIFE, which has received research funding from AstraZeneca Gothenburg, Mölndal, Sweden, and Bayer Pharma AG, Berlin, Germany. L.A.G.R. has also received honoraria for serving on scientific advisory boards for Bayer. F.G.R.F. has received honoraria for serving on scientific advisory boards for AstraZeneca, Bayer and Merck. S. J. was an employee of AstraZeneca Gothenburg, Mölndal, Sweden, at the time of the study. A.M.A. is an employee of AstraZeneca Cambridge, Cambridge, UK., (Schattauer GmbH Stuttgart.)

Objectives: To assess time trends in symptomatic peripheral artery disease (PAD) incidence and prevalence, and secondary preventive therapy., Design: Cohort study using The Health Improvement Network., Setting: UK primary care., Participants: Individuals aged 50-89 years identified annually between 2000 and 2014. Participants with symptomatic PAD were identified using Read codes., Outcome Measures: Incidence and prevalence of symptomatic PAD from 2000 to 2014, overall and by sex and age. Proportion of patients prescribed secondary preventive therapy with acetylsalicylic acid (ASA), clopidogrel, an ACE inhibitor, an angiotensin receptor blocker (ARB) and/or a statin., Results: The incidence of symptomatic PAD per 10 000 person-years decreased over time, from 38.6 (men: 51.0; women: 28.7) in 2000 to 17.3 (men: 23.1; women: 12.4) in 2014. The prevalence of symptomatic PAD decreased from 3.4% (men: 4.5%; women: 2.5%) in 2000 to 2.4% (men: 3.1%; women: 1.7%) in 2014. Incidence and prevalence decreases were observed in all age groups. The proportions of patients prescribed ASA monotherapy, clopidogrel monotherapy and dual antiplatelet therapy in the 2 months after PAD diagnosis were 42.7%, 2.9% and 2.5%, respectively, during 2000-2003, and 44.7%, 11.0% and 5.2%, respectively, during 2012-2014. For ACE inhibitor/ARB therapy and statins, proportions in the 2 months after diagnosis were 30.2% and 31.2%, respectively, during 2000-2003, and 45.1% and 65.9%, respectively, during 2012-2014., Conclusion: The incidence and prevalence of symptomatic PAD diagnosed in UK primary care are decreasing. A large proportion of the population with PAD in clinical practice does not receive guideline-recommended secondary prevention therapy., Competing Interests: Competing interests: LC-S and LAGR are employees of CEIFE, which has received research funding from AstraZeneca Gothenburg, Mölndal, Sweden, and Bayer Pharma AG, Berlin, Germany. LAGR has also received honoraria for serving on scientific advisory boards for AstraZeneca and Bayer. FGRF has received honoraria for serving on scientific advisory boards for AstraZeneca, Bayer and Merck. SJ is an employee of AstraZeneca Gothenburg, Mölndal, Sweden. AMA is an employee of AstraZeneca Cambridge, Cambridge, UK., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: Although there is no overall association between statin use and intracerebral hemorrhage (ICH), whether there is an increased risk among those with a history of ischemic stroke (IS) or transient ischemic attack (TIA) remains controversial. We evaluated the relationship of preadmission statin use with the risk of ICH in patients with a history of IS or TIA in a population-based cohort., Methods: The Health Improvement Network primary care database in the United Kingdom was used to identify new users of low-dose aspirin and a matched comparison. Both cohorts were followed to identify incident cases of ICH, with validation by manual review of patient records and linkage to hospitalization data. In a nested case-control study, we compared the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for ICH based on statin use in the subgroup of individuals with history of IS/TIA., Results: Last statin use within 1 year of ICH (OR, 0.92; 95% CI [confidence interval], 0.60-1.4), last use between 8 days and 1 year (OR, 1.81; 95% CI, 0.99-3.28), and statin use at the time of ICH (OR, 0.77; 95% CI, 0.49-1.21) were not associated with the overall ICH risk among 157 patients with ICH and 884 controls with a history of IS/TIA. There was also no difference in 30-day rates of fatal (OR, 0.82; 95% CI, 0.41-1.64) or nonfatal (OR, 0.90; 95% CI, 0.51-1.57) ICH., Conclusions: Statin use was not associated with an increased risk of ICH among patients with a previous history of IS/TIA., (© 2017 American Heart Association, Inc.)

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.