Risk of agranulocytosis with metamizole in comparison with alternative medications based on health records in Spain.

PURPOSE: We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs). METHODS: A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2 years in 2005-2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7 days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7 days before). RESULTS: The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37-40 days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92-26.99] and 4.40 [0.90-21.57] versus NSAID, and 3.31 [1.17-9.34] and 2.45 [0.68-8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57-5.65] versus NSAID. CONCLUSIONS: Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded.

Effectiveness of homologous/heterologous booster COVID-19 vaccination schedules against severe illness in general population and clinical subgroups in three European countries.

Using 4 data-sources (Spain, Italy, United Kingdom) data and a 1:1 matched cohort study, we aimed to estimate vaccine effectiveness (VE) in preventing SARS-CoV-2 infections with hospitalisations (±30 days) and death (±56 days) in general population and clinical subgroups with homologous/heterologous booster schedules (Comirnaty-BNT and Spikevax-MOD original COVID-19 vaccines) by comparison with unboosted individuals, during Delta and beginning of Omicron variants. Hazard Ratio (HR, by Cox models) and VE ([1-HR]*100) were calculated by inverse probability weights. Between December 2020-February 2022, in adults without prior SARS-CoV-2 infection, we matched 5.5 million people (>1 million with immunodeficiency, 343,727 with cancer) with a booster (3rd) dose by considering doses 1 and 2 vaccine brands and calendar time, age, sex, region, and comorbidities (immunodeficiency, cancer, severe renal disease, transplant recipient, Down Syndrome). We studied booster doses of BNT and MOD administered after doses 1 and 2 with BNT, MOD, or Oxford-AstraZeneca during a median follow-up between 9 and 16 weeks. BNT or MOD showed VE ranging from 70 to 86% across data sources as heterologous 3rd doses, whereas it was 42-88% as homologous 3rd doses. Depending on the severity and available follow-up, 3rd-dose effectiveness lasted between 1 and 5 months. In people with immunodeficiency and cancer, protection across data sources was detected with both heterologous (VE = 54-83%) and homologous (VE = 49-80%) 3rd doses. Overall, both heterologous and homologous 3rd doses with BTN or MOD showed additional protection against the severe effects of SARS-CoV-2 infections for the general population and for patients at potentially high risk of severe COVID-19 (elderly, people with immunodeficiency and cancer) in comparison with two doses schemes during Delta or early Omicron periods. The early VE after vaccination may be due to less testing among vaccinated pairs and unknown confounders, deserving cautious interpretation. The VE wane over time needs further in-depth research to properly envisage when or whether a booster of those vaccines should be administered.

Assessment of thyroiditis risk associated with HPV vaccination among girls aged 9-18 years: A time-varying cohort study.

BACKGROUND: Previous studies have suggested a relationship between human papillomavirus vaccine and autoimmune diseases, including thyroiditis. Thus, we aimed to evaluate the risk of thyroiditis associated with HPV vaccination among girls using the Primary Care Database For Pharmacoepidemiological Research (BIFAP) in Spain. METHODS: In this retrospective cohort study, girls in BIFAP aged 9-18 years from 2007 to 2016, free of past thyroiditis and HPV vaccination, were included. Hazard Ratios (HRs; 95% CI) of thyroiditis were calculated within exposed periods (up to 2 years of vaccination) and post-exposed periods (from 2 years after vaccination onwards) compared with non-exposed periods, overall, by dose and by type of vaccine, adjusted for potential confounders collected at different times. In a post-hoc analysis, we moved back the thyroiditis date (30 days) as a theoretical delay in diagnosis. RESULTS: Out of the 388,411 girls included in the cohort, 153,924 were vaccinated against HPV and 480 thyroiditis (253 autoimmune) cases were identified (334 non-exposed; 103 exposed; 43 post-exposed). Adjusted HR was 1.18 [95% CI: 0.79-1.76] for exposed (1.25 [0.77-2.04] for bi- and 1.15 [0.76-1.76] for quadri-valent vaccines) and 1.26 [0.74-2.14] for post-exposed periods. HR was 1.50 [0.87-2.59] for the 1st dose, 1.13 [0.66-1.91] for the 2nd and 1.11 [0.71-1.72] for the 3rd one. When the diagnosis date was moved back, the risk was 1.14 [0.76-1.70] for exposed period, being 1.80 [0.86-3.76] and 1.40 [0.74-2.66] after 1st dose of bi- and quadri-valent, respectively. CONCLUSIONS: We did not observe an increased risk of thyroiditis following HPV vaccination (whether bi- or quadri-valent). Even though the point estimate was higher after 1st HPV vaccination dose than after subsequent doses, a dose-effect was not confirmed. Results remained similar after applying a lag time.

Papillomavirus vaccination and Guillain-Barre Syndrome among girls: A cohort study in Spain.

BACKGROUND: Studies of the association of Guillain-Barré Syndrome (GBS) with papillomavirus vaccination (HPVv; scheduled from 2007) have provided contradicting results, probably due to the low frequency of this disease. We aimed at estimating that risk relative to non-vaccination among girls, by using the Spanish Primary Care Database for Pharmacoepidemiological Research (BIFAP). METHODS: A cohort study of girls aged 9-18 years during 2007-2016 free of GBS or HPVv was selected and followed up to GBS diagnosis. Follow-up time was divided by time-varying HPVv exposure and confounders. Crude Incidence rates (IR per 1,000,000 person-years (py)) and adjusted Hazard Ratios (HR) of GBS were estimated anytime after vaccination compared to non-exposed periods. HRs were also estimated for the first 90 days after HPVv (risk-window) and thereafter. RESULTS: Out of 388,849 girls, of which 154,255 were vaccinated, 6 'confirmed' GBS cases occurred during non-exposure periods (IR of 5.83 per million person-years; 95% CI: 2.62-12.97) and 3 'confirmed' cases anytime after vaccination (IR of 7.87; 95% CI: 2.54-24.39). The resulting adjusted HR anytime after vaccination was 1.24 (95% CI: 0.19-8.00). All three cases occurred after the risk window of 90 days with an HR of 1.77 (95% CI: 0.25-12.54) for post-exposure periods as compared with non-exposure. Since zero cases occurred during the risk window, no HR could be estimated for exposed periods. CONCLUSIONS: Incidences of GBS were in line with the range previously reported for young people, supporting the potential of BIFAP for performing studies on GBS. However, a lack of power may be present for quantifying the relative risk of such a rare disease after the vaccination among the study cohort, where we can only exclude an increased risk of 8-times relative to no vaccination.

Evaluation of the Risk of Inflammatory Bowel Disease after the HPV Vaccination in Primary Care in Spain: A Time-Varying Cohort Analysis of Around 390,000 Girls.

INTRODUCTION: A link between the human papillomavirus vaccination (HPVv) and inflammatory bowel disease (IBD) has been suggested. OBJECTIVE: We aimed to estimate the risk of IBD following HPVv compared with periods not exposed to the vaccines. METHODS: Primary healthcare records (Spanish Primary Care Database For Pharmacoepidemiological Research [BIFAP]) were used in a cohort study of girls in Spain aged 9-18 years between 2007 and 2016 free of IBD or HPVv at study entrance. During the follow-up to IBD diagnosis, time-varying HPVv exposure and confounders were assessed in Cox models to estimate the hazard ratio (HRs) of IBD in the 2 years after HPVv (exposed period) and thereafter (post-exposed) compared with the no exposure periods. In a post hoc analysis, we moved the IBD date back 30 days as a theoretical delay in diagnosis confirmation. RESULTS: The cohort comprised 388,669 girls; 154,174 of these received the HPVv, and 88 IBD cases occurred (55 non-exposed, 22 exposed [after first N = 6, second N = 2, or third N = 14 dose] and 11 in post-exposed periods). The adjusted HR was 1.66 (95% confidence interval [CI] 0.68-4.05) for exposed and 1.10 (95% CI 0.37-3.24) for post-exposed periods. The HR for the first dose was 3.94 (95% CI 1.19-13.02). No association was found for the second or third doses. Post hoc, the HR was 1.83 (95% CI 0.72-4.69) for exposed periods (N = 18), and 1.84 (95% CI 0.35-9.83; N = 2), 1.50 (95% CI 0.40-5.63; N = 4) and 1.98 (95% CI 0.71-5.49; N = 12) after the first, second and third doses, respectively. CONCLUSIONS: This study did not show an increased risk of IBD following 2 years of HPVv exposure. However, an increased risk of IBD diagnosis was observed following the first vaccination dose (1-34 days), which is likely attributable to the clinical recommendation to vaccinate upon onset of IBD symptoms.

An Estimation of the Incidence of Thyroiditis Among Girls in Primary Care in Spain

Objective: As for other auto-immune processes, thyroiditis is monitored after vaccinations. The aim was to estimate the baseline incidence of thyroiditis among girls, before investigating papillomavirus vaccination as a potential risk factor. Methods: Observational cohort study including girls aged 9-18 years and registered between 2002-2016 in the Spanish Primary Care Database for Pharmacoepidemiological Research. Girls were followed until a thyroiditis occurred, 19 years of age, left the cohort, died, or the study ended. Anonymized records were reviewed for diagnosis confirmation (endocrine discharge letter and/or free-text comments) in a random sample. Incidence rate (IR) per 105 person years (/105 py) was estimated. Results: The cohort numbered 480,169 girls, of whom 641 had a record of thyroiditis: 346 autoimmune thyroiditis; 17 thyroiditis of other types; and 278 unspecified. Incidence of recorded thyroiditis increased with age, from 23.96 at age 9 years to 47.91 at age 14 years, and stabilized around 31.06-34.43 among girls aged 15-18 years. Of the 98 records reviewed, 60.2% were 'confirmed' cases, 32.7% 'possible' and 7.1% were discarded. After correction for discarded cases, IR=20.83 'confirmed' cases, increasing to 32.12/105 py when 'confirmed' plus 'possible' cases were included. Between 2002-2005, incidences were lower (16.28 and 20.93 cases/105 py) than in the period 2007-2016 (21.17 and 33.78 cases/105 py) for 'confirmed' and 'confirmed' plus 'possible', respectively. Conclusion: Two-thirds of the recorded thyroiditis included confirmatory evidence. The incidence of thyroiditis among girls increased with age and in the later period, and remained stable among girls aged 15-18 years.

Prescribers' compliance with summary of product characteristics of dabigatran, rivaroxaban and apixaban-A European comparative drug utilization study.

Despite a tremendous increase of direct oral anticoagulants (DOACs) prescriptions in recent years, only few data is available analysing prescribers' adherence to Summary of Product Characteristics (SmPC). We aimed to assess adherence to registered indications, contraindications, special warnings/precautions, and potential drug-drug interactions for three DOAC compounds (dabigatran, rivaroxaban, and apixaban) in six databases of five European countries (The Netherlands, United Kingdom, Spain, Denmark, and Germany). We included adult patients (≥18 years) initiating DOACs between 2008 and 2015. For several SmPC items, broad definitions were used due to ambiguous SmPC terms or lacking data in some databases. Within the study period, a DOAC was initiated in 407 576 patients (rivaroxaban: 240 985 (59.1%), dabigatran: 95 303 (23.4%), and apixaban: 71 288 (17.5%)). In 2015, non-valvular atrial fibrillation was the most common indication (>60% in most databases). For the whole study period, a substantial variation between the databases was found regarding the proportion of patients with at least one contraindication (inter-database range [IDR]: 8.2%-55.7%), with at least one special warning/precaution (IDR: 35.8%-75.2%) and with at least one potential drug-drug interaction (IDR: 22.4%-54.1%). In 2015, the most frequent contraindication was "malignant neoplasm" (IDR: 0.7%-21.3%) whereas the most frequent special warning/precaution was "prescribing to the elderly" (≥75 years; IDR: 25.0%-66.4%). The most common single compound class interaction was "concomitant use of non-steroidal anti-inflammatory drugs" (IDR: 3.0%-25.3%). Contraindications, special warnings/precautions, and potential drug-drug interactions were present in a relevant number of new DOAC users. Due to broad definitions used for some SmPC terms, overall proportions for contraindications are prone to overestimation. However, for unambiguous SmPC terms documented in the databases sufficiently, the respective estimates can be considered valid. Differences between databases might be related to "true" differences in prescription behaviour, but could also be partially due to differences in database characteristics.

The recording and prevalence of Inflammatory bowel disease in girls' primary care medical Spanish records.

PURPOSE: Inflammatory bowel disease (IBD) recording validation among girls in the Spanish Primary Care Database For Pharmacoepidemiological Research (BIFAP). METHODS: In this observational study, girls aged 9 to 18 years registered in BIFAP between 2002 and 2016, were followed up until there was a recorded IBD diagnosis or a referral to specialist indicating IBD. Anonymized profiles were reviewed to retrieve diagnosis confirmation (a positive colonoscopy or biopsy, specialist, or physician's comments mentioning the IBD diagnosis) or discarding (negative procedure results, alternative diagnosis, or family history). "possible" IBD were profiles missing that evidence, or had suspected IBD. The prescriptions of intestinal anti-inflammatory agents, azatioprine, and mercaptopurine were collected. The prevalence of IBD was estimated after review. RESULTS: Out of 480 634 girls, 323 had a first ever recorded IBD, of which, 37.8% (N = 122) were "confirmed" incident IBD diagnosis, 19.8% (N = 64) discarded and 38.7% (N = 125) "possible" IBD. Additionally, 12 IBD records (3.7%) referred to prevalent IBD. Prescriptions were recorded in 94.3% (confirmed), 63.2% (possible), 83.3% (prevalent), and 3.1% (discarded) IBD cases. Prevalence was 52.83 "confirmed" or 93.58/105 girls when "possible" IBD were added. CONCLUSIONS: For a third of the girls, the first recorded IBD included evidence confirming the diagnosis while most of those with missing evidence had treatment indicated for IBD. For research focused in sensitivity, an algorithm including "possible" plus "confirmed" episodes is recommended, whereas only "confirmed" to guarantee higher predictive value. Prevalence suggests that IBD is not a rare disease among girls.

Age-specific vaccination coverage estimates for influenza, human papillomavirus and measles containing vaccines from seven population-based healthcare databases from four EU countries - The ADVANCE project.

BACKGROUND: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk monitoring of vaccines using existing healthcare databases in Europe. We estimated vaccine coverage from electronic healthcare databases as part of a fit-for-purpose assessment for vaccine benefit-risk studies. METHODS: A retrospective dynamic cohort study was conducted through a distributed network approach. Coverage with measles-vaccine for birth year 2006, human papillomavirus (HPV)-vaccine for birth years 1990-2000 and influenza-vaccine for birth years 1920-1950 was estimated using period-prevalence and inverse probability weighting methods. Seven databases from four countries participated: Italy (Pedianet, Val Padana), Spain (BIFAP, SIDIAP), UK (RCGP-RSC, THIN), Denmark (SSI/AUH). Database access providers extracted the data, transformed it into a common structure and ran an R-script locally. The created output tables were shared and pooled at a central server. RESULTS: The total study population comprised 274,616 persons for measles-vaccine, 2,011,666 persons for HPV-vaccine and 14,904,033 persons for influenza-vaccine. Measles-vaccine coverage varied from 84.3% (Denmark) to 96.5% (Italy, Val Padana) for the first dose and from 82.8% (Italy, Val Padana) to 90.9% (UK) for the second dose at the age of 7 years. The HPV-vaccine coverage, aggregated over birth years 1997-2000, ranged from 60% (UK) to 88.3% (Denmark) at the age of 15 years. The influenza-vaccine coverage for the influenza seasons from 2009 to 2015 for persons aged 65 years and more was roughly stable around 43% in Denmark and around 68% in the UK while a decrease from 58 to 50% was observed in Catalonia (Spain). CONCLUSIONS: We obtained detailed, age-specific coverage estimates though a common procedure. We discussed between database comparability and comparability to published national estimates.

The Longitudinal Incidence of Human Papillomavirus Vaccination in Spanish Primary Care in the First 10 Years After Approval.

BACKGROUND: In Spain, girls are vaccinated against human papillomavirus (HPV) in the primary care setting, according to a national vaccination programme. Vaccination is voluntary and is covered by the public health system. OBJECTIVES: The aim of the study was to estimate the incidence and patterns of HPV vaccination amongst girls in primary care in Spain. METHODS: A cohort study was performed using the information recorded in the Spanish Primary Care Database for Pharmacoepidemiological Research (BIFAP) from 7.9 million patients from seven Spanish regions, between 2001 and 2016 (56.6% of the regional population). Data available in BIFAP include patient age, sex, life-style factors, clinical events, specialist referrals, prescriptions, and vaccinations as recorded by the primary care physician (PCP) or administering nurse. The study cohort comprised all girls aged 9-18 years registered in BIFAP between 1st January of 2007 and 31st December of 2016 who had at least 1 year of clinical record information with their PCP (inclusion criteria). The date the inclusion criteria were met was designated as the start date to the study cohort contribution. In order to estimate the incidence of HPV vaccination (initiation of vaccination schedule), girls with an HPV vaccination recorded before the start date or without vaccination date were excluded. Girls forming the study cohort were followed from start date until there was a recorded HPV vaccination, they reached 19 years of age or died, end of available information, or 31st December 2016. The person-time of all patients forming the study cohort was reckoned in the incidence estimations. The follow-up was replicated yearly from 2007 to 2016. The cumulative incidence (CuIn) of vaccination by birth cohort, year and region, was estimated using life tables (proportion of vaccination by intervals in which the denominator is the initial population corrected for losses). RESULTS: Of 388,690 girls forming the study population, 154,211 initiated the vaccination during 2007-2016. Ages ranged from 12 to 14 years at first dose in 84.5% of vaccinated girls, 42.79% received a quadrivalent vaccine, 21.86% a bivalent vaccine, and 35.35% an unknown type. Of the vaccinated population, 48.0% were completely vaccinated with a three-dose schedule and 28.9% with a two-dose schedule, 20.2% received one dose and 3.0% two doses in a three-dose schedule, at a maximum of 10 years of follow-up. The CuIn was highest among girls aged either 13 or 14 years over all regions (reaching 92.8% and 89.7%, respectively), and aged 12 in some regions/years (up to 89.8%). Girls aged 15 years were also vaccinated (although showing lower yearly incidence, i.e. < 69.1%) in two regions. The coverage was broadened to younger girls (11 years) during the last years of the study period in some regions. CONCLUSIONS: According to BIFAP primary care data, a high incidence of vaccination among girls aged 13-14 years was observed. Vaccination among younger and older girls were less common, although they reached high incidence in some regions and/or years. Most vaccination patterns adjusted to a complete vaccination regimen, as recommended posology.

RETRACTED ARTICLE: The Longitudinal Incidence of Human Papillomavirus Vaccination in Spanish Primary Care in the First 6 Years After Approval.

BACKGROUND: In Spain, girls and women are vaccinated against human papillomavirus (HPV) in the primary care setting, according to a national vaccination program. Vaccination is voluntary and the cost is covered by the public health system. OBJECTIVES: The aim of the study was to estimate the incidence and patterns of HPV vaccination amongst girls in Spain. METHODS: A cohort study was performed using the information recorded in the Spanish Primary Care Database for Pharmacoepidemiological Research (BIFAP) from 7.4 million patients from eight Spanish regions, between 2001 and 2013 (56% of the regional population). Data available in BIFAP include patient age, sex, lifestyle factors, clinical events, specialist referrals, prescriptions, and vaccinations as recorded by the primary care physician (PCP) or administering nurse. The study cohort comprised all girls aged 11-18 years registered in BIFAP between 1 January 2007 and 31 December 2013 who had at least 1 year of clinical record information with their PCP (inclusion criteria). The date the inclusion criteria were met was designated as the start date of the study cohort contribution. In order to estimate the incidence of HPV vaccination, girls forming the study cohort were followed from start date until there was a recorded HPV vaccination, they reached 19 years of age or died, the end of available information, or 31 December 2013. The person-time of all patients forming the study cohort was taken into account in the incidence estimations. The cumulative incidence (CuIn) of vaccination by birth cohort, year and region was estimated using life-tables (proportion of vaccination by intervals in which the denominator is the initial population corrected for losses). RESULTS: Out of 273,098 girls forming the study population, 81,461 were vaccinated during 2007-2013. Age ranged from 12 to 14 years at first dose in 86.0% of vaccinated girls; 54.1% received a quadrivalent vaccine, 21.9% a bivalent vaccine, and 24.0% an unknown type. Out of the vaccinated population, 87.9% received three doses, 8.2% two and 3.9% one dose, at a maximum of 7 years of follow-up. By calendar year and region, the CuIn reached 70.0-95.8% for birth cohorts between 1993 and 1999, 28.6-99.0% for births cohorts between 1990 and 1992, and exceptionally, 70.6-99.8% for births cohorts between 2000 and 2002 in three regions. CONCLUSIONS: According to BIFAP primary care data, a high incidence of vaccination among girls aged 13-15 years was observed. Vaccination among younger and older girls was less common although they reached high incidence in those regions that included girls aged 11-18 years in mass programs. Most vaccination patterns adjusted to a three-dose regimen, as recommended.

The recording of human papillomavirus (HPV) vaccination in BIFAP primary care database: A validation study.

PURPOSE: In Spain, a human papillomavirus (HPV) vaccine was firstly marketed in 2006 and mainly administered in primary care (PC) practices for girls/women or schools. As for all vaccines, a valid data source is required for research on observational effectiveness or safety. The objective of this study is to identify and validate HPV vaccinations recorded among women in The Primary Care Database For Pharmacoepidemiological Research (BIFAP) from 2007. METHODS: BIFAP includes a Vaccination File filled by PC practitionners and pediatricians. Information on women with HPV vaccinations recorded at any age was identified and validated according to whether (1) doses adhered to the following standard intervals: 27 to 269 days between first and second doses, >55 days between second and third doses, and <366 between first and third doses, and (2) additional information recorded in clinical records confirmed (through recording the brand, batch, expiring date, administration site, or vaccination comment) or refuted the vaccination and date. The latter was retrieved through manual review of anonymous records randomly selected. RESULTS: One hundred seventeen thousand seventy-three women with HPV vaccination records were identified (mean age 14.7 years); 82.5% had three jabs, 87.3% in recommended intervals. A sample of 978 patients' records, including 2245 jabs, was reviewed. Of the 363 jabs with additional information, 91% confirmed the vaccination. Confirmatory data was more frequent when doses strictly adhered to recommendations (96.8%-100%) than not (60.0%-85.7%). CONCLUSIONS: In BIFAP, a cohort of women vaccinated against HPV, mostly with three doses in recommended intervals, was identified. Although additional information about the vaccination was scarce, when present, it highly confirmed it, making BIFAP a potential data source for HPV vaccine research.

The impact of different strategies to handle missing data on both precision and bias in a drug safety study: a multidatabase multinational population-based cohort study.

BACKGROUND: Missing data are often an issue in electronic medical records (EMRs) research. However, there are many ways that people deal with missing data in drug safety studies. AIM: To compare the risk estimates resulting from different strategies for the handling of missing data in the study of venous thromboembolism (VTE) risk associated with antiosteoporotic medications (AOM). METHODS: New users of AOM (alendronic acid, other bisphosphonates, strontium ranelate, selective estrogen receptor modulators, teriparatide, or denosumab) aged ≥50 years during 1998-2014 were identified in two Spanish (the Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria [BIFAP] and EpiChron cohort) and one UK (Clinical Practice Research Datalink [CPRD]) EMR. Hazard ratios (HRs) according to AOM (with alendronic acid as reference) were calculated adjusting for VTE risk factors, body mass index (that was missing in 61% of patients included in the three databases), and smoking (that was missing in 23% of patients) in the year of AOM therapy initiation. HRs and standard errors obtained using cross-sectional multiple imputation (MI) (reference method) were compared to complete case (CC) analysis - using only patients with complete data - and longitudinal MI - adding to the cross-sectional MI model the body mass index/smoking values as recorded in the year before and after therapy initiation. RESULTS: Overall, 422/95,057 (0.4%), 19/12,688 (0.1%), and 2,051/161,202 (1.3%) VTE cases/participants were seen in BIFAP, EpiChron, and CPRD, respectively. HRs moved from 100.00% underestimation to 40.31% overestimation in CC compared with cross-sectional MI, while longitudinal MI methods provided similar risk estimates compared with cross-sectional MI. Precision for HR improved in cross-sectional MI versus CC by up to 160.28%, while longitudinal MI improved precision (compared with cross-sectional) only minimally (up to 0.80%). CONCLUSION: CC may substantially affect relative risk estimation in EMR-based drug safety studies, since missing data are not often completely at random. Little improvement was seen in these data in terms of power with the inclusion of longitudinal MI compared with cross-sectional MI. The strategy for handling missing data in drug safety studies can have a large impact on both risk estimates and precision.

Secular trends of use of anti-osteoporotic treatments in Spain: A population-based cohort study including over 1.5million people and more than 12years of follow-up.

OBJECTIVE: Different regulatory actions for anti-osteoporotic medication (AOM) were taken during the last years, including marketing of new drugs, safety warnings, or restrictions on the indications. We aimed to characterise the secular trends of AOM use in Spain from 2001 to 2013. METHODS: A cohort study using the Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP), was performed. BIFAP includes anonym records for 4million patients. Participants entered the study when aged ≥50years in 2001-2013 and after 1year of data available, and were followed to an AOM prescription (including alendronate, other bisphosphonates, SERM (selective estrogen receptor modulators), strontium ranelate, teriparatide or denosumab), death, lost or the end of December 2013. Prevalence (%) and incidence rate (IR/1000person-years (py)) of AOM users were computed by years and sex. RESULTS: Out of 1.5million participants, 135,410 received AOM treatment during 2001-2013. Prevalence was 6.1% (women) and 1.1% (men), that increased from 2001 (2.0%) to 2009 (7.6%) to decrease thereafter. Out of them, 95,057 were incident. The IR was 24.90 (women) and 2.77 (men), that increased from 2001 (21.25 and 1.96) to 2007 (35.84 and 3.64), and decreased to 12.48 and 1.81 (2013). IRs were highest for bisphosphonates along the years (ranging 3.70-14.73 and 0.57-1.75 in women and men respectively), followed by SERM up to 2005 (6.51-9.02 and 0.06-0.07), and strontium ranelate from 2006 (4.66 and 0.45) to 2012 (2.05 and 0.26). IR for teriparatide increased from marketing in 2004 (0.10-1.01 and 0.02-0.29), as was denosumab from marketing in 2011 (0.03-2.64 and 0.09-0.15). CONCLUSIONS: Population-based estimates of AOM use in Spain peaked in 2007-2009 and decreased thereafter, irrespective of age and sex. New treatments were ten times higher in women than men. Bisphosphonates were the most frequently prescribed class, followed by SERM in women before 2006, strontium otherwise till 2012, and denosumab in women or teriparatide in men in 2013. Changes in the osteoporosis criteria, fracture risk assessment strategies, and regulatory actions for AOM around the time, may explain that trend.

Cessation rate of anti-osteoporosis treatments and risk factors in Spanish primary care settings: a population-based cohort analysis.

Among 95,057 patients ≥50 years with new anti-osteoporosis medications (AOM) (2001-2013) in primary care, 1-year cessation was 51% (28%-68%), higher in men, smokers, patients with missing lifestyle data, and out normal BMI, and lower in those aged 60-79, with recent fractures or other anti-osteoporotics, suggesting non-severe osteoporosis and less risk awareness. PURPOSE: Low compliance to anti-osteoporosis medications (AOM) has been previously reported. We aimed to estimate 1-year cessation rates of different AOMs as used in Spanish healthcare settings, and to identify associated risk factors. METHODS: A cohort study was performed using primary care records data (BIFAP). Patients entered the cohort when aged 50 years in 2001-2013, with ≥1 year of data available, and identified as incident users of AOM (1-year washout). Participants were divided into six cohorts: alendronate, other oral bisphosphonates, selective oestrogen receptor modulators, strontium ranelate, teriparatide, and denosumab. Patients were followed from therapy initiation to the earliest of cessation (90-day refill gap), switching (to alternative AOM), loss to follow-up, death, or end of 2013. One-year therapy cessation was estimated using life tables. Hazard ratios (of cessation) according to age, sex, lifestyle factors, morbidity, and co-medication were estimated after stepwise backwards selection. RESULTS: A total of 95,057 AOM users were identified (91% women; mean age 68). One-year cessation was 51% overall, highest for strontium ranelate (68%), and lowest for denosumab (28%). Cessation probability was higher in men (14% to 2.1-fold), smokers (>6%), and patients with missing BMI (19-28%) or smoking (6-20%) data, and overweight/obese/underweight (7% to 2.6-fold increase compared to normal weight). Patients aged 60-79 years, with a recent fracture or other drugs used for osteoporosis, had better persistence. CONCLUSIONS: Over half of the patients initiating AOM stopped therapy within the first year after initiation. The described risk factors for cessation could be proxies for non-severe osteoporosis, and/or disease/risk awareness, which could inform the targeting of high-risk patients for monitoring and/or interventions aimed at improving persistence.

The reporting and diagnosis of uterine fibroids in the UK: an observational study.

BACKGROUND: Uterine fibroids (UFs) are the most common benign tumour in women, and many undergo hysterectomy or uterus-preserving procedures (UPPs) to manage their symptoms. We aimed to validate the recording of UFs in a primary care database, The Health Improvement Network (THIN), and to determine the incidence of UFs in the UK. METHODS: In this observational study, women in THIN aged 15-54 years between January 2000 and December 2009 with no previous record of UFs, hysterectomy or UPPs were identified. Individuals were followed up until there was a Read code indicating UFs, they reached 55 years of age or died, or the study ended. Among those without a UF code, women were identified with a code for hysterectomy, UPPs or heavy menstrual bleeding (HMB). Anonymized patient profiles from each category were randomly selected and reviewed. Subsequently, primary care physicians were asked to complete questionnaires to verify the diagnosis for a randomly selected subgroup. RESULTS: In total, 737,638 women were identified who met the initial inclusion criteria. The numbers of women with a code for UFs, hysterectomy, UPPs and HMB were 9380, 11,002, 3220 and 60,915, respectively; the proportions of confirmed cases of UFs were 88.8, 29.7, 57.7 and 15.9 %. The estimated number of women with UFs was 23,140 (64.0 % without a recorded UF diagnosis). The overall incidence of UFs was 5.8 per 1000 woman-years. CONCLUSIONS: UFs were confirmed in a high proportion of women with UF Read codes. However, almost two-thirds of cases were identified among women with a code for hysterectomy, UPPs or HMB. These results show that UFs are under-recorded in UK primary care, and suggest that primary care physicians tend to code the symptoms of UFs more often than the diagnosis.

Risk factors for diabetic retinopathy in people with Type 2 diabetes: A case-control study in a UK primary care setting.

AIM: To identify risk factors of diabetic retinopathy (DR) among people with Type 2 diabetes mellitus in UK primary care. METHODS: A case-control study nested in a cohort of incident Type 2 diabetes identified in The Health Improvement Network database from 2000 to 2007. Cases were people with DR (N=7735) and controls were a DR-free sample (N=9395). No age restrictions were applied. Adjusted odds ratios and 95% CIs were estimated. RESULTS: 21% of DR cases were identified during the first semester after Type 2 diabetes diagnosis. After controlling for delay on the Type 2 diabetes diagnosis, the DR risk increased with the duration of diabetes. DR increased with a mean systolic BP ≥150mmHg (1.18; 1.10-1.27), high alcohol consumption (1.34; 1.11-1.61), glycated haemoglobin (≥75 to <86: 1.14; 1.00-1.31; ≥86 to <97mmol/mol: 1.25; 1.07-1.45; ≥97mmol/mol: 1.21; 1.07-1.37), microalbuminuria (1.16; 1.06-1.27), and retinal vein occlusion (2.47; 1.67-3.66). Glaucoma and retinal arterial occlusion showed an OR of 0.71 (0.60-0.84) and 0.63 (0.40-1.01), respectively. HDL ≥1.55mmol/l (0.88; 0.80-0.98), high triglycerides (2.3-5.6mmol/l: 0.90; 0.82-0.99; >5.6mmol/l: 0.85; 0.64-1.13) or smoking (0.89; 0.81-0.97) had a slightly reduced DR risk. Users of hypoglycaemic agents had an increased DR risk. CONCLUSION: Some DR cases were identified near the diabetes diagnosis date suggesting that a delayed diabetes diagnosis is still common. Glaucoma, retinal arterial occlusion and high HDL levels were inversely associated with DR, while retinal vein occlusion, alcohol and other well-known risk factors were positively associated.

The incidence of hysterectomy, uterus-preserving procedures and recurrent treatment in the management of uterine fibroids.

OBJECTIVE: To determine the incidence of hysterectomy and uterus-preserving procedures (UPPs) among women with uterine fibroids (UFs) and the incidence of further procedures after a UPP. STUDY DESIGN: This was an observational study using a primary care database, The Health Improvement Network (THIN). Women in THIN with UFs aged 15-54 years between January 2000 and December 2009 were eligible for study. The UPPs examined were myomectomy, endometrial ablation (EA) and uterine artery embolization (UAE). Using Read codes, women were followed up until one of the following was met: there was a record of hysterectomy or UPPs, they died or the study ended (end of 2010). RESULTS: The cumulative incidence of hysterectomy or UPPs was 23.6% at 1 year, and 40.9% after the follow-up period (median 3.6 years). At the end of the follow-up period, the cumulative incidences of hysterectomy, myomectomy, EA and UAE were 33.0%, 3.9%, 6.4% and 1.9%, respectively. For women initially treated with a UPP, the cumulative incidence of second procedures was 11.5% at 1 year. At the end of the follow-up period (median 2.7 years), the cumulative incidence of further procedures was 26.1%, and the cumulative incidences of women undergoing hysterectomy, myomectomy, EA and UAE were 19.0%, 4.3%, 3.4% and 1.4%, respectively. CONCLUSIONS: Women considering UPPs for the management of UFs should be made aware that the incidence of further treatments is high, with hysterectomy being the most frequent procedure undergone.

Androgen deprivation therapy and the risk of coronary heart disease and heart failure in patients with prostate cancer: a nested case-control study in UK primary care.

BACKGROUND: Androgen deprivation therapy (ADT) is used to delay tumour development and improve survival in patients with prostate cancer. However, several randomized controlled trials and observational studies have suggested that ADT may increase the risk of cardiovascular events. OBJECTIVE: The aim of the study was to evaluate the risk of coronary heart disease (CHD) and heart failure (HF) in patients with prostate cancer receiving ADT in UK primary care, and to evaluate the risks associated with individual ADT and combination ADT. METHODS: The UK General Practice Research Database was used to identify a cohort of patients with a first prostate cancer diagnosis during 1999-2005. These patients were followed up to assess the occurrence of acute myocardial infarction (AMI), death from CHD, incident HF and hospitalization due to acute decompensated HF. Nested case-control analyses were performed to assess the risk of these outcomes associated with anti-androgen therapy, as well as different types of ADT and combinations of ADT. RESULTS: Current anti-androgen use was associated with a significant increase in the risk of hospitalization due to HF (odds ratio [OR] 2.15; 95% CI 1.08, 4.29), but not of incident HF, CHD or AMI. When assessed individually, there was no significant association of bicalutamide or cyproterone use with the risk of AMI or CHD. Current use of bicalutamide 50 mg/day was associated with a significant increase in the risk of HF (OR 3.28; 95% CI 1.31, 8.18); however, this increased risk of HF was only found in patients taking bicalutamide 50 mg/day in combination with luteinizing hormone-releasing hormone (LHRH) receptor agonists. There were no cases of hospitalized HF in patients taking bicalutamide 50 mg/day as monotherapy and there was no significant association between current use of bicalutamide 150 mg/day and the risk of hospitalized HF. Combination therapy with LHRH agonists and anti-androgens was associated with a significant increase in the risk of CHD (OR 4.35; 95% CI 1.94, 9.75), AMI (OR 3.57; 95% CI 1.44, 8.86), incident HF (OR 3.19; 95% CI 1.10, 9.27) and hospitalized HF (OR 3.39; 95% CI 1.07, 10.70) compared with non-use of these drugs. CONCLUSIONS: In men with prostate cancer, combination therapy with LHRH agonists and anti-androgens is associated with significant increases in the risk of CHD, AMI, incident HF and hospitalized HF. Individual therapies do not appear to increase the risk of these outcomes.

Hospitalised ischaemic cerebrovascular accident and risk factors in a primary care database.

PURPOSE: Ischaemic cerebrovascular accident (ICVA) is a common cause of morbidity and mortality. Identification of risk factors can reduce its incidence. We aim to estimate the incidence rate (IR) of hospitalised ICVA in the general population by sex and quantify its risk associated with several factors. METHODS: We followed up 907, 001 individuals aged 40-84 years during a mean of 3.63 years to ascertain the first episode of hospitalised ICVA between 2000 and 2004 using a UK primary care database. We evaluated the risk factors for ICVA through unconditional logistic regression (OR) with a nested case-control analysis, using 2953 incident cases and 10, 000 random controls frequency-matched by age, sex and year. RESULTS: The IR of hospitalised ICVA was 1.94 (95%CI: 1.87-2.01) per 1000 person-years in men and 1.59 (95%CI: 1.53-1.65) in women. The IR ratio adjusted by age was 1.35 (95%CI: 1.28-1.43). Major risk factors for the first ICVA were atrial fibrillation (AF) (OR of 1.96 (95%CI: 1.59-2.42) for men and 3.54 (95%CI: 2.85-4.39) for women), smoking, epilepsy and hypertension. AF patients on anticoagulant therapy presented a reduced risk of ICVA (OR: 0.39; 95%CI: 0.27-0.56) in both sexes. Hypertensive women that discontinued the treatment had an increased risk (OR: 2.53; 95%CI: 1.63-3.91). CONCLUSIONS: Men had higher incidence of hospitalised ICVA than women. AF was the major risk factor for ICVA (more in women than men), followed by smoking. Among AF patients, those under anticoagulant therapy showed a significant reduced risk of first ICVA. Antihypertensive drug discontinuation increased the risk of ICVA among women.