Applying two approaches to detect unmeasured confounding due to time-varying variables in a self-controlled risk interval design evaluating COVID-19 vaccine safety signals, using myocarditis as a case example.

We test the robustness of the self-controlled risk interval (SCRI) design in a setting where time between doses may introduce time-varying confounding, using both negative control outcomes (NCOs) and quantitative bias analysis (QBA). All vaccinated cases identified from 5 European databases between 1 September 2020 and end of data availability were included. Exposures were doses 1-3 of the Pfizer, Moderna, AstraZeneca, and Janssen COVID-19 vaccines; outcomes were myocarditis and otitis externa (NCO). The SCRI used a 60-day control window and dose-specific 28-day risk windows, stratified by vaccine brand and adjusted for calendar time. The QBA included two scenarios: (i) baseline probability of the confounder was higher in the control window and (ii) vice versa. The NCO was not associated with any of the COVID-19 vaccine types or doses except Moderna dose 1 (IRR = 1.09, 95%CI 1.01-1.09). The QBA suggested even the strongest literature-reported confounder (COVID-19; RRmyocarditis = 18.3) could only explain away part of the observed effect from IRR = 3 to IRR = 1.40. The SCRI seems robust to unmeasured confounding in the COVID-19 setting, although a strong unmeasured confounder could bias the observed effect upward. Replication of our findings for other safety signals would strengthen this conclusion.

Effect of tramadol and DOACs with special attention to dabigatran on concomitant use, on the risk of mayor bleeding using BIFAP database in Spain.

BACKGROUND: Tramadol, a weak opioid, inhibits the reuptake of serotonin, a key feature on vascular homeostasis. A suspected interaction exists between dabigatran and tramadol, which might trigger an excess on risk of bleeding however, there is a gap in knowledge on this topic. PURPOSE: To estimate the effects of tramadol, dabigatran and concomitant use on the risk of hospitalized major bleeds (Gastrointestinal bleeding and intra-extracranial bleeds). METHODS: Among a validated established cohort of new users of oral anticoagulants for non-valvular atrial fibrillation (NVAF) aged 18 years or older, we identified all hospitalized bleed episodes (GIB and extra/intracranial bleeds) within 2008-2015. A nested case-control analysis was conducted using conditional logistic regression. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated for dabigatran, tramadol, and concomitant use. Several sensitivity analyses were carried out. RESULTS: aORs (95%CIs) for current use of only dabigatran, only tramadol and concomitant users were 1.73 (1.37-2.18) and 1.38 (1.13-1.67) and 2.04 (0.74-5.67) compared with non-users of both drugs (>365 days). aORs for current continuers and non-continuer users of dabigatran were 1.36 (1.00-1.86) and 2.19 (1.61-2.98), respectively. For the latter, non-continuer users with a short duration of dabigatran cumulated the highest risk (3.36 [1.88-5.99]). There also was an increased risk with concomitant use of tramadol and rivaroxaban (2.24 [1.19-4.21]), or antagonist of vitamin K (1.30 [1.00-1.69]). CONCLUSION: There was a trend towards and increased risk of excess bleeds when using concomitantly with dabigatran. The effect decreases with a narrower definition of current use.

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

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

Comparing risk of major bleeding between users of different oral anticoagulants in patients with nonvalvular atrial fibrillation.

AIMS: The introduction of direct oral anticoagulants (DOACs) has broadened the treatment arsenal for nonvalvular atrial fibrillation, but observational studies on the benefit-risk balance of DOACs compared to vitamin K antagonists (VKAs) are needed. The aim of this study was to characterize the risk of major bleeding in DOAC users using longitudinal data collected from electronic health care databases from 4 different EU-countries analysed with a common study protocol. METHODS: A cohort study was conducted among new users (≥18 years) of DOACs or VKAs with nonvalvular atrial fibrillation using data from the UK, Spain, Germany and Denmark. The incidence of major bleeding events (overall and by bleeding site) was compared between current use of DOACs and VKAs. Cox regression analysis was used to calculate hazard ratios and 95% confidence intervals (CI) and adjust for confounders. RESULTS/CONCLUSION: Overall, 251 719 patients were included across the 4 study cohorts (mean age ~75 years, % females between 41.3 and 54.3%), with overall hazard ratios of major bleeding risk for DOACs vs VKAs ranging between 0.84 (95% CI: 0.79-0.90) in Denmark and 1.13 (95% CI 1.02-1.25) in the UK. When stratifying according to the bleeding site, risk of gastrointestinal bleeding was increased by 48-67% in dabigatran users and 30-50% for rivaroxaban users compared to VKA users in all data sources except Denmark. Compared to VKAs, apixaban was not associated with an increased risk of gastrointestinal bleeding in all data sources and seemed to be associated with the lowest risk of major bleeding events compared to dabigatran and rivaroxaban.

A strategy for assessment and validation of major bleeding cases in a primary health care database in Spain.

PURPOSE: This study aims to validate major bleeding (MB) cases within a cohort of new users of direct oral anticoagulants (DOACs) in Electronic health records (EHRs) from primary care in Spain (BIFAP), introducing more efficient techniques and automating the process of validation in the pharmacoepidemiologic research with EHR data as much as possible. METHODS: Registered bleedings were identified in a cohort of new users of DOACs in BIFAP using ICPC 2 and ICD 9 codes; we ascertained these bleedings as MB through a validation strategy based on the MB definition from the International Society on Thrombosis and Hemostasis, which used hospitalization and critical localization as proxies. We assessed hospitalization with hospital discharge information (only available for some years and regions) and a free text-based algorithm created to identify hospitalization in EHR's clinical notes. Incidence rates (IR) of MB were evaluated by bleeding type. RESULTS: The study cohort included 104 614 patients, with 274521.5 p-y of follow up. There were 6143 registered bleedings during the study period (519 intracranial bleeding - ICB, 4606 gastrointestinal bleeding - GIB, 1018 extracranial bleeding - ECB), from which 1679 were confirmed as MB (416 ICB, 1086 GIB, and 177 ECB). The free text-based semi-automatic algorithm had moderate recall (0.59), but high specificity (0.99), and precision (0.94). CONCLUSION: The combination of hospitalization and critical localization is a valid approach to validate MB in EHRs with incomplete information. The use of more automatic methods for case validation instead of manual review of clinical notes is favored.

Use of hydrochlorothiazide and risk of skin cancer in a large nested case-control study in Spain.

PURPOSE: Hydrochlorothiazide (HCTZ) use has been linked to skin cancer in northern European countries. We assessed the association between HCTZ exposure and risk of malignant melanoma (MM) and keratinocyte carcinoma (KC) in a European Mediterranean population. METHODS: Two parallel nested case-control studies were conducted in Spain using two electronic primary healthcare databases, each one providing data on both exposure and outcomes: SIDIAP and BIFAP. Cancer cases were matched to 10 controls by age and gender through risk-set sampling. The ORs and 95% CI for MM and KC associated with previous HCTZ use were estimated using conditional logistic regression. In BIFAP, KC cases were further identified as basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). RESULTS: In adjusted analyses, both ever and cumulative high (≥50,000 mg) use of HCTZ were associated with an increased risk of KC. The risk estimates for high use were 1.30 (1.26-1.34) in SIDIAP and 1.20 (1.12-1.30) in BIFAP, with a lower risk for BCC (1.11 [1.02-1.21]) than for SCC (1.71 [1.45-2.02]). A dose-response relationship was observed between cumulative doses of HCTZ and KC risk. Inconsistent results were found for high use of HCTZ and risk of MM: 1.25 (1.09-1.43) in SIDIAP and 0.85 (0.64-1.13) in BIFAP. CONCLUSIONS: In this European Mediterranean population, a high cumulative use of HCTZ was related to an increased risk of KC with a clear dose-response pattern.

Major bleeding in users of direct oral anticoagulants in atrial fibrillation: A pooled analysis of results from multiple population-based cohort studies.

OBJECTIVE: To establish the risk of major bleeding in direct oral anticoagulant (DOAC) users (overall and by class) versus vitamin K antagonist (VKA) users, using health care databases from four European countries and six provinces in Canada. METHODS: A retrospective cohort study was performed according to a similar protocol. First-users of VKAs or DOACs with a diagnosis of non-valvular atrial fibrillation (NVAF) were included. The main outcome of interest was major bleeding and secondary outcomes included gastrointestinal (GI) bleeding and intracranial haemorrhage (ICH). Incidence rates of events per 1000 person years were calculated. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox proportional hazard regression model. Exposure and confounders were measured and analysed in a time-dependant way. Risk estimates were pooled using a random effect model. RESULTS: 421 523 patients were included. The risk of major bleeding for the group of DOACs compared to VKAs showed a pooled HR of 0.94 (95% CI: 0.87-1.02). Rivaroxaban showed a modestly increased risk (HR 1.11, 95% CI: 1.06-1.16). Apixaban and dabigatran showed a decreased risk of respectively HR 0.76 (95% CI: 0.69-0.84) and HR 0.85 (95% CI: 0.75-0.96). CONCLUSIONS: This study confirms that the risk of major bleeding of DOACs compared to VKAs is not increased when combining all DOACs. However, we observed a modest higher risk of major bleeding for rivaroxaban, whereas for apixaban and dabigatran lower risks of major bleeding were observed compared to VKAs.

Impact of pre-exposure time bias in self-controlled case series when the event conditions the exposure: Hip/femur fracture and use of benzodiazepines as a case study.

BACKGROUND: In self-controlled case series (SCCS), the event should not condition the probability of subsequent exposure. If this assumption is not met, an important bias could take place. The association of hip/femur fracture (HFF) and use of benzodiazepines (BDZ) has a bidirectional causal relationship and can serve as case study to investigate the impact of this methodological issue. OBJECTIVES: To assess the magnitude of bias introduced in a SCCS when HFF conditions the posterior exposure to BDZ and explore ways to correct it. METHODS: Four thousand four hundred fifty cases of HFF who had at least one BZD prescription were selected from the primary care health record database BIFAP. Exposure to BZD was divided into non-use, current, recent, and past use. Conditional Poisson regression was used to estimate incidence rate ratios (IRRs) of HFF among current vs non-use/past, adjusted for age. To investigate possible event-exposure dependence, a pre-exposure time of different lengths (15, 30, and 60 days) was excluded from the reference category to evaluate the IRR. RESULTS: IRR of HHF for current use was 0.79 (0.72-0.86); removing 30 days, IRR was 1.43 (1.31-1.57). Removing 15 days, IRR was 1.29 (1.18-1.41), and removing 60 days, IRR was 1.56 (1.42-1.72). A pre-exposure period up to 182 days was necessary to remove such effect giving an IRR of 1.64 (1.48-1.81). CONCLUSIONS: HFF remarkably conditioned the use of BDZs resulting in seriously biased IRRs when this association was studied through a SCCS design. The use of pre-exposure periods of different lengths helped to correct this error.

An algorithm to identify pregnancies in BIFAP Primary Care database in Spain: Results from a cohort of 155 419 pregnancies.

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.

Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP): A data resource for pharmacoepidemiology in Spain.

PURPOSE: Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) is a population based database administered by the AEMPS (Spanish Agency for Medicines) of longitudinal electronic medical records (EMR) of patients attended in primary care. Its main purpose is to serve as source of information for independent studies on drug safety and support of medicines regulation activities. This article aim is to describe the characteristics of BIFAP, how to access the database and a summary of its potential for research. METHODS: Health problems are registered by primary care physicians as episodes of care and include socio-demographic data, results of diagnostic procedures, lifestyle data, general data, and interventions. A proportion of data on hospitalizations and specialist care are currently available through linkage with other data sources. EMRs of the Spanish healthcare system are provided by the regional administrations. Specific data extraction and standardization processes are performed. RESULTS: BIFAP includes data from 12 million patients starting in 2001 and updated annually. Validation of drug and diagnosis definitions has been ascertained. Participation in international collaborative projects and a number of articles in peer reviewed journals reflect its contribution to the knowledge of the risks associated with medicines and drug utilization patterns. CONCLUSIONS: BIFAP is a useful tool for generating scientific evidence on medicines related issues, helping regulatory decision making in Europe. The main strengths of BIFAP are related to large sample size, population-based, longitudinal nature and annual update of data. BIFAP shares common challenges with similar data sources including accurate and efficient identification of health outcomes and of treatment exposure.

Incidence of direct oral anticoagulant use in patients with nonvalvular atrial fibrillation and characteristics of users in 6 European countries (2008-2015): A cross-national drug utilization study.

AIMS: To estimate the incidence of direct oral anticoagulant drug (DOAC) use in patients with nonvalvular atrial fibrillation and to describe user and treatment characteristics in 8 European healthcare databases representing 6 European countries. METHODS: Longitudinal drug utilization study from January 2008 to December 2015. A common protocol approach was applied. Annual period incidences and direct standardisation by age and sex were performed. Dose adjustment related to change in age and by renal function as well as concomitant use of potentially interacting drugs were assessed. RESULTS: A total of 186 405 new DOAC users (age ≥18 years) were identified. Standardized incidences varied from 1.93-2.60 and 0.11-8.71 users/10 000 (2011-2015) for dabigatran and rivaroxaban, respectively, and from 0.01-8.12 users/10 000 (2012-2015) for apixaban. In 2015, the DOAC incidence ranged from 9 to 28/10 000 inhabitants in SIDIAP (Spain) and DNR (Denmark) respectively. There were differences in population coverage among the databases. Only 1 database includes the total reference population (DNR) while others are considered a population representative sample (CPRD, BIFAP, SIDIAP, EGB, Mondriaan). They also varied in the type of drug data source (administrative, clinical). Dose adjustment ranged from 4.6% in BIFAP (Spain) to 15.6% in EGB (France). Concomitant use of interacting drugs varied between 16.4% (SIDIAP) and 70.5% (EGB). Cardiovascular comorbidities ranged from 25.4% in Mondriaan (The Netherlands) to 82.9% in AOK Nordwest (Germany). CONCLUSION: Overall, apixaban and rivaroxaban increased its use during the study period while dabigatran decreased. There was variability in patient characteristics such as comorbidities, potentially interacting drugs and dose adjustment. (EMA/2015/27/PH).

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.

Risk of acute liver injury associated with use of antibiotics. Comparative cohort and nested case-control studies using two primary care databases in Europe.

PURPOSE: To assess the impact of varying study designs, exposure and outcome definitions on the risk of acute liver injury (ALI) associated with antibiotic use. METHODS: The source population comprised of patients registered in two primary care databases, in the UK and in Spain. We identified a cohort consisting of new users of antibiotics during the study period (2004-2009) and non-users during the study period or in the previous year. Cases with ALI were identified within this cohort and classified as definite or probable, based on recorded medical information. The relative risk (RR) of ALI associated with antibiotic use was computed using Poisson regression. For the nested case-control analyses, up to five controls were matched to each case by age, sex, date and practice (in CPRD) and odds ratios (OR) were computed with conditional logistic regression. RESULTS: The age, sex and year adjusted RRs of definite ALI in the current antibiotic use periods was 10.04 (95% CI: 6.97-14.47) in CPRD and 5.76 (95% CI: 3.46-9.59) in BIFAP. In the case-control analyses adjusting for life-style, comorbidities and use of medications, the OR of ALI for current users of antibiotics was and 5.7 (95% CI: 3.46-9.36) in CPRD and 2.6 (95% CI: 1.26-5.37) in BIFAP. CONCLUSION: Guided by a common protocol, both cohort and case-control study designs found an increased risk of ALI associated with the use of antibiotics in both databases, independent of the exposure and case definitions used. However, the magnitude of the risk was higher in CPRD compared to BIFAP.

Methodological comparison of marginal structural model, time-varying Cox regression, and propensity score methods: the example of antidepressant use and the risk of hip fracture.

BACKGROUND: Observational studies including time-varying treatments are prone to confounding. We compared time-varying Cox regression analysis, propensity score (PS) methods, and marginal structural models (MSMs) in a study of antidepressant [selective serotonin reuptake inhibitors (SSRIs)] use and the risk of hip fracture. METHODS: A cohort of patients with a first prescription for antidepressants (SSRI or tricyclic antidepressants) was extracted from the Dutch Mondriaan and Spanish Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) general practice databases for the period 2001-2009. The net (total) effect of SSRI versus no SSRI on the risk of hip fracture was estimated using time-varying Cox regression, stratification and covariate adjustment using the PS, and MSM. In MSM, censoring was accounted for by inverse probability of censoring weights. RESULTS: The crude hazard ratio (HR) of SSRI use versus no SSRI use on hip fracture was 1.75 (95%CI: 1.12, 2.72) in Mondriaan and 2.09 (1.89, 2.32) in BIFAP. After confounding adjustment using time-varying Cox regression, stratification, and covariate adjustment using the PS, HRs increased in Mondriaan [2.59 (1.63, 4.12), 2.64 (1.63, 4.25), and 2.82 (1.63, 4.25), respectively] and decreased in BIFAP [1.56 (1.40, 1.73), 1.54 (1.39, 1.71), and 1.61 (1.45, 1.78), respectively]. MSMs with stabilized weights yielded HR 2.15 (1.30, 3.55) in Mondriaan and 1.63 (1.28, 2.07) in BIFAP when accounting for censoring and 2.13 (1.32, 3.45) in Mondriaan and 1.66 (1.30, 2.12) in BIFAP without accounting for censoring. CONCLUSIONS: In this empirical study, differences between the different methods to control for time-dependent confounding were small. The observed differences in treatment effect estimates between the databases are likely attributable to different confounding information in the datasets, illustrating that adequate information on (time-varying) confounding is crucial to prevent bias.

Do case-only designs yield consistent results across design and different databases? A case study of hip fractures and benzodiazepines.

BACKGROUND: The case-crossover (CXO) and self-controlled case series (SCCS) designs are increasingly used in pharmacoepidemiology. In both, relative risk estimates are obtained within persons, implicitly controlling for time-fixed confounding variables. OBJECTIVES: To examine the consistency of relative risk estimates of hip/femur fractures (HFF) associated with the use of benzodiazepines (BZD) across case-only designs in two databases (DBs), when a common protocol was applied. METHODS: CXO and SCCS studies were conducted in BIFAP (Spain) and CPRD (UK). Exposure to BZD was divided into non-use, current, recent and past use. For CXO, odds ratios (OR; 95%CI) of current use versus non-use/past were estimated using conditional logistic regression adjusted for co-medications (AOR). For the SCCS, conditional Poisson regression was used to estimate incidence rate ratios (IRR; 95%CI) of current use versus non/past-use, adjusted for age. To investigate possible event-exposure dependence the relative risk in the 30 days prior to first BZD exposure was also evaluated. RESULTS: In the CXO current use of BZD was associated with an increased risk of HFF in both DBs, AORBIFAP = 1.47 (1.29-1.67) and AORCPRD = 1.55 (1.41-1.70). In the SCCS, IRRs for current exposure was 0.79 (0.72-0.86) in BIFAP and 1.21 (1.13-1.30) in CPRD. However, when we considered separately the 30-day pre-exposure period, the IRR for current period was 1.43 (1.31-1.57) in BIFAP and 1.37 (1.27-1.47) in CPRD. CONCLUSIONS: CXO designs yielded consistent results across DBs, while initial SCCS analyses did not. Accounting for event-exposure dependence, estimates derived from SCCS were more consistent across DBs and designs.

Case-only designs for studying the association of antidepressants and hip or femur fracture.

PURPOSE: The purpose of this study is to evaluate the performance and validity of the case-crossover (CCO) and self-controlled case-series (SCCS) designs when studying the association between hip/femur fracture (HF) and antidepressant (AD) use in general practitioner databases. In addition, comparability with cohort and case-control designs is discussed. METHODS: Adult patients with HF and who received an AD prescription during 2001-2009 were identified from UK's The Health Improvement Network (THIN) and the Dutch Mondriaan databases. AD exposure was classified into current, recent and past/non-use (reference). In the CCO, for each patient, a case moment (date of HF) and four prior control moments at -91, -182, -273 and -365 days were defined. In SCCS, incidence of HF was compared between exposure states. Conditional logistic regression was used in the CCO and Poisson regression in the SCCS to compute odds ratios and incidence rate ratios, respectively. In CCO, we adjusted for time-varying co-medication and in SCCS for age. RESULTS: Adjusted estimates for the effect of current AD exposure on HF were higher in the CCO (co-medication-adjusted odds ratio, THIN: 2.24, 95% confidence interval [CI]: 2.04-2.47; Mondriaan: 2.57, 95%CI [1.50, 4.43]) than in the SCCS (age-adjusted incidence rate ratio, THIN: 1.41, 95%CI [1.32, 1.49]; Mondriaan: 2.14, 95%CI [1.51, 3.03]). The latter were comparable with the traditional designs. CONCLUSION: Case-only designs confirmed the association between AD and HF. The CCO design violated assumptions in this study with regard to exchangeability and length of exposure, and transient effects on outcome. The SCCS seems to be an appropriate design for assessing AD-HF association.

Prevalence of antibiotic use: a comparison across various European health care data sources.

PURPOSE: There is widespread concern about increases in antibiotic use, but comparative data from different European countries on rates of use are lacking. This study was designed to measure and understand the variation in antibiotic utilization across five European countries. METHODS: Seven European healthcare databases with access to primary care data from Denmark, Germany, the Netherlands, Spain and the UK were used to measure and compare the point and 1-year-period prevalence of antibiotic use between 2004 and 2009. Descriptive analyses were stratified by gender, age and type of antibiotic. Separate analyses were performed to measure the most common underlying indications leading to the prescription of an antibiotic. RESULTS: The average yearly period prevalence of antibiotic use varied from 15 (Netherlands) to 30 (Spain) users per 100 patients. A higher prevalence of antibiotic use by female patients, the very young (0-9 years) and old (80+ years), was observed in all databases. The lowest point prevalence was recorded in June and September and ranged from 0.51 (Netherlands) to 1.47 (UK) per 100 patients per day. Twelve percent (Netherlands) to forty-nine (Spain) percent of all users were diagnosed with a respiratory tract infection, and the most common type of antibiotic prescribed were penicillin. CONCLUSION: Using identical methodology in seven EU databases to assess antibiotic use allowed us to compare drug usage patterns across Europe. Our results contribute quantitatively to the true understanding of similarities and differences in the use of antibiotic agents in different EU countries.

Hip/femur fractures associated with the use of benzodiazepines (anxiolytics, hypnotics and related drugs): a methodological approach to assess consistencies across databases from the PROTECT-EU project.

BACKGROUND: Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. OBJECTIVES: The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. METHODS: To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. RESULTS: Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. CONCLUSIONS: Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs.

Understanding inconsistency in the results from observational pharmacoepidemiological studies: the case of antidepressant use and risk of hip/femur fractures.

PURPOSE: Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs. METHODS: Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture. A common protocol and statistical analysis plan was applied to harmonize study design and conduct between data sources. RESULTS: Current use of antidepressants was consistently associated with a 1.5 to 2.5-fold increased risk of hip/femur fractures in all data sources with both designs, with estimates for SSRIs generally higher than those for TCAs. In general, risk estimates in Mondriaan, the smallest data source, were higher compared to the other data sources. This difference may be partially explained by an interaction between SSRI and age in Mondriaan. Adjustment for GP-recorded lifestyle factors and matching on general practice had negligible impact on adjusted relative risk estimates. CONCLUSION: We found a consistent increased risk of hip/femur fracture with current use of antidepressants across different databases and different designs. Applying similar pharmacoepidemiological study methods resulted in similar risks for TCA use and some variation for SSRI use. Some of these differences may express real (or natural) variance in the exposure-outcome co-occurrences.

Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project.

PURPOSE: Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. METHODS: Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. RESULTS: Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10,000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. CONCLUSION: Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences.