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Introduction The public–private ADVANCE collaboration developed and tested a system to generate evidence on vaccine benefits and risks using European electronic healthcare databases. In the safety of vaccines, background incidence rates are key to allow proper monitoring and assessment. The goals of this study were to compute age-, sex-, and calendar-year stratified incidence rates of nine autoimmune diseases in seven European healthcare databases from four countries and to assess validity by comparing with published data. Methods Event rates were calculated for the following outcomes: acute disseminated encephalomyelitis, Bell’s palsy, Guillain–Barré syndrome, immune thrombocytopenia purpura, Kawasaki disease, optic neuritis, narcolepsy, systemic lupus erythematosus, and transverse myelitis. Cases were identified by diagnosis codes. Participating organizations/databases originated from Denmark, Italy, Spain, and the UK. The source population comprised all persons registered, with at least 1 year of data prior to the study start, or follow-up from birth. Stratified incidence rates were computed per database over the period 2003 to 2014. Results Between 2003 and 2014, 148,947 incident cases of nine autoimmune diseases were identified. Crude incidence rates were highest for Bell’s palsy [23.8/100,000 person-years (PYs), 95% confidence interval (CI) 23.6–24.1] and lowest for Kawasaki disease (0.7/100,000 PYs, 95% CI 0.6–0.7). Specific patterns were observed by sex, age, calendar time, and data sources. Rates were comparable with published estimates. Conclusion A range of autoimmune events could be identified in the ADVANCE system. Estimation of rates indicated consistency across selected European healthcare databases, as well as consistency with US published data. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-020-01031-1.

Introduction: The Accelerated Development of Vaccine benefit-risk Collaboration in Europe (ADVANCE) public-private collaboration, aimed to develop and test a system for rapid benefit-risk monitoring of vaccines using healthcare databases in Europe. The objective of this proof-of-concept (POC) study was to test the feasibility of the ADVANCE system to generate incidence rates (IRs) per 1000 person-years and incidence rate ratios (IRRs) for risks associated with whole cell- (wP) and acellular- (aP) pertussis vaccines, occurring in event-specific risk windows in children prior to their pre-school-entry booster. Methods: The study population comprised almost 5.1 million children aged 1 month to

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 (B/R) monitoring of vaccines using electronic health record (eHR) databases in Europe. Proof-of-concept studies were designed to assess the proposed processes and system for generating the required evidence to perform B/R assessment and near-real time monitoring of vaccines. We aimed to test B/R methodologies for vaccines, using the comparison of the B/R profiles of whole-cell (wP) and acellular pertussis (aP) vaccine formulations in children as an example. Methods: We used multi-criteria decision analysis (MCDA) to structure the B/R assessment combined with individual-level state transition modelling to build the B/R effects table. In the state transition model, we simulated the number of events in two hypothetical cohorts of 1 million children followed from first pertussis dose till pre-school-entry booster (or six years of age, whichever occurred first), with one cohort receiving wP, and the other aP. The benefits were reductions in pertussis incidence and complications. The risks were increased incidences of febrile convulsions, fever, hypotonic-hyporesponsive episodes, injection-site reactions and persistent crying. Most model parameters were informed by estimates (coverage, background incidences, relative risks) from eHR databases from Denmark (SSI), Spain (BIFAP and SIDIAP), Italy (Pedianet) and the UK (RCGP-RSC and THIN). Preferences were elicited from clinical and epidemiological experts. Results: Using state transition modelling to build the B/R effects table facilitated the comparison of different vaccine effects (e.g. immediate vaccine risks vs long-term vaccine benefits). Estimates from eHR databases could be used to inform the simulation model. The model results could be easily combined with preference weights to obtain B/R scores. Conclusion: Existing B/R methodology, modelling and estimates from eHR databases can be successfully used for B/R assessment of vaccines.

The Accelerated Development of VAccine benefit-risk Collaboration in Europe (ADVANCE), a public-private consortium, implemented and tested a distributed network system for the generation of evidence on the benefits-risks of marketed vaccines in Europe. We tested the system by estimating the incidence rate (IR) of pertussis and pertussis-related complications in children vaccinated with acellular (aP) and whole-cell (wP) pertussis vaccine. Data from seven electronic databases from four countries (Denmark: AUH and SSI, Spain: SIDIAP and BIFAP, UK: THIN and RCGP RSC and Italy: Pedianet) were included in a retrospective cohort analysis. Exposure was defined as any pertussis vaccination (aP or wP). The follow-up time started 14 days after the first dose. Children who had received any pertussis vaccine from January 1990 to December 2015 were included (those who switched type, or had unknown type were excluded). The outcomes of interest were confirmed or suspected pertussis and pertussis-related pneumonia and generalised convulsions within one month of pertussis diagnosis and death within three months of pertussis diagnosis. The cohort comprised 2,886,367 children ≤5 years of age. Data on wP and aP vaccination were available in three and seven databases, respectively. The IRs (per 100,000 person-years) for pertussis varied largely and ranged between 0.15 (95% CI: 0.12; 0.19) and 1.15 (95% CI: 1.07; 1.23), and the trends over time was consistent with those observed from national surveillance databases for confirmed pertussis. The pertussis IRs decreased as the number of wP and aP vaccine doses increased. Pertussis-related complications were rare (89 pneumonia, 7 generalised convulsions and no deaths) and their relative risk (vs. non-pertussis) could not be reliably estimated. The study demonstrated the feasibility of the ADVANCE system to estimate the change in pertussis IRs following pertussis vaccination. Larger sample sizes would provide additional power to compare the risk for complications between children with and without pertussis. The feasibility of vaccine-type specific effectiveness studies may be considered in the future.

Introduction The public-private ADVANCE consortium (Accelerated development of vaccine benefit-risk collaboration in Europe) aimed to assess if electronic healthcare databases can provide fit-for purpose data for collaborative, distributed studies and monitoring of vaccine coverage, benefits and risks of vaccines. Objective To evaluate if European healthcare databases can be used to estimate vaccine coverage, benefit and/or risk using pertussis-containing vaccines as an example. Methods Characterisation was conducted using open-source Java-based (Jerboa) software and R scripts. We obtained: (i) The general characteristics of the database and data source (meta-data) and (ii) a detailed description of the database population (size, representatively of age/sex of national population, rounding of birth dates, delay between birth and database entry), vaccinations (number of vaccine doses, recording of doses, pattern of doses by age and coverage) and events of interest (diagnosis codes, incidence rates). A total of nine databases (primary care, regional/national record linkage) provided data on events (pertussis, pneumonia, death, fever, convulsions, injection site reactions, hypotonic hypo-responsive episode, persistent crying) and vaccines (acellular pertussis and whole cell pertussis) related to the pertussis proof of concept studies. Results The databases contained data for a total population of 44 million individuals. Seven databases had recorded doses of vaccines. The pertussis coverage estimates were similar to those reported by the World Health Organisation (WHO). Incidence rates of events were comparable in magnitude and age-distribution between databases with the same characteristics. Several conditions (persistent crying and somnolence) were not captured by the databases for which outcomes were restricted to hospital discharge diagnoses. Conclusion The database characterisation programs and workflows allowed for an efficient, transparent and standardised description and verification of electronic healthcare databases which may participate in pertussis vaccine coverage, benefit and risk studies. This approach is ready to be used for other vaccines/events to create readiness for participation in other vaccine related studies.

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 vaccine benefit-risk monitoring using existing European healthcare databases. Incidence rate (IR) estimates of vaccination-associated adverse events that are needed to model vaccination risks can be calculated from existing healthcare databases when vaccination (exposure) data are available. We assessed different methods to derive IRs in risk periods following vaccination when exposure data are missing in one database, using estimated IRs and IRRs from other databases for febrile seizures, fever and persistent crying. IRs were estimated for children aged 0–5 years in outcome-specific risk and non-risk periods following the first dose of acellular pertussis (aP) vaccination in four primary care databases and one hospital database. We compared derived and observed IRs in each database using three methods: 1) multiplication of non-risk period IR for database i by IR ratio (IRR) obtained from meta-analysis of IRRs estimated using the self-controlled case-series method, from databases other than i; 2) same method as 1, but multiplying with background IR; and 3) meta-analyses of observed IRs from databases other than i. IRs for febrile seizures were lower in primary care databases than the hospital database. The derived IR for febrile seizures using data from primary care databases was lower than that observed in the hospital database, and using data from the hospital database gave a higher derived IR than that observed in the primary care database. For fever and persistent crying the opposite was observed. We demonstrated that missing IRs for a post-vaccination period can be derived but that the type of database and the method of event data capture can have an impact on potential bias. We recommend IRs are derived using data from similar database types (hospital or primary care) with caution as even this can give heterogeneous results.

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 (B/R) monitoring of vaccines using European healthcare databases. Event misclassification can result in biased estimates. Using different algorithms for identifying cases of Bordetella pertussis (BorPer) infection as a test case, we aimed to describe a strategy to quantify event misclassification, when manual chart review is not feasible. Methods: Four participating databases retrieved data from primary care (PC) setting: BIFAP: (Spain), THIN and RCGP RSC (UK) and PEDIANET (Italy); SIDIAP (Spain) retrieved data from both PC and hospital settings. BorPer algorithms were defined by healthcare setting, data domain (diagnoses, drugs, or laboratory tests) and concept sets (specific or unspecified pertussis). Algorithm- and database-specific BorPer incidence rates (IRs) were estimated in children aged 0–14 years enrolled in 2012 and 2014 and followed up until the end of each calendar year and compared with IRs of confirmed pertussis from the ECDC surveillance system (TESSy). Novel formulas were used to approximate validity indices, based on a small set of assumptions. They were applied to approximately estimate positive predictive value (PPV) and sensitivity in SIDIAP. Results: The number of cases and the estimated BorPer IRs per 100,000 person-years in PC, using data representing 3,173,268 person-years, were 0 (IR = 0.0), 21 (IR = 4.3), 21 (IR = 5.1), 79 (IR = 5.7), and 2 (IR = 2.3) in BIFAP, SIDIAP, THIN, RCGP RSC and PEDIANET respectively. The IRs for combined specific/unspecified pertussis were higher than TESSy, suggesting that some false positives had been included. In SIDIAP the estimated IR was 45.0 when discharge diagnoses were included. The sensitivity and PPV of combined PC specific and unspecific diagnoses for BorPer cases in SIDIAP were approximately 85% and 72%, respectively. Conclusion: Retrieving BorPer cases using only specific concepts has low sensitivity in PC databases, while including cases retrieved by unspecified concepts introduces false positives, which were approximately estimated to be 28% in one database. The share of cases that cannot be retrieved from a PC database because they are only seen in hospital was approximately estimated to be 15% in one database. This study demonstrated that quantifying the impact of different event-finding algorithms across databases and benchmarking with disease surveillance data can provide approximate estimates of algorithm validity.

Background To describe patterns of antibiotic outpatient use in 3 European countries, including 2 new pediatric-specific quality indicators (QIs). Methods A cohort study was conducted, 2001-2010, using electronic primary care records of 2,196,312 children up to 14 (Pedianet, Italy) or 18 years (The Health Improvement Network, United Kingdom; Integrated Primary Care Information database, The Netherlands) contributing 12,079,620 person-years. Prevalence rates of antibiotic prescribing per year were calculated and antibiotics accounting (drug utilization) for 90% of all antibiotic prescriptions were identified (drug utilization 90% method). The ratio between users of broad to narrow-spectrum penicillins, cephalosporins and macrolides (B/N ratio) and 2 pediatric-specific QIs: the proportion of amoxicillin users (amoxicillin index) and the ratio between users of amoxicillin to broad-spectrum penicillins, cephalosporins and macrolides (A/B ratio) were determined. Results The overall annual prevalence of antibiotic prescriptions was 18.0% in the Netherlands, 36.2% in the United Kingdom and 52.0% in Italy. Use was maximal in the first years of life. The number of antibiotics accounting for the drug utilization 90% was comparable. The B/N ratio varied widely from 0.3 to 74.7. The amoxicillin index was highest in the Netherlands and the United Kingdom (50-60%), lowest in Italy (30%) and worsened over time in the United Kingdom and Italy. The A/B ratio in 2010 was 0.3 in Italy, 1.7 in the Netherlands and 5.4 in the United Kingdom. Conclusions The patterns of antibiotic prescribing varied highly with age and country. The pediatric-specific QIs combined with the total prevalence rate of use provide a clear picture of the trends of community childhood antibiotic prescribing, allowing monitoring of the impact of policy interventions.

Altres ajuts: This trial was funded by Eli Lilly and Company. There are sparse real-world data on severe asthma exacerbations (SAE) in children. This multinational cohort study assessed the incidence of and risk factors for SAE and the incidence of asthma-related rehospitalization in children with asthma. Asthma patients 5-17 years old with ≥1 year of follow-up were identified in six European electronic databases from the Netherlands, Italy, the UK, Denmark and Spain in 2008-2013. Asthma was defined as ≥1 asthma-specific disease code within 3 months of prescriptions/dispensing of asthma medication. Severe asthma was defined as high-dosed inhaled corticosteroids plus a second controller. SAE was defined by systemic corticosteroids, emergency department visit and/or hospitalization all for reason of asthma. Risk factors for SAE were estimated by Poisson regression analyses. The cohort consisted of 212 060 paediatric asthma patients contributing to 678 625 patient-years (PY). SAE rates ranged between 17 and 198/1000 PY and were higher in severe asthma and highest in severe asthma patients with a history of exacerbations. Prior SAE (incidence rate ratio 3-45) and younger age increased the SAE risk in all countries, whereas obesity, atopy and GERD were a risk factor in some but not all countries. Rehospitalization rates were up to 79% within 1 year. In a real-world setting, SAE rates were highest in children with severe asthma with a history of exacerbations. Many severe asthma patients were rehospitalized within 1 year. Asthma management focusing on prevention of SAE is important to reduce the burden of asthma.

Background Data on the risk of death following an asthma exacerbation are scarce. With this multinational cohort study, we assessed all-cause mortality rates, mortality rates following an exacerbation, and patient characteristics associated with all-cause mortality in asthma. Methods Asthma patients aged ≥18 years and with ≥1 year of follow-up were identified in 5 European electronic databases from the Netherlands, Italy, UK, Denmark and Spain during the study period January 1, 2008–December 31, 2013. Patients with asthma-COPD overlap were excluded. Severe asthma was defined as use of high dose ICS + use of a second controller. Severe asthma exacerbations were defined as emergency department visits, hospitalizations or systemic corticosteroid use, all for reason of asthma. Results The cohort consisted of 586,436 asthma patients of which 42,611 patients (7.3%) had severe asthma. The age and sex standardized all-cause mortality rates ranged between databases from 5.2 to 9.5/1000 person-years (PY) in asthma, and between 11.3 and 14.8/1000 PY in severe asthma. The all-cause mortality rate in the first week following a severe asthma exacerbation ranged between 14.1 and 59.9/1000 PY. Mortality rates remained high in the first month following a severe asthma exacerbation and decreased thereafter. Higher age, male gender, comorbidity, smoking, and previous severe asthma exacerbations were associated with mortality. Conclusion All-cause mortality following a severe exacerbation is high, especially in the first month following the event. Smoking cessation, comorbidity-management and asthma-treatment focusing on the prevention of exacerbations might reduce associated mortality.

Background: There is sparse real life evidence on the risk factors and incidence of asthma exacerbations (AE) in children. Aims: To assess incidence and risk factors of AE in children with moderate to severe asthma in real life. Methods: Patients aged 5-17 years with ≥1 year of follow-up were identified in six European electronic health record databases from the Netherlands, Italy, UK, Denmark and Spain in 2008-2013. Asthma was defined as >1 asthma prescription within 3 months of an asthma diagnose code, severe asthma also required use of high dose inhaled corticosteroids combined with controller therapy. AE was defined as need of oral steroids, emergency department visit or hospitalization for asthma. Risk factors for AE were estimated by multivariate Poisson regression analyses. Results: The cohort consisted of 226, 343 asthma patients (mean age in the databases 7.2-14.8 years), contributing 723, 674 patient years (PY). The proportion of severe asthma ranged between 1.6-15.5%. AE rates ranged between 17-188/1, 000 PY, and were higher in severe asthma patients (41-326/1, 000 PY). In most databases girls had a higher AE rate than boys from adolescence on, and vice versa in young children. The risk was mainly increased by previous AE (incidence rate: 3-29), and also by atopy and high blood eosinophilia (≥300 cells/uL). Obesity was a risk factor of AE in some databases. Conclusions: In a real world setting, we showed high AE rates, with highest rates in children with severe asthma. Risk of exacerbation depended on age, gender, comorbidities and previous AE. Asthma management focusing on prevention of AE is important to reduce the burden of asthma. Funding: GSK funded (PRJ2284)

Introduction Acute gastroenteritis (AGE) is one of the most important causes of morbidity and mortality in childhood. Among all the causative agents of AGE, rotavirus (RV) is the most common pathogen. The aim of this study is to estimate the incidence by age group of rotavirus gastroenteritis (RVGE) in children Materials and Methods This was an observational, retrospective, cohort study using the Pedianet database that included all children aged ˂12 years with a diagnosis of AGE or acute diarrhea, and registered on the network during the period from January 2002 to December 2008. Since development of the model was specifically based on data collected during the Rotavirus gastroenteritis Epidemiology and Viral types in Europe Accounting for Losses in Public Health and Society Study (REVEAL study), RVGE estimation was restricted to children aged Results A total of 128,154 children Conclusions The Pedianet database was found to be a useful instrument for collecting information about the number and main features of AGE episodes at the primary care level in Italy. The statistical model presented in this study has proved reliable to predict RV-positive cases. Epidemiological results showed a consistent RVGE incidence from year to year in children less than 5 years old at the primary care level and underlined the persistent contribution of RV infections to the winter workload of Italian FPs.

Aim Electronic healthcare record (EHR)-based surveillance systems are increasingly being developed to support early detection of safety signals. It is unknown what the power of such a system is for surveillance among children and adolescents. In this paper we provide estimates of the number and classes of drugs, and incidence rates (IRs) of events, that can be monitored in children and adolescents (0-18 years). Methods Data were obtained from seven population-based EHR databases in Denmark, Italy, and the Netherlands during the period 1996-2010. We estimated the number of drugs for which specific adverse events can be monitored as a function of actual drug use, minimally detectable relative risk (RR) and IRs for 10 events. Results The population comprised 4 838 146 individuals (25 575 132 person years (PYs)), who were prescribed 2170 drugs (1 610 631 PYs drug-exposure). Half of the total drug-exposure in PYs was covered by only 18 drugs (0.8%). For a relatively frequent event like upper gastrointestinal bleeding there were 39 drugs for which an association with a RR ≥4, if present, could be investigated. The corresponding number of drugs was eight for a rare event like anaphylactic shock. Conclusion Drug use in children is rare and shows little variation. The number of drugs with enough exposure to detect rare adverse events in children and adolescents within an EHR-based surveillance system such as EU-ADR is limited. Use of additional sources of paediatric drug exposure information and global collaboration are imperative in order to optimize EHR data for paediatric safety surveillance.

Background: Although early onset asthma has been well characterised, data on adult onset asthma are scarce. Aims: To describe characteristics of adult onset asthma using data from 5 European electronic health record (EHR) databases in the study period 2008-2013. Methods: Asthma patients aged ≥18 yrs at diagnosis (COPD excluded) and with ≥1 year of follow-up were identified in EHR databases from the Netherlands (IPCI), Italy (HSD), UK (CPRD), Denmark (AUH) and Spain (SIDIAP). Patients were categorised into early adult onset asthma (>=18-39 yrs) or late onset asthma (>=40 yrs) based on the age at diagnosis. Characteristics were assessed at study start. Differences were tested with Chi-Square and Mann Whitney U test. The analysis was repeated in severe asthma only (use of high dose ICS + controller therapy for ≥120 days). Results: We included 504,745 patients (median age from 44.5-48.0 yrs) with asthma of whom 40,193 (8.0%) had severe asthma. The proportion of late onset asthma was 56.8% (range 56-60.1% across database) which increased to 70.4% (range 66.5-91.6%) in severe asthma. Compared to early adult onset asthma, patients with late onset asthma were less frequently atopic (range 9.2-28.7% across database vs. 21.5-39.5%), suffered more frequently from chronic rhinosinusitis (0.4-11.2% vs. 0.2-8.0%) and/or nasal polyposis (0.6-4.6% vs. 0.3-1.7%), GERD (2.8-14.3% vs. 0.9-7.5%) and obesity (10.5-72.2% vs. 9.3-54.7%) and had lower median IgE levels (63-91 vs. 108-226 IU/L)(all significant). Similar patterns were observed among severe asthma only. Conclusion: Differences in comorbidity in late onset vs. early adult onset asthma may be important for asthma management. GSK funded (PRJ2284)

Background The Observational Medical Outcomes Partnership (OMOP) has just completed a large scale empirical evaluation of statistical methods and analysis choices for risks identification in longitudinal observational healthcare data. This experiment drew data from four large US health insurance claims databases and one US electronic health record (EHR) database, but it is unclear to what extend the findings of this study apply to other data sources. Objective To replicate the OMOP experiment in six European EHR databases. Research Design Six databases of the EU-ADR (Exploring and Understanding Adverse Drug Reactions) database network participated in this study: Aarhus (Denmark), ARS (Italy), HealthSearch (Italy), IPCI (the Netherlands), Pedianet (Italy), and Pharmo (the Netherlands). All methods in the OMOP experiment were applied to a collection of 165 positive and 234 negative control drug- outcome pairs across four outcomes: acute liver injury, acute myocardial infarction, acute kidney injury, and upper gastrointestinal bleeding. Area under the receiver operator characteristics curve (AUC) was computed per database and for a combination of all six databases using metaanalysis for random effects. We provide expected values of estimation error as well, based on negative controls. Results Similarly to the US experiment, high predictive accuracy was found (AUC[0.8) for some analyses. Selfcontrolled designs, such as self-controlled case series, IC temporal pattern discovery and self-controlled cohort achieved higher performance than other methods, both in terms of predictive accuracy and observed bias. Conclusions The major findings of the recent OMOP experiment were also observed in the European databases.

Background. Rotavirus (RV) is the commonest pathogen in the hospital and primary care settings, followed by Adenovirus (AV) and Norovirus (NV). Only few studies that assess the burden of RV gastroenteritis at the community level have been carried out.Objectives. To estimate incidence, disease characteristics, seasonal distribution, and working days lost by parents of RV, AV, and NV gastroenteritis leading to a family pediatrician (FP) visit among children < 5 years.Methods. 12-month, observational, prospective, FP-based study has been carried out using Pedianet database.Results. RVGE incidence was 1.04 per 100 person-years with the highest incidence in the first 2 years of life. Incidences of AVGEs (1.74) and NVGEs (1.51) were slightly higher with similar characteristics regarding age distribution and symptoms. Risk of hospitalisation, access to emergency room (ER), and workdays lost from parents were not significantly different in RVGEs compared to the other viral infections.Conclusions. Features of RVGE in terms of hospitalisation length and indirect cost are lower than those reported in previous studies. Results of the present study reflect the large variability of data present in the literature. This observation underlines the utility of primary care networks for AGE surveillance and further studies on community-acquired gastroenteritis in children.

Purpose To provide estimates of the number and types of drugs that can be monitored for safety surveillance using electronic healthcare databases. Methods Using data from eight European databases (administrative claims, medical records) and in the context of a cohort study, we determined the amount of drug exposure required for signal detection across varying magnitudes of relative risk (RR). We provide estimates of the number and types of drugs that can be monitored as a function of actual use, minimal detectable RR, and empirically derived incidence rates for the following adverse events: (i) acute myocardial infarction; (ii) acute renal failure; (iii) anaphylactic shock; (iv) bullous eruptions; (v) rhabdomyolysis; and (vi) upper gastrointestinal bleeding. We performed data simulation to see how expansion of database size would influence the capabilities of such system. Results Data from 19647452 individuals (59594132person-years follow-up) who used 2289 drugs in the EU-ADR network show that for a frequent event such as acute myocardial infarction, there are 531 drugs (23% of total) for which an association with RR=2, if present, can be investigated.For a rareevent suchas rhabdomyolysis, thereare 19 drugs (1%)for which an association ofsame magnitude canbe investigated. Conclusion Active surveillance using healthcare data-based networks for signal detection is feasible, although the leverage to do so may be low for infrequently used drugs and for rare outcomes. Extending database network size to include data from heterogeneous populations and increasing follow-up time are warranted to maximize leverage of these surveillance systems. Copyright © 2012 John Wiley & Sons, Ltd. key words—active drug safety surveillance; drug safety monitoring; signal detection; electronic healthcare records; electronic healthcare databases; EU-ADR

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cough and cold medicines are frequently used in children to treat upper respiratory tract infections without solid proof of benefits. • Safety issues have been raised about the use of these drugs in young children. • In 2007 international warnings were issued advising against use of these drugs in young children. WHAT THIS STUDY ADDS • Cough and cold medicines prescribing by primary care physicians has not really been influenced by international warnings in the Netherlands, where no additional national warnings were made and only partially in Italy. • A concerted action should be taken in Europe to advise strongly against the OTC use and prescription of cough and cold medicines in young children. AIM The aim of the study was to assess the influence of national and international warnings on the prescription rates of cough and cold medicines (CCMs) in the youngest children (

Asthma drugs are amongst the most frequently used drugs in childhood, but international comparisons on type and indication of use are lacking. The aim of this study was to describe asthma drug use in children with and without asthma in the Netherlands (NL), Italy (IT), and the United Kingdom (UK). We conducted a retrospective analysis of outpatient medical records of children 018 years from 1 January 2000 until 31 December 2005. For all children, prescription rates of asthma drugs were studied by country, age, asthma diagnosis, and off-label status. One-year prevalence rates were calculated per 100 children per patient-year (PY). The cohort consisted of 671,831 children of whom 49,442 had been diagnosed with asthma at any time during follow-up. beta 2-mimetics and inhaled steroids were the most frequently prescribed asthma drug classes in NL (4.9 and 4.1/100 PY), the UK (8.7 and 5.3/100 PY) and IT (7.2 and 16.2/100 PY), respectively. Xanthines, anticholinergics, leukotriene receptor antagonists, and anti-allergics were prescribed in less than one child per 100 per year. In patients without asthma, beta 2-mimetics were used most frequently. Country differences were highest for steroids, (Italy highest), and for beta 2-mimetics (the UK highest). Off-label use was low, and most pronounced for beta 2-mimetics in children

The Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA) trial demonstrated the benefits of combined antihypertensive/lipid-lowering treatment over antihypertensive treatment alone in hypertensive patients with > or =3 additional cardiovascular (CV) risk factors. We assessed the prevalence and treatment of patients with hypertension and > or =3 additional CV risk factors in The Netherlands and Italy in a retrospective cohort study using the Integrated Primary Care Information (IPCI) database in The Netherlands and the Health Search/Thales Database (HSD) in Italy. Patients aged > or =16 years, with 1 year of valid database history, diagnosed and/or treated for hypertension (>140/90 mmHg) during 2000-2002 were included in the study. The IPCI and HSD populations consisted of approximately 175000 and approximately 325000 patients, respectively. The prevalence of hypertension increased from 20.3 to 22.3% in the IPCI, and from 19.0 to 21.8% in the HSD during 2000-2002. The prevalence of > or =3 concomitant risk factors among hypertensive patients increased from 31.2 and 31.1% in 2000 to 34.2 and 39.3% in 2002 in the IPCI and HSD, respectively. From 2000 to 2002, among hypertensive patients with > or =3 CV risk factors and no prior symptomatic CV disease (CVD) approximately 54-57% in the IPCI and 80-83% in the HSD received antihypertensive treatment. In these patients, the use of combined antihypertensive and lipid-lowering treatment increased from 14.2 to 17.6% in the IPCI and from 15.5 to 17.4% in the HSD from 2000 to 2002. This study shows that primary prevention of CVD in hypertensive patients in The Netherlands and Italy could be improved.

Background: There are limited population-based data on the incidence rate (IR) of severe exacerbations (SE) in asthma. Aims: To assess the real world burden of SE and risk of rehospitalisation following an SE using data from 6 European electronic health record databases in the study period 2008-2013. Methods: Patients with asthma, aged ≥5 years and with ≥1 year of follow-up were identified in EHR databases from the Netherlands (IPCI), Italy (HSD and Pedianet), UK (CPRD), Denmark (AUH) and Spain (SIDIAP).Severe asthma was defined as use of high dose ICS + controller therapy for ≥120 days. SE was defined as ED-visit, hospitalization or corticosteroid course for asthma. IRs were calculated for controlled and uncontrolled (≥2 SE in 1 year prior) asthma as the number of SEs divided by the total person-years (PY) during follow-up. Rehospitalisation rates were assessed at 1 month and at 1 year following an asthma-hospitalization. The cumulative incidence (CI) of SE was calculated from the IR. Results: The cohort included 855,806 asthma patients. In severe asthma (n=66,148), the overall IR of SE (per 1000PY) was 46.2 in Pedianet (pediatrics only), 123.4 in HSD, 170.3 in AUH, 172.9 in IPCI, 218.5 in CPRD and 418.0 in SIDIAP. IRs of SE were 4 to 11 fold higher in uncontrolled vs. controlled asthma. Rehospitalization occurred in 7.5-18.4% of patients at 1-month and increased to 34.2-55.3% at 1-year post-hospitalization. Conclusion: In severe asthma patients, the risk of SE is high and up to 18% of patients are rehospitalized during the 1 month post-hospitalization. Prevention of SE, particularly those associated with hospitalization, is important to reduce the burden of asthma. Funding: GSK (PRJ2284).

Background: Patients with severe asthma are at risk of severe exacerbations (SE), which are associated with considerable morbidity and premature death. There is sparse real world evidence on mortality following SE. Aims: To assess the all-cause mortality rate (MR) and MR following SE in patients with asthma and severe asthma using data from six European electronic health record (EHR) databases in the study period 2008-2013. Methods: Patients with asthma, aged ≥5 years and with ≥1 year of follow-up were identified in EHR databases from the Netherlands (IPCI), Italy (HSD and Pedianet), UK (CPRD), Denmark (AUH) and Spain (SIDIAP). Severe asthma was defined as use of high dose ICS + controller therapy for at least 120 days. SE was defined as ED-visit, hospitalization or corticosteroid course for asthma. MR was calculated by dividing the number of deaths by the total person-years (PY). MR following SE was assessed at different time points (7,14,30,90 or 365 days). The cumulative incidence (CI) of mortality was calculated from the IR. Results: The cohort consisted of 855,806 asthma patients. The proportion of severe asthma ranged between 1.7-10.0% (mean age 53.7-62.6 yrs; Pedianet: 9.3 yrs). The all-cause MR in severe asthma ranged between 16.0-33.4/1000PY. MR post-SE in the 1 st week was 26.3-109.5/1000PY (CI0.05-0.21%), and was significantly higher following an ED-visit/hospitalisation alone (57.9-239.4/1000PY; CI0.11-0.46%). Conclusions: MR following an SE is high, especially in the 1 st week following ED- visit/hospitalization. Up to 0.5% of patients died within 7 days of admission. ED visits/hospitalizations should be avoided through improved asthma control. Funding: GSK (PRJ2284).

Background and Objective Spontaneous reporting systems (SRSs) remain the cornerstone of post-marketing drug safety surveillance despite their well-known limitations. Judicious use of other available data sources is essential to enable better detection, strengthening and validation of signals. In this study, we investigated the potential of electronic healthcare records (EHRs) to be used alongside an SRS as an independent system, with the aim of improving signal detection. Methods A signal detection strategy, focused on a limited set of adverse events deemed important in pharmacovigilance, was performed retrospectively in two data sources—(1) the Exploring and Understanding Adverse Drug Reactions (EU-ADR) database network and (2) the EudraVigilance database—using data between 2000 and 2010. Five events were considered for analysis: (1) acute myocardial infarction (AMI); (2) bullous eruption; (3) hip fracture; (4) acute pancreatitis; and (5) upper gastrointestinal bleeding (UGIB). Potential signals identified in each system were verified using the current published literature. The complementarity of the two systems to detect signals was expressed as the percentage of the unilaterally identified signals out of the total number of confirmed signals. As a proxy for the associated costs, the number of signals that needed to be reviewed to detect one true signal (number needed to detect [NND]) was calculated. The relationship between the background frequency of the events and the capability of each system to detect signals was also investigated. Results The contribution of each system to signal detection appeared to be correlated with the background incidence of the events, being directly proportional to the incidence in EU-ADR and inversely proportional in EudraVigilance. EudraVigilance was particularly valuable in identifying bullous eruption and acute pancreatitis (71 and 42 % of signals were correctly identified from the total pool of known associations, respectively), while EU-ADR was most useful in identifying hip fractures (60 %). Both systems contributed reasonably well to identification of signals related to UGIB (45 % in EudraVigilance, 40 % in EU-ADR) but only fairly for signals related to AMI (25 % in EU-ADR, 20 % in EudraVigilance). The costs associated with detection of signals were variable across events; however, it was often more costly to detect safety signals in EU-ADR than in EudraVigilance (median NNDs: 7 versus 5). Conclusion An EHR-based system may have additional value for signal detection, alongside already established systems, especially in the presence of adverse events with a high background incidence. While the SRS appeared to be more cost effective overall, for some events the costs associated with signal detection in the EHR might be justifiable. Electronic supplementary material The online version of this article (doi:10.1007/s40264-015-0341-5) contains supplementary material, which is available to authorized users.

A prospective pharmacovigilance signal detection study, comparing the real-world healthcare data (EU-ADR) and two spontaneous reporting system (SRS) databases, US FDA's Adverse Event Reporting System and WHO's Vigibase is reported. The study compared drug safety signals found in the EU-ADR and SRS databases. The potential for signal detection in the EU-ADR system was found to be dependent on frequency of the event and utilization of drugs in the general population. The EU-ADR system may have a greater potential for detecting signals for events occurring at higher frequency in general population and those that are commonly not considered as potentially a drug-induced event. Factors influencing various differences between the datasets are discussed along with potential limitations and applications to pharmacovigilance practice.

Aims The objective of this population-based, retrospective cohort study was to investigate the incidence and initial antibiotic treatment of secondary intra-abdominal infections (sIAI) and to assess whether inappropriate initial antibiotic therapy affects patient outcomes. Methods All patients hospitalized for sIAI (1995–1998) were identified in the PHARMO Record Linkage System, a patient-centric database including pharmacy dispensing records from community pharmacies linked to hospitalization records in the Netherlands. Complementary in-hospital antibiotic drug use was obtained from the computerized inpatient pharmacy files. The patient outcomes considered were switch to second-line antibiotic treatment, re-operation, and death. In addition, a composite variable clinical failure was constructed based on the above-mentioned outcomes. Furthermore, the effect of clinical failure on length of hospital stay and costs of hospitalization was assessed. Associations between appropriateness of initial antibiotic treatment and outcomes were estimated using multivariate logistic and linear regression models. Results In the source population of 228 000 persons, 175 cases were classified as sIAI (mean age 49.3 ± 24.5, 50.9% male) resulting in an incidence of 2.3/10 000 person-years [95% confidence interval (CI) 2.0, 2.7]. Initial antibiotic treatment was appropriate for 84% of the cases. The risk of clinical failure was 17.1%. Inappropriate initial antibiotic treatment increased the risk of clinical failure 3.4-fold (95% CI 1.3, 9.1). Length of hospital stay and costs of hospitalization were significantly increased for patients with clinical failure. Conclusions Inappropriate choice of initial antibiotic therapy in sIAI patients leads to more clinical failure resulting in a longer hospital stay and higher costs of hospitalization compared with appropriate initial antibiotic therapy.

Background Data mining in spontaneous reporting databases has shown that drug-induced liver injury is infrequently reported in children. Objectives Our objectives were to (i) identify drugs potentially associated with acute liver injury (ALI) in children and adolescents using electronic healthcare record (EHR) data; and (ii) to evaluate the significance and novelty of these associations. Methods We identified potential cases of ALI during exposure to any prescribed/dispensed drug for individuals 1 and in the presence of at least three exposed cases of ALI. Potentially new signals were distinguished from already known associations concerning ALI (whether in adults and/or in the paediatric population) through manual review of published literature and drug product labels. Results The study population comprised 4,838,146 individuals aged < 18 years, who contributed an overall 25,575,132 person-years of follow-up. Within this population, we identified 1,015 potential cases of ALI. Overall, 20 positive drug-ALI associations were detected. The associations between ALI and domperidone, flunisolide and human insulin were considered as potentially new signals. Citalopram and cetirizine have been previously described as hepatotoxic in adults but not in children, while all remaining associations were already known in both adults and children. Conclusions Data mining of multiple EHR databases for signal detection confirmed known associations between ALI and several drugs, and identified some potentially new signals in children that require further investigation through formal epidemiologic studies. This study shows that EHRs may complement traditional spontaneous reporting systems for signal detection and strengthening.

Background Data on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project. Methods We used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0–18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children. Results The source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest). Conclusions Patterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children.

Background & Aims: Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin increases the risk of upper gastrointestinal bleeding (UGIB). Guidelines suggest avoiding certain drug combinations, yet little is known about the magnitude of their interactions. We estimated the risk of UGIB during concomitant use of nonselective (ns)NSAIDs, cyclooxygenase -2 selective inhibitors (COX-2 inhibitors), and low-dose aspirin with other drugs. Methods: We performed a case series analysis of data from 114,835 patients with UGIB (930,888 person-years of follow-up) identified from 7 population-based health care databases (approximately 20 million subjects). Each patient served as his or her own control. Drug exposure was determined based on prescriptions of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin, alone and in combination with other drugs that affect the risk of UGIB. We measured relative risk (incidence rate ratio [IRR] during drug exposure vs nonexposure) and excess risk due to concomitant drug exposure (relative excess risk due to interaction [RERI]). Results: Monotherapy with nsNSAIDs increased the risk of diagnosis of UGIB (IRR, 4.3) to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of UGIB; concomitant nsNSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and also produced the greatest excess risk (RERI, 5.5). Concomitant use of nsNSAIDs and aldosterone antagonists produced an IRR for UGIB of 11.0 (RERI, 4.5). Excess risk from concomitant use of nsNSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from use of COX-2 inhibitors with SSRIs was 1.9 and that for use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of nsNSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9. Conclusions: Based on a case series analysis, concomitant use of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with SSRIs significantly increases the risk of UGIB. Concomitant use of nsNSAIDs or low-dose aspirin, but not COX-2 inhibitors, with corticosteroids, aldosterone antagonists, or anticoagulants produces significant excess risk of UGIB. © 2014 AGA Institute.

Background: Drug-related adverse events remain an important cause of morbidity and mortality and impose huge burden on healthcare costs. Routinely collected electronic healthcare data give a good snapshot of how drugs are being used in ‘real-world’ settings. Objective: To describe a strategy that identifies potentially drug-induced acute myocardial infarction (AMI) from a large international healthcare data network. Methods: Post-marketing safety surveillance was conducted in seven population-based healthcare databases in three countries (Denmark, Italy, and the Netherlands) using anonymised demographic, clinical, and prescription/dispensing data representing 21,171,291 individuals with 154,474,063 person-years of follow-up in the period 1996–2010. Primary care physicians’ medical records and administrative claims containing reimbursements for filled prescriptions, laboratory tests, and hospitalisations were evaluated using a three-tier triage system of detection, filtering, and substantiation that generated a list of drugs potentially associated with AMI. Outcome of interest was statistically significant increased risk of AMI during drug exposure that has not been previously described in current literature and is biologically plausible. Results: Overall, 163 drugs were identified to be associated with increased risk of AMI during preliminary screening. Of these, 124 drugs were eliminated after adjustment for possible bias and confounding. With subsequent application of criteria for novelty and biological plausibility, association with AMI remained for nine drugs (‘prime suspects’): azithromycin; erythromycin; roxithromycin; metoclopramide; cisapride; domperidone; betamethasone; fluconazole; and megestrol acetate. Limitations: Although global health status, co-morbidities, and time-invariant factors were adjusted for, residual confounding cannot be ruled out. Conclusion: A strategy to identify potentially drug-induced AMI from electronic healthcare data has been proposed that takes into account not only statistical association, but also public health relevance, novelty, and biological plausibility. Although this strategy needs to be further evaluated using other healthcare data sources, the list of ‘prime suspects’ makes a good starting point for further clinical, laboratory, and epidemiologic investigation. This research has been funded by the European Commission’s Seventh Framework Programme (FP7/2007–2013) under grant no. 215847–The EU-ADR Project.

Acute liver failure is idiopathic and drug-related in, respectively, around 50 and 15 % of children. Population-based, epidemiologic data about the pattern of disease manifestation and incidence of less severe acute liver injury, either idiopathic or potentially drug-attributed are limited in children and adolescents. (i) To assess the incidence of idiopathic acute liver injury (ALI) and its clinical features in children and adolescent outpatients; and (ii) to investigate the role of the drug as a potential cause of ALI which is considered idiopathic. A retrospective cohort study was performed during the years 2000-2008. Data were retrieved from three longitudinal electronic healthcare databases in two European countries: Pedianet and Health Search/CSD Longitudinal Patient Database from Italy and the Integrated Primary Care Information database from The Netherlands. Cases of idiopathic acute liver injury in population aged < 18 years were identified by exclusion of all competing causes of liver injury (e.g. viral, autoimmune hepatitis), according to CIOMS criteria. The potential role of drug exposure as actual underlying cause of idiopathic ALI was detected through signal detection mining techniques. Both pooled and country-specific incidence rates [IR/100,000 person-years (PYs)] of idiopathic ALI and pooled adjusted rate ratios (RR) of drugs identified as a potential cause of idiopathic ALI, plus 95 % confidence intervals (CI) were estimated using the custom-built software Jerboa. Among 785 definite cases of idiopathic ALI, the pooled IR was 62.4/100,000 PYs (95 % CI 58.1-66.8). The country-specific IR was higher in Italy (73.0/100,000 PYs, 95 % CI 67.8-78.4) than in The Netherlands (21.0/100,000 PYs, 95 % CI 16.0-27.2) and increased with age in both countries. Isolated elevations of liver enzymes were reported in around two-thirds of cases in Italy, while in The Netherlands the cases were more often identified by a combination of signs/symptoms. Among drugs detected as potential underlying cause of idiopathic ALI, clarithromycin (RR 25.9, 95 % CI 13.4-50), amoxicillin/clavulanic acid (RR 18.6, 95 % CI 11.3-30.6), and amoxicillin (RR 7.5, 95 % CI 3.4-16.8) were associated with the highest risk compared to non-use. The incidence of idiopathic ALI in paediatrics is relatively low and comparable with adults. Clinical presentations differ between the two European countries. Signal detection in healthcare databases allowed identifying antibiotics as the drugs mostly associated with ALI with apparently unknown aetiology.

BACKGROUND: Drug safety monitoring relies primarily on spontaneous reporting, but electronic health care record databases offer a possible alternative for the detection of adverse drug reactions (ADRs). OBJECTIVES: To evaluate the relative performance of different statistical methods for detecting drug-adverse event associations in electronic health care record data representing potential ADRs. RESEARCH DESIGN: Data from 7 databases across 3 countries in Europe comprising over 20 million subjects were used to compute the relative risk estimates for drug-event pairs using 10 different methods, including those developed for spontaneous reporting systems, cohort methods such as the longitudinal gamma poisson shrinker, and case-based methods such as case-control. The newly developed method "longitudinal evaluation of observational profiles of adverse events related to drugs" (LEOPARD) was used to remove associations likely caused by protopathic bias. Data from the different databases were combined by pooling of data, and by meta-analysis for random effects. A reference standard of known ADRs and negative controls was created to evaluate the performance of the method. MEASURES: The area under the curve of the receiver operator characteristic curve was calculated for each method, both with and without LEOPARD filtering. RESULTS: The highest area under the curve (0.83) was achieved by the combination of either longitudinal gamma poisson shrinker or case-control with LEOPARD filtering, but the performance between methods differed little. LEOPARD increased the overall performance, but flagged several known ADRs as caused by protopathic bias. CONCLUSIONS: Combinations of methods demonstrate good performance in distinguishing known ADRs from negative controls, and we assume that these could also be used to detect new drug safety signals.

Background The incidence of acute otitis media (AOM) vary from country to country. Geographical variations together with differences in study designs, reporting and settings play a role. We assessed the incidence of AOM in Italian children seen by primary care paediatricians (PCPs), and described the methods used to diagnose the disease. Methods This secondary data analysis from the Pedianet database considered children aged 0 – 6 years between 01/2003 and 12/2007. The AOM episodes were identified and validated by means of patient diaries. Incidence rates/100 person-years (PY) were calculated for total AOM and for single or recurrent AOM. Results The 92,373 children (52.1% males) were followed up for a total of 227,361 PY: 23,039 (24.9%) presented 38,241 episodes of AOM (94.6% single episodes and 5.4% recurrent episodes). The total incidence rate of AOM in the 5-year period was 16.8 episodes per 100 PY (95% CI: 16.7-16.9), including single AOM (15.9 episodes per 100 PY; 95% CI: 15.7-16.1) and recurrent AOM (0.9 episodes per 100 PY; 95% CI: 0.9-0.9). There was a slight and continuously negative trend decrease over time (annual percent change −4.6%; 95%CI: -5.3, -3.9%). The AOM incidence rate varied with age, peaking in children aged 3 to 4 years (22.2 episodes per 100 PY; 95% CI 21.8-22.7). The vast majority of the AOM episodes (36,842/38,241, 96.3%) were diagnosed using a static otoscope; a pneumatic otoscope was used in only 3.7%. Conclusions Our data fill a gap in our knowledge of the incidence of AOM in Italy, and indicate that AOM represents a considerable burden for the Italian PCP system. Educational programmes concerning the diagnosis of AOM are needed, as are further studies to monitor the incidence in relation to the introduction of wider pneumococcal conjugate vaccines.

BackgroundSuboptimal use of antibiotics may lead to antimicrobial resistance. The aim of this study was to develop and assess two new quality indicators (QIs) of optimal community-based prescribing applied to childhood community antibiotic (AB) prescribing in three European countries.MethodsA cohort study was conducted using electronic primary care medical records of 2,195,312 children up to 14 (Italy, Pedianet database, 2001–2010) or 18 years of age (UK, THIN database, 1995–2010; the Netherlands, IPCI database, 1996–2010) contributing for a total of 12,079,620 person-years (PYs). Prevalence rates of antibiotic prescribing were defined as the number of children with at least one antibiotic prescription per year and were expressed as the number of users per 100 PYs (%). Quality of prescribing was determined using four QIs: the drug utilisation 90% method, the ratio between users of broad and narrow spectrum penicillins, cephalosporins and macrolides (B/N ratio) and two new QMs: (i) the overall proportion of amoxicillin users (amoxicillin index, AI); (ii) the ratio between users of amoxicillin and those of broad spectrum antibiotics (the A/B ratio).ResultsThe overall annual prevalence of antibiotic prescriptions was 18% in the Netherlands, 36.2% in the UK and 52% in Italy. Prevalence was highest in the youngest children. Almost half of all prescriptions included amoxicillin with or without clavulanic acid. Cephalosporins were frequently prescribed in Italy. The AI provided trends for the utilization of a relatively narrow spectrum option targeting acute respiratory infections, and was highest in the Netherlands and in the UK (50–60%) and lower in Italy (30%), with a slight decrease over time in the UK and Italy. The overall B/N ratio varied between countries from 0.3 to 74.7, whereas the overall A/B ratio varied less from 0.5 in Italy to 6 in the UK, indicating a substantial proportion of narrower-spectrum prescribing in the UK.ConclusionsThe prevalence of antibiotic prescribing varied highly with age and country. A combination of total antibiotic prevalence and quality of prescribing based on amoxicillin use provide a clear picture of community childhood antibiotic prescribing. These measures could be used to evaluate the impact of programs aiming at reduction of AB use and appropriate antibiotic prescribing.

Background and Aims: Little is known about the epidemiology of acute gastroenteritis (AGE) and intussusception (IS) or gastrointestinal obstruction (GO) in Italy. We conducted a retrospective study to assess AGE incidence and symptoms, 1-month hospitalization risk, and IS incidence among Italian children. Methods: A dynamic cohort study was conducted using the PEDIANET general practice research database. The study population comprised 79,949 children aged

Background and Objective. Results from a relatively small case-control study recently showed that niflumic acid increases the risk of serious mucocutaneous reactions in children. As a consequence, the Italian Ministry of Health sent a “Dear Doctor” letter in June 2001 to warn pediatricians about the alleged adverse effects. The objective of this study was to estimate and compare the incidence of mild and severe mucocutaneous reactions among children using niflumic acid, other nonsteroidal antiinflammatory drugs (NSAIDs), or nonopioid analgesics. Design. Retrospective cohort study. Setting. Italy is one of the few countries in which a specific primary care system is devoted to children up to 14 years of age: every child is registered at birth and receives free medical care from 1 of the ∼6000 family pediatricians working for the National Health Service. This study was conducted with the Pedianet network of Italian family pediatricians who use computerized electronic patient records for routine care; 185 pediatricians participated in the study. The patient records comprise information on demographics, diagnoses, symptoms, prescriptions, referrals, laboratory examinations, and hospitalizations. Participants. Children aged 0 to 14 years and registered with 1 of the collaborating pediatricians between January 1, 1998, and May 31, 2001. Main Outcome Measures. The incidence rate of severe (hospitalized or referred) and mild mucocutaneous reactions (exanthema, disseminated or localized pruritus, urticaria, angioedema, fixed eruption, dermatitis, erythema multiforme, vesicles, bullae, pustules, toxic epidermal necrolysis, purpura, and vasculitis) was estimated during use of niflumic acid, other NSAIDs, or nonopioid analgesics. For each episode of drug use, the following covariates were assessed: age, gender, region, year, indication for study drug, use of antibiotics, antimycotic agents, glucocorticoids, and other NSAIDs. Multivariate Poisson regression analysis was used to estimate the adjusted relative risk of mucocutaneous disorders during use of niflumic acid compared with use of other NSAIDs or use of acetaminophen alone. Results. The population included 193727 children, 45351 of whom received at least 1 of the study drugs. The most frequently prescribed drugs were niflumic acid, acetaminophen, and propionic acid derivatives (ketoprofen and flurbiprofen). Users of niflumic acid (n = 32150) were younger and slightly more often had otitis media or upper respiratory tract infections as an indication compared with the other NSAIDs. During use of the various study drugs we identified 1451 mild mucocutaneous events and 42 severe reactions. The incidence rates of severe and mild mucocutaneous reactions after the administration of any study drug were 10.3 per 100000 exposure person-days and 3.7 per 1000 exposure person-days, respectively. Both incidence rates decreased strongly with increasing age. In comparison with other NSAIDs, the adjusted relative risks of niflumic acid were 0.5 (95% confidence interval: 0.23–1.27) for severe and 0.9 (95% confidence interval: 0.79–1.11) for mild mucocutaneous reactions. The use of acetaminophen as a reference category instead of other NSAIDs, restriction of the children to those who received NSAIDs for respiratory tract infections, or restriction to those who did not use antibiotics never revealed an increased risk of serious or mild mucocutaneous reactions during use of niflumic acid. Conclusions. In comparison with other NSAIDs or acetaminophen, niflumic acid is not associated with an increased risk of severe or mild mucocutaneous reactions in children. This was true for the different age groups and various types of mucocutaneous reactions, was independent of the concomitant use of antibiotics, and was not sensitive to changes in our assumptions regarding exposure and outcomes.

Screening, treatment and monitoring guidelines for hypertension and hypercholesterolaemia have been developed to assist physicians in providing evidence-based health care. We conducted a retrospective study to assess the management of patients with these single or combined conditions.This was a retrospective cohort study conducted using data from the Integrated Primary Care Information (IPCI) project based in The Netherlands. Management of hypertension and hypercholesterolaemia was assessed from 2000-2003 by measuring the numbers of patients screened for these conditions, treated pharmacologically and monitored for treatment success.Approximately 11%, 3% and 10% of participants were eligible for screening for hypertension alone, hypercholesterolaemia alone and both conditions, respectively. Blood pressure screening was high in patients eligible for both blood pressure and cholesterol screening (86%), whereas cholesterol screening was low (56%). Among patients newly identified with hypertension or hypercholesterolaemia who were eligible for pharmacotherapy, 29% and 43% respectively were not treated within one year of diagnosis. Undertreatment was significantly lower in patients with both conditions (24% and 37% for antihypertensive and lipid-lowering treatment, respectively and 28% were not treated for both). Among newly treated patients, in the first year of treatment there was no record of a blood pressure or cholesterol assessment, for 35% and 72%, respectively.Management was sub-optimal in patients with hypertension or hypercholesterolaemia as well as in those with both of these conditions. The results of this study are likely to be widely applicable, particularly to other European and industrialised countries that have similar free-access health care systems to The Netherlands.

Aim: Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin (LDA) increases the risk of upper gastrointestinal bleeding (UGIB). Although clinical guidelines suggest to avoid certain drug combinations, little is known about the magnitude of interaction between different NSAIDs and specific drug groups. This is partly due to the need of a large sample for studying drug interactions. Understanding drug synergism is important to develop strategies to minimize the risk of UGIB. Design: A self-controlled case series analysis was performed using data from seven population-based healthcare databases located in three countries (Denmark, Italy, and the Netherlands). UGIB cases were identified based on disease classification codes. Drug exposure was classified into mutually exclusive groups. Interaction of the three main groups (non-selective (ns)NSAIDs, coxibs and LDA) with other drugs was examined. Incidence rate ratios (IRRs) of UGIB during exposure (and corresponding 95% CI) were obtained by Poisson regression modeling. Interaction was assessed on additive (with relative excess risk due to interaction, RERI) and multiplicative scale. Results: In total 114,835 UGIB cases, with corresponding follow-up of 930,888 personyears, were analyzed. Monotherapy with nsNSAIDs was associated with a higher IRR than monotherapy with coxibs or LDA (IRR 4.3; 2.9 and 3.1 respectively). The IRR was highest for concomitant use of nsNSAIDs and steroids (IRR 12.8; 95% CI: 11.2-14.7), which also demonstrated the highest additive interaction (RERI 5.5)(Figure 1). The IRR for nsNSAIDs and aldosterone antagonists was 11.0 (95%CI 8.6 -14.0) and RERI 4.5. Selective serotonin re-uptake inhibitors (SSRIs) and anticoagulants combined with either nsNSAIDs, coxibs or LDA increased the risk of UGIB significantly and also to a greater extent than expected based on the sum of the individual drugs (RERI 1.6;1.9 and 0.5 for SSRIs and 2.4;0.1 and 1.9 for anticoagulants, respectively). Only for the combination of LDA and antiplatelets was apart from additive, also multiplicative interaction observed (IRR 5.4; 95%CI: 4.7-6.4; RERI 1.7). Increasing age was associated with a higher IRR. Stratifying by age showed that for all drugs older persons (.60 years) had a higher IRR compared to younger persons ( ,60 years), except for combinations of nsNSAIDs+anticoagulants and coxibs+steroids. Conclusion: Concomitant use of SSRIs with nsNSAIDs, coxibs or LDA significantly increases the risk of UGIB up to seven-fold. Concomitant use of steroids, anticoagulants or antiplatelets with nsNSAIDs or LDA, but not with coxibs, showed an increased risk of UGIB, up to thirteen-fold. These increased risks were greater than the sum of the risks of individual drugs. This knowledge is of clinical relevance and can help clinicians in tailoring therapy to minimize UGI adverse events.

P-549 Key Words: Cardiovascular Risk, Concomitant Hypertension and Dyslipidemia

Objective To provide an overview of drug use in children in three European countries. Design Retrospective cohort study, 2000-5. Setting Primary care research databases in the Netherlands (IPCI), United Kingdom (IMS-DA), and Italy (Pedianet). Participants 675 868 children aged up to 14 (Italy) or 18 (UK and Netherlands). Main outcome measure Prevalence of use per year calculated by drug class (anatomical and therapeutic). Prevalence of “recurrent/chronic” use (three or more prescriptions a year) and “non-recurrent” or “acute” use (less than three prescriptions a year) within each therapeutic class. Descriptions of the top five most commonly used drugs evaluated for off label status within each anatomical class. Results Three levels of drug use could be distinguished in the study population: high (>10/100 children per year), moderate (1-10/100 children per year), and low (