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Introduction: Antibiotics are the most commonly prescribed drug class in children. Real-world data mining on the paediatric population showed potential associations between antibiotic use and acute liver injury. Objective: We assessed risk estimates of liver injury associated with antibiotic use in children and adolescent outpatients. Methods: A large, multi-database, population-based, case-control study was performed in people <18 years of age from two European countries (Italy and The Netherlands) during the period 2000–2008. All potential cases of liver injury were automatically extracted from three databases and then manually validated based on Council for International Organizations of Medical Sciences (CIOMS) criteria and by exclusion of all competing causes for liver injury. Up to 100 control participants were sampled for each case and were matched on index date of the event, age, sex and database. Based on prescription data, antibiotic exposure was categorized as current, recent or past use by calculating the time period between the end of prescription and the index date. Multivariate conditional logistic regression analyses were applied to calculate odds ratios (ORs) as a measure of the association (with 95% confidence interval [CI]). Results: We identified 938 cases of liver injury and matched to 93,665 controls. Current use of overall antibiotics is associated with a threefold increased risk of liver injury compared with past use (adjusted OR [ORadj] 3.22, 95% CI 2.57–4.03). With regard to individual antibiotics, the risk is significantly increased for current use of each antibiotic (p < 0.005), except for azithromycin. Risk estimates vary from the lowest ORadj of 1.86 (95% CI 1.08–3.21) for amoxicillin to the highest ORadj of 24.16 (95% CI 11.78–49.54) for cotrimoxazole (i.e. sulphamethoxazole/trimethoprim) and 26.70 (95% CI 12.09–58.96) for ceftriaxone. Sensitivity analyses confirm the associations for ceftriaxone, cotrimoxazole, and clarithromycin. Con

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: To describe the utilisation of antibiotics in children and adolescents across 5 European countries based on the same drug utilisation measures and age groups. Special attention was given to age-group-specific distributions of antibiotic subgroups, since comparison in this regard between countries is lacking so far. Methods: Outpatient paediatric prescriptions of systemic antibiotics during the years 2005-2008 were analysed using health care databases from the UK, the Netherlands, Denmark, Italy and Germany. Annual antibiotic prescription rates per 1,000 person years were estimated for each database and stratified by age (<= 4, 5-9, 10-14, 15-18 years). Age-group-specific distributions of antibiotic subgroups were calculated for 2008. Results: With 957 prescriptions per 1000 person years, the highest annual prescription rate in the year 2008 was found in the Italian region Emilia Romagna followed by Germany (561), the UK (555), Denmark (481) and the Netherlands (294). Seasonal peaks during winter months were most pronounced in countries with high utilisation. Age-group-specific use varied substantially between countries with regard to total prescribing and distributions of antibiotic subgroups. However, prescription rates were highest among children in the age group <= 4 years in all countries, predominantly due to high use of broad spectrum penicillins. Conclusions: Strong increases of antibiotic prescriptions in winter months in high utilising countries most likely result from frequent antibiotic treatment of mostly viral infections. This and strong variations of overall and age-group-specific distributions of antibiotic subgroups across countries, suggests that antibiotics are inappropriately used to a large extent.

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 <18 years old from the EU-ADR network, which includes seven databases from three countries, covering the years 1996-2010. Several new methods for signal detection were applied to identify all statistically significant associations between drugs and ALI. A drug was considered statistically significantly associated with ALI, using all other time as a reference category, if the 95 % CI lower band of the relative risk was >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 investig

Background: There is growing evidence that ergot dopamine agonists may induce cardiac valve regurgitation (CVR) in persons with Parkinson's disease. It is unclear whether the CVR risk is increased with ergot-dopamine agonist use in persons with hyperprolactinaemia, in whom the dose is much lower. Objective: The aim of the study was to explore the association between different dopamine agonists and CVR in patients with Parkinson's disease or hyperprolactinaemia. Design: Nested case-control studies conducted separately in cohorts of Parkinson's disease and hyperprolactinaemia patients. Cases were patients who developed newly diagnosed CVR. Controls were CVR-free patients from the same cohorts and were matched to cases by age, sex, database and calendar year. Setting and Patients: Study patients were identified from over 4.5 million persons in The Health Improvement Network (THIN; UK), Health Search (Italy), and Integrated Primary Care Information (IPCI; the Netherlands) general practice databases in the years 1996-2007. The Parkinson's disease cohort included new users of dopamine agonists or levodopa, while the hyperprolactinaemia cohort included new users or non-users of dopamine agonists. Main Outcome Measure: Risk of newly diagnosed CVR with dopamine agonist use compared with levodopa use in the Parkinson's disease cohort, and dopamine agonist-naive patients in the hyperprolactinaemia cohort. Results: In the Parkinson's disease cohort (7893 dopamine agonist users, 11 766 levodopa users), 85 incident CVR cases were identified. Increased CVR risk was observed for ergot dopamine agonists (adjusted OR [ORadj] 3.82; 95% CI 2.14, 6.81), but not for non-ergot dopamine agonists (ORadj 1.20; 95% CI 0.63, 2.29). In the hyperprolactinaemia cohort (6740 dopamine agonist users and 14 299 dopamine agonist-naive patients), 37 CVR cases were identified during a mean follow-up of 4.5 years and 3.5 years for new users and non-users of dopamine agonists, respectively. However, no as

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: Little is known about the upper gastrointestinal (UGI) protective effect of gastroprotective agents (GPAs) in COX-2-specific inhibitors (coxib)-users. Objectives: To study the association between GPA adherence and UGI complications among coxib-users. Methods: We used primary care data from the United Kingdom's (UK) General Practice Research Database , the Dutch (NL) Integrated Primary Care Information database, and the Italian (IT) Health Search/Thales Database. A case-control study was conducted within a cohort of coxib+GPA users aged ≥ 50 yrs. Episodes of coxib use were defined as a period of coxib use with gaps between subsequent prescriptions that were no longer than 100% of the duration of the previous coxib prescription. Patients could have more than one episode of coxib use during follow-up, but only if at least a 180-days NSAID-free period was present prior to the start of each episode. Cases with UGI complications (UGI bleeding and diagnosed symptomatic UGI ulcers) during or within 60 days after coxib use were matched to controls on age, gender, database, and calendar time. Adherence to GPAs was calculated over the most recent episode of coxib use prior to the index date as the proportion of coxib treatment days covered (PDC) by a GPA prescription. Adherence was expressed as a continuous variable as well as categorical (low (PDC<20%) / moderate (PDC 20-80%) / high adherence (PDC>80%)). Adjusted odds ratios (OR) with 95% confidence intervals (95%CI) were calculated using conditional logistic regression. Results: 98,940 coxib episodes were counted in the coxib user cohort (UK: 52,698; NL: 7,201, IT: 39,041). In 16,442 (16.6%) of the eligible coxib episodes a GPA was prescribed (UK: 21.2%; NL: 13.4%, IT: 11.0%). Of the GPA users, 7.2% had low adherence (PDC<20%), 33.1% had moderate adherence (PDC 20-80%), and 59.7% had high adherence (PDC>80%). Overall, mean pooled adherence was 0.76±0.30 (UK: 0.79±0.29; NL: 0.85±0.27; IT: 0.66±0.30). Only 18% used

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) have known associated upper gastrointestinal (UGI) risks . Gastro-protective agents (GPAs) are co-prescribed to lower the risk of UGI complications, but patient adherence is suboptimal. Aim: To study the association between GPA adherence and UGI complications in non-selective (ns)NSAID users ≥ 50 yrs. Methods: A multi-database nested case-control study was conducted using primary care data from the General Practice Research Database (United Kingdom (UK), 1998-2008), the Integrated Primary Care Information database (The Netherlands (NL), 1996-2007) and the Health Search Database (Italy (IT), 2000-2007). The study was nested within a cohort of new nsNSAID users ≥ 50 yrs. Episodes of nsNSAID use were defined as a period of nsNSAID use with gaps between subsequent prescriptions that were no longer than the duration of the previous prescription. Patients could have more than one episode of nsNSAID use during follow-up, but only if at least a 180-day NSAID-free period was present prior to the start of each episode. Cases with UGI complications (UGI bleeding and (un)complicated UGI ulcers) during or within 60 days after nsNSAID use were matched to controls on age, gender, database, and calendar time. Adherence to GPAs was calculated over the most recent episode of nsNSAID use prior to the index date as the proportion of NSAID treatment days covered (PDC) by a GPA prescription. Adjusted odds ratios (OR) with 95% confidence intervals (95%CI) were calculated using multivariate conditional logistic regression analysis. Results: 1,107,266 nsNSAID episodes were counted in the nsNSAID user cohort (UK: 647,615; NL: 78,853, IT: 380,798). In 117,307 (10.6%) of the nsNSAID episodes a GPA was prescribed (UK: 11.6%; NL: 7.8%, IT: 9.5%). Of the GPA users, 4.9% had a PDC ratio <20% (low adherence), 27.0% had a PDC ratio between 20-80% (partial adherence) and 68.1% had a PDC ratio >80% (high adherence). Mean PDC was 0.81±0.2

Background: To reduce the risk of upper gastrointestinal (UGI) complications related to non-steroidal anti-inflammatory drugs (NSAIDs), gastroprotective strategies (GPS) are recommended in patients at risk. Aim: To compare GPS prescription behaviour by general practitioners (GP) in 3 European countries. Methods: We conducted a population-based cohort study in 3 GP databases: 1) United Kingdom's (UK) GP Research Database (1998-2008), 2) Italy's (IT) Health Search/Thales Database (2000-2007), and 3) the Dutch (NL) Integrated Primary Care Information database (1996-2006). Study cohorts comprised all incident NSAID users ≥50 yrs. As preventive strategies we considered: 1) co-prescription of proton pump inhibitors, double dose H2-receptor antagonists, or misoprostol, or 2) use of a cyclooxygenase- 2-specific inhibitor (coxib). Consistent with American College of Gastroenterology treatment guidelines, appropriate prescription was defined as the use of a GPS in NSAID users with ≥1 UGI risk factor (history of UGI bleeding/ulceration, age ≥ 65 yrs, concomitant use of anticoagulants, aspirin, or corticosteroids) and also no GPS in patients without UGI risk factors. Under-prescription was defined as no GPS in patients with ≥1 UGI risk factor. Over-prescription was the presence of a GPS in patients with no UGI risk factors. Results: The study populations comprised of 384,649 UK (mean age: 64.8 yrs, 41% male), 179,030 IT (mean age: 64.6 yrs, 41.7% male) and 55,005 NL NSAID users (mean age: 63.4 yrs, 42.6% male). In the UK, appropriate prescription increased from 51% in 1998 to 59% in 2008 (linear trend (lt) p<0.001) and over-prescription from 3% to 7% (lt p=0.04). Underprescription fell from 46% to 34% (lt p<0.001). In IT, appropriate prescription rose from 46% in 2000 to 60% in 2007 (lt p<0.001) and over-prescription from 3% to 8% (lt p= 0.74), while under-prescription fell from 51% to 32% (lt p=0.01). In the NL, appropriate prescription rose from 53% in 1996 to 63% in 2006 (lt

Background: According to safety alerts from the U.S. Food and Drug Administration, pneumonia is one of the most frequently reported causes of death in elderly patients with dementia who are treated with antipsychotic drugs. However, epidemiologic evidence of the association between antipsychotic drug use and pneumonia is limited. Objective: To evaluate whether typical or atypical antipsychotic use is associated with fatal or nonfatal pneumonia in elderly persons. Design: Population-based, nested case-control study. Setting: Dutch Integrated Primary Care Information database. Patients: Cohort of persons who used an antipsychotic drug, were 65 years or older, and were registered in the IPCI database from 1996 to 2006. Case patients were all persons with incident community-acquired pneumonia. Up to 20 control participants were matched to each case patient on the basis of age, sex, and date of onset. Measurements: Risk for fatal or nonfatal community-acquired pneumonia with atypical and typical antipsychotic use. Anti-psychotic exposure was categorized by type, timing, and daily dose, and the association with pneumonia was assessed by using conditional logistic regression. Results: 258 case patients with incident pneumonia were matched to 1686 control participants. Sixty-five (25%) of the case patients died in 30 days, and their disease was considered fatal. Current use of either atypical (odds ratio [OR], 2.61 [95% CI, 1.48 to 4.61]) or typical (OR, 1.76 [CI, 1.22 to 2.53]) antipsychotic drugs was associated with a dose-dependent increase in the risk for pneumonia compared with past use of antipsychotic drugs. Only atypical antipsychotic drugs were associated with an increase in the risk for fatal pneumonia (OR, 5.97 [CI, 1.49 to 23.98]). Limitations: Antipsychotic exposure was based on prescription files. Residual confounding due to unmeasured covariates or severity of disease was possible. Conclusion: The use of either atypical or typical antipsychotic drugs in elder

AIMS: To study whether listed putative corrected QT (QTc)-prolonging psychotropic drugs indeed prolong the QTc interval under everyday circumstances and to evaluate whether this is a class effect or an individual drug effect, we conducted a prospective population-based cohort study. METHODS: This study was conducted as part of the Rotterdam Study and included 3377 men and 4845 women (>or=55 years) who had triennial electrocardiograms (ECGs). The primary end points of the study were the length of the QTc interval at each ECG, the difference in QTc interval between consecutive ECGs within one person, and the risk of an abnormally prolonged QTc interval. Drug use at the index date was obtained from automated dispensing records. The associations were examined by means of a repeated measurement analysis, adjusted for age, sex, diabetes mellitus, hypertension, myocardial infarction, heart failure, and use of class 1 QTc-prolonging drugs. RESULTS: Of the 8222 participants, 813 participants (9.9%) developed QTc prolongation during follow-up and 492 participants (74.4% women) used psychotropic drugs at the time of an ECG. Starting tricyclic antidepressants increased the QTc interval significantly with 6.9 milliseconds (95% confidence interval [CI], 3.1-10.7 milliseconds) between consecutive ECGs in comparison with consecutive ECGs of participants not using tricyclic antidepressants, in particular starting amitriptyline (8.5 milliseconds; 95% CI, 2.8-14.2 milliseconds), maprotiline (13.9 milliseconds; 95% CI, 3.6-24.3 milliseconds), and nortriptyline (35.3 milliseconds; 95% CI, 8.0-62.6 milliseconds). Starting lithium also increased the QTc interval significantly (18.6 milliseconds; 95% CI, 4.8-32.4 milliseconds). CONCLUSIONS: In this population-based prospective cohort study, we confirmed the importance of antidepressants and antipsychotics as potential contributors to QTc prolongation. Especially, starting tricyclic antidepressant drugs (as a class) is associated with a sig

Objectives To compare rates of treatment discontinuation of and changes in initial antihypertensive drug therapy in the natural setting of treatment dispensation of Italy, Sweden and the Netherlands. Methods The cohorts included all the 23 715 (Italy), 20 289 (Sweden), and 5801 (the Netherlands) patients aged 40-70 years who received their first antihypertensive drug prescription from July 1, 2006 to September 30, 2006. Discontinuation was assumed if no antihypertensive drug was issued within 90 days following the end of the latest antihypertensive dispensation. Addition or replacement of the initial medication during the 90-day interval were defined as treatment combination or treatment switching. Results At 9 months after treatment initiation, the discontinuation rate of any antihypertensive drug was 24%. Compared with Italian patients, the discontinuation rate was significantly lower in Swedish [hazard ratios: 0.52, 95% confidence interval (CI): 0.50-0.54] and Dutch patients (hazard ratio: 0.79, 95% CI: 0.75-0.84). Almost 21 and 16% of patients who started on monotherapy respectively combined with and switched to another antihypertensive drug. Compared with Italian patients, the adjusted hazard rate of combining was lower in Swedish patients (hazard ratio: 0.83, 95% CI: 0.79-0.87). The hazard rate of switching was lower in Swedish and Dutch patients than in Italians (hazard ratios: 0.83, 95% CI: 0.79-0.88 and hazard ratio: 0.77, 95% CI: 0.71 -0.84 respectively). Conclusion Management of hypertension is unsatisfactory worldwide due to a very high rate of treatment discontinuation or insufficient use of proper treatment strategies. © 2009 Wolters Kluwer Health Lippincott Williams & Wilkins.

Objectives: Guidelines for the screening, treatment, and monitoring of modifiable cardiovascular risk factors such as hypertension (HTN) and dyslipidemia (DYS), have been developed to assist physicians in lowering the global risk of cardiovascular disease (CVD). This study assessed the management of patients with these conditions in a primary care setting in Italy. Methods: This was a retrospective cohort study conducted in 2000–2002 using the Italian Health Search Database (HSD). The management of HTN (blood pressure [BP] 140/90 mmHg) and DYS (total cholesterol 5 mmol/L [193 mg/dL]) was assessed by measuring the numbers of patients screened for one or both conditions, the numbers treated pharmacologically, and the numbers monitored for treatment success. Management patterns were stratified by history of cardiovascular events. Results: Blood pressure screening at a population level was approximately 35% for HTN in each year whereas for DYS, it increased from 26% in 2000 to 32% in 2002. Over the study period, the prevalence of HTN increased from 19% to 23%, whereas the prevalence for DYS doubled (from 14% to 28%). For both HTN and DYS these prevalences were substantially lower than national survey estimates (23% versus 48% for HTN and 16% versus 57% for DYS in 2001). Among patients with newly identified HTN or DYS, eligible for reimbursed pharmacological treatment, 26% and 82%, respectively, were not treated within 1 year of diagnosis. Treatment levels were higher in patients with a history of CVD, but were still far from optimal. Monitoring of BP and cholesterol in the first year of treatment was sub-optimal e.g. 36% of newly-treated HTN patients had no record of a BP evaluation and 32% of newly-treated DYS patients had no record of a cholesterol assessment. Blood pressure monitoring was slightly higher in patients with a history of CVD. Extrapolation to all new HTN and DYS patients showed that less than 50% of patients with HTN and 12% of those with DYS were adequa