Prevalence and incidence rate of hospital admissions related to medication between 2008 and 2013 in The Netherlands.

PURPOSE: In 2009 a Dutch guideline was published containing recommendations to reduce Hospital Admissions Related to Medications (HARMs). This study aims to examine time-trends of HARMs and their potential preventability between 2008 and 2013 in The Netherlands. METHODS: A retrospective prevalence study was conducted using the Dutch PHARMO Database Network. A semi-automated pre-selection was used to make a crude identification of possible HARMs of which four samples were selected. These were independently assessed with respect to causality and potential preventability by a physician and pharmacist. The results were stratified by age into 18-64 years and 65 years and older. For these groups the net prevalences and incidence rates of HARMs and potentially preventable HARMs were calculated for the years 2008, 2009, 2011 and 2013. RESULTS: Four samples of 467 (2008), 447 (2009), 446 (2011) and 408 (2013) admissions were assessed. The net prevalence of HARMs in the 18-64 years group was approximately four times smaller compared to the older group with a mean prevalence of 2.7% (95% confidence interval [CI]:2.4%-3.0%) and 10.2% (95%CI: 9.7%-10.7%) respectively. The potential preventability was 25.1% (18.4%-31.8%) and 48.3% (95%CI: 44.8%-51.8%), respectively. The prevalence of HARMs in both groups did not change significantly between 2008 and 2013 with 2.4% (95%CI: 1.9%-3.0%) and 10.0% (95%CI: 9.0%-11.0%) in 2008 and 3.1% (2.7%-3.5%) and 10.4% (95%CI: 9.4%-11.4%) in 2013, respectively. CONCLUSION: Despite efforts to reduce HARMs, the prevalence did not decrease over time. Additional measures are therefore necessary, especially in the elderly population.

Using Prescription Patterns in Primary Care to Derive New Quality Indicators for Childhood Community Antibiotic Prescribing.

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.

Pediatric Drug Safety Surveillance in FDA-AERS: A Description of Adverse Events from GRiP Project.

Individual case safety reports (ICSRs) are a cornerstone in drug safety surveillance. The knowledge on using these data specifically for children is limited. We studied characteristics of pediatric ICSRs reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Public available ICSRs reported in children (0-18 years) to FAERS were downloaded from the FDA-website for the period Jan 2004-Dec 2011. Characteristics of these ICSRs, including the reported drugs and events, were described and stratified by age-groups. We included 106,122 pediatric ICSRs (55% boys and 58% from United States) with a median of 1 drug [range 1-3] and 1 event [1-2] per ICSR. Mean age was 9.1 years. 90% was submitted through expedited (15-days) (65%) or periodic reporting (25%) and 10% by non-manufacturers. The proportion and type of pediatric ICSRs reported were relatively stable over time. Most commonly reported drug classes by decreasing frequency were 'nervous system drugs' (58%), 'antineoplastics' (32%) and 'anti-infectives' (25%). Most commonly reported system organ classes were 'general' (13%), 'nervous system' (12%) and 'psychiatric' (11%) disorders. Duration of use could be calculated for 19.7% of the reported drugs, of which 14.5% concerned drugs being used long-term (>6 months). Knowledge on the distribution of the drug classes and events within FAERS is a key first step in developing pediatric specific methods for drug safety surveillance. Because of several differences in terms of drugs and events among age-categories, drug safety signal detection analysis in children needs to be stratified by each age group.

Quick assessment of drug-related admissions over time (QUADRAT study).

PURPOSE: To develop a computerized prescreening procedure for the identification of possible/probably Hospital Admissions potential Related to Medications (HARMs). METHOD: Pairs of drugs and reasons for hospitalization (generated automatically from the PHARMO record linkage database by using two data mining techniques) were assessed manually to determine whether they represented pharmacologically plausible adverse drug events (PP-ADEs). Two crude samples of these PP-ADEs (from 2005 and 2008) were examined manually to establish causality and preventability on the basis of hospital discharge letters plus medication dispensing data. The results were used to calculate the positive predictive value (PPV) of the crude causality PP-ADEs, the net percentage of possible/probably HARMs, and their potential preventability. RESULTS: Data mining by Gamma Poisson Shrinkage and trend analysis produced 1330 and 2941 significant drug-event pairs, respectively. After manual assessment, 307 different PP-ADEs remained. The annual prevalence of these PP-ADEs was stable at approximately 8% throughout 2000-2009. Manual assessment of two samples of crude PP-ADEs showed that their causality PPV was 53.7% (95%CI: 52.7%-54.7%) in 2005 and 47.9% (95%CI: 46.9%-49.0%) in 2008. The net contribution of possible/probably HARMs to all acute admissions was 4.6% (95%CI: 4.5%-4.8%) in 2005 and 3.9% (95%CI: 3.8%-4.0%) in 2008. The potential preventability of all possible/probably HARMs in the two samples was 19.3% (95%CI: 18.5-20.1). CONCLUSION: Automated pre-selection of PP-ADEs is an efficient way to monitor crude trends. Further validation and manual assessment of the automatically selected hospitalizations is necessary to get a more detailed and precise picture.

The role of electronic healthcare record databases in paediatric drug safety surveillance: a retrospective cohort study.

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.

Pediatric drug safety signal detection: a new drug-event reference set for performance testing of data-mining methods and systems.

BACKGROUND: Better evidence regarding drug safety in the pediatric population might be generated from existing data sources such as spontaneous reporting systems and electronic healthcare records. The Global Research in Paediatrics (GRiP)-Network of Excellence aims to develop pediatric-specific methods that can be applied to these data sources. A reference set of positive and negative drug-event associations is required. OBJECTIVE: The aim of this study was to develop a pediatric-specific reference set of positive and negative drug-event associations. METHODS: Considering user patterns and expert opinion, 16 drugs that are used in individuals aged 0-18 years were selected and evaluated against 16 events, regarded as important safety outcomes. A cross-table of unique drug-event pairs was created. Each pair was classified as potential positive or negative control based on information from the drug's Summary of Product Characteristics and Micromedex. If both information sources consistently listed the event as an adverse event, the combination was reviewed as potential positive control. If both did not, the combination was evaluated as potential negative control. Further evaluation was based on published literature. RESULTS: Selected drugs include ibuprofen, flucloxacillin, domperidone, methylphenidate, montelukast, quinine, and cyproterone/ethinylestradiol. Selected events include bullous eruption, aplastic anemia, ventricular arrhythmia, sudden death, acute kidney injury, psychosis, and seizure. Altogether, 256 unique combinations were reviewed, yielding 37 positive (17 with evidence from the pediatric population and 20 with evidence from adults only) and 90 negative control pairs, with the remainder being unclassifiable. CONCLUSION: We propose a drug-event reference set that can be used to compare different signal detection methods in the pediatric population.

Signal detection of potentially drug-induced acute liver injury in children using a multi-country healthcare database network.

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 investigation through formal epidemiologic studies. This study shows that EHRs may complement traditional spontaneous reporting systems for signal detection and strengthening.

Idiopathic acute liver injury in paediatric outpatients: incidence and signal detection in two European countries.

BACKGROUND: 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. OBJECTIVES: (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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Prescribing of rosiglitazone and pioglitazone following safety signals: analysis of trends in dispensing patterns in the Netherlands from 1998 to 2008.

BACKGROUND: Relevant safety signals in the EU are regularly communicated in so-called 'Direct Healthcare Professional Communications' (DHPCs) or European Medicines Agency (EMA) press releases. Trends of a decrease in the use of rosiglitazone following regulatory safety warnings have been described in the US. In the EU, however, relatively little is known about dispensing patterns following DHPCs or other safety signals such as EMA press releases. OBJECTIVE: The objective of this study was to analyse trends in dispensing patterns of rosiglitazone and pioglitazone following DHPCs and EMA press releases in the EU member state, the Netherlands. METHODS: Data for this study were obtained from the PHARMO Record Linking System, which includes drug dispensing records from community pharmacies of approximately 2.5 million individuals in the Netherlands. Over the period 1998-2008 an auto-regressive, integrated, moving average model (ARIMA) was fitted. The DHPC letters or EMA press releases were used as determinants. Adjustments were made for publication of certain literature. Stratification was performed for dispensings prescribed by general practitioners (GPs) and those prescribed by specialists. RESULTS: For rosiglitazone, four EMA press releases and two DHPCs were issued; for pioglitazone, one DHPC was issued. The number of rosiglitazone dispensings prescribed by GPs decreased significantly after publication of DHPCs and EMA press releases concerning the risk of macular oedema and risk of fractures (both p-values 0.001). The number of rosiglitazone dispensings decreased statistically significantly after publication of EMA press releases 2 and 3 concerning cardiovascular risks but not for EMA press release 4. Adjustment for certain publications in the literature reduced the effect of communicated safety issues on the proportion of dispensings. CONCLUSIONS: Although it is difficult to disentangle the effect of DHPCs and EMA press releases from the effect of reports published in the literature, our results suggest that prescribers may react to such safety communications.

Vaccine-based subgroup analysis in VigiBase: effect on sensitivity in paediatric signal detection.

BACKGROUND: Data mining of spontaneously reported adverse drug reactions (ADRs), using measures of disproportionality, is a valuable first evaluation step for drug safety signal detection. Of all ADRs reported for children and adolescents within VigiBase, vaccine-ADR pairs comprise more than half of the reports. ADRs concerning vaccines differ with respect to type and seriousness from other drugs, and therefore may influence signal detection for non-vaccine drugs if not accounted for appropriately. The potential influence of vaccines on safety signal detection for drugs was recently raised by the CIOMS Working Group VIII, who proposed that it may be appropriate to undertake automatic signal detection using both medicines and vaccines, and some analysis using vaccines only. However, it has not described for which types of ADRs or drugs subgroup analysis is beneficial. OBJECTIVE: The aim of the study was to study the methodological aspects concerning the influence of a high prevalence of vaccine-related ADRs on signal detection within paediatric ADR data. METHODS: We analysed all paediatric Individual Case Safety Reports (ICSRs) received by VigiBase between 2000 and 2006, and calculated the reporting odds ratio (ROR) for all unique drug-ADR pairs with at least three reports. The ROR was additionally calculated in subgroups of vaccine-ADR pairs and non-vaccine-ADR pairs and further in different age groups. A proportional change in the ROR for the different subgroups was calculated and the change in the number of signals of disproportional reporting (SDRs) after subgroup analysis was assessed. RESULTS: Of all paediatric ICSRs (N = 218 840, of which 117 877 were vaccine-related), a total of 26 203 unique drug-ADR pairs were eligible for inclusion (5586 vaccine-related). A total of 1637 vaccine-related SDRs and 13 375 non-vaccine-related SDRs were detected in the crude analysis. Subgroup analysis by restricting to either vaccines or non-vaccines revealed 494 additional SDRs for vaccines (+30.2%) and 821 additional SDRs for non-vaccines (+6.1%). Subgroup analyses were only beneficial for non-vaccines if the ADR of interest was reported uncommonly for non-vaccines and beneficial for vaccines if the ADR was reported uncommonly for vaccines. Subgroup analysis for ADRs that were reported commonly for either vaccines or non-vaccines led to the disappearance of 272 SDRs for vaccines and 2721 SDRs for non-vaccines. We could empirically derive a model that predicts the change in ROR in the subgroups based on the proportion of vaccines within the total dataset. CONCLUSION: The high proportion of vaccine-related reports within paediatric ADR data has a large and mathematically predictable impact on signal detection in paediatric ADR data. Subgroup analysis reveals new SDRs that potentially represent genuine safety signals. The most inclusive and sensitive signal detection method would be the combination of a crude and subgroup-based data mining approach, based on the ratio between the proportion of vaccines within the ADR of interest and within all other ADRs.

Safety of pandemic H1N1 vaccines in children and adolescents.

During the 2009 influenza A (H1N1) pandemic several pandemic H1N1 vaccines were licensed using fast track procedures, with relatively limited data on the safety in children and adolescents. Different extensive safety monitoring efforts were put in place to ensure timely detection of adverse events following immunization. These combined efforts have generated large amounts of data on the safety of the different pandemic H1N1 vaccines, also in children and adolescents. In this overview we shortly summarize the safety experience with seasonal influenza vaccines as a background and focus on the clinical and post marketing safety data of the pandemic H1N1 vaccines in children. We identified 25 different clinical studies including 10,505 children and adolescents, both healthy and with underlying medical conditions, between the ages of 6 months and 23 years. In addition, large monitoring efforts have resulted in large amounts of data, with almost 13,000 individual case reports in children and adolescents to the WHO. However, the diversity in methods and data presentation in clinical study publications and publications of spontaneous reports hampered the analysis of safety of the different vaccines. As a result, relatively little has been learned on the comparative safety of these pandemic H1N1 vaccines - particularly in children. It should be a collective effort to give added value to the enormous work going into the individual studies by adhering to available guidelines for the collection, analysis, and presentation of vaccine safety data in clinical studies and to guidance for the clinical investigation of medicinal products in the pediatric population. Importantly the pandemic has brought us the beginning of an infrastructure for collaborative vaccine safety studies in the EU, USA and globally.

Changes during exercise of ECG intervals related to increased risk for ventricular arrhythmia in repaired tetralogy of Fallot and their relationship to right ventricular size and function.

PURPOSE: Our study aimed to assess pro-arrhythmogenic electrocardiographic changes during maximal physical exercise in patients operated for Tetralogy of Fallot (TOF). METHODS: TOF patients prospectively underwent: 1) bicycle ergometry, 2) cardiac MRI, and 3) 24-hour Holter. ECG data was analyzed at rest, at 60% of peak exercise and at peak exercise. R-R duration, QRS-, QT- and JT-duration and dispersions were assessed. Changes of ECG parameters during exercise were calculated and correlated to RV volume, RVEF, RV wall-mass, PR-percentage and VO(2max). Exercise ECG data from healthy controls were used as reference. RESULTS: Thirty-one patients (mean age at repair (SD) 0.8 (0.5) years, age at study 16 (5) years) and 25 controls (age 12 (2) years) were included. With exercise mean QTc and JTc dispersions increased in patients (p<0.001), but not in controls. At peak exercise JTc dispersion was larger in patients (p<0.01). QTc did not change with exercise in patients (p=0.14) and decreased in controls (p<0.05). At all levels of exercise mean QTc, QRS and QRS dispersion were larger in patients (all p<0.001). Significant associations were found for; 1) a larger increase of JTc dispersion with a higher PR-percentage, a larger RV volume, a larger RV wall-mass, 2) a larger QTc increase with a larger RV volume and worse RVEF. CONCLUSION: During physical exercise inhomogeneity of repolarisation, known to predispose for re-entry ventricular arrhythmia, increases in repaired TOF. Larger inhomogeneity is found with more severe PR.